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Quanta for 2021 will be undergoing a name change to be announced shortly as well as Quanta is in the process of expanding its product line from 4 SKUs to 38 by summer. We will also be introducing all new branding with new color schemes, new packaging, and exciting celebrity endorsements for the pain relief products and a newly introduced beauty product line. Quanta will also be working on a men’s cosmetic line in conjunction with one of the celebrity endorsements planned for late 2021. The company has hired an advertising agency to help with the rollout of the new branding expected second quarter 2021. This will work in conjunction with a major push the company is on the path of with some major big box retail chains.
Quanta Basics
Quanta is a cutting-edge technology platform whose patented, proprietary technology harnesses advances in quantum biology to increase the potency of active ingredients. Currently, Quanta supports product formulations in pain management, anti-inflammation, skincare, agriculture, nutritional supplements, and plant-based consumables. Ultimately, Quanta’s mission is to deliver better, more effective ingredients to elevate product efficacy, reduce waste and facilitate healthier, more sustainable consumption.
The established resonance theory behind Quanta’s polarization process has many potential applications. From potentiating bio-ingredients to produce more-effective carbon-trapping plants to transformative anti-aging solutions Quanta’s technology has the opportunity to upend how commercial products are made and the benefits from them. Already we see multi-trillion-dollar global industries benefiting from Quanta’s technology.
Our proof of concept, Quanta’s market-leading CBD pain-relief rub (“Muscle Rub”), is only the first in a series of paradigm shift products to emerge from our labs. At the heart of its well-documented effectiveness is our proprietary “polarization” process, which uses electromagnetic force to markedly enhance bioactivity at the molecular level—a polarized active ingredient is more soluble and creates stronger bonds with the body’s receptors. This allows us to enhance ingredients so they work faster and more powerfully without the use of chemical by-products or cellular penetration. Quanta believes this natural solution has nearly limitless applications in the world of plant-based consumer products.
Quanta is involved in ambitious projects that we believe will reshape the next wave of climate science, sustainability, nutrition, and more. Having harnessed the technology of the future, Quanta is dedicated to bringing tomorrow’s health and wellness solutions to the billions in need today.
Discovery Synopsys
Using our product development process and business-to-business and direct-to-consumer sales approaches as a benchmark for future business, we developed the Quanta business model. Our technology’s unique ability to strengthen ingredients renders them more potent without added chemicals or penetrating cells means Quanta is in a first-of-its-kind position in the market. As the world’s first company focused on Quantum Biology we sit in a strong, but unique position in the market.
Our ability to increase ingredient efficacy by up to 500% means we are in a rare position to truly disrupt many areas of material science.
Quanta’s technology renders products superior to any on the market today. A 30% re-purchase rate (on one SKU alone) illustrates consumer appetite for the product.
Upcoming products and ventures will be designed to achieve or surpass this level of consumer benefit and uptake.
Quanta Business Model in 3 P’s: Potentiation, Partners, and Profits
After two years we believe the best possible model for the long-term success of the company is collaborating with best-in-class partners through joint ventures for new verticals, products, and research. These joint ventures may involve a jointly owned special purpose entity or they may be entirely based on contractual obligations.
Our mission has never been to create the best novel products on the planet. Our mission has always been to revolutionize the way formulations are developed and how products perform. We seek to work with the best product makers in the world to positively impact as many industries as possible.
The unique ability to increase the ingredient and product performance opens the doors for major opportunities. Higher performing ingredients mean less is needed to make a strong impact (increased margins, increase overall efficacy). We proved this with our Muscle Rub, which uses approximately 1/3 the CBD of competing products with demonstrably improved results.
The level of potentiation delivered by Quanta allows our partners the unique ability to provide higher-performing products, lower material costs, more competitive pricing and increased profit margins. In short, our partners will be able to make better performing, more affordable products with a higher repeat purchase. This is true disruption and consumer utopia.
We aim to work with groups that specialize in manufacturing, marketing, selling and distributing existing product lines that utilize ingredients we can potentiate. Partners like this facilitate efficient market delivery of joint innovations.
We believe this strategy provides greater shareholder value, enhances revenue potential, defrays upfront expenses and affords us the ability to raise capital for new projects without massive dilution.
Ultimately, these ventures would result in licensing out our technology to other reputable brands and companies to create co-branded products whereas the term “Powered by Quanta” becomes as recognized as “Intel Inside.”
https://sec.report/Document/0001493152-21-008846/
darron427,
ENZC HAS to go through the regulatory PROTOCOLS to SAFELY prove their technology. They already went through clinical trials for ITV-1 in Buglaria with positive results so we already know where this is headed.
Here is an example of how another terd turn out when they went through the regulatory protocols and are on the verge of an IND.
2013:
Scorpion Venom: Can It Really Cure What Ails You?
Dominican-based company promises scorpion venom drug can help fight cancer.
Russian émigré Dr. Arthur Mikaelian and his company, Medolife, produce a drug called Escozine, whose sole active ingredient is blue scorpion venom. Medolife said Escozine is an effective cancer treatment because a peptide in the venom called chlorotoxin -- the same chemical that paralyzes prey -- also happens to target and kill cancer cells.
Dr. Len Lichtenfeld, the deputy medical director of the American Cancer Society, is skeptical of the cancer-curing properties of Escozine and cautioned against patients substituting alternative medicines for traditional cancer treatments, such as radiation and chemotherapy.
"There's no reasonable scientific evidence to show that this drug works in treating patients with cancer," Lichtenfeld said.
In the company's eight-year clinical study, which enrolled 8,302 cancer patients with varying disease type and severity, Escozine was found to have a near 90 percent success rate in improving quality of life, which included everything from decreased pain to increased survival rates. But the company acknowledged that the study was not peer-reviewed, and the results of their trial are not accepted by the American standards of science.
https://abcnews.go.com/Health/scorpion-venom-cure-ails/story?id=20755012
Fast Forward to 2021:
BURBANK, CA / ACCESSWIRE / January 27, 2021 / Medolife Rx, Inc., ("Medolife") a majority owned subsidiary of Quanta, Inc. (OTC PINK:QNTA) today announced In a recent study, a total of 400 patients in the Dominican Republic - where, a majority tested positive for COVID-19, and a small portion were COVID-19 symptomatic even though they tested negative for COVID-19 - reported a 100 percent improvement in symptoms after being administered Escozine®. Many of the patients participating in the study reported severe COVID-19 symptoms, such as difficulty breathing, pain and high fever, which Escozine® was able to relieve within 5 days of treatment. Even patients under ventilators were discharged within days, thanks to this novel product. Located in Santo Domingo, Dominican Republic, The Cruz Jiminian Clinic has carried out this ongoing study since August 2020, and has reported 0 COVID-19 related deaths after the clinic began administering Escozine®. Escozine®, produced by Medolife Rx, Inc., ("Medolife"), is a therapeutic consisting of small molecule peptides derived from a specific species of scorpions, Rhopalurus princeps, endemic to the Dominican Republic. After the successful study, Escozine® is on fast-track to be registered with the Ministry of Health in the Dominican Republic in Q1 2021. Medolife also submitted the study data to the US FDA, which is currently under review for permission to repeat the clinical trial in the United States. In addition to supporting the recovery of COVID-19 patients, Escozine® was registered and certified for cancer treatment by the Ministry of Health in the Dominican Republic in 2010.
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=163538871
Medolife Rx Announces Positive Pre-Clinical Results Showing Up to 95 Percent Cancer Cell Apoptosis with Introduction of Lead Cancer Drug Candidate
BURBANK, Calif., April 08, 2021 (GLOBE NEWSWIRE) -- via NewMediaWire – Medolife Rx, Inc. ("Medolife"), a global integrated bioceutical company with R&D, manufacturing, and consumer product distribution, which is a majority owned subsidiary of Quanta, Inc. (OTC PINK: QNTA), announced today pre-clinical study results conducted at one of the leading cancer research centers in the United States showing that the Company’s lead drug candidate Escozine® caused up to 95 percent Specific Induced Apoptosis (SIA) in various types of Leukemia cancer cells. Such a result is significant not only to the Company’s ongoing clinical research, but could have tremendous effects on cancer treatments worldwide.
https://www.biospace.com/article/releases/medolife-rx-announces-positive-pre-clinical-results-showing-up-to-95-percent-cancer-cell-apoptosis-with-introduction-of-lead-cancer-drug-candidate/
Medolife Rx Submits Final Data Set to FDA for IND Filing on Lead Drug Candidate
BURBANK, Calif., April 13, 2021 (GLOBE NEWSWIRE) -- via NewMediaWire – Medolife Rx, Inc. ("Medolife"), a global integrated bioceutical company with R&D, manufacturing, and consumer product distribution, which is a majority owned subsidiary of Quanta, Inc. (OTC PINK: QNTA), announced today that it has filed its final set of data requested by the US Food and Drug Administration (FDA) for its Pre-Investigational New Drug (PIND #150335) filing on its lead drug candidate Escozine® as a COVID-19 therapeutic. Along with the submission of a batch of Escozine® previously announced specifically produced for the FDA, the Company believes that this will be the last submission necessary in order to receive IND designation from the regulatory body in the United States.
https://www.otcmarkets.com/stock/QNTA/news/story?e&id=1862474
No matter how GREAT one may think their technology is PROTOCOLS must be followed to get your product to the market in the biotech space.
ENZC time will come.
Medolife's Therapeutic Scorpion Peptide Proves Successful in Treating COVID-19 Patients in Dominican Republic Study
BURBANK, CA / ACCESSWIRE / January 27, 2021 / Medolife Rx, Inc., ("Medolife") a majority owned subsidiary of Quanta, Inc. (OTC PINK:QNTA) today announced In a recent study, a total of 400 patients in the Dominican Republic - where, a majority tested positive for COVID-19, and a small portion were COVID-19 symptomatic even though they tested negative for COVID-19 - reported a 100 percent improvement in symptoms after being administered Escozine®. Many of the patients participating in the study reported severe COVID-19 symptoms, such as difficulty breathing, pain and high fever, which Escozine® was able to relieve within 5 days of treatment. Even patients under ventilators were discharged within days, thanks to this novel product. Located in Santo Domingo, Dominican Republic, The Cruz Jiminian Clinic has carried out this ongoing study since August 2020, and has reported 0 COVID-19 related deaths after the clinic began administering Escozine®. Escozine®, produced by Medolife Rx, Inc., ("Medolife"), is a therapeutic consisting of small molecule peptides derived from a specific species of scorpions, Rhopalurus princeps, endemic to the Dominican Republic. After the successful study, Escozine® is on fast-track to be registered with the Ministry of Health in the Dominican Republic in Q1 2021. Medolife also submitted the study data to the US FDA, which is currently under review for permission to repeat the clinical trial in the United States. In addition to supporting the recovery of COVID-19 patients, Escozine® was registered and certified for cancer treatment by the Ministry of Health in the Dominican Republic in 2010.
Scorpion Venom Most Expensive Liquid in the World
From treating cancer to pain management to fighting viral infections, this unique peptide has a vast range of therapeutic applications. In the last decade, a growing interest from Big Pharma companies has caused an increase in the liquid's value: costing $39 million per gallon.
Medolife's Dominican Republic Scorpion Reservation is one of the largest breeding grounds for scorpions on earth. Combined with the company's more than 15 years of research, Medolife is positioned to continue developing groundbreaking formulas and pharmaceutical-grade medications for consumer use.
Pharma's Growing Interest in Scorpion Peptide-Based Therapeutics
Venom has been studied for therapeutic uses for decades. In 2015, the European FP7 Venomics Project studied over 200 animal species worldwide for venom-to-drug development.
Currently, six peptide drugs on the market are derived from venoms, and the pharmaceutical industry has demonstrated a growing interest in these naturally derived therapeutics. The first venom-derived drug, Captopril, was developed by Bristol-Myers Squibb. The drug, derived from snake venom, was approved for use in the 1980s to treat high blood pressure.
Snail venom was used in the development of Prialt®, which is used to treat pain. Also, Byetta®, used to treat type 2 diabetes, was derived from a lizard.
How Venom-Based Drugs Work
The Rhopalurus princeps venom contains a small molecular peptide that can pass through the blood-brain barrier in the body. Four small molecular peptides in the venom can attack various diseases in humans. To do this, it blocks small-conductance chloride, sodium, potassium and calcium ion channels, and it also binds preferentially to abnormal and cancerous cells, leaving the normal cells intact. Medolife holds exclusive rights to the Rhopalurus princeps scorpion per the agreement signed with the Ministry of Environment and Natural Resources of the Dominican Republic.
https://www.biospace.com/article/releases/medolife-s-therapeutic-scorpion-peptide-proves-successful-in-treating-covid-19-patients-in-dominican-republic-study/
HOUSTON WE HAVE LIFTOFF
Medolife Rx Announces Positive Pre-Clinical Results Showing Up to 95 Percent Cancer Cell Apoptosis with Introduction of Lead Cancer Drug Candidate
Published: Apr 08, 2021
BURBANK, Calif., April 08, 2021 (GLOBE NEWSWIRE) -- via NewMediaWire – Medolife Rx, Inc. ("Medolife"), a global integrated bioceutical company with R&D, manufacturing, and consumer product distribution, which is a majority owned subsidiary of Quanta, Inc. (OTC PINK: QNTA), announced today pre-clinical study results conducted at one of the leading cancer research centers in the United States showing that the Company’s lead drug candidate Escozine® caused up to 95 percent Specific Induced Apoptosis (SIA) in various types of Leukemia cancer cells. Such a result is significant not only to the Company’s ongoing clinical research, but could have tremendous effects on cancer treatments worldwide.
The study was broken into two objectives:
a. to evaluate the effect of Escozine® at four different concentration levels on the induction of apoptosis in five cancer cell lines: K-562: Human Chronic Myeloid Leukemia (CML); MEC-1: Human Chronic B Cell Leukemia; NAMALWA: Human Burkitt Lymphoma; RAJI: Human Burkitt Lymphoma, TP53 Wild Type; RAMOS: Human Burkitt Lymphoma, TP53 Mutated
b. to evaluate the effect of Escozine® at four different concentration levels on the induction of apoptosis in four Chronic Lymphocytic Leukemia (CLL) patients, two at high-risk and two at low-risk levels
The result of the first objective was that cell death was observed in all cell lines when treated with Escozine® after 48 hours of incubation. The effect on cell death was dependent on the concentration level of Escozine®, with insignificant cell death being observed in concentration levels from 10-30 percent, a variation of cell death between 5-40 percent at a 50 percent concentration of Escozine®, and a greater than 95 percent cell death in all cell lines when Escozine® was included at 100 percent concentration, with the exception of RAMOS, which showed an approximate 50 percent cell death rate.
In the second part of the study, cells were taken from four CLL human patients, two High Risk (HR) and two Low Risk (LR). The cells were introduced to Escozine® at varying concentrations, and the results showed that both HR patients reported minimal effects at concentrations of 10 percent and 30 percent of Escozine®; however, at concentrations of 50 percent, cell death occurred in approximately 50 percent of cells, and at 100 percent concentration levels, over 95 percent cell death was observed. In LR patients, similar results were observed with higher concentrations of Escozine® at 50 percent and 100 percent inclusion where high levels of cell death were observed. The results were consistent with the cell line portion of the study, confirming that Escozine at higher concentrations can cause SIA, or cell death, in greater than 95 percent of cancer cells.
“These results not only met our expectations, but exceeded them,” said Medolife CEO Dr. Arthur Mikaelian. “This study was conducted at one of the leading academic cancer research institutes in the United States under some of the most stringent guidelines. While we knew that Escozine had cancer fighting therapeutic benefits, to see over 95 percent of cancer cells killed when introduced to the drug was truly groundbreaking. Cancer is one of the leading causes of death worldwide and finding an effective therapeutic is known as the holy grail of medicine. While we still have research to conduct in order to prove this drug is an effective treatment for cancer, results like these from such a credible institution will pave the way for this further exploration.”
Escozine® is a polarized solution of the Rhopalurus princeps scorpion peptide owned by Medolife. It is currently undergoing clinical research in the Dominican Republic (DR) as well as the United States for the treatment of cancer and COVID-19. The Company has an exclusive agreement with the Ministry of Health in the DR where it hopes to have product registration for Escozine® in short order after having conducted safety studies on over 500 patients. Additionally, the Company has filed data with the US Food and Drug Administration (FDA) on Escozine® and has formulated a batch of the drug candidate specifically for submission to the regulatory body. Previous clinical research on Escozine® showed the drug’s efficacy in eliminating cancer lines in ovarian and bladder cancers. Cell lines are commonly used in in vitro model systems in many drug discovery research programs. They retain most of the genetic properties of the cancer of origin and provide researchers with an indefinite source of biological material for experimental purposes. A doctor in the DR recently endorsed the use of Escozine® in patients with various cancer treatment regimens, only furthering the drug’s acceptance as a viable potential treatment for cancer.
https://www.biospace.com/article/releases/medolife-rx-announces-positive-pre-clinical-results-showing-up-to-95-percent-cancer-cell-apoptosis-with-introduction-of-lead-cancer-drug-candidate/
ENZC hopefully will get some funding like IMNM once the y get the audit complete.
ENZC has 29,900% increase from its low of 0.0005 to its cureent price.
ENZC move to .95 was a WHOPPING 189,900% increase.
ENZC will eventually break the 189,900% increase sooner or later.
Charles is a VISIONARY!
HOUSTON, WE HAVE LIFT OFF!!!
Charles Cotropia on Jul 18 2017
We are now on a new trajectory which every investor should evaluate.
We have just returned from a week long stay in India where we met with Serum Institute (www.seruminstitute.com) at its offices in Pune India. We were invited to meet with Serum’s technical staff and its CEO based on our technology for producing our fully human monoclonal antibody for treating HIV. At the meeting, Serum agreed take our antibody forward through clinical trials – a program that will entail a commitment by Serum of approximately $40 Million.
Who is Serum? Serum is the largest producer of vaccines in the world (not just India, but in the world). It also has an extensive portfolio of monoclonal antibodies that are being developed for treating certain diseases, including rabies, dengue fever and respiratory syncytia (RSV). Thus, Serum is a seasoned participant in the relatively new world of monoclonal antibodies. A dedicated portion of its current biopharma campus in Pune (shown here) is devoted to monoclonal antibodies.
Its new expansion facility (which will open in 2018-19) will have an entire floor dedicated to monoclonal antibodies.
Its expressed company goal is to introduce 2 new monoclonal antibodies each years.
How does all this fit with our technology? Serum openly recognizes that our antibody as one of the most promising in the search for a monoclonal antibody for treating HIV. It also knows that once a successful monoclonal antibody is confirmed, a vaccine can be produced as well. Our technology fits perfectly with its corporate goal and its company expertise. Specifically, we have a proprietary methodology for producing monoclonal antibodies against many diseases – for both humans and for animals. This methodology can be used to produce anti-monoclonal antibodies against a number of diseases effecting humans and animals. www.bioclonetics.com/anti-hiv-technology.html.
In the partnership we hope to conclude with Serum, we will complete the confirmation of the molecular sequence of our monoclonal antibody – required for the next step leading to animal and clinical trials. From our sequencing, Serum will produce the recombinant form of the antibody. We will conduct the verification testing of the recombinant and then Serum will conduct animal and then human trials – a $40 Million investment.
Serum’s expertise in the field, its world class production facilities and capability and its belief in our technology make it and its team the perfect partner for us. Serum’s willingness to invest in our technology assures that our technology will have its opportunity to accomplish our goal of providing a worldwide therapy for HIV.
We ask that you share this progress update with your friends and those interested in investment in our technology and its future.
Best regards,
Charles Cotropia
CEO, BioClonetics Immunotherapeutics, Inc.
https://wefunder.com/updates/90585-houston-we-have-lift-off
Yea right.
Long before FDA approval this will continue to move.
Look like you missed the last Press Release or you just didn't read it.
Monoclonal Antibodies for Treatment of HIV Milestones
1st Milestone: Testing of anti-HIV Monoclonal Antibodies at University of Montana
Status: in process. Time to completion: 1 month
2nd Milestone: Broad-based neutralization testing of existing anti-HIV Monoclonal Antibodies at University of Strasbourg, France
Status; in process. Time to completion: 2 months
3rd Milestone: Animal Studies of anti-HIV Monoclonal Antibodies at California National Primate Research Center, University of Southern California
Time to completion: 6 months following in vitro testing in process.
4th Milestone: Using Artificial Intelligence, identification of additional conserved immutable target sites (epitopes) on the HIV-1 virus
Status: Completed
5th Milestone: Production of additional Monoclonal Antibodies targeting identified sites (epitopes) on the HIV virus
Status: in process. Time to completion: 5-6 months
COVID-19
We are proud of the significant advances we have made in the development of Monoclonal Antibodies for treating Covid-19. We have reported that the Monoclonal Antibodies being produced by the Company will target immutable, conserved sites on SARS-CoV-2 (Coronavirus) that exist on the variant strains of the virus from the UK, Brazil, and South African.
These findings are considered highly significant in that the Center for Disease Control ("CDC") has reported these "variants of concern" are ones "for which there is evidence of an increase in transmissibility, more severe disease (meaning increased hospitalizations or deaths), a significant reduction in neutralization by antibodies generated during previous infection or vaccination, reduced effectiveness of treatments or vaccines, or diagnostic detection failures."
Our AI platform developed in collaboration with Denver Scientific has been one of our many successes. The patentable discoveries will be significant in our ongoing partnering dialogue with pharmaceutical companies interested in treatments for the Coronavirus and numerous other infectious diseases.
We intent to expedite our development of anti-Coronavirus Monoclonal Antibodies including an eventual fast-track clinical trial to progress to market.
SARS-CoV-2 (Coronavirus) Monoclonal Antibodies Milestones
1st Milestone: Using Artificial Intelligence, identification of conserved immutable target sites (epitopes) on the Coronavirus
Status: Completed
2nd Milestone: Production of Monoclonal Antibodies targeting identified sites (epitopes) on the SARS-CoV-2 virus
Status: In process. Time to completion: 3-4 months
3rd Milestone: Fast-Track Clinical Studies
Time to Completion: 6 months following production of Monoclonal Antibodies
ITV-1 anti-HIV Therapeutics
Clinical trials are planned for the Company's patented anti-HIV therapeutics ITV-1. Earlier this year, we announced the execution of Articles of Association to form International Medical Partners ("IMPL"), a Bulgarian Limited Liability Company of which the Company is 50% owner. The Company's partners in IMBL will fund the total cost of the Clinical trials under the European Medicine Agency (the "EMA") standards and the application cost for the EMA permit for the Company's ITV-1 patented therapeutics for treating HIV. Under the Mutual Recognition Agreement (the "MRA") between the EMA and the United States Federal Drug Administration (the "FDA"), the Company believes that issuance of the EMA permit for the ITV-1 compound could qualify ENZC's treatment for recognition by the FDA. IMBL has entered negotiations to engage a CRO to begin the clinical trials required under EMA standards.
We will have a definitive timeline for the expected date of initiation and completion of clinical trials in the coming weeks.
Production of Monoclonal Antibodies for HTLV-1/2
We are committed to developing "universal, durable and broadly neutralizing" Monoclonal Antibodies for many infectious diseases. We have an "intent to partner" agreement with a pharmaceutical company to create Monoclonal Antibodies against HTLV-1/2. We expect to complete the production by the end of 2021.
Monoclonal Antibodies for HTLV-1/2
1st Milestone: Using Artificial Intelligence, identification of conserved immutable target sites (epitopes) on the HTLV1/2 virus
Time to Completion: 2-3 months
2nd Milestone: Creation of anti-HTLV1/2 Monoclonal Antibodies
Time to completion: 6-8 months following identification of target epitopes
CEO Charles Cotropia said, "The strength of our company lies in our multiple technology platforms and the ability to produce fully human Monoclonal Antibodies against conserved and immutable targets on identified viruses. The viruses that may be addressed using our technology range from HIV to the Coronavirus to HTLV-1/2 to Ebola and many more. These numerous targeted viruses and bacteria are listed on our website [http://enzolytics.com/proprietary-therapeutics/]. We will continue to provide updates on our developments and progress toward completing the milestones we have set. We thank all our shareholders for their ongoing support of our Company and its technologies."
How humanizing mAbs has led to better drugs
Antibodies from human cells
Single B cell antibody technologies use the robust response of the human immune system to generate fully human mAbs. These methods only require a few cells, which can be rapidly and efficiently isolated from either peripheral blood mononuclear cells (PBMCs) or lymphoid tissues. Fluorescence-activated cell sorting is widely utilized to identify specific B cells based on their expression of cell surface markers, and a process called antigen baiting using antigen-coated magnetic beads and fluorescence-conjugated antigens is used to select antigen-specific cells.
After single B cells are isolated, expressed immunoglobulin transcripts are amplified using reverse transcription polymerase chain reaction (RT-PCR), and then cloned and expressed in mammalian cell lines.
Single B cell isolation and cloning can be used to rapidly develop immunotherapies for infectious diseases. Human mAbs have been generated by the single B cell method for bacterial, parasitic, viral, and autoimmune diseases.
Choice of cell line impacts transition from development to production
Therapeutic mAbs require a mammalian expression system that provides the cell machinery required to glycosylate, fold, orient, and covalently bind antibody peptide chains to produce the complete, biologically functional molecule. Lower organism expression platforms can be used if the product is a mAb fragment or where glycosylation is simpler, or not required.
Antibody genes of interest are introduced into a suitable expression vector and transfected into cell lines for antibody expression and secretion. Expression vectors are designed to maximize mAb expression and ensure cell line stabilization through host cell codon optimization and the addition of highly efficient transcription, secretion, selection, and integration elements.
Chinese hamster ovary (CHO) cells are a popular host for producing therapeutic mAbs as they are suited to high-yield production of recombinant proteins and are good at performing the post-translational modifications required to produce the correct high-level conformation of an active mAb.
Mammalian cell lines have been adapted to suspension culture and engineered for enhanced functions (e.g., introducing glycosylation pathways and resistance to apoptosis). These newer cell lines support high cell densities and product high mAb titers, so are suitable for production in large scale-fed batches, perfusion systems, or continuous culture techniques. Commercially developed CHO cell lines with enhanced stability are used in many current mAb therapeutic expression platforms.
The ability to produce transient CHO-derived mAbs early during biotherapeutic development is highly desirable, as products will closely mimic the final CQAs of the mAb when manufactured at bioproduction scales.
The future of therapeutic monoclonal antibodies
As our understanding of the molecular mechanisms underlying disease grows, opportunities for the development of new mAb-based drugs increase. In the last decade the focus has been on producing mAbs for cancer immunotherapy, inflammatory diseases, and autoimmune diseases, but they are becoming increasingly important in treatments and prophylaxis for infectious diseases such as fungal diseases, Ebola, and the novel coronavirus SARS-CoV-2. In the future, mAbs could be used to target multidrug-resistant pathogens and may help prevent the emergence of antimicrobial resistance.
The therapeutic antibody field is also exploring the use of new modality antibodies such as bispecific and trispecific antibodies that recognize multiple epitopes on the same antigen, single-domain antibodies that can more easily penetrate tissues, and antibody–drug conjugates for targeting chemotherapy agents to specific cell types. Some bispecific antibodies and antibody–drug conjugates are already on the market, with several more in development.
One thing is certain, therapeutic monoclonal antibodies are going to continue to increase in importance for many years to come.
https://www.thermofisher.com/us/en/home/biotech-lab-solutions/biotech-learning-center/monoclonal-antibodies-therapeutics.html
Development of therapeutic antibodies for the treatment of diseases
It has been more than three decades since the first monoclonal antibody was approved by the United States Food and Drug Administration (US FDA) in 1986, and during this time, antibody engineering has dramatically evolved. Current antibody drugs have increasingly fewer adverse effects due to their high specificity. As a result, therapeutic antibodies have become the predominant class of new drugs developed in recent years. Over the past five years, antibodies have become the best-selling drugs in the pharmaceutical market, and in 2018, eight of the top ten bestselling drugs worldwide were biologics. The global therapeutic monoclonal antibody market was valued at approximately US$115.2 billion in 2018 and is expected to generate revenue of $150 billion by the end of 2019 and $300 billion by 2025. Thus, the market for therapeutic antibody drugs has experienced explosive growth as new drugs have been approved for treating various human diseases, including many cancers, autoimmune, metabolic and infectious diseases. As of December 2019, 79 therapeutic mAbs have been approved by the US FDA, but there is still significant growth potential. This review summarizes the latest market trends and outlines the preeminent antibody engineering technologies used in the development of therapeutic antibody drugs, such as humanization of monoclonal antibodies, phage display, the human antibody mouse, single B cell antibody technology, and affinity maturation. Finally, future applications and perspectives are also discussed.
One exceptional advance that accelerated the approval of therapeutic mAbs was the generation of humanized antibodies by the complementary-determining region (CDR) grafting technique [10]. In CDR grafting, non-human antibody CDR sequences are transplanted into a human framework sequence in order to maintain target specificity [10] (Fig. 2c). The first humanized mAb approved by the US FDA in 1997 was the anti-IL-2 receptor, daclizumab, for the prevention of transplant rejection (Fig. 1) [11]. The humanization of antibodies made it possible to clinically apply a new class of biologics directed against diseases that require long-term treatment, such as cancer and autoimmune diseases [12].
Based on the success of humanized mAbs in the clinic, a key discovery technology to obtain fully human mAbs (Fig. 2d) was developed in 1990 by Sir Gregory P. Winter [10, 13]. This technique was based on phage display, wherein diverse exogenous genes are incorporated into filamentous bacteriophages to compose a library. The library proteins are then presented on the phage surface as fusions with a phage coat protein, allowing the selection of specific binders and affinity characteristics. The phage display technique was first introduced by George P. Smith [14] and comprises a powerful method for the rapid identification of peptides or antibody fragments, such as single chain fragment variable (scFv) or Fab, that bind a variety of target molecules (proteins, cell-surface glycans and receptors) [15] (Fig. 3b). The Nobel Prize in Chemistry 2018 was awarded to George P. Smith and Sir Gregory P. Winter. George Smith developed phage-displayed peptides, which can be used to evolve new proteins [14]. Gregory P. Winter was able to apply the phage-displayed antibody library to the discovery and isolation of antibodies [13]. Phage display technology has also been used for antibody maturation by site-directed mutagenesis of CDR and affinity selection. Based on these techniques, the first fully human therapeutic antibody, adalimumab (Humira), an anti-tumor necrosis factor a (TNFa) human antibody [16], was approved in 2002 by the US FDA for rheumatoid arthritis (Fig. 1). Until now, nine human antibody drugs generated by phage display have been approved by the US FDA (Table 5).
Therapeutic antibodies currently approved as disease treatments
The mAb market enjoys a healthy pipeline and is expected to grow at an increasing pace, with a current valuation of $115.2 billion in 2018 [44]. Despite this high growth potential, new companies are unlikely to take over large shares of the market, which is currently dominated by seven companies: Genentech (30.8%), Abbvie (20.0%), Johnson & Johnson (13.6%), Bristol-Myers Squibb (6.5%), Merck Sharp & Dohme (5.6%), Novartis (5.5%), Amgen (4.9%), with other companies comprising the remaining 13% [44].
Many mAbs products achieved annual sales of over US$3 billion in 2018 (Fig. 1), while six (adalimumab, nivolumab, pembrolizumab, trastuzumab, bevacizumab, rituximab) had sales of more than $6 billion (Table 2). Adalimumab (Humira) had the highest sales figure ever recorded for a biopharmaceutical product, nearly $19.9 billion. The top ten selling mAb products in 2018 are listed in Table 2. Top-selling mAb drugs were ranked based on sales or revenue reported by biological or pharmacological companies in press announcements, conference calls, annual reports or investor materials throughout 2018. For each drug, the name, sponsors, disease indications, and 2018 sales are shown.
mAbs are increasingly used for a broad range of targets; oncology, immunology, and hematology remain the most prevalent medical applications [45]. Most mAbs have multiple disease indications and at least one that is cancer-related (lymphoma, myeloma, melanoma, glioblastoma, neuroblastoma, sarcoma, colorectal, lung, breast, ovarian, head and neck cancers). As such, oncological diseases are the medical specialty most accessible to mAb treatments [45]. Moreover, the number of target proteins known to function as either stimulatory or inhibitory checkpoints of the immune system has dramatically expanded, and numerous antibody therapeutics targeting programmed cell death protein 1 (PD-1, cemiplimab, nivolumab, pembrolizumab), its ligand programmed death-ligand 1 (PD-L1, durvalumab, avelumab, atezolizumab) or cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4, ipilimumab) have been granted marketing approvals [46].
Adalimumab (Humira) was the world’s best-selling drug in 2018. Adalimumab is a subcutaneously administered biological disease modifier used for the treatment of rheumatoid arthritis and other TNFa-mediated chronic debilitating diseases. It was originally launched by Abbvie in the United States after gaining approval from the US FDA in 2002. It has been shown that Adalimumab reduces the signs and symptoms of moderate to severe rheumatoid arthritis in adults, and it is also used to treat psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriasis, hidradenitis suppurativa, uveitis, and juvenile idiopathic arthritis [47, 48]. It may be used alone or in combination with disease-modifying anti-rheumatic drugs [49].
Immune checkpoints are important for maintaining self-tolerance and tempering physiologic immune responses in peripheral tissues. Therefore, the molecules underlying checkpoints have recently drawn considerable interest in cancer immunotherapy [50]. Both nivolumab (Opdivo) and pembrolizumab (Keytruda) are anti-PD-1 mAbs and were the second and third best-selling mAb drugs in 2018 (Table 2). Nivolumab is a human antibody, which blocks a signal that normally prevents activated T cells from attacking cancer cells. The target for nivolumab is the PD-1 receptor, and the antibody blocks the interaction of PD-1 with its ligands, PD-L1 and PD-L2, releasing PD-1 pathway-mediated immune inhibition [51, 52]. Pembrolizumab is a humanized antibody used in cancer immunotherapy to treat melanoma, lung cancer, head and neck cancer, Hodgkin’s lymphoma, and stomach cancer [53,54,55]. Pembrolizumab is a first-line treatment for NSCLC if cancer cells overexpresse PD-L1 and have no mutations in EGFR or in anaplastic lymphoma kinase [56, 57]. Large randomized clinical trials indicated that NSCLC patients treated with nivolumab and pembrolizumab (both approved by the US FDA in 2014) showed increased overall survival compared with docetaxel, the standard second-line treatment [58].
A total of 12 new mAbs were approved in the US during 2018. The majority of these products were approved for non-cancer indications, perhaps reflecting the higher approval success rate for antibodies as treatments for other diseases. Three antibodies (erenumab, galcanezumab, and fremaezumab) were approved for migraine prevention, and one (Ibalizumab) is used for human immunodeficiency virus (HIV) infection. The three migraine-preventing drugs, Erenumab (Aimovig), galcanezumab (Emgality), and fremaezumab (Ajovy), are mAbs that block the activity of calcitonin gene-related peptide (CGRP) receptor in migraine etiology [59]. CGRP acts through a heteromeric receptor, which is composed of a G protein-coupled receptor(calcitonin receptor-like receptor: CALCRL) and receptor activity-modifying protein 1 (RAMP1) [60, 61]. Both galcanezumab and fremaezumab bind to CGRP and block its binding to the receptor. However, erenumab is the only one of the three antibodies to target the extracellular domains of human G protein-coupled receptors CALCRL and RAMP1,interfering with the CGRP binding pocket [62].
Many mAbs are under development for treatment of infectious diseases, currently only four have been approved by the US FDA: raxibacumab and obiltoxaximab for treatment of inhalational anthrax [63], palivizumab for prevention of respiratory syncytial virus in high-risk infants [64], and ibalizumab for treatment of HIV infection patients [65]. Ibalizumab (Trogarzo) is a humanized IgG4 mAb that is used as a CD4 domain 2-directed post-attachment HIV-1 inhibitor. The US FDA approved ibalizumab for adult patients infected with HIV who were previously treated and are resistant to currently available therapies.
Therapeutic antibodies currently in clinical trials
Companies are currently sponsoring clinical studies for more than 570 mAbs. Of these, approximately 90% are early-stage studies designed to assess safety (Phase I) or safety and preliminary efficacy (Phase I/II or Phase II) in patient populations. Most of the mAbs in Phase I (~?70%) are for cancer treatment, and the proportions of mAbs intended to treat cancer are similar for those currently in Phase II and late-stage clinical studies (pivotal Phase II, Phase II/III or Phase III) [2].
Twenty-nine novel antibody therapeutics were in late-stage clinical studies for non-cancer indications in 2018. Among the trials for these mAbs, no single therapeutic area predominated, but 40% were for immune-mediated disorders, which comprised the largest group. From this group of potential treatments, leronlimab and brolucizumab entered regulatory review by the end of 2018, and five mAbs (eptinezumab, teprotumumab, crizanlizumab, satralizumab, and tanezumab) may enter regulatory review in 2019. In comparison, there were 33 novel antibody therapeutics in late-stage clinical studies for cancer indications in 2018. Antibody therapeutics for solid tumors clearly predominated, with less than 20% of the candidates intended solely for hematological malignancies. Five mAbs (isatuximab, spartalizumab, tafasitamab, dostarlimab, and ublituximab) license applications were submitted to the US FDA in 2019 [2].
Isatuximab is an anti-CD38 IgG1 chimeric mAb under evaluation as a treatment for patients with multiple myeloma (MM). Combinations of isatuximab and different chemotherapies are being tested in three Phase III studies (ICARIA, IKEMA, and IMROZ) on MM patients. The ICARIA study (NCT02990338) is evaluating the effects of isatuximab in combination with pomalidomide and dexamethasone compared to chemotherapy only in patients with refractory or relapsed MM. Pivotal Phase III ICARIA-MM trial results demonstrated that isatuximab combination therapy showed statistically significant improvements compared to pomalidomide and dexamethasone alone in patients with relapsed or refractory MM in 2019. The US FDA has accepted for review the biologics license application for isatuximab for the treatment relapsed or refractory MM patients. The target action date for the FDA decision is April 2020 [66]. The IKEMA (NCT03275285) and IMROZ (NCT03319667) studies are evaluating the isatuximab with other chemotherapeautic combinations in MM patients [67].
Spartalizumab is a humanized IgG4 mAb that binds PD-1 with sub-nanomolar affinity and blocks its interaction with PD-L1/PD-L2, preventing PD-1-mediated inhibitory signaling and leading to T-cell activation. Clinical study of Spartalizumab is underway with a randomized, double-blind, placebo-controlled Phase III COMBI-i study (NCT02967692), which is evaluating the safety and efficacy of dabrafenib and trametinib in combination with spartalizumab compared to matching placebo in previously untreated patients with BRAF V600-mutant unresectable or metastatic melanoma. The primary endpoints of the study are an assessment of dose-limiting toxicities, changes in PD-L1 levels and CD8+ cells in the tumor microenvironment, and progression-free survival. Key secondary endpoints are overall survival, overall response rate and duration of response. The estimated primary completion date of the study is September 2019 [68].
Dostarlimab is an anti-PD-1 mAb that may be useful as a treatment for several types of cancers. GlaxoSmithKline announced results from a Phase I dose escalation and cohort expansion study (GARNET; NCT02715284) in 2018, which is expected to support a biologics license application submission to the US FDA in 2019. Dostarlimab is being assessed in patients with advanced solid tumors who have limited available treatment options in the GARNET study. The drug is administered at a dose of 500?mg every 3?weeks for the first 4?cycles, and 1000?mg every 6?weeks thereafter in four patient cohorts: microsatellite instability high (MSI-H) endometrial cancer, MSI-H non-endometrial cancer, microsatellite-stable endometrial cancer, and non-small cell lung cancer. Dostarlimab is also being evaluated in another Phase III study (NCT03602859), which is comparing platinum-based therapy with dostarlimab and niraparib versus standard of care platinum-based therapy as first-line treatment of Stage III or IV non-mucinous epithelial ovarian cancer [69].
Ublituximab is a glyco-engineered anti-CD20 antibody currently under clinical investigation in five late-stage clinical studies for different cancers (chronic lymphocytic leukemia, CLL, non-Hodgkin’s lymphoma) and non-cancer (multiple sclerosis) indications. Three Phase III studies are exploring the efficacy of ublituximab in combination with other anti-cancer agents. Among these studies, the UNITY-CLL Phase III study (NCT02612311) is evaluating the combination of ublituximab and TGR-1202, a PI3K delta inhibitor, compared to anti-CD20 obinutuzumab plus chlorambucil in untreated and previously treated CLL patients. Two other Phase III studies (ULTIMATE 1, NCT03277261 and ULTIMATE 2, NCT03277248) are evaluating the efficacy and safety of ublituximab compared to teriflunomide in 440 patients with relapsing multiple sclerosis [70].
Methodologies for developing therapeutic antibodies
Human, humanized, chimeric, and murine antibodies respectively account for 51, 34.7, 12.5, and 2.8% of all mAbs in clinical use, making human and humanized mAbs the dominant modalities in the field of therapeutic antibodies. In the next section, we first introduce techniques for antibody humanization. Then, we describe three technical platforms related to the generation of fully human antibodies, including phage display, transgenic mice and single B cell antibody isolation (Fig. 3). Last, we describe the use of an affinity maturation method to optimize antibody binding activity.
Humanization of mAbs
Due to the availability, low cost and quick production time for mouse mAbs, humanization of mouse mAbs has been implemented on a large scale. Non-humanized murine mAbs have many disadvantages as treatments. For example, patients treated with mouse mAbs will produce a rapid human anti-mouse antibody (HAMA) response. HAMAs will not only hasten the clearance of mouse mAbs but may also produce undesirable allergic reactions and tumor penetration. Moreover, the ability of patients to initiate antibody-dependent cellular cytotoxicity (ADCC) in response to murine fragment crystallizable region (Fc) is limited. On the other hand, humanized mAbs are able to effectively exert effector functions while decreasing the immunogenicity of murine antibodies.
Generation of humanized mAbs
Humanized mAbs, of which only the CDRs of the light and heavy chains are murine, entered clinical development for the first time in 1988 [71, 72]. CDR grafting is one of the most popular techniques in the production of humanized mAbs and was originally developed by Gregory P. Winter in 1986 [9]. Using this technology, non-human CDR sequences are transplanted into human framework sequences, allowing the antibody to maintain the binding activity to the target antigen [9]. The first US FDA approved CDR-grafted humanized mAb occurred in 1997 for daclizumab, which binds the IL-2 receptor and is used to prevent transplant rejection [11]. Queen and collaborators [73] developed daclizumab not only using CDR grafting, but also using the human framework that is maximally homologous to the murine framework, in order to decrease the loss of antigen recognition. In some cases, certain amino acids in the murine framework are crucial to maintain antibody binding activity. These residues may cooperate with CDRs to present an antibody paratope or directly interact with antigens. Currently, these crucial framework residues can be identified by observing the structure of antibody-antigen complex by X-ray crystallography, cryo-electron microscopy and computer-aided protein homology modelling [74]. The positions of amino acids in the framework may then be considered for restore by ‘human back to mouse’ mutations in CDR-grafted humanized antibodies, thereby improving the affinity and stability of the final product. Currently, web servers are being developed by integrated bioinformatics and antibody structure databases for rendering humanization experiments [75, 76]. They provide the tools for human template selection, grafting, back-mutation evaluation, and antibody modeling. However, if the binding activity of antibodies is still compromised, it should be further performed affinity maturation to improve this situation.
Multiple methods have been developed to quantify the humanness of the variable region of mAbs. Abhinandan and Martin designed a tool called “H-score” to assess the “degree of humanness” of antibody sequences, which calculates the mean sequence identity compared to a subset of human variable region sequences database [77]. A germinality index was defined subsequent to assist germline humanization of a macaque antibody [78]. G-score was derived from the H-score to improve classification of germline framework sequence [79]. T20 score analyzer was established under a large database of ~?38,700 human antibody variable region sequences to clearly separate human sequences from mouse sequences and many other species as well [80]. It was used to reveal similarities between humanized antibodies and fully human antibodies. These humanness score tools are available online and allow assisting the generation of humanized antibody [80].
The use of humanized antibodies has helped greatly to improve clinical tolerance of mAb therapeutics. Such intricate control over antibody sequences has opened the door to engineering mAbs for a wide range of possible applications in medicine. Currently, half of all mAbs used to treat humans are chimeric or humanized (Fig. 2, Table 1). One of the most well-known humanized antibodies is Trastuzumab (Herceptin), which was approved in 1998 and achieved annual sales of over $7 billion in 2018 (Table 2). Trastuzumab is used for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer and gastroesophageal junction adenocarcinoma [57, 58].
Immunogenicity of antibody-based therapeutics
The use of mAbs in a clinical setting should have several essential biophysical properties, including high antigen binding activity, high stability, and low immunogenicity [81]. Antibody immunogenicity means the degree of the host immune system can recognize and react to these therapeutic agents. Anti-drug antibodies (ADA) induced by the immune system can be found while immunogenicity occurring in patients administered with antibody drugs. Anti-drug antibodies have the potential to neutralize therapeutic agents, which can reduce the efficacy of the drugs [82]. Importantly, anti-drug antibodies may further cause adverse effects ranging from skin rashes to systemic inflammatory responses in the patients, which can impact both safety and efficacy of the antibody drugs in clinic use [83]. Immunogenicity is influenced by several factors, such as drug dosage, administration strategy (route and combination), impurities contamination, aggregates arising from Ab/Ag binding complex, and structural features (sequence variation and glycosylation) [84].
Humanized antibodies harbor human sequence in constant regions and nearly all human sequence in Fv, of which only CDRs are murine grafted. Antibodies of more human-like usually allow them to be higher tolerant and lower immunogenic in a clinical setting. For example, Perpetua et al. showed a case to support this concept [85]. They compared a humanized anti-CD52 antibody with its parental murine version and demonstrated humanization offers a significant reduction in immunogenicity. However, humanized antibodies retain murine CDRs which could be regarded as foreign antigens by host immune systems and eventually arise immunogenicity. For example, ADA was detected in 0.5% of women with metastatic breast cancer, who were treated with Trastuzumab during their therapeutic courses [86]. Recently, an immunogenicity analysis result from clinical data showed the ADA rates were 7.1% (21/296) in the HER-2 positive breast cancer patients with treatment of Trastuzumab [87]. The variation of immunogenicity in the same antibody drug may be caused by many potential factors: the age, race, genetic background, other related diseases, and programs of drugs administration.
The CDRs and frameworks of fully human antibodies are derived for human immunoglobulin gene repertoires, thus which can theoretically bypass immunogenicity. However, several fully human antibodies have been reported to induce marked immune responses when administrated in patients [88]. Adalimumab (Humira), a human IgG1, has been reported to generate significant immune responses through eliciting anti-idiotypic antibody in a part of patients (5–89%) which varies depending on the disease and the therapy [89, 90]. Golimumab (Simponi), a fully human anti-TNFa antibody, combining with methotrexate for treatment of rheumatoid arthritis cause 16% of patients producing anti-drug antibodies [91]. One reason of these scenarios is that Fv sequence of human antibodies is not identical to human germline: antibody evolution through VJ and VDJ random recombination, as well as affinity maturation naturally occurring in vivo through somatic hypermutation. Until now, there are no in vitro or in-silico assays can precisely analyze the immunogenicity of antibody. In vivo assessments are usually used to evaluate the immunogenicity, of which the result will ameliorate design and engineering of antibody therapeutics to reduce the potential for inducing anti-drug antibodies.
Generation of human antibodies by phage display
Overview of antibody phage libraries
Phage display is the first and still the most widely used technology for in vitro antibody selection. The strategy was developed based on the excellent work of George P. Smith in 1985 [14], who used recombinant DNA techniques to fuse foreign peptides with a coat protein (pIII) of bacteriophage M13 in order to display peptides on the bacteriophage surface. He then created “antibody-selectable phage vectors” and described an in vitro method that enabled affinity selection of antigen-specific phage-displayed antibodies from 108-fold excess phage pools [92]. It was later discovered that scFv, small antibody formats, can be expressed on phage filaments. At the time, there were three different research institutions independently establishing phage-displayed scFv or Fab antibody libraries: the MRC Laboratory of Molecular Biology in the UK [13, 93, 94], the German Cancer Research Center in Germany [95], and Scripps Research Institute in the USA [96]. Since then, these phage-displayed antibody libraries have proven to be a reliable discovery platform for the identification of potent, fully human mAbs [97].
The process of identifying mAbs from a phage-displayed library begins with antibody-library construction (Fig. 4a). The variable heavy (VH) and variable light (VL) polymerase chain reaction (PCR) products, representing the Ig gene-encoding repertoire, are ligated into a phage display vector (phagemid). High quality mRNA from human peripheral blood mononuclear cells (PBMCs) is reverse-transcribed into cDNA. The different VH and VL chain-region gene families are then amplified using specific primers to amplify all transcribed variable regions within the Ig repertoire [98, 99]. The format of antibodies in a phage-displayed library can be either scFv or Fab fragments (Fig. 4b); scFvs are composed of the VH and VL domain connected by a short flexible linker. Antibody Fab fragments displayed on the phage coat protein have comparably higher structural stability and can be readily converted to intact IgG antibodies, usually without impairing binding activity [100, 101]. The elegance of phage-displayed libraries is apparent in the linkage between antibody phenotype (specificity and sensitivity) and genotype (genetic information) via the phage particle. Due to the small size and high solubility (1013 particles/ml) of phage particles, repertoire sizes up to 1011 independent clones can be efficiently produced and displayed in a single library [102,103,104].
https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-019-0592-z
Production Processes for Monoclonal Antibodies
Antibodies are glycoprotein structures with immune activity. They are able to identify or induce a neutralizing immune response when they identify foreign bodies such as bacteria, viruses, or tumor cells. Immunoglobulins are produced and secreted by B lymphocytes in response to the presence of antigens. The first monoclonal antibodies (mAbs) have emerged from a survey of hybridomas, and nowadays mAbs are produced mostly from cultivations of these cells. Additionally, there are studies and patents using a range of cells and microorganisms engineered for the production of mAbs at commercial scale. For some years, new methodologies have advanced with new production processes, allowing scale-up production and market introduction. Large-scale production has revolutionized the market for monoclonal antibodies by boosting its production and becoming a more practical method of production. Production techniques have only had a sizable breakthrough due to molecular techniques. Various systems of production are used, including animal cells, microorganisms, plants, and mammary glands. All of these require the technological development of production process such as a stirrer, a wave bioreactor, and roller bottles.
With the advent of genetic engineering, it has been possible to develop new methods to obtain monoclonal antibodies, both for improvement with regard to these humanized antibodies and for production models. Advances in molecular and cell biology for the development of more efficient antibodies have allowed advances in diagnostic and therapeutic areas. Such advances have triggered improvements in production processes, allowing for the reduction of production costs and thus leading to an increase in the popularization of treatments with mAbs.
All process improvements provide a consistent and reproducible production of large quantities of mAbs at a moderate cost.
Large-scale production has revolutionized the market for monoclonal antibodies by boosting its production, making this a more practical method of production. Production techniques have only had a sizable breakthrough due to molecular techniques.
In general, a process of commercial production of mAb begins with the generation of an mAb by immunizing an animal or by molecular biology methods involving the identification and optimization of the coding DNA sequence and the construction and identification of a stable high-producing clone. Improvements in cultivation are similar to those applied in other bioproducts that rely on culturing microorganisms or cells, requiring the development of a well-designed culturing process comprising the full range of control and associated operations that will support technical evaluations.
mAbs production processes in wave or single-use bioreactor (SUBs) are characterized by flexibility and low operating costs when compared to the production processes in fixed stainless steel vats. The development of bioprocesses involving these production platforms can reap greater acceptance by the industry.
Drugs based on mAbs have been controlled by regulatory agencies around the world. Therefore, it is necessary to elaborate regulatory protocols accompanying the increase in production and the nuances of the characteristics of this class of drugs.
mAbs production techniques
Hybridoma and phage display
Milstein and Köhler described the first technique developed for stable monoclonal antibody production in 1975. This technique consists of creating a hybridoma, a stable hybrid cell capable of producing a single type of antibody against a specific epitope present in an antigen. Hybridoma construction was initially produced from murine models. The technique consists of removing a pool of activated B lymphocytes from an immunized animal spleen and combining them with immortalized myeloma cells unable to produce the enzyme hypoxanthine-guanine-phosphoribosyltransferase (HGPRT), an important enzyme present in the salvage pathway, one of the pathways responsible for nucleotide production [1]. To select hybridoma cells, the pool of cells resulting from the fusion (a mix of hybridoma cells and non-fused B lymphocytes and myeloma cells) are cultivated in a selective medium containing aminopterin, which inhibits the nucleotide de novo synthesis. Myeloma cells lack the salvage pathway for nucleotide production. When they are exposed to aminopterin present in selective medium, the de novo synthesis is also blocked, and as a result, myeloma cells are no longer viable since all major pathways for nucleotide production are blocked. In contrast, non-fused, activated B lymphocytes can survive as their salvage pathway works perfectly and they can continue nucleotide production even if the de novo pathway is blocked by aminopterin. However, these cells are not immortalized and can replicate only a limited number of times after which they eventually die. With this in mind, only cells capable of replicating indefinitely and synthesizing nucleotides through the salvage pathway can survive through selection conditions, and these cells are the hybridomas.
In spite of the fact that the primary recombinant mAbs were delivered utilizing this innovation—including the first medication approved by the Food and Drug Administration (FDA) for therapeutic proposes (Table 1)—the great contribution of this technology was mostly to elucidate immune response mechanisms and control in vitro antibody production. Therefore, mAb hybridoma production from murine sources exhibits a genuine downside in human therapeutics (Figure 1).
After a few infusions, murine antibody molecules trigger the human anti-mouse antibody (HAMA) response of the human immune system [1, 12]. To work around this issue, new methodologies have been developed to deliver antibodies similar to human molecules, so the technology evolved to less immunogenic chimeric antibodies (constant regions of human antibodies linked to the variable region of the murine source), creating a new set of therapeutic possibilities (Figure 1). Subsequently, the need for an even less immunogenic alternative boosted the production of humanized antibodies (only the region that interacts with the antigen epitope is from mouse origin) (Figure 1). Even fully human antibodies (Figure 1) can be produced from genetically modified mice [13].
A great improvement in mAb production has come with the development of phage display libraries. This methodology helps to investigate interactions between molecules (protein-protein, protein-peptide, and protein-DNA) and consists, basically, in cloning Fab-region-coding genes amplified from B lymphocytes into bacteriophage plasmid vectors. Then the bacterium can be transformed with these vectors, going on to express the heterologous genes from a viral capsid. This capsid contains viral proteins and proteins encoded by the Fab sequence received by that specific cell. Once the library is complete, the affinity between proteins produced from different Fab regions can be tested against the antigen of interest and the cell transformed with the plasmid that contains those genes can be readily sequenced. The advantages of this methodology are the following: the same library has the potential to generate a great number of new antibodies, it is an in vitro process, so it does not require animal immunizations steps, and because of that, toxic antigens can be tested. Also, a greater variety of antigens can be tested, and antibody molecules can be rapidly obtained [13].
Culture production factors
Cell lines
One of the most critical steps in developing an mAb production system is to choose the cell line. The cells must be stable and secrete the desired protein with the correct conformation at high levels. Based on these requirements, the mammalian cell is the most commonly chosen expression system for mAb production. The main advantage of a mammalian expression system is that the cellular machinery is adapted for the production, processing, and secretion of highly complex molecules. The great majority of commercial mAbs are produced in Chinese hamster ovary (CHO) and NS0 cells, originating from plasmacytoma cells that were modified until IgG generation in nonsecreting B cells. Genetic modifications in CHO cells have generated cell lines capable of producing a high quantity of humanized mAbs. These cell lines were able to secrete up to 100 pg/cell/day [14]. Other modifications led to a high production of a chimeric mAb, ranging from 80 to 110 pg/cell/day [15]. NS0 modifications also have been made, leading to higher mAb production rates, ranging from 20 to 50 pg/cell/day [16]. In smaller quantities, hybridoma cell lines are also used in industrial mAb production. Some hybridoma strains are reported to have a production rate up to 80 pg/cell/day [16]. In spite of this, different mammalian cell lines and even more peculiar expression systems such as genetically modified plant cells, genetically modified insect cells, and genetically modified microorganism cells have also been used in mAb production and have gained space in the biopharmaceutical industry [1, 8]
Microorganisms modified by genetic engineering techniques have attracted much focus in industry, because these cells are simpler to handle and to modify when compared to animal cells. Other advantages of production methods using genetically modified microorganisms are that these cells have well-defined expression systems, and the production methodology is reproducible and easy to validate. Modified yeast cells, such as Pichia pastoris have a great potential for usage since these cells are known to achieve high secretion levels of heterologous proteins. Yeast cultivation systems for mAb production are easier scale-up and are cheaper when compared to mammalian cell cultivation systems. They can be cultivated in regular stirred tank bioreactors, in batch, or in feed-batch modes of operation. Generally, microorganisms do not have physicochemical and biological characteristics for the appropriate expression and posttranslational processing of mAbs [4].
Modified plants have also gained attention since plants are easy to cultivate and propagate. Other cultivation advantages such as cheap medium, low maintenance cost, and high production yields make plant production a cheaper alternative when compared to mammalian cell cultures [17]. However, there are some limitations—different glycosylation patterns and post-translational processing can also make plant cell utilization difficult [17].
Production platforms
The cell culture for mAb production can follow three different types of processes. The simplest of them is batch production, which consists of a closed system where a bioreactor is sterilized and prepared with a medium containing all the nutrients needed for cellular growth and product manufacturing and then, cells are inoculated. There is no feeding system with fresh medium or withdrawal of spent medium. As the process runs, nutrient concentration decreases and waste metabolites are produced, lowering cell viability. In spite of being a simple process, batch is not the most suitable type of production platform for mammalian cell cultures, as the environment inside the reactor quickly becomes unfavorable for cell growth and, at the same time, waste product concentration increases. Cultivation factors such as initial nutrient concentration and waste metabolite production directly determine the maximum concentration that cells can reach in a bath culture. Generally, this type of cultivation reaches a maximum density of 1–2 × 106 cells/mL, and then the cell viability drops rapidly [1]. The production process lasts for 4–7 days, when productivity reaches certain concentration of interest [1]. Supernatant is collected and the product is recovered by downstream processes. The time that each batch takes to finish also depends on the production kinetics. If the production is growth dependent (production occurs concomitantly with cellular growth), batch processes can be stopped as soon as cells reach the stationary phase. But if the product is not associated with growth (production only starts when the growth rate decreases), the culture needs to be carried for a longer period of time since production only starts at stationary phase.
In contrast to batch, a second type of production process utilized is continuous fermentation. There are two types of continuous production: chemostat cultures and perfusion cultures. Concerning chemostat cultures, fresh medium is added to the bioreactor and fermented medium is removed along with cells at a constant flow rate so that the culture volume remains unchanged. The flow rate (dilution rate) controls cellular growth and when these two variables are equal, the bioreactor reaches equilibrium—cell concentration, nutrient concentration, and product concentration are held constant. In this context, the culture can be kept in equilibrium for several months reaching a cell density of 10–30 × 106 cells/mL [1]. To avoid viable cell loss along with the constant outflow of the by-products of cell metabolism, many manufacturing plants have developed a cell-recycling system and thus, the perfusion culture method was developed where cells are kept inside the bioreactor. The disadvantages of continuous fermentation are the use of a large amount of expensive culture media and the difficulty in recovering the product, which comes out fairly diluted. These two disadvantages are consequences of the constant medium flow rate. To work around the product dilution problem, some production manufacturing plants have ultrafiltration systems which retain the product inside the bioreactor [18]. Another obstacle of this type of process is that the establishment of culture conditions for a stable industrial production plant can take months. For this to occur, the strain used must be very stable and have its physiological aspects clearly elucidated, such as growth rate, productivity, and response to certain stress conditions. It is not uncommon to hear that numerous attempts are made before the settlement of a stable production plant is achieved, but, once settled, this production process can bring many advantages, since it can be operated in smaller-volume bioreactors, and therefore have greater production flexibility.
The third type of process for producing monoclonal antibodies is by far the most utilized at industrial scale, which is fed-batch process. In this process, the cell density reaches 8–12 × 106 cells/mL, and cell viability in the bioreactor is enhanced by controlled nutrient addition at specified intervals [1]. The production process can take 12–20 days [1]. Usually, the same medium used in the initial culture is also used for feeding, but in a more concentrated version. The feeding solution composition can be designed to supply the cells based on their metabolic state at different culture phases by analyzing and identifying the spent medium nutrients that are being more consumed. Furthermore, the medium used in feeding can be modified to promote cell growth or to stimulate molecule production, since different components may modify the behavior of cells, changing the metabolism for different purposes. The feed solution can also be designed to minimize the production of waste metabolites that cause cell stress when in excess. However, their production is not completely avoidable as they eventually reach harmful concentrations. It is relatively easy to scale up and operate this system. More summarized data about the advantages and disadvantages of each process for mAb production can be seen in Table 2.
A lot of effort has been made to increase cell longevity in batch and feed-batch modes of operation. It is expected that the longer the cells are maintained viable, the greater the antibodies’ production will be. So, in order to maintain cell viability, some culture parameters can be optimized, such as culture media, feed solution, and mAb secretion rates and by-product production. To improve mAb titers in the batch platform, the start medium can be supplemented with glucose and amino acids, increasing mAb production up to eightfold when compared with regular media [9, 26]. Improvements for the fed-batch platform can be achieved by adjustments in feed solution, as mentioned before. Feed solutions containing glucose and aminoacids/glutamine have been reported to increase mAb titers from two to fourfold, reaching production of up to 2 g/L, when compared with the batch production platform [19].
The optimization of the antibody secretion rate can be achieved by high-density cell cultivation. On a fed-batch platform, a high cell cultivation culture can reach an mAb productivity rate of 0.94 g/L/day and a final titration of 17 g/L, while a continuous culture performed at high density conditions can reach final titration and productivity rates of 0.8 and 1.6 g/L/day, respectively [20]. Optimizing mAb secretion highly depends on the cell line chosen for production. Each cell strain can be influenced by the manufacturing conditions and respond differently to increasing or decreasing mAb production and secretion [19]. The accumulation of toxic by-products is a great bottleneck in manufacturing processes since they can inhibit cell growth and then directly affect mAb production. Although a few strategies to minimize this by-product accumulation have shown to be promising, some are not applicable for a large-scale production. Optimizing medium composition and feed solutions with substrates that reduce toxic compound production is the most common strategy used at industrial scales of production [19].
Although most mAbs are produced by fed-batch process, there are tendencies indicating that in the future many bioprocesses will be operated in continuous platforms, especially for the production of biopharmaceuticals. On these platforms, the production system will be coupled to upstream and downstream processes [21]. However, for this to actually happen, a great improvement in technological development still needs to be achieved.
Conclusions and perspectives
Actually, the trade of monoclonal antibodies makes up half of marketed biopharmaceuticals, reaching $ 75 billion. For some years, new development methodologies of antibodies have advanced with new production processes, allowing scale-up production and market introduction, and demands for high-quality biologics will continue to increase in the coming decades. Generally, processes are similar to those applied in the scheduling for other bioproducts/biosimilars that rely on culturing microorganisms or cells, requiring the development of a well-designed culturing process comprising the full range of control and associated operations that will support technical evaluations.
In combination with increasing pressure from regulatory agencies for enhanced quality and lower process costs from the health care systems, we are facing an important challenge. It will be necessary to make changes in plant design aiming for highly flexible multi-purpose facilities for small production volumes.
https://www.intechopen.com/books/fermentation-processes/production-processes-for-monoclonal-antibodies
What is a Monoclonal Antibody?
Monoclonal antibodies (mAbs) are antigen-recognizing glycoproteins that are made by identical immune cells, all of which are clones of a unique parent cell. Since 2014, FDA has approved at least five monoclonal antibodies per year, and this trend shows no signs of slowing. These therapies encompass a number of indications such as autoimmune disorders, infectious diseases, and oncology, among others.
Due to their exquisite specificity, monoclonal antibodies embody the promise of precision medicine, which is to develop therapies that are specifically tailored to a particular target. The advantage of such a strategy is clear: for example, instead of treating a patient with conventional chemotherapy, which is toxic not only to tumor cells but to normal cells as well, a monoclonal antibody therapy can selectively target the cancer via recognition of specific surface antigens that are over-expressed on tumor cells and not expressed (or at least to the same degree) on normal cells.
Despite their promise, monoclonal antibodies have not had a smooth road to approval. Over the years, even seemingly well-designed monoclonal antibodies have often resulted in unacceptable adverse reactions, more times than not sending researchers back to the drawing board to devise new ways to make the technology viable. The big breakthrough that pushed monoclonal antibodies from a good idea to a clinically useful tool came about with the advent of antibody humanization. To understand antibody humanization, it is helpful to review a brief history of monoclonal antibodies.
The Origin of Monoclonal Antibodies
In 1986, Orthoclone OKT3® (muromonab-CD3) became the first monoclonal antibody approved by the FDA. Its production was based on the Nobel-winning work of Kohler and Milstein on murine hybridoma technology. This technology, part of which is still used in the generation of some modern monoclonal antibodies, had several steps. The first step involved generating a specific immune response in mice by injecting them with a particular antigen. In the case of muromonab, the antigen was the T-cell co-receptor CD3. This resulted in the mouse’s immune system producing antibodies against CD3. Antibody-producing cells, however, are typically short-lived, and thus not great candidates for the mass production of a therapeutic antibody. To get around this limitation, the second step of the process involved isolating the antibody-producing mouse cells and fusing them with immortalized myeloma tumor cells. This step resulted in the creation of hybrid cells that could produce antibodies but also had the replicative properties of tumor cells.
The problem with using monoclonal antibodies secreted directly from these hybrid cells, however, became apparent almost immediately. The human immune system is trained to attack anything it sees as foreign. Since muromonab was a mouse protein and thus foreign to the human immune system, patients treated with the drug generated anti-mouse antibodies, limiting the effectiveness of the drug and creating serious side effects. The story of monoclonal antibody therapeutics might have ended with muromonab had it not been for advances in genetic engineering made in the late 1980s and early 1990s.
Humanized Monoclonal Antibodies Today
The newest generation of therapeutic antibodies includes what are referred to as fully human monoclonal antibodies. Fully human monoclonal antibodies are produced by one of two very different routes. The first route, used to make Vectibix® (panitumumab, approved in 2006), is very similar to the murine hybridoma process. The major difference is that the mice used to produce fully human monoclonal antibodies have been genetically altered to carry human antibody genes rather than mouse antibody genes. Thus, no part of the eventual therapeutic monoclonal antibody is mouse-derived. The second route, used to make Humira® (adalimumab, approved in 2002), uses a technology called phage display to identify optimal CDRs. Phage display involves inserting a genetic library of CDRs into a type of virus that infects bacteria (bacteriophages). The phages then express the CDRs, allowing for easy screening of the CDRs exhibiting the strongest antigen binding. Once the best CDRs are identified, they are then grafted onto a human antibody scaffold. Fully human monoclonal antibodies generally show a lower incidence of ADAs than their humanized counterparts, but immune responses to fully human monoclonal antibodies still persist and vary widely by product and indication.
Conclusions
Regardless of the exact path that gives rise to the next generation of monoclonal antibody therapies, one thing is for certain: therapeutic antibodies can do things that few small molecules can, and as such will remain firmly a part of the drug development landscape for years to come.
https://www.nuventra.com/resources/blog/monoclonal-antibodies-past-present-and-future/
Enzolytics Technologies Targeting HIV and the CoronaVirus
Interview conducted by:
Lynn Fosse, Senior Editor
CEOCFO Magazine
Published – December 7, 2020
CEOCFO: What is your funding position? Development and eventually commercialization are very expensive.
Mr. Cotropia: Yes, that is a very relevant question. We will be securing long term financing for advancing our technology. We have begun the process of producing variants of our existing anti-HIV monoclonal antibodies and identifying target site on the CoronaVirus for producing multiple antibodies against that virus. We are extending our lab capabilities on the Texas A&M University campus at its Institute for Pre-clinical Studies where we will be producing both addition monoclonal antibodies against HIV and the against the CoronaVirus. For HIV, we will be combining the anti-HIV neutralizing antibodies with the anti-HIV peptide—which is also immunomodulating—that has been previously clinically tested by Enzolytics to have beneficial effect in HIV patients. The funding we arrange will take us through that development which will include animal trials to be followed by human clinical trials of these therapeutics.
[b[color=green]]Success in these steps will bring the necessary funding for success. Demonstrating positive results will translate into the necessary funding due to the dire need for these therapies.[/color] As I mentioned, there is not going to be one bullet that fends off either the HIV virus or the CoronaVirus. It will be necessary to have more than one. We welcome Eli Lilly and Regeneron in their initial antibody production and that success is all to be rewarded and celebrated. However, as we have seen in the past with HIV, it is going to be a very difficult to completely control the CoronaVirus and all of its mutated forms. Success will require multiple therapeutics and we know that monoclonal antibodies will certainly be in the picture and in the front line of successful treatments.
Another important aspect of our technology is that identification of a neutralizable binding site on the virus can lead to the creation of a vaccine – one that would be of a different format from the current mRNA vaccines now being produced. Specifically, the vaccine would be based on the known broadly neutralizing antibody and the highly conserved binding site to produce an active immunization that would not comprise nor incorporate an immunization process using nucleic acid constructs. In this process, a protective active immunization would use the neutralizable binding site on the virus as subunit peptide vaccine. Use of peptide sub-unit immunogens in active immunization obviates the concerns for weak humoral immune response, theoretical risks of insertional mutagenesis, and provocation of an autoimmune response, in other words, concerns associated with immune response outcomes that are related to DNA and mRNA vaccination.
Therefore, different vaccines may be produced in very different ways, some of which hopefully will be very effective and very safe as to their long-term effect on the human body. A safe vaccine can be expected, based on a subunit peptide vaccine formulation using the neutralizable bind site on the virus in its development.
ENZC is more than a “ONE TRICK PONY”
Trick one:
ITV-1 has been through clinical trials successfully however they must be done again to get through the proper approvals before hitting the market. This will take a year or longer however it is a moot point as we already know what the results will be. This is Harry H Zhabilov “Pet Project” that he wants to see through.
Trick two:
Clone 3 + ITV-1 synergized for a combined monoclonal antibodies.
We will be producing both addition monoclonal antibodies against HIV and the against the CoronaVirus. For HIV, we will be combining the anti-HIV neutralizing antibodies with the anti-HIV peptide—which is also immunomodulating—that has been previously clinically tested by Enzolytics to have beneficial effect in HIV patients. The funding we arrange will take us through that development which will include animal trials to be followed by human clinical trials of these therapeutics.
Success in these steps will bring the necessary funding for success. Demonstrating positive results will translate into the necessary funding due to the dire need for these therapies.
Trick three:
Coronavirus monoclonal antibodies.
Trick four:
Patents, Patents and more Patents.
GIDDY UP
ENZC is a Biotech company and nothing happens quickly with such companies.
ENZC has made tremendous progress since the merger.
The biggest setback was not being able to get the ITV-1 to the market without doing the trials again.
The trials will be redone and they probably won't be finished until next year.
Once ENZC reach certain milestones with the monoclonal antibodes they have been producing they have an expectation of Big Pharma coming on board.
Two of the key milestones is the animal testing and toxicology tests as these will help determine how safe it is to test on humans.
ENZC is just following the PROTOCOLS necessary to move their tech foward.
It is just going to take time.
Many things good and not so good will be happening along the way.
Michigan coronavirus data for Wednesday, April 14: Closing in on new daily case record
Michigan is averaging more than 7,000 new cases of COVID-19 per day for the first time since Nov. 23 as it continues to lead all other states in new cases per capita.
At the peak of the fall surge, there were three days in which the seven-day average sat above 7,000, and it peaked at 7,270 on Nov. 21. Now, the state is up to 7,014 cases per day and climbing.
Four counties in the state’s “thumb” lead the way in cases per capita. Huron, St. Clair, Sanilac and Tuscola counties each have more than 1,000 cases per million residents per day.
Four additional counties -- Macomb, Otsego, Lapeer and Arenac -- are above 900 cases per million per day, and another 10 are higher than 800 per day.
For context, the top level of the state’s six-level risk assessment is “>150 new cases per 1 million people.” Seventy-five counties are at that level.
Below is a look at state and county numbers for new cases and positivity rates, as well as statewide numbers on hospitalizations, deaths and vaccinations.
New cases: The state is averaging 7,014 new cases a day.
The daily case average jumped another 18% from last week.
In two weeks, Michigan has gone from reporting 4,680 new cases per day to 7,014. On Tuesday, there were 8,867 new cases -- indicating the average is likely still climbing.
The top counties in cases per capita over the past seven days: Huron, St. Clair, Sanilac, Tuscola and Macomb.
The good news is Michigan’s positive test rate has seen a slight decline in recent days. The bad news: it’s still three-times higher than the threshold recommended by health officials for closing schools and communities.
The seven-day positivity rate is about where it was a week ago, which matched the peak of the fall surge.
Sixty-nine of the state’s 83 counties reported increases in positivity rates week-over-week.
The top ten positivity rates came from Huron, Sanilac, Tuscola, Oceana, St. Clair, Missaukee, Lapeer, Iosco, Wexford and Newaygo counties. However, all 10 counties did report declines in their rates week-over-week.
State health officials noted last week that the high positive test rates not only indicate high case rates, but that not enough residents are getting tested.
Hospitalizations: 4,250 inpatients on Tuesday
Michigan had 4,205 adults patients and 45 pediatric patients hospitalized with confirmed or suspected COVID-19 on Tuesday, April 14. That includes 842 patients in the ICU.
By comparison, there were 2,687 patients hospitalized on Thursday, April 1, with 511 in the ICU.
Health systems are closing in on the patient totals from last spring’s initial surge, and some hospitals have already begun postponing elective surgeries.
Deaths: The state is averaging 41 deaths a day.
That compares to an average of 31 deaths a day a week ago, and 23 deaths per day two weeks ago. The current death rate is the highest since Feb. 8.
Deaths are a lagging factor, but typically follow a surge in cases and hospitalizations by a few weeks. State officials have said they’re closely monitoring this data.
Vaccinations: 41.9% of adults have received at least one dose
Through Monday, April 12, there were 3,389,738 Michiganders with at least one dose of vaccine, and more than 2.2 million who had completed their vaccine regimen.
About 27.5% of residents 16 years and older have completed their vaccination.
Below is a breakdown by age group of adults who have gotten at least one dose of vaccine and those who are fully immunized.
75 and older: 70% initiated; 61.3% completed.
65 to 74: 70.8% initiated; 60.8% completed.
50 to 64: 49.5% initiated; 29.1% completed.
40 to 49: 34% initiated; 18.1% completed.
30 to 39: 30.6% initiated; 15.6% completed.
20 to 29: 21.1% initiated; 10.1% completed.
16 to 19: 13.5% initiated; 2.9% completed.
State’s overall risk assessment: All regions at highest level
All eight of Michigan’s MI Start regions are back to Level E in the state’s overall risk assessment for the second consecutive week.
In assigning the risk scores, Michigan Department of Health and Human Services looks at factors such as new cases and deaths per capita, test positivity rates, number of tests administered and emergency department visits for COVID-19 symptoms. The scale used by MDHHS has six levels -- “low” plus Levels A-E.
That was the old Enzolytics Inc.
The new Enzolytics Inc. doesn't have to prove anything.
What ENZC has to do it get results and go through the protocols to get their products to the market.
How do they get monoclonal antibodies to the market?
1. Make the monoclonal antibodies
2. Have the monoclonal antibodies tested on animals
3. Have Toxicology tests done
4. Manufacturing Information
5. Clinical Protocols and Investigator Information
Has ENZC done of the above or is it just a SCAM company stringing INVESTORS along?
ENZC may BECOME the BEST EVER PIECE of SCIENCE (POS) known to MANKIND.
Below is a timeline of ENZC’s progress since April 2020. The timeline clearly shows ENZC is making progress in moving their technology through the necessary protocols to get their products to the market place, upgrade to the OTCQB and increase the value of the company. What has happen thus far has not happen quickly and to get to the end game (the marketplace) will not happen quickly either. There have been setbacks and probably be others in the future. ENZC has made significant use of Artificial Intelligence (AI), its proprietary technologies and collaborations to assist in the further producing of monoclonal antibodies.
How do they get these antibodies to the market?
1. Make the monoclonal antibodies
2. Have the monoclonal antibodies tested on animals
3. Have Toxicology tests done
4. Manufacturing Information
5. Clinical Protocols and Investigator Information
Has ENZC done of the above or is it just a SCAM company stringing INVESTORS along?
ENZC may BECOME the BEST EVER PIECE of SCIENCE (POS) known to MANKIND>
ENZC TIMELINE:
April 16, 2020 Regain Current Status with OTC Markets
April 16, 2020 Open operation in the Dallas, Tx area where the company has relocated
September 16, 2020 Enzolytics, Inc. today announced the execution of a non-binding letter of intent (the "LOI") to merge with BioClonetics Immunotherapeutics, Inc. ("BCLS" or "BioClonetics") a biotech company located in Dallas Texas.
September 16, 2020 The Companies plan to conduct binding studies combining the therapeutics produced by both companies to evaluate the beneficial effects and increased binding capability of the BioClonetics Clone 3 antibodies to multiple HIV isolates.
September 16, 2020 Thereafter, PBMC based in-vitro neutralization studies will be conducted with the Enzolytics ITV-1 peptide in combination with the BioClonetics Clone 3 antibodies. Based on the results, the best combination with be tested in primate studies at the California National Primate Research Center University of California, Davis, California.
October 1, 2020 BioClonetics is in the final stage of development of a parent monoclonal antibody ("mAb") (designated as Clone 3), which is non-toxic and has shown in initial in vitro testing to be effective against more than 95% of all strains and viral subtypes of HIV-1 against which it has been tested.
October 1, 2020 In anticipation of ENZC bringing current its OTC filings the Company has made application to OTC Markets for membership. Once the Membership Application is approved by OTC Markets, the Company will begin filing its delinquent quarters.
October 14, 2020 Enzolytics, Inc. today announced the execution of a binding letter of intent (the "LOI") to merge with BioClonetics Immunotherapeutics, Inc. ("BCLS" or "BioClonetics") a biotech company located in Dallas Texas, replacing the earlier non-binding letter signed on September 12, 2020.
October 14, 2020 BioClonetics is in the final stage of development of a parent monoclonal antibody ("mAbs") (designated as Clone 3), which is non-toxic and has shown in initial in vitro testing to be effective against more than 95% of all strains and viral subtypes of HIV-1 against which it has been tested.
October 14, 2020 ENZC is in the process of compiling the information to bring current its OTC filings. The company has begun the process of identifying a clinical research organization for the preparation of pre-IND protocols for submission to the FDA and is also in the final interviews with several pharmaceutical manufacturing companies to produce the validation order.
October 19, 2020 Additionally, we will use AI (artificial intelligence) to analyze the 16,000 known sequences of different SARS-Cov-2 viruses that have now been catalogued in the Los Alamos National Laboratory, with multiple different strains identified. By using computer analysis, several conserved (expectedly immutable and neutralizable) sites on the virus can be identified and additional monoclonal antibodies produced against these- to be used in a monoclonal antibody "cocktail".
October 19, 2020 All of our steps are taken with two objectives in mind. First our focus is on creating successful therapeutics against infectious diseases, including HIV and now our focus on the Coronavirus. Secondly, our efforts are also intended to increase the value of our technology and the value of our company - which directly translates into value for our investors. Please know that these are our two guiding objectives with every effort we make.
October 22, 2020 Enzolytics, Inc. announced the appointment, by the Board of Directors of the Company, on October 20 of Charles Cotropia to the position of CEO of Enzolytics. Mr. Cotropia also serves as CEO of ENZC's Merger target BioClonetics Immunotherapeutics, Inc. ("BCLS" or "BioClonetics"), Harry Zhabilov the former CEO of ENZC has taken the position of CSO. Charles Cotropia was appointed to the ENZC Board of Directors on October 1, 2020. Simultaneously, Harry Zhabilov was appointed to the BCLS board.
October 22, 2020 Enzolytics' application with OTC Markets was approved and ENZC has begun the process of bringing its filings current having filed the September 30, 2018 report.
October 22, 2020 In addition, management of ENZC is scheduling a meeting with a GMP manufacturer anticipated to take place before the end of the month.
October 22, 2020 The Company has also procured a commitment for funding of $500,000.00 to be used for implementation of the planned combined operations and the initial steps of the merged business strategy of creating successful therapeutics against infectious diseases thereby increasing the value of the Company's technology and the value of the Company through the combination the Enzolytics ITV-1 peptide in conjunction with BioClonetics' anti-HIV monoclonal antibodies. As part of this initial $500,000.00 funding, the Company and certain of its current convertible debt holders have agreed to a standstill on the issuance of any additional shares from conversions of debt.
November 10, 2020 Enzolytics, Inc. announced the appointment of Ronald Moss, M.D., to the Medical Advisory Board of the Company.
Dr. Moss has an extensive 25-year background as an executive with numerous Biotechnology companies including direct clinical experience. He has a respected history of leveraging leadership, analytical analysis and clinical experience to assist companies through the complexity of drug development. He has extensive clinical and regulatory management expertise in guiding programs through Phase I, II, and III clinical trials, including IND and NDA experience. He is skilled at forging innovative partnerships with regulatory agencies, the NIH and large pharmaceutical entities.
November 13, 2020 We are making great progress on our plans to further develop additional anti-HIV monoclonal antibodies and to now begin the production of fully human monoclonal antibodies targeting the CoronaVirus. On December 1, we are expanding our lab to the campus of Texas A&M University at its Institute for Preclinical Studies. This expansion will allow us to complete production of monoclonal antibodies against both the HIV virus and the CoronaVirus and collaborate with the biopharma experts on the campus. Although we have NIH grant applications pending for the production of anti-HIV and anti-CoronaVirus monoclonal antibodies, we have secured funding that allows us to proceed without delay.
November 13, 2020 Here is why we are confident in our technology:
It will be imperative that produced antibodies target a conserved and immutable site on the virus - otherwise the antibody (over time) will be rendered ineffective due to mutation - known as "virus escape". Our anti-HIV monoclonal antibody targets an immutable virus site on the HIV virus - one that is constant within virtually all 6000 now known different HIV isolates (strains) of the virus. The CoronaVirus has structure correlative to that of the HIV virus. Because our primary anti-HIV monoclonal antibody has been proven to neutralize numerous different strains of the HIV virus in tests in 5 international labs, and knowing the binding site on the HIV virus to which our antibody binds resulting in neutralization, this knowledge provides insight necessary to identifying corresponding structure (amino acid sequences) on the CoronaVirus that should be targeted to effectively neutralize the CoronaVirus. Moreover, we have proprietary methodology needed to produce anti-CoronaVirus monoclonal antibodies targeting such known - to us - sites.
November 13, 2020 Additionally, our antibodies retain the original natural antibody affinity and specificity and have lower risk of immunogenicity when used as a therapeutic. They will provide broad-spectrum coverage against viral variants with increased potency, stability as a single-domain molecule, and, in the recombinant form, will have accessibility to the virus epitopes (binding sites) not accessible with a whole antibody. We are actively moving forward in our production and testing of such antibodies.
December 1, 2020 Enzolytics, Inc. (OTC Markets "ENZC" or the "Company") announced the execution of the definitive business combination agreement successfully merging the biotech companies Enzolytics, Inc. and BioClonetics Immunotherapeutics, Inc. on World AIDS Day.
December 1, 2020 The Company has recently confirmed plans to test its monoclonal antibodies at the University of Strasbourg, France, under the direction of Dr. Christiane Moog, Ph.D., Research Director at INSERM, University of Strasbourg, a leading specialist in conducting the preferred PBMC based in vitro neutralization assays protocol for anti-HIV monoclonal antibodies. Additional testing of the Company's antibodies is also being planned at San Raffaele Scientific Institute, Milan, Italy, under the direction of a further expert in the field, Dr. Gabriella Scarlatti, M.D., Ph.D., Head of Viral Evolution and Transmission Unit at San Raffaele Scientific Institute.
December 1, 2020 The therapies of Enzolytics' two technologies, that produced by Enzolytics and that created by BioClonetics will be tested in combination and are expected to be synergistic.
December 1, 2020 Additionally, the Company has identified correlative structure between the HIV virus and the CoronaVirus and, with its capability to produce targeted monoclonal antibodies, is moving forward to produce monoclonal antibodies targeting the CoronaVirus. The Company is extending its lab capabilities on the Texas A&M University campus at the Institute for Pre-clinical Studies, where it will be producing both addition monoclonal antibodies against HIV and the against the CoronaVirus.
December 1, 2020 The Company's addition of Dr. Ronald Moss, MD, to its Medical Advisory Board has provided experienced guidance for its strategies and in its planned testing and validation of its therapeutics in animal and clinical trials.
December 10, 2020 Enzolytics, Inc. (OTC PINK:ENZC or the "Company") today announced the filing of a provisional patent with the U.S. Patent Office on December 9, 2020 for a treatment of Multiple Sclerosis developed by Harry Zhabilov, titled NUCLEAR PROTEINS ISOLATED FROM MAMALIAN SPINAL CORD (SCNP) IMMUNE FACTOR, Ser. No. 62/123341. The Company received confirmation of filing from the U.S. Patent Office today.
December 10, 2020 Charles Cotropia, CEO stated, "The management team at ENZC is focused on the development of its proprietary technologies and this is a continuation of what is expected to be an expanding pipeline of products for treating serious illnesses."
December 14, 2020 Enzolytics, Inc has engaged SAMM SOLUTIONS, INC. (DBA BTS Research), through a Master Service Agreement ("MSA"), to conduct a toxicity study on the Company's Flagship compound ITV-1. The Company has previously tested the compound in successful Clinical Trials in Bulgaria, but FDA regulations require separate Toxicity tests before an Investigational New Drug process may begin in the United States. SEE NOTE 1
December 30, 2020 Both management teams were committed to this mission, and even before the completion of the combination documentation, transition of our organizations began by my appointment to the Enzolytics' Board as a Director and CEO and appointment of Harry Zhabilov to the BCLS Board. This allowed us to share information for assimilating our proprietary information for research and development purposes and for streamlining the administrative function to accelerate future growth.
December 30, 2020 Currently, the Company has requested proposals from several PCAOB accounting firms to provide quotes for Audits of the Company's current and prior year Financial Statements in order to become fully reporting. Bids were requested to be provided by mid-January, and the Company anticipates making a decision by the end of January 2021.
December 30, 2020 Our new lab is being opened on the campus of Texas A&M University in the University's Institute for Preclinical Studies. Here we will expand our development capabilities for the production of additional monoclonal antibodies targeting immutable sites on the HIV and SARS-CoV-2 viruses. In addition to those primary targets on these viruses already known to us, we have engaged an artificial intelligence (AI) and genetics and molecular biology data science team to curate the thousands of isolates (strains) now known as existing in both the HIV virus and the SARS-CoV-2 virus. This process will allow us to identify conserved, immutable targets against which monoclonal antibodies are to be produced.
December 30, 2020 Testing of the newly produced monoclonal antibodies is also being arranged. This includes testing of our now being produced recombinant anti-HIV monoclonal antibodies created from the parent antibody. Such testing is now scheduled for early 2021 at the University of Strasbourg in Strasbourg, France.
December 30, 2020 In addition to these successes, we have been very successful in raising necessary funding to execute our plans. Our initial $500,000 raise is being followed with $1 million being funded in the next 30 days, and additional investment is being made into the Company by officers of the Company, bringing the total raised since the signing of the non-binding letter of intent to $1.7 million.
December 30, 2020 The Company has also negotiated a debt exchange whereby most of the existing convertible debt has been exchanged for equity instruments that have a two-year conversion clause to postpone conversions for the next two years. We believe this step, along with the reorganization under Section 251 G that was initiated prior to the closing of the combination agreement, will significantly enhance the equity position of the Company.
December 30, 2020 The Company acknowledges the enthusiasm of our investor base, and in response to their desire for up-to-date information, we are updating our website and will be launching it in the New Year.
January 11, 2021 Enzolytics, Inc today, announced it has accepted a proposal from a Houston based PCAOB Audit firm to Audit the Company's year-end financial statements, subject to the receipt and acceptance of the engagement letter. The proposal covers the 2019 and 2020 calendar years for filing with the OTC Markets.
January 19, 2021 Enzolytics, Inc. (OTC PINK:ENZC)(the "Company") today, announced it has received the official filing receipt from the U.S. Patent Office confirming the filing of its patent application for "Nuclear Proteins Isolated from Mammalian Spinal Cord Immune Factor - Pharmaceutical Composition for Treatment" and has received the third tranche of the $1.2 million dollar financing.
February 1, 2021 Enzolytics, Inc today announced it has identified seven additional conserved, expectedly immutable sites on the HIV virus against which it plans to produce targeted anti-HIV monoclonal antibodies. The Company's primary anti-HIV monoclonal antibody targets one conserved site on the HIV virus, which site is 98% conserved (either directly or by way of conservative amino acid substitutions) over all 87,336 HIV isolates which have now been curated (analyzed) by the Company using Artificial Intelligence (AI). Additional conserved target sites (some with 98% conserved sequences) have now been identified against which fully human anti-HIV monoclonal antibodies will be produced in its lab on the campus of Texas A&M University in the University's Institute for Preclinical Studies. The significance of producing multiple monoclonal antibodies targeting multiple conserved sites is recognized by experts as a critical approach to effective therapy. This allows the administration of a "cocktail" of antibodies, all targeting conserved and expectedly immutable sites.
February 1, 2021 Additionally, the Company's Genetics and Molecular Biology data science team is now screening (using computer analysis/Artificial Intelligence [AI]) more than 275,000 CoronaVirus isolates now known, to also identify conserved sites which expectedly are immutable. From this information, anti-SARS-CoV-2 (CoronaVirus) monoclonal antibodies will be produced. The significance of producing monoclonal antibodies against conserved target sites on targeted viruses is made evident by the mutant strains of the CoronaVirus currently surfacing in the U.S, South Africa, Brazil, United Kingdom and around the world. The same virus mutation exists with HIV, as well as other well-known viruses. As a virus mutates, a therapeutic becomes ineffective when it neutralizes by attacking a site that changes. By targeting an immutable site, a therapeutic is not affected by the mutation. This is well understood by the necessity to produce a new flu vaccine with each flu season, namely because the flu virus mutates. Producing therapeutics that target a conserved site on viruses makes possible the production of a therapeutic that is not rendered ineffective by virus mutation, and therefore can be applied successfully both universally around the world and durably over time.
February 1, 2021 Additionally, the Company's Genetics and Molecular Biology data science team is now screening (using computer analysis/Artificial Intelligence [AI]) more than 275,000 CoronaVirus isolates now known, to also identify conserved sites which expectedly are immutable. From this information, anti-SARS-CoV-2 (CoronaVirus) monoclonal antibodies will be produced.
February 1, 2021 The Company is also applying Artificial Intelligence [AI] to scan the hundreds of thousands of isolates that exist in 14 other prevalent viruses, ranging from influenza to Rabies to Ebola. Using the Company's proprietary technique for producing fully human monoclonal antibodies directed against these infectious diseases, the Company will produce multiple neutralizing monoclonal antibodies against these viruses. The significance of this approach is well recognized by experts in virology due to the ability of all viruses to mutate and render ineffective initially developed therapeutics.
February 1, 2021 Production of the Company's primary anti-HIV monoclonal antibodies is underway at Genscript Labs. Testing of these newly produced monoclonal antibodies is scheduled for early 2021 at the University of Strasbourg in Strasbourg France. Thereafter, Macaque trials are planned at the California National Primate Research Center, Univ. of California, Davis, CA. SEE NOTE 1
February 1, 2021 Based on this information, the Company took the following actions. On January 28th, a notice of default and termination was registered with the courts in Sofia of the Sub License Agreement issued to IMMB BG. The company has entered into negotiations with a supportive group in Bulgaria to form a new entity and enter a funding agreement to cover any new cost of clinical trials under EMA standards and permitting by the EMA. Strategically, the Company believes that the actions will be cost effective resulting in a significant advancement of the Company's therapeutic portfolio.
February 1, 2021 As stated in the year end update, proposals were recently requested from several PCAOB accounting firms to provide quotes for Audits of the Company's current and prior year Financial Statements in order to become fully reporting. The Company has engaged MaloneBailey, LLC of Houston, Texas as its PCAOB accounting firm and has begun the audit process. It is still the Company's plan to complete the two-year audit as quickly as possible but will file the December 31, 2021 Annual Report Financial Statements pursuant to the OTC Markets Pink Basic Disclosure Guidelines immediately upon completion to allow time to complete the two-year audits and remain current with our filings.
February 16, 2021 Enzolytics, Inc. announced today the results of an in vitro study of the Company's ITV-1/IPF peptide treatment that demonstrated the broad efficacy with low toxicity. The Company's ITV-1 peptide was tested against human corona virus 229E Strain (HCoV-229E) and exhibited comparable efficacy but with a 20-fold lower toxicity than the widely used anti-influenza medicine Tamiflu®.
February 22, 2021 Enzolytics, Inc. (OTC Markets "ENZC" or the "Company") today announced the execution of Articles of Association to form International Medical Partners ("IMPL") a Bulgarian Limited Liability Company of which the Company is 50% owner. The Company's partners in IMBL are a group of successful Bulgarian businessmen who will fund the cost of the Clinical trials under the European Medicine Agency (the "EMA") standards and the application cost for the EMA permit for the Company's ITV-1 patented therapeutics for treating HIV. Under the Mutual Recognition Agreement (the "MRA") between the EMA and the United States Federal Drug Administration (the "FDA"), the company believes that issuance of the EMA permit for the ITV-1 compound should qualify ENZC's treatment for recognition by the FDA. IMBL has entered negotiations to engage Clinic Design to begin the clinical trials that may be required under EMA standards.
February 22, 2021 The Audits of the Company's current and prior year Financial Statements are in process and the application for OTCQB is being prepared for submission upon issuance of the Audited Statements. The Company plans to complete the two-year audit as quickly as possible but will file the December 31, 2021 Annual Report Financial Statements pursuant to the OTC Markets Pink Basic Disclosure Guidelines. The Company anticipates filing the financial statements under the Basic Disclosure Guidelines for December 31, 2020 in the coming weeks before the filing deadline of March 31, 2021.
February 22, 2021 Enzolytics, Inc. today announced it has identified eleven conserved, expectedly immutable sites (epitopes) on the Coronavirus against which it is producing targeted anti-SARS-CoV-2 monoclonal antibodies. Using computer analysis (Artificial Intelligence [AI]), the Company's genetics and molecular biology data science team has now screened more than 50,512 Coronavirus isolates currently known and has identified conserved sites which expectedly are immutable. The 11 conserved sequences identified on the virus isolates curated have been identified on the basis that they are 98.71% to 99.29% conserved over the entirety of the 50,512 Coronavirus isolates analyzed.
February 22, 2021 The Company has filed a comprehensive patent application covering these discoveries. This initial application has been filed in the U.S. and will be extended to claim international patent coverage through the International Patent Cooperation Treaty (PCT) to which 153 countries subscribe. The patent coverage sought includes patent claims on the discovered epitope/antigens, vaccine claims, antibody claims, and related prophylactic/therapeutic method claims relating to the epitope/antigens.
February 22, 2021 As the Company has previously reported, it is also curating (analyzing) the amino acid sequences of other major viruses and will file patent applications claiming the identified antigens/epitopes and associated therapeutics. Using AI analysis, the Company is now identifying and will claim the conserved epitopes/antigens on the infectious diseases caused by HIV-2, Influenza A and B, H1N1 influenza, Respiratory syncytial virus (RSV), Small-Pox, Ebola Virus, Tetanus, Diphtheria, HTLV-1/2, Rabies, Herpes zoster, Varicella zoster, Anthrax, Mason-Pfizer monkey virus (MPMV), Visna virus (VISNA) and mouse mammary tumor virus (MMTV). Patent applications will be filed claiming the inventive findings. Patent claims will cover the discovered epitope/antigens, with proposed vaccine claims, antibody claims, and related prophylactic/therapeutic method claims relating to these identified epitope/antigens.
February 22, 2021 The Company has clarified the lack of significance of the prior expired Company patents covering the Company's "parent" Clone 3 anti-HIV antibody. The expired Company patents were issued on the "parent" Clone 3 antibody. As is the case with virtually all parent antibodies, the parent antibody is a "slow producer" - which means it could not produce sufficient antibody therapeutics to treat the 36 million individuals infected with HIV. Thus, a recombinant form of the antibody had to be created employing a fast-producing CHO cell line. This has been accomplished by the Company and patent applications are pending claiming the recombinant form of the antibody, the form that will be used in patient therapy. The term of issued patents will be 20 years from filings, such filings having been made in 2020.
March 8, 2021 Enzolytics, Inc. (OTC PINK:ENZC) (the "Company") today announced it has filed for patent protection on the identified 8 conserved sites on the HIV-1 virus, some with over 98% conserved sequences. These applications will be extended to international filings under the Patent Cooperation Treaty (PCT) allowing the Company to seek patent coverage in 153 countries.
March 16, 2021 Enzolytics, Inc. (OTC Markets "ENZC" or the "Company") today announced the formalization of corporate legal documents pursuant to Articles of Association forming International Medical Partners ("IMPL") a Bulgarian Limited Liability Company of which the Company is 50% owner. The agreements are with the Company's partners in IMBL formed with a group of successful Bulgarian businessmen.
March 16, 2021 As a team, the Company with IMPL is moving forward to complete the initial production and certification of its ITV-1 patented therapeutics for treating HIV leading to the planned clinical trials under the European Medicine Agency (the "EMA"). A commitment for funding of the cost of clinical trials under EMA guidelines and cost associated with the issuance of an EMA permit are part of the negotiated agreements. Under the Mutual Recognition Agreement (the "MRA") between the EMA and the United States Federal Drug Administration (the "FDA"), the Company's belief is that issuance of the EMA permit for the ITV-1 compound should qualify ENZC's treatment for recognition by the FDA. IMBL has entered negotiations to engage Clinic Design to begin the clinical trials that is expected to be required under EMA standards. In addition, the Company is negotiating with an International known and respected European Contract Manufacturing organization ("CMO") to manufacture the required quantities of the ITV-1 Treatment to facilitate the clinical trials and permitting process under EMA guidelines.
March 22, 2021 Enzolytics, Inc. (OTC PINK:ENZC or the "Company") today announced it has filed NIH grant applications seeking funding for its production of monoclonal antibodies targeting the identified conversed epitope sites on both the HIV-1 and the SARS-CoV-2 viruses. Using its recent discovery of conserved sites on both viruses, the Company has filed updated NIH grant applications for funding for the production of monoclonal antibodies against these conserved sites on both viruses.
March 22, 2021 Using these new discoveries, the Company has bolstered its applications to the NIH seeking funding based on these additional discoveries. By renewing its applications with these significant additional discoveries, the prospect of grant funding is increased.
These revised applications incorporate the focus on the capability to produce multiple (a "cocktail" of) monoclonal antibodies for therapeutic treatment. While the Company sees value in pursuing NIH grant funding, the progress of the Company is not in any way affected or delayed by awaiting the review of such applications. Preparing such applications allows the Company to marshal its technology in a detailed confidential technical presentation that can be used in discussing our technology with potential biotech partners.
March 22, 2021 Additionally, the Company has entered negotiations with Pro Wave Ad Product ("PWA"), a Bulgarian Company, to supply the raw material for PWA's Contract in India for the production of a spray modulating the immune system under U.S. Patent No. 8,309,072 owned by Zhabilov Trust. This contract is valued at more than $50 million to PWA. This is the only approved use of this technology as a nutraceutical. The FDA issued a nutraceutical number to Harry Zhabilov on October 12, 2018. The first delivery under this agreement with PWA is expected to be in late spring 2021. The value to the Company is yet to be determined.
April 5, 2021 In a significant development, recent findings have revealed that the monoclonal antibodies being produced by the Company against targeted sites on the Coronavirus are directed against epitopes that exist conservatively on each of the variant strains of the virus from the UK, Brazil and South African. SEE NOTE 1
NOTE 1
The IND application must contain information in three broad areas:
Animal Pharmacology and Toxicology Studies - Preclinical data to permit an assessment as to whether the product is reasonably safe for initial testing in humans. Also included are any previous experience with the drug in humans (often foreign use).
Manufacturing Information - Information pertaining to the composition, manufacturer, stability, and controls used for manufacturing the drug substance and the drug product. This information is assessed to ensure that the company can adequately produce and supply consistent batches of the drug.
Clinical Protocols and Investigator Information - Detailed protocols for proposed clinical studies to assess whether the initial-phase trials will expose subjects to unnecessary risks. Also, information on the qualifications of clinical investigators--professionals (generally physicians) who oversee the administration of the experimental compound--to assess whether they are qualified to fulfill their clinical trial duties. Finally, commitments to obtain informed consent from the research subjects, to obtain review of the study by an institutional review board (IRB), and to adhere to the investigational new drug regulations.
ENZC is not a SCAM.
Enzolytics, Inc. is a drug development company committed to the commercialization of its proprietary proteins for the treatment of debilitating infectious diseases. Enzolytics is committed to creating drugs for the better health of mankind.
Our mission is clear – to create therapeutics that are effective and affordable for treating infectious diseases that plague the world. This goal includes the development of therapeutics and monoclonal antibodies targeting infectious diseases, including the CoronaVirus. Our ultimate objective is to provide such therapeutics to improve health around the world.
Enzolytics, Inc. is a Texas-based biotech company committed to the development and commercialization of its proprietary proteins and monoclonal antibodies for the treatment of infectious diseases, including HIV-1, Hepatitis (A, B, C), rabies, influenza A and B, tetanus and diphtheria. The Company’s multiple therapeutics also are being developed to treat Rheumatoid Arthritis and certain forms of cancer. Our technology for producing fully human monoclonal antibodies is now being employed to produce anti-SARS-CoV-2 (CoronaVirus) monoclonal antibodies for treating COVID-19.
The Company’s scientific team, Harry Zhabilov, Joseph Cotropia MD, and Gaurav Chandra MD, pioneered the Company’s proprietary therapeutics for treating infectious diseases, including HIV-1, Hepatitis (A, B, C), rabies, influenza A and B, tetanus, and diphtheria. The Company’s therapeutics may also be used to treat Rheumatoid Arthritis and certain forms of cancer.
The Company has also pioneered a proprietary method for creating human cell lines that produce fully human monoclonal antibodies directed against many infectious diseases. One antibody (designated as CLONE 3) has been demonstrated in tests in 5 international labs to fully neutralize over 95% of all strains and viral subtypes of HIV-1 against which it has been tested.
These HIV therapeutics may be used as an immunotherapeutic treatment for individuals with HIV/AIDS. They may also be developed for use as a prophylactic and therapeutic vaccine to prevent uninfected populations from contracting the HIV virus. Treatment using the fully human anti-HIV antibody will be far superior to current ARV therapy for several significant reasons: (1) the therapy will be effective and non-toxic, (2) will not require lifetime treatment, and (3) will be far less expensive.
Final testing of the Company’s anti-HIV mAb in PBMC neutralization assays is currently being completed, to be followed by animal trials at the California National Primate Research Center, UC Davis (Davis, CA).
The anti-HIV therapies of Enzolytics’ two technologies, that produced by Enzolytics and created at BioClonetics, are expected to be synergistic in treating HIV. Tests to establish such synergy are scheduled.
The Company’s proprietary methodology may also be applied to produce monoclonal antibodies against other infectious diseases. This includes the production of monoclonal antibodies against the SARS-CoV-2 virus (CoronaVirus), as well as other infectious diseases, including HIV-2, anthrax, smallpox, H1N1 influenza, herpes zoster, varicella zoster, Rh (+) auto-immune disease, and the Ebolavirus. A Company program is underway to produce monoclonal antibodies against the SARS-CoV-2 virus (CoronaVirus). Such production will be achieved using the proprietary methodology used to previously produce monoclonal antibodies (mAbs) against HIV, rabies, influenza A, influenza B, tetanus, and diphtheria.
Having produced neutralizing antibodies against the HIV-1 virus and recognizing a significant correlative structure between the HIV virus and the SARS-CoV-2 virus, the Company is developing anti-SARS-Cov-2 (CoronaVirus) monoclonal antibodies using its proprietary technology. These antibodies are expected to provide a therapeutic for patients infected with COVID-19. Identification of these neutralizable epitopes also will permit the production of a phage display anti-SARS-CoV-2 (CoronaVirus) vaccine.
Production of these monoclonal antibodies is being conducted in the Company’s lab at the Texas A&M University Institute for Preclinical Studies in College Station, Texas.
Biologics, specifically fully human neutralizing monoclonal antibodies directed against infectious disease, is considered the new frontier in biotechnology. In the past, the initial starting products were “humanized” rat and mouse mAbs being created for therapeutic use. “Humanized” immunoglobulins are the major immunotherapeutic that is prevalent today. What sets the Company’s antibody technology apart from that employed by other pharma? The Company’s technology permits the cloning of human or animal immune system cells. With the Company’s proprietary methodologies, stable parent hybridomas cell lines can be created that produce fully human antibodies.
Enzolytics specializes in the creation of human neutralizing monoclonal antibodies, not “humanized” mouse or rat counterparts, as are many mAb therapeutics in pharmaceutical use today. The Company’s technological methodologies have developed an effective, strong, and robust portfolio of biologics that have a pharmaceutical application with significant benefits to patients or animals in the global marketplace. From an identified and created parent hybridoma cell line, four distinct and effective products can be produced: (1) fully human neutralizing monoclonal antibody—directed against any pathogen based disease entity—through use in passive immunotherapy; (2) an effective humoral active vaccine that is safe and effective; (3) an oral mini-antibody peptide-based medication with an efficacy that is equivalent to the immunologic capacity of the monoclonal antibody produced by parent hybridoma cell; and (4) an entry-fusion inhibitor that is immunologic in character and scope. The applications are broad, effective, and beneficial for immunotherapeutic use.
The methodologies and processes for creating immortalized cells that stably produce human monoclonal antibodies are Company proprietary trade secrets.
You said:
If ENZC was such a TRASH TICKER it would have FALLEN a lot more than 80%
like the other OTC tickers, however it didnot.
WHY?
ENZC is an up and coming DEVELOPMENTAL COMPANY.
It is all in BLACK and WHITE in the PRESS RELEASES.
What ENZC is trying to accomplish didnot happen overnight, it was well planned out and there have been setbacks and will be more setbachs however ENZC continues to press on.
The company was a mess FINANCIALLY.
They were behind in the reporting.
The had 100 of millions of shares in toxic financing.
Their Phase III trial for ITV-1 although successful has to be done again to get proper regulatory approval.
So what did they do?
It all started more than a year ago.
Here is where ENZC publicly stated THIS IS NOT FROM OUR COMPANY!!!
Enzolytics Comments on Recent Market Activity and Shareholder Update
DALLAS, TX / ACCESSWIRE / February 6, 2020 / Enzolytics- (OTC Pink Sheet-ENZC) was notified by FINRA that an unauthorized press release titled, "Enzolytics Inc., Launches Coronavirus Prevention Kit" was distributed to the public. Enzolytics and its management had no knowledge of this press release in any manner, and disavows any information contained in this press release. The company does not have a "Coronavirus Prevention Kit" and finds the claim reckless and fraudulent.
Enzolytics, Inc., Inc. is diligently working to bring its filings current and continue with its initiatives for the commercialization of its proprietary proteins for the treatment of HIV.
PLANO, TX / ACCESSWIRE / April 16, 2020 / Enzolytics- (OTC PINK:ENZC) is pleased to update shareholders on the current corporate initiatives. The company has retained SEC counsel for the purpose of updating all corporate information, financials and to bring the company current from a public company perspective and allow the achievement of the company objectives.
The immediate goals include:
- Regain Current Status with OTC Markets
- Open operation in the Dallas, Tx area where the company has relocated
- Identify a CMO, Contract Manufacturing Organization, to produce the validation batch for Immunotech Laboratories BG-Europe.
- Assist Immunotech Laboratories BG-Europe in the registration of ImmunH as an Immunomodulator for HIV treatment.
- Further our development in North America of our Flagship HIV immune treatment compound IPF
PLANO, TX / ACCESSWIRE / September 16, 2020 / Enzolytics, Inc. (OTC PINK:ENZC or the "Company") today announced the execution of a non-binding letter of intent (the "LOI") to merge with BioClonetics Immunotherapeutics, Inc. ("BCLS" or "BioClonetics") a biotech company located in Dallas Texas.
The link below has all ENZC Press Releases:
https://marketwirenews.com/stock/enzc/news/
This is an Analysis of what may become of ENZC.
Analysis:
ENZC is a penny stock and as with penny stock there is a high risk that one could lose most if not all of their investment. The possibility exist that all we have witness up-to date is one of the most intricate frauds in the history of the stock market.
MOST OTC stocks are 80% or more from their highs just a month and a half ago.
The majority of the OTC MARKET was on fire than. Many stocks apparently for an unknown reason reached RECORD HIGHS.
It is all in BLACK ad WHITE:
CBBT:
Date Open High Low Close* Adj Close** Volume
Feb 12, 2021 0.3409 0.3490 0.2900 0.3220 0.3220 12,475,225
Feb 11, 2021 0.3901 0.3901 0.2900 0.3025 0.3025 20,342,113
Feb 10, 2021 0.4250 0.4300 0.3200 0.3900 0.3900 17,599,657
Feb 09, 2021 0.4400 0.4700 0.3216 0.3700 0.3700 30,634,434
Feb 08, 2021 0.2750 0.3700 0.2500 0.3675 0.3675 42,136,742
Feb 05, 2021 0.1870 0.2410 0.1799 0.2300 0.2300 30,845,521
Feb 04, 2021 0.1546 0.1895 0.1458 0.1795 0.1795 18,970,787
Feb 03, 2021 0.1490 0.1500 0.1400 0.1455 0.1455 10,603,471
Feb 02, 2021 0.1450 0.1450 0.1300 0.1373 0.1373 9,224,502
Feb 01, 2021 0.1310 0.1490 0.1135 0.1385 0.1385 25,409,177
ENZC:
Feb 12, 2021 0.6550 0.6650 0.4710 0.5491 0.5491 73,860,125
Feb 11, 2021 0.7500 0.7700 0.6000 0.6591 0.6591 38,765,419
Feb 10, 2021 0.9000 0.9200 0.5500 0.7174 0.7174 81,248,598
Feb 09, 2021 0.8110 0.9580 0.7472 0.8290 0.8290 62,155,509
Feb 08, 2021 0.5801 0.7400 0.5790 0.7390 0.7390 64,850,555
Feb 05, 2021 0.5370 0.5610 0.5000 0.5240 0.5240 69,394,498
Feb 04, 2021 0.3700 0.5670 0.3600 0.4775 0.4775 122,968,998
Feb 03, 2021 0.2920 0.3630 0.2854 0.3430 0.3430 84,232,468
Feb 02, 2021 0.2610 0.2929 0.2420 0.2850 0.2850 65,849,048
Feb 01, 2021 0.1992 0.2450 0.1900 0.2229 0.2229 41,865,413
INQD:
Feb 12, 2021 0.0310 0.0310 0.0240 0.0250 0.0250 32,603,847
Feb 11, 2021 0.0318 0.0397 0.0278 0.0310 0.0310 42,305,701
Feb 10, 2021 0.0350 0.0390 0.0200 0.0339 0.0339 79,197,039
Feb 09, 2021 0.0200 0.0350 0.0180 0.0298 0.0298 63,030,498
Feb 08, 2021 0.0160 0.0215 0.0150 0.0199 0.0199 59,117,532
Feb 05, 2021 0.0140 0.0190 0.0100 0.0138 0.0138 84,534,654
Feb 04, 2021 0.0073 0.0139 0.0073 0.0135 0.0135 65,516,047
Feb 03, 2021 0.0058 0.0076 0.0055 0.0076 0.0076 22,718,931
Feb 02, 2021 0.0068 0.0070 0.0059 0.0060 0.0060 10,435,695
Feb 01, 2021 0.0060 0.0074 0.0030 0.0065 0.0065 45,156,309
DPLS:
Feb 12, 2021 0.0360 0.0380 0.0300 0.0318 0.0318 114,177,138
Feb 11, 2021 0.0398 0.0398 0.0311 0.0340 0.0340 116,745,158
Feb 10, 2021 0.0440 0.0490 0.0300 0.0350 0.0350 280,842,242
Feb 09, 2021 0.0278 0.0510 0.0230 0.0395 0.0395 413,874,246
Feb 08, 2021 0.0130 0.0295 0.0116 0.0276 0.0276 549,903,929
Feb 05, 2021 0.0111 0.0125 0.0100 0.0113 0.0113 218,714,977
Feb 04, 2021 0.0130 0.0130 0.0090 0.0103 0.0103 301,076,429
Feb 03, 2021 0.0135 0.0135 0.0115 0.0120 0.0120 184,201,913
Feb 02, 2021 0.0136 0.0145 0.0120 0.0130 0.0130 174,684,160
Feb 01, 2021 0.0146 0.0146 0.0115 0.0128 0.0128 263,759,145
HBRM:
Feb 12, 2021 0.0036 0.0036 0.0030 0.0031 0.0031 488,725,635
Feb 11, 2021 0.0040 0.0044 0.0032 0.0036 0.0036 386,388,565
Feb 10, 2021 0.0045 0.0047 0.0035 0.0040 0.0040 444,221,048
Feb 09, 2021 0.0045 0.0048 0.0035 0.0041 0.0041 816,522,982
Feb 08, 2021 0.0033 0.0048 0.0030 0.0046 0.0046 166,437,727
Feb 05, 2021 0.0022 0.0029 0.0021 0.0027 0.0027 940,295,827
Feb 04, 2021 0.0022 0.0022 0.0019 0.0021 0.0021 392,011,035
Feb 03, 2021 0.0023 0.0024 0.0020 0.0021 0.0021 444,292,106
Feb 02, 2021 0.0022 0.0023 0.0019 0.0022 0.0022 580,300,558
Feb 01, 2021 0.0021 0.0021 0.0018 0.0020 0.0020 258,713,05
CELZ:
Feb 12, 2021 0.0709 0.0790 0.0500 0.0680 0.0680 41,601,800
Feb 11, 2021 0.0900 0.1000 0.0680 0.0729 0.0729 58,290,500
Feb 10, 2021 0.0899 0.1300 0.0610 0.0900 0.0900 142,441,700
Feb 09, 2021 0.0330 0.0840 0.0250 0.0806 0.0806 240,831,500
Feb 08, 2021 0.0278 0.0341 0.0177 0.0310 0.0310 68,661,100
Feb 05, 2021 0.0246 0.0260 0.0240 0.0259 0.0259 18,832,300
Feb 04, 2021 0.0261 0.0278 0.0240 0.0250 0.0250 28,888,500
Feb 03, 2021 0.0278 0.0280 0.0240 0.0259 0.0259 21,029,800
Feb 02, 2021 0.0284 0.0284 0.0230 0.0270 0.0270 20,872,300
Feb 01, 2021 0.0258 0.0290 0.0250 0.0256 0.0256 35,544,900
HCMC:
Feb 12, 2021 0.0059 0.0059 0.0038 0.0043 0.0043 2,392
Feb 11, 2021 0.0049 0.0065 0.0047 0.0049 0.0049 807
Feb 10, 2021 0.0042 0.0045 0.0037 0.0043 0.0043 744
Feb 09, 2021 0.0035 0.0039 0.0031 0.0034 0.0034 236,364,249
Feb 08, 2021 0.0018 0.0048 0.0017 0.0027 0.0027 291
Feb 05, 2021 0.0018 0.0018 0.0015 0.0016 0.0016 1,992
Feb 04, 2021 0.0018 0.0018 0.0015 0.0017 0.0017 3,465
Feb 03, 2021 0.0017 0.0050 0.0015 0.0016 0.0016 389,401,432
Feb 02, 2021 0.0019 0.0020 0.0010 0.0014 0.0014 2,086
Feb 01, 2021 0.0014 0.0020 0.0010 0.0019 0.0019 131
If one were to LOOK at any of the ABOVE tickers, one would see they are all down SIGNIFICANTLY from the HIGHS of FEBRUARY.
Does ENZC fit the definition of A Pump and Dump?
First one would need to idenitfy what a Pump and Dump is:
Pump-and-dump is a scheme that attempts to boost the price of a stock through recommendations based on false, misleading or greatly exaggerated statements. ... Then, once the price of the stock has been increased sufficiently by unsuspecting marks, the promoters then sell the stock at high prices.
So now the we know what a pump and dump is, ENZC clearly does not qualify.
So what is ENZC?
I'm glad you asked.
It is not a dotcom BOMB.
It is a RECENTLY organized combination of two (2) companies into one.
PLANO, TX / ACCESSWIRE / December 1, 2020 / Enzolytics, Inc. (OTC Markets "ENZC" or the "Company") announced the execution of the definitive business combination agreement successfully merging the biotech companies Enzolytics, Inc. and BioClonetics Immunotherapeutics, Inc. on World AIDS Day.
Through a merger of biotech companies, Enzolytics now advances two separate but complementary therapy platforms for treating infectious diseases, targeting HIV and the CoronaVirus. One technology, invented by Harry Zhabilov, the CSO of the Company, is a patented antiviral peptide that has been tested in clinical studies at the National Center of Infectious and Parasitic Diseases in Bulgaria. In these trials, the therapeutic, known as ITV-1, demonstrated effectiveness in the treatment of HIV patients in various stages of the disease. In trials conducted in 31 patients, the therapeutic showed efficacy, with 68% of those individuals tested experiencing an increase in CD4 + T lymphocytes. This increase was accompanied by an increase in the CD4/CD8 index and CD4% in over 50% of those tested. The increase in these parameters demonstrated statistical significance compared to the control group. The absolute number and the relative percent of CD8 + T lymphocytes were also decreased. And the viral load in 80.5% of those tested was below the threshold of detection. This Enzolytics anti-HIV treatment is now being advanced through the certification stage to thereafter be made available for patient therapy.
Enzolytics, Inc. is a drug development company committed to the commercialization of its proprietary proteins for the treatment of debilitating infectious diseases. Enzolytics is committed to creating drugs for the better health of mankind.
Our mission is clear – to create therapeutics that are effective and affordable for treating infectious diseases that plague the world. This goal includes the development of therapeutics and monoclonal antibodies targeting infectious diseases, including the CoronaVirus. Our ultimate objective is to provide such therapeutics to improve health around the world.
Enzolytics, Inc. is a Texas-based biotech company committed to the development and commercialization of its proprietary proteins and monoclonal antibodies for the treatment of infectious diseases, including HIV-1, Hepatitis (A, B, C), rabies, influenza A and B, tetanus and diphtheria. The Company’s multiple therapeutics also are being developed to treat Rheumatoid Arthritis and certain forms of cancer. Our technology for producing fully human monoclonal antibodies is now being employed to produce anti-SARS-CoV-2 (CoronaVirus) monoclonal antibodies for treating COVID-19.
OUR TECHNOLOGY
Enzolytics is a Texas-based biotechnology company with both patented anti-HIV therapeutics and a proprietary methodology for producing fully human IgG1 monoclonal antibodies for treating infectious diseases with non-toxic passive immunotherapy. The Company has clinically tested its anti-HIV therapeutics known as ITV-1. ITV-1 is a suspension of Inactivated Pepsin Fragment (IPF), a purified extract of porcine pepsin. ITV-1 has been shown to strengthen the immune system and may be used to facilitate a broad range of applications. ITV-1 has been tested in HIV patients in a clinical trial conducted under the strict guidelines of the European Union, where it demonstrated beneficial outcomes. Additionally, the Company has created a proprietary cell line that produces fully human monoclonal antibodies that target and neutralize the HIV virus.
The Company’s scientific team, Harry Zhabilov, Joseph Cotropia MD, and Gaurav Chandra MD, pioneered the Company’s proprietary therapeutics for treating infectious diseases, including HIV-1, Hepatitis (A, B, C), rabies, influenza A and B, tetanus, and diphtheria. The Company’s therapeutics may also be used to treat Rheumatoid Arthritis and certain forms of cancer.
The Company has also pioneered a proprietary method for creating human cell lines that produce fully human monoclonal antibodies directed against many infectious diseases. One antibody (designated as CLONE 3) has been demonstrated in tests in 5 international labs to fully neutralize over 95% of all strains and viral subtypes of HIV-1 against which it has been tested.
These HIV therapeutics may be used as an immunotherapeutic treatment for individuals with HIV/AIDS. They may also be developed for use as a prophylactic and therapeutic vaccine to prevent uninfected populations from contracting the HIV virus. Treatment using the fully human anti-HIV antibody will be far superior to current ARV therapy for several significant reasons: (1) the therapy will be effective and non-toxic, (2) will not require lifetime treatment, and (3) will be far less expensive.
Thus, for the patient, immunotherapy will be remarkably different — it will be safer, provide a much-needed immunotherapeutic cure rather than requiring lifelong treatment, and costs substantially less than current antiretroviral therapy.
The Company also has created human cell lines that produce human antibodies against other infectious diseases, including rabies, influenza, tetanus, and diphtheria. As a part of its mission, the Company is testing these antibodies to prepare them for use as therapies against these diseases.
OUR SCIENCE
Enzolytics, Inc. is committed to the development and commercialization of its proprietary therapeutics for the treatment of debilitating infectious diseases. The Company’s technology is broad, including technology for treating HIV-1, Hepatitis (A, B, C), Rheumatoid Arthritis, certain forms of cancer, rabies, influenza A and B, tetanus, and diphtheria. The Company’s therapies are also being developed to treat chronic infection and certain forms of cancer.
As a result of the recent acquisition of the biotech company BioClonetics Immunotherapeutics, Inc., Enzolytics is now advancing additional complementary therapeutic platforms for treating infectious diseases, including a focus on the production of anti-SARS-CoV-2 (CoronaVirus) monoclonal antibodies to treat COVID-19.
Inactivated Pepsin Fragment (IPF) Technology
One Company technology, invented by Harry Zhabilov, the CSO of the Company, includes a patented antiviral peptide that has been tested in clinical studies at the National Center of Infectious and Parasitic Diseases in Bulgaria. This therapeutic, known as ITV-1, is a suspension of Inactivated Pepsin Fragment (IPF), a purified extract of porcine pepsin. ITV-1 has been shown to strengthen the immune system and may be used to facilitate a broad range of applications. ITV-1 has been tested in HIV patients in a clinical trial conducted under the strict guidelines of the European Union. HIV patients tested in these trials showed the following beneficial outcomes:
Improvement in the immune indices in the absolute number of Ly, CD3 T, CD4 T, CD8 T, B Ly, NK and in the percentage of CD3 T, CD4 T, CD8 T, B Ly, NK, and of the index CD4/CD8.
Decrease in the viral load.
Demonstrated beneficial effect on opportunistic infections.
Demonstrated very good compatibility with all of the other modern antiretroviral drugs.
Demonstrated very good tolerance in all patients and complete absence of side effects.
This Enzolytics anti-HIV treatment is now being advanced through the certification stage, after which it will be available for patient therapy. ITV-1 also has also demonstrated a positive effect on different kinds of cancer due to its ability to stimulatesstimulate the immune system.
Fully Human Monoclonal Antibody Technology
With the recent acquisition of the technology created by BioClonetics Immunotherapeutics, Inc., the Company has additional and complementary technology for producing fully human monoclonal antibodies (mAbs) that neutralize the HIV virus. The Company is in the final development of the recombinant of the parent antibody (identified as “Clone 3”), which has been shown in in vitro tests conduction in 5 international laboratories to fully neutralized over 95% of all strains and viral subtypes of HIV-1 against which it was tested. The basis for its broad-spectrum efficacy is the fact that Clone 3 mAb targets an immutable epitope on the HIV virus. The targeted epitope has remained present in 98% (either directly or by way of conserved substitutions) of all now known 87,336 HIV isolates analyzed by the Company’s use of artificial intelligence. The failure of other mAbs, such as the Vaccine Research Group VRC01 [Bar KJ, et al. Effect of HIV Antibody VRC01 on Viral Rebound after Treatment Interruption. N Engl J Med. 2016;375(21):2037-50. PMCID|5292134] resulted from the targeting of mutable epitopes of the HIV virus.
Final testing of the Company’s anti-HIV mAb in PBMC neutralization assays is currently being completed, to be followed by animal trials at the California National Primate Research Center, UC Davis (Davis, CA).
The anti-HIV therapies of Enzolytics’ two technologies, that produced by Enzolytics and created at BioClonetics, are expected to be synergistic in treating HIV. Tests to establish such synergy are scheduled.
Anti-CoronaVirus Monoclonal Antibodies
The Company’s proprietary methodology may also be applied to produce monoclonal antibodies against other infectious diseases. This includes the production of monoclonal antibodies against the SARS-CoV-2 virus (CoronaVirus), as well as other infectious diseases, including HIV-2, anthrax, smallpox, H1N1 influenza, herpes zoster, varicella zoster, Rh (+) auto-immune disease, and the Ebolavirus. A Company program is underway to produce monoclonal antibodies against the SARS-CoV-2 virus (CoronaVirus). Such production will be achieved using the proprietary methodology used to previously produce monoclonal antibodies (mAbs) against HIV, rabies, influenza A, influenza B, tetanus, and diphtheria.
Having produced neutralizing antibodies against the HIV-1 virus and recognizing a significant correlative structure between the HIV virus and the SARS-CoV-2 virus, the Company is developing anti-SARS-Cov-2 (CoronaVirus) monoclonal antibodies using its proprietary technology. These antibodies are expected to provide a therapeutic for patients infected with COVID-19. Identification of these neutralizable epitopes also will permit the production of a phage display anti-SARS-CoV-2 (CoronaVirus) vaccine.
Production of these monoclonal antibodies is being conducted in the Company’s lab at the Texas A&M University Institute for Preclinical Studies in College Station, Texas.
INTELLECTUAL PROPERTY
The Company protects its technology through an aggressive strategy to cover its intellectual property. The Company’s intellectual property includes:
Issued Patents
Enzolytics is the owner of the following issued U.S. Patents covering its technology relating to a peptide that has been demonstrated in clinical trials to provide anti-HIV-1 retroviral benefit in vivo.
U.S. Patent No. 7,479,538, issued January 20, 2009, entitled Irreversibly-Inactivated Pepsinogen Fragment and Pharmaceutical Compositions Comprising the Same for Detecting, Preventing and Treating HIV
U.S. Patent No. 8,066,982, issued November 29, 2011, entitled Irreversibly-Inactivated Pepsinogen Fragment and Pharmaceutical Compositions Comprising the Same for Detecting, Preventing, and Treating HIV.
These patents cover an Inactivated Pepsin Fragment (IPF) identified and characterized by the amino acid sequence GDEPLENYLDTEYF. This peptide has demonstrated a significant in vitro binding affinity for HIV-1 gp 120 and gp 41 and human CD4 cells. The peptide exhibits antiretroviral activity in vivo, particularly anti-HIV-1 activity. IPF appears to modulate helper T1 cells’ expression of elaborate cytokines INFy, IL-2, which selectively promote cell-mediated immune response and subsequently stimulate cytotoxic lymphocytes. These lymphocytes have a prominent role in the host’s immunologic response to HIV infection. Proteins encoded by these pathogens enter the endogenous pathway for antigen presentation and are expressed on the surface of the infected cell as a complex with class I MHC – proteins. IPF appears to present a novel mechanism to reduce the viral burden and stimulate innate immune responses to the virus for patients with significant antiretroviral resistance.
Proprietary Cell Line Producing Clone 3 anti-HIV monoclonal antibody
The Company’s Clone 3 cell line, which produces fully human monoclonal antibodies (mAbs) that specifically target and neutralize the HIV-1 virus, is proprietary to the Company.
Pending Patent Applications
The Company has the following pending patents covering its anti-HIV monoclonal antibody technology:
Pending Patent covering the recombinant of the Clone 3 antibody. This form of the Clone 3 antibody is prepared using the known amino acid sequence of the antibody in conjunction with a high producing CHO cell line for generating recombinant form of the monoclonal antibodies that will ultimately be used in patient application.
Pending Patent coverage of small molecules (mini-peptides) for commercial use derived from the structure of the Clone 3 antibody for interrupting and preventing binding between the HIV virus and the human CD4+ cell.
Coverage is directed to blocking peptides that bind to and neutralize the HIV virus, and
Competitive peptides that bind to the target CD4+ cells at the point of virus access into the human cell to prevent infection.
Pending Patent covering the proprietary methodology for producing fully human neutralizing monoclonal antibodies against infectious diseases, including Rabies, influenza A, influenza B, Tetanus, Diphtheria, HIV-2, Anthrax, Smallpox, H1N1 influenza, Herpes Zoster, Varicella Zoster and Ebola.
Pending Patent covering the proprietary methodology for produced anti-antigen monoclonal antibodies to produce vaccines to achieve a broad and durable humoral protective antibody response against the corresponding infectious agent.
Proprietary Methodology for Producing Fully Human Monoclonal Antibodies
The Company proprietary mAb methodologies & immunotherapeutic technologies platform will be used to create therapeutics for treatments of viral infectious diseases against:
HIV-2
Anthrax
Smallpox
H1N1 Influenza
Herpes Zoster
Varicella Zoster
Ebola
The Company antibody-based immunotherapeutic platform can be utilized for both human and all animal infectious-disease applications.
In addition to the anti-HIV monoclonal antibodies produced by the Company, the Company currently has also produced fully human monoclonal antibodies against:
Rabies
Influenza A
Influenza B
Tetanus
Diphtheria
The Significance of the Methodology for Producing Fully Human Therapeutic Monoclonal Antibodies
Biologics, specifically fully human neutralizing monoclonal antibodies directed against infectious disease, is considered the new frontier in biotechnology. In the past, the initial starting products were “humanized” rat and mouse mAbs being created for therapeutic use. “Humanized” immunoglobulins are the major immunotherapeutic that is prevalent today. What sets the Company’s antibody technology apart from that employed by other pharma? The Company’s technology permits the cloning of human or animal immune system cells. With the Company’s proprietary methodologies, stable parent hybridomas cell lines can be created that produce fully human antibodies.
Enzolytics specializes in the creation of human neutralizing monoclonal antibodies, not “humanized” mouse or rat counterparts, as are many mAb therapeutics in pharmaceutical use today. The Company’s technological methodologies have developed an effective, strong, and robust portfolio of biologics that have a pharmaceutical application with significant benefits to patients or animals in the global marketplace. From an identified and created parent hybridoma cell line, four distinct and effective products can be produced: (1) fully human neutralizing monoclonal antibody—directed against any pathogen based disease entity—through use in passive immunotherapy; (2) an effective humoral active vaccine that is safe and effective; (3) an oral mini-antibody peptide-based medication with an efficacy that is equivalent to the immunologic capacity of the monoclonal antibody produced by parent hybridoma cell; and (4) an entry-fusion inhibitor that is immunologic in character and scope. The applications are broad, effective, and beneficial for immunotherapeutic use.
The methodologies and processes for creating immortalized cells that stably produce human monoclonal antibodies are Company proprietary trade secrets.
Anti-HIV Technology and Products
Using its proprietary technology, The Company has created a proprietary cell line that produces a fully human monoclonal antibody (known as Clone 3) that specifically targets and neutralizes the HIV virus (i.e., renders the virus incapable of reproduction). This capability to neutralize the virus means that Clone 3 may be used successfully to treat those infected with HIV and provide an ideal immunogen in the development of an active anti-HIV/AIDS vaccine that is both prophylactic and therapeutic.
Additional supplemental products may be produced as well, for example, vaginal creams for prevention of transmission of the virus. Additionally, Clone 3 has the potential to enormously reduce the incidence of mother-to-child transmission (MTCT) of the virus. Not only might it prevent in-utero viral transmission but, postnatally, effective treatment can be administered without fear of antiretroviral (ARV) toxicity or resistance.
Each of these distinct products flows from the Company’s technology. The first is the use of the antibody itself or a recombinant of the antibody. The second is the Clone 3 vaccine, the third is a mini-antibody or paratope of the Clone 3 antibody, and the fourth is a competitive binding entry-fusion inhibitor that prevents infectivity.
In addition to the Clone 3 monoclonal antibody against HIV, the Company has also created human monoclonal antibodies against other infectious diseases, including rabies, influenza A, influenza B, tetanus, and diphtheria. This immunotherapeutic technology platform can be readily applied to creating monoclonal antibodies against other pathogenic diseases, including the SARAS-CoV-2 (CoronaVirus), HIV-2, anthrax, smallpox, H1N1 influenza, herpes zoster, varicella zoster, Rh (+) auto=immune disease, and the Ebolavirus. The Company’s antibody-based Immunotherapeutics platform can be utilized across both human and animal infectious-disease applications. For example, the technology can be used to produce treatment for elephant and equine diseases that threaten these species.
The mAbs PLAYBOOK:
What has ENZC done?
CHECK THE PRESS RELEASES and follow RULES OF ENGAGEMENT BY THE FDA
Development of Monoclonal
Antibody Products Targeting SARSCoV-2, Including Addressing the
Impact of Emerging Variants,
During the COVID-19
Public Health Emergency
Guidance for Industry
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research
INTRODUCTION
FDA plays a critical role in protecting the United States from threats such as emerging infectiousdiseases, including the Coronavirus Disease 2019 (COVID-19) pandemic. FDA is committed to providing timely guidance to support response efforts to this pandemic.
FDA is issuing this guidance to provide recommendations to sponsors on the development of monoclonal antibody products targeting SARS-CoV-2, including addressing the impact of emerging variants, during the COVID-19 public health emergency.
This policy is intended to remain in effect only for the duration of the public health emergency related to COVID-19 declared by the Secretary of Health and Human Services (HHS) on January 31, 2020, effective January 27, 2020, including any renewals made by the HHS Secretary in accordance with section 319(a)(2) of the Public Health Service Act (PHS Act) (42 U.S.C. 247d(a)(2)).
DISCUSSION
A. Guiding Principles
Sponsors of monoclonal antibody products targeting SARS-CoV-2 should consider the following guiding principles:
• Given the serious concerns raised by the emergence of SARS-CoV-2 variants, FDAintends to leverage its emergency authorities under section 564 of the FD&C Act, when appropriate, to foster the development and availability of therapeutics for use during the current public health emergency. When scientifically supported, FDA will streamline the
data necessary to support the development of monoclonal antibody products targeting SARS-CoV-2 and also expedite the review of these data.
• Given the dynamic public health situation created by changes in the prevalence of new variants over time, FDA’s streamlined approach will depend on its current assessment of benefit and risk for the intended use and population, the monoclonal antibody’s expected
coverage of important emerging variants, as well as FDA’s then-current understanding of SARS-CoV-2.
• FDA strongly recommends that individual monoclonal antibody products be developed with the expectation that they will be combined with one or more monoclonal antibody products that bind to different epitopes5 to minimize the risk of losing activity against emergent variants. FDA encourages collaborations between sponsors of individual monoclonal antibody products to address this unmet medical need.
Development Program Considerations to Support Use Under an EUA
Chemistry, Manufacturing, and Controls
Sponsors of monoclonal antibody products targeting SARS-CoV-2 should consider the following chemistry, manufacturing, and controls recommendations:
• When feasible and scientifically supported, sponsors should attempt to leverageexperience obtained from other monoclonal antibody products in development and already licensed monoclonal antibody therapies. Specific examples include the following:
? The use of existing manufacturing platforms to establish a manufacturing process for investigational product development
? The selection of manufacturing facilities6 that have experience in manufacturing biotechnology products and have a history of recent inspection(s) (including using information shared by trusted foreign regulatory partners through mutual recognition agreements7)
? The potential to utilize already obtained modular data for viral clearance validation,and a purification process validation (e.g., impurity clearance)
? The selection of analytical methods that have already been qualified or validated.This may include adapting potency assay9 formats (including binding assays and/or neutralizing assays) with revised reagents that evaluate new variant protein(s) or pseudotyped virus/virus-like particles in the assay(s)
? The exploration of opportunities for less-experienced manufacturers to partner with those with more experience to leverage all available development tools
? The use of data that may be available from public consortia or partnerships that may contribute to understanding product performance
? The leveraging of related product quality data (e.g., formulation development) tosupport in-use stability and compatibility
? The use of prior development experience to anticipate the best dosage form, route of administration, and formulation (composition) selection
• FDA strongly recommends that sponsors discuss with FDA in advance (well before they occur) time-critical elements of the development program. Specific examples include the following:
? A plan that describes key aspects of the manufacturing development, including plans for scale-up
? Comparability protocols that include a detailed description of tests and acceptance criteria to evaluate the impact of manufacturing process changes on product quality
? A strategy for establishing a shelf life for the intended monoclonal antibody product targeting SARS-CoV-2. This may include opportunities to leverage related product data to justify the proposed shelf life
• Certain approaches may be appropriate for limited early phase development to enable rapid introduction of the product into clinical trials. Specific examples include the following:
? Use of a stable cell pool in lieu of a clonally derived cell bank to generate early clinical batches
? Consideration of interim results from limited safety testing results (e.g., for cell banks, unprocessed bulk harvest) to begin first-in-human (FIH) clinical trial(s) with full study reports to be available at time negotiated with FDA and submitted to the investigational new drug application (IND)
? Flexibility in the amount of stability study results provided in the IND submission to support the initiation of FIH clinical trials
? Use of two robust orthogonal virus clearance steps when modular/generic virus clearance data are not available.
? Manufacture of limited early clinical batches for FIH clinical trial(s) by mixing and diluting with sterile filtration employing aseptic technique10 rather than traditional
drug product manufacturing.
• FDA may not require completed process validation (excluding sterilization process validation) to support an EUA. However, sufficient process characterization is expected and should be consistent with the overall benefit-risk assessment of the product. If only limited process validation data are provided, the sponsor can propose additional elements for the control strategy. These elements can include additional controls in the manufacturing processes, taking into consideration the criticality assessment for individual process parameters, the ranges proposed for a given parameter, or the inclusion of additional in-process measurements or release specifications.
Pharmacology Toxicology
Sponsors of monoclonal antibody products targeting SARS-CoV-2 should consider the following[/i]
pharmacology toxicology recommendations:
• The Agency intends to be flexible regarding selected nonclinical safety data submission expectations (e.g., timing of data submission to the IND) for monoclonal antibody products targeting SARS-CoV-2 to support clinical trial initiation. The degree of flexibility warranted will be influenced by the benefit-risk assessment for the intended
population (e.g., hospitalized, nonhospitalized, healthy trial subjects) and the potential coverage of important emerging variants. Thus, FDA strongly recommends that sponsors discuss the nonclinical requirements to support product administration in a specific clinical trial with the Agency through the pre-IND consultation process.
• Nonclinical safety assessment for monoclonal antibody products targeting SARS-CoV-2 should follow approaches outlined in the International Council for Harmonisation (ICH) guidance for industry S6(R1) Preclinical Safety Evaluation of Biotechnology-Delivered
Pharmaceuticals (May 2012) and conduct the following:
? A tissue cross reactivity (TCR) study using a panel of human tissues.
When a monoclonal antibody binds to human tissues in the TCR study, FDA recommends evaluating monoclonal antibody binding to select tissues from nonclinical species to assist in species selection for repeat-dose toxicology testing. When binding of potential clinical concern is observed (e.g., cell membrane binding), FDA recommends discussing these data with the Agency because additional studies may be needed to help inform the potential clinical relevance of the findings.
? A short duration (i.e., 3 weeks of treatment) repeat-dose toxicology study in a single species, using the clinical formulation and route of administration(s) intended for clinical administration, that includes all standard toxicity endpoints including toxicokinetic analysis. FDA also recommends discussing specific study design considerations with the Agency.
• Toxicology studies with specific monoclonal antibody combinations are not needed for monoclonal antibody products targeting SARS-CoV-2 proteins, so monoclonal antibody products can be evaluated separately in toxicology studies. If a sponsor evaluates monoclonal antibody products in combination, FDA recommends using the same ratio intended for clinical administration.
• To support administration of monoclonal antibody products during pregnancy, FDA recommends conducting a TCR study using relevant human tissues or studies using alternative protein interaction technologies, with appropriate justification. If no specific concerns are identified in the repeat-dose toxicology and TCR studies, developmental and
reproductive toxicology studies are not needed.
Virology
Sponsors of monoclonal antibody products targeting SARS-CoV-2 should consider the following
virology recommendations:
• A broad approach should initially be used to characterize the impact of amino acid changes, insertions, or deletions throughout the monoclonal antibody target protein to identify regions where changes specifically impact monoclonal antibody binding or activity, and subsequent analyses and surveillance can focus on these regions.
• Sponsors should monitor SARS-CoV-2 genomic databases continually for emerging SARS-CoV-2 variants and should evaluate phenotypically any specific variants that are prevalent or becoming prevalent that harbor substitutions in or near the target epitope.
The sponsor should conduct a more thorough analysis to include other substitutions at the same amino acid positions.
• Sponsors should characterize the epitopes to which monoclonal antibody products bind to enable identification of polymorphisms, which may affect binding, and to inform decisions regarding monoclonal antibody products planned for use in a combination therapy.
• Sponsors should characterize monoclonal antibody products with respect to epitope binding (affinity equilibrium dissociation constant (KD) and noncompetitive binding). The sponsor should characterize the mechanism of action for SARS-CoV-2 neutralization (e.g., blocking spike protein/receptor binding domain interaction with ACE2).
• The sponsor should determine the neutralizing activity (half maximal effective concentration (EC50) value) of investigational monoclonal antibody products, individually and if applicable in combination, against an array of circulating variants representing the diversity of the target protein and epitope to which the monoclonal antibody binds.
• The sponsor should evaluate the neutralizing activity of monoclonal antibodies,individually and if applicable in combination, against SARS-CoV-2 variants orpseudovirus harboring substitutions known to confer reduced susceptibility to other authorized or approved antibody products targeting SARS-CoV-2 infectivity.
• SARS-CoV-2 or pseudovirus should be serially passaged in cell culture in the presence of the monoclonal antibody product, individually and if applicable in combination, to select for resistant variants to understand the potential risk and nature of treatment-emergent
resistance. Sponsors should characterize genotypically and phenotypically the variants selected in this manner. Sponsors should determine the effect of resistance-associatedsubstitutions on approved and authorized monoclonal antibody products. These studies should be conducted under appropriate biocontainment.
• Clinical protocols should include detailed plans to (1) characterize the impact of SARSCoV-2 genetic variability on clinical and virologic outcomes (i.e., baseline resistance
analyses) and (2) identify SARS-CoV-2 genetic changes associated with treatment (i.e., treatment-emergent resistance analyses).
• Sponsors should also reference the guidance for industry COVID-19: Developing Drugs and Biological Products for Treatment or Prevention (February 2021) and the guidancefor industry Antiviral Product Development — Conducting and Submitting Virology Studies to the Agency (June 2006).
Clinical
Sponsors of monoclonal antibody products targeting SARS-CoV-2 should consider the following clinical recommendations:
In general, sponsors should design monoclonal antibody product development programs evaluating the treatment or prevention of COVID-19 to assess the effect of investigational products on clinically meaningful aspects of the disease.
? An example of an acceptable endpoint to support an EUA for the treatment of outpatients with mild to moderate disease would be the proportion of patients with COVID-19 related hospitalizations or deaths from any cause through at least 28 days.
? Sponsors considering the use of a surrogate endpoint (e.g., viral pharmacodynamic endpoint) to support an EUA in situations where viral variants have affected the efficacy of currently authorized or approved treatment options should seek early input from the Agency on their proposals.
• Sponsors should scientifically justify the selection of doses and regimens for phase 3 trials and discuss with the Agency.
• Sponsors should enroll patients from populations disproportionately impacted by the COVID-19 pandemic (e.g., racial and ethnic minorities).
• The size and composition of the safety database needed to support an EUA will depend on factors such as the monoclonal antibody product’s proposed use (e.g., treatment versus prevention), the proposed patient population, and the extent and nature of the prior clinical experience with the product and with related products.
• Sponsors should also reference the guidance for industry COVID-19: Developing Drugs and Biological Products for Treatment or Prevention for additional recommendations on trial populations, trial design, efficacy endpoints, safety, and statistical considerations.
COLLEGE STATION, TX / ACCESSWIRE / April 5, 2021 / Enzolytics, Inc. (OTC PINK:ENZC) (or the "Company").
In a significant development, recent findings have revealed that the monoclonal antibodies being produced by the Company against targeted sites on the Coronavirus are directed against epitopes that exist conservatively on each of the variant strains of the virus from the UK, Brazil and South African.
This discovery is significant in Enzolytics' continued commitment to producing therapeutics for the treatment of COVID-19. Specifically, Enzolytics is creating human heterohybridoma cell lines using convalescent human patients' peripheral "immune" human B cells to create fully human monoclonal antibodies directed individually against the identified conserved sites on the virus and against both S1 protein and S2 (transmembrane) protein on the Coronavirus.
https://marketwirenews.com/news-releases/coronavirus-targeted-epitopes-claimed-in-enzolytics--8878275105121776.html
The advancements in technology and manufacturing processes have allowed the development of new derivatives, biosimilar or advanced improved versions for approved antibodies each year for treatment regimen. There are more than 700 antibody-based molecules that are in different stages of phase I/II/ III clinical trials targeting new unique targets. To date, approximately more than 80 monoclonal antibodies (mAbs) have been approved. A total of 7 novel antibody therapeutics had been granted the first approval either in the United States or European Union in the year 2019, representing approximately 20% of the total number of approved drugs. Most of these licenced mAbs or their derivatives are either of hybridoma origin or their improvised engineered versions. Even with the recent development of high throughput mAb generation technologies, hybridoma is the most favoured method due to its indigenous nature to preserve natural cognate antibody pairing information and preserves innate functions of immune cells. The recent advent of antibody engineering technology has superseded the species level barriers and has shown success in isolation of hybridoma across phylogenetically distinct species. This has led to the isolation of monoclonal antibodies against human targets that are conserved and non-immunogenic in the rodent. In this review, we have discussed in detail about hybridoma technology, its expansion towards different animal species, the importance of antibodies isolated from different animal sources that are useful in biological applications, advantages, and limitations. This review also summarizes the challenges and recent progress associated with hybridoma development, and how it has been overcome in these years to provide new insights for the isolation of mAbs.
Human hybridoma technology which allows the direct generation of human antibodies in a native form, is the most direct effective approach for the production of natural therapeutic and diagnostic antibodies with no additional modifications require [54]. It is believed to be the most promising and convenient technological platform for the isolation of therapeutic mAbs. However, success of human hybridoma technology for the therapeutic purposes has been limited since years due to several technical challenges like unavailability of human fusion partners, as most of the fusion partners available are from rodent origin or hetero-myelomas. A fusion of human B cells with different fusion partners limits the use of these mAbs for therapeutic applications. Several hetero-myelomas fusion has been successfully employed for the generation of mAbs of human origin for different diseases like HIV [28], [55], Chikungunya [56], [57], Dengue [58] etc. However, such hybridomas are unstable, leads to a loss in the ability of antibody secretion hence there is a challenge in achieving desired pharmacokinetic characteristics of natural human antibodies in terms of distribution, metabolism and excretion [54]. Several scientific groups have attempted to develop natural human fusion partner cell lines but limited success stories are reported using these fully human fusion partners. One such example of fusion cell is Human Karyochi cells which were successfully used to develop complete human stable hybridomas with IgG secreting properties for several months. The fusion efficiency of these Human Karyochi cells was in the range of 10-5 to 10-3 with no reports on the endogenous generation of immunoglobulin or chains that can interfere with subsequent synthesis, assembly and purification of mAbs.
Keywords: Hybridoma, Clinical trials, Monoclonal antibodies, Biosimilar, Therapeutics, Antibody engineering
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255167/
Who is selling Shares?
Does not matter.
What matters is RESULTS from the COMPANY!
People need to understand that this is a BIOTECH company and before any product hits the market CERTAIN PROTOCOLS MUST be followed such as animal trials, toxicology tests ect..
ENZC has to accomplish these steps to move to the next stage.
Some are done, some are being done and some will be done.
ENZC has been updating us as things happen.
Will ENZC SUCCEED?
We will see.
So far So good.
The BOTTOM LINE is SIMPLE if ENZC continues to meet the proper PROTOCOLS to get their PRODUCTS to the marketplace the STOCK PRICE will eventually FOLLOW.
I GUARANTEE IT.
Why did the company run to 95 cents?
Because the WHOLE OTC Market was running at the time.
CBBT:
Date Open High Low Close* Adj Close** Volume
Feb 12, 2021 0.3409 0.3490 0.2900 0.3220 0.3220 12,475,225
Feb 11, 2021 0.3901 0.3901 0.2900 0.3025 0.3025 20,342,113
Feb 10, 2021 0.4250 0.4300 0.3200 0.3900 0.3900 17,599,657
Feb 09, 2021 0.4400 0.4700 0.3216 0.3700 0.3700 30,634,434
Feb 08, 2021 0.2750 0.3700 0.2500 0.3675 0.3675 42,136,742
Feb 05, 2021 0.1870 0.2410 0.1799 0.2300 0.2300 30,845,521
Feb 04, 2021 0.1546 0.1895 0.1458 0.1795 0.1795 18,970,787
Feb 03, 2021 0.1490 0.1500 0.1400 0.1455 0.1455 10,603,471
Feb 02, 2021 0.1450 0.1450 0.1300 0.1373 0.1373 9,224,502
Feb 01, 2021 0.1310 0.1490 0.1135 0.1385 0.1385 25,409,177
ENZC:
Feb 12, 2021 0.6550 0.6650 0.4710 0.5491 0.5491 73,860,125
Feb 11, 2021 0.7500 0.7700 0.6000 0.6591 0.6591 38,765,419
Feb 10, 2021 0.9000 0.9200 0.5500 0.7174 0.7174 81,248,598
Feb 09, 2021 0.8110 0.9580 0.7472 0.8290 0.8290 62,155,509
Feb 08, 2021 0.5801 0.7400 0.5790 0.7390 0.7390 64,850,555
Feb 05, 2021 0.5370 0.5610 0.5000 0.5240 0.5240 69,394,498
Feb 04, 2021 0.3700 0.5670 0.3600 0.4775 0.4775 122,968,998
Feb 03, 2021 0.2920 0.3630 0.2854 0.3430 0.3430 84,232,468
Feb 02, 2021 0.2610 0.2929 0.2420 0.2850 0.2850 65,849,048
Feb 01, 2021 0.1992 0.2450 0.1900 0.2229 0.2229 41,865,413
INQD:
Feb 12, 2021 0.0310 0.0310 0.0240 0.0250 0.0250 32,603,847
Feb 11, 2021 0.0318 0.0397 0.0278 0.0310 0.0310 42,305,701
Feb 10, 2021 0.0350 0.0390 0.0200 0.0339 0.0339 79,197,039
Feb 09, 2021 0.0200 0.0350 0.0180 0.0298 0.0298 63,030,498
Feb 08, 2021 0.0160 0.0215 0.0150 0.0199 0.0199 59,117,532
Feb 05, 2021 0.0140 0.0190 0.0100 0.0138 0.0138 84,534,654
Feb 04, 2021 0.0073 0.0139 0.0073 0.0135 0.0135 65,516,047
Feb 03, 2021 0.0058 0.0076 0.0055 0.0076 0.0076 22,718,931
Feb 02, 2021 0.0068 0.0070 0.0059 0.0060 0.0060 10,435,695
Feb 01, 2021 0.0060 0.0074 0.0030 0.0065 0.0065 45,156,309
DPLS:
Feb 12, 2021 0.0360 0.0380 0.0300 0.0318 0.0318 114,177,138
Feb 11, 2021 0.0398 0.0398 0.0311 0.0340 0.0340 116,745,158
Feb 10, 2021 0.0440 0.0490 0.0300 0.0350 0.0350 280,842,242
Feb 09, 2021 0.0278 0.0510 0.0230 0.0395 0.0395 413,874,246
Feb 08, 2021 0.0130 0.0295 0.0116 0.0276 0.0276 549,903,929
Feb 05, 2021 0.0111 0.0125 0.0100 0.0113 0.0113 218,714,977
Feb 04, 2021 0.0130 0.0130 0.0090 0.0103 0.0103 301,076,429
Feb 03, 2021 0.0135 0.0135 0.0115 0.0120 0.0120 184,201,913
Feb 02, 2021 0.0136 0.0145 0.0120 0.0130 0.0130 174,684,160
Feb 01, 2021 0.0146 0.0146 0.0115 0.0128 0.0128 263,759,145
HBRM:
Feb 12, 2021 0.0036 0.0036 0.0030 0.0031 0.0031 488,725,635
Feb 11, 2021 0.0040 0.0044 0.0032 0.0036 0.0036 386,388,565
Feb 10, 2021 0.0045 0.0047 0.0035 0.0040 0.0040 444,221,048
Feb 09, 2021 0.0045 0.0048 0.0035 0.0041 0.0041 816,522,982
Feb 08, 2021 0.0033 0.0048 0.0030 0.0046 0.0046 166,437,727
Feb 05, 2021 0.0022 0.0029 0.0021 0.0027 0.0027 940,295,827
Feb 04, 2021 0.0022 0.0022 0.0019 0.0021 0.0021 392,011,035
Feb 03, 2021 0.0023 0.0024 0.0020 0.0021 0.0021 444,292,106
Feb 02, 2021 0.0022 0.0023 0.0019 0.0022 0.0022 580,300,558
Feb 01, 2021 0.0021 0.0021 0.0018 0.0020 0.0020 258,713,05
CELZ:
Feb 12, 2021 0.0709 0.0790 0.0500 0.0680 0.0680 41,601,800
Feb 11, 2021 0.0900 0.1000 0.0680 0.0729 0.0729 58,290,500
Feb 10, 2021 0.0899 0.1300 0.0610 0.0900 0.0900 142,441,700
Feb 09, 2021 0.0330 0.0840 0.0250 0.0806 0.0806 240,831,500
Feb 08, 2021 0.0278 0.0341 0.0177 0.0310 0.0310 68,661,100
Feb 05, 2021 0.0246 0.0260 0.0240 0.0259 0.0259 18,832,300
Feb 04, 2021 0.0261 0.0278 0.0240 0.0250 0.0250 28,888,500
Feb 03, 2021 0.0278 0.0280 0.0240 0.0259 0.0259 21,029,800
Feb 02, 2021 0.0284 0.0284 0.0230 0.0270 0.0270 20,872,300
Feb 01, 2021 0.0258 0.0290 0.0250 0.0256 0.0256 35,544,900
HCMC:
Feb 12, 2021 0.0059 0.0059 0.0038 0.0043 0.0043 2,392
Feb 11, 2021 0.0049 0.0065 0.0047 0.0049 0.0049 807
Feb 10, 2021 0.0042 0.0045 0.0037 0.0043 0.0043 744
Feb 09, 2021 0.0035 0.0039 0.0031 0.0034 0.0034 236,364,249
Feb 08, 2021 0.0018 0.0048 0.0017 0.0027 0.0027 291
Feb 05, 2021 0.0018 0.0018 0.0015 0.0016 0.0016 1,992
Feb 04, 2021 0.0018 0.0018 0.0015 0.0017 0.0017 3,465
Feb 03, 2021 0.0017 0.0050 0.0015 0.0016 0.0016 389,401,432
Feb 02, 2021 0.0019 0.0020 0.0010 0.0014 0.0014 2,086
Feb 01, 2021 0.0014 0.0020 0.0010 0.0019 0.0019 131
If one were to LOOK at any of the ABOVE tickers, one would see they are all down SIGNIFICANTLY form the HIGHS of FEBRUARY.
Because they DOT their i and CROSS their t ENZC is the place to be!
ENZC is very thorough is their execution of their business plan and communicating to shareholders. They tell you what they are going to do, they do it and they tell you what they did.
What is ENZC going to do?
1. Enzolytics, Inc, a drug development company with a focus on debilitating infectious diseases, announced on September 16, the execution of a non-binding letter of intent to merge with BioClonetics Immunotherapeutics, Inc. a biotechnology company located in Dallas Texas, USA.
2. The Companies plan to conduct binding studies combining the therapeutics produced by both companies to evaluate the beneficial effects and increased binding capability of the BioClonetics Clone 3 antibodies to multiple HIV isolates.
3. Thereafter, PBMC based in-vitro neutralization studies will be conducted with the Enzolytics ITV-1 peptide in combination with the BioClonetics Clone 3 antibodies. Based on the results, the best combination with be tested in primate studies at the California National Primate Research Center University of California, Davis, California.
4. BioClonetics has been invited by the National Science Foundation (NSF) to submit an application for funding for development of anti-SARS-Cov-2 monoclonal antibodies using its proprietary technology. Such application to the NSF and a corresponding application to the NIH are now pending.
5. ENZC is in the process of compiling the information to bring current its OTC filings. The company has several additional initiatives which it will work towards the remainder of 2020 and into 2021. The company has begun the process of identifying a clinical research organization for the preparation of pre-IND protocols for submission to the FDA.
6. The Company is also looking to expand its medical advisory board with individuals that have direct experience taking medical products through the regulatory process and bringing them to market. The Company's intent is to take the ITV-1 treatment, which has already successfully completed Phase III clinical trials at the Specialized Hospital for Active Treatment of Infectious and Parasite Diseases in Sofia, Bulgaria, through the permitting process and begin the process of gaining regulatory approval with the FDA in the United States.
7. The proposed merger anticipated in the non-binding LOI will result in Charles Cotropia being appointed as CEO of the merged entity and Harry Zhabilov and Joseph Cotropia, MD, being appointed as co-CSO. Gaurav Chandra, MD, will serve as COO of the merged entity. Additional details will be disclosed as the transaction progresses.
8. Enzolytics, Inc. (OTC PINK:ENZC) (or the "Company") today announced the execution of a binding letter of intent (the "LOI") to merge with BioClonetics Immunotherapeutics, Inc. ("BCLS" or "BioClonetics") a biotech company located in Dallas Texas, replacing the earlier non-binding letter signed on September 12, 2020.
9. All of our steps are taken with two objectives in mind. First our focus is on creating successful therapeutics against infectious diseases, including HIV and now our focus on the Coronavirus. Secondly, our efforts are also intended to increase the value of our technology and the value of our company - which directly translates into value for our investors. Please know that these are our two guiding objectives with every effort we make.
10. Our plans are to test in combination the Enzolytics ITV-1 peptide in conjunction with our anti-HIV monoclonal antibodies. There is reason to believe that there will be synergistic effect achieved with this combination therapy.
11. As we have reported earlier, we have applications pending with the National Institute of Health (NIH) and the National Science Foundation (NSF) for further development of our anti-HIV monoclonal antibodies and our proposed production of anti-SARS-CoV-2 (Coronavirus) antibodies. These applications are being reviewed now. Without regard to the success or lack of success of these applications, our combination of technologies with Enzolytics will provide funding for our direct progress with the precise proposals now submitted to the NIH and NSF. As outlined in detail in these applications, we will use our proprietary methodology to produce additional monoclonal antibodies against HIV that specifically target conserved, immutable sites on the virus. Recall that others, including the NIH in conjunction with Vaccine Research Center attempted for years to produce monoclonal antibodies against HIV and failed because of "virus escape" – a euphonism for the fact that their antibodies targeted a site that mutates allowing the virus to "escape" over time.
12. In addition, management of ENZC is scheduling a meeting with a GMP manufacturer anticipated to take place before the end of the month.
13. We are making great progress on our plans to further develop additional anti-HIV monoclonal antibodies and to now begin the production of fully human monoclonal antibodies targeting the CoronaVirus. On December 1, we are expanding our lab to the campus of Texas A&M University at its Institute for Preclinical Studies. This expansion will allow us to complete production of monoclonal antibodies against both the HIV virus and the CoronaVirus and collaborate with the biopharma experts on the campus. Although we have NIH grant applications pending for the production of anti-HIV and anti-CoronaVirus monoclonal antibodies, we have secured funding that allows us to proceed without delay.
14. Enzolytics, Inc. (OTC PINK:ENZC or the "Company") has engaged SAMM SOLUTIONS, INC. (DBA BTS Research), through a Master Service Agreement ("MSA"), to conduct a toxicity study on the Company's Flagship compound ITV-1. The Company has previously tested the compound in successful Clinical Trials in Bulgaria, but FDA regulations require separate Toxicity tests before an Investigational New Drug process may begin in the United States.
15. Currently, the Company has requested proposals from several PCAOB accounting firms to provide quotes for Audits of the Company's current and prior year Financial Statements in order to become fully reporting. Bids were requested to be provided by mid-January, and the Company anticipates making a decision by the end of January 2021.
What has ENZC done?
1. Enzolytics and BioClonetics merged.
2. NSF and NIH applications submitted.
3. Submitted financial reports to get ENZC current and got current.
4. Appointed Dr. Ronald Moss to Medical Advisory Board.
5. Appointed Charles Cotropia CEO.
6. Appointed Harry Zhabilov and Joseph Cotropia, MD as co-CSO.
7. Increased the value of our technology and the value of our company.
8. Provided funding for on-going operations.
9. Set up Lab at Texas A&M University Institute for Preclinical Studies.
10. Accepted a proposal from a Houston based PCAOB Audit firm to Audit the Company's year-end financial statements.
It is all in ENZC press releases:
What ENZC is going to do.
What ENZC has done.
What ENZC has told its Shareholders what it has accomplished.
All in black and white and GREEN all over!!!
ENZC News and Press, Enzolytics Inc
Coronavirus Targeted Epitopes Claimed in Enzolytics' Pending Patent Applications are Verified as Fully Conserved in the UK, Brazil and South African Variants of the Coronavirus (SARS-COV-2)
COLLEGE STATION, TX / ACCESSWIRE / April 5, 2021 / Enzolytics, Inc. (OTC PINK:ENZC) (or the "Company"). In a significant development, recent findings have revealed that the monoclonal antibodies being produced by the Company against targeted sites on the Coronavirus are directed against epi...
April 05, 2021 10:00:00 am | ACCESSWIRE |
Enzolytics Announces the Filing of Updated NIH Grant Applications Incorporating Newly Identified Conserved Epitopes on Both the HIV-1 and SARS-CoV-2 Viruses; Other Corporate Updates
COLLEGE STATION, TX / ACCESSWIRE / March 22, 2021 / Enzolytics, Inc. (OTC PINK:ENZC or the "Company") today announced it has filed NIH grant applications seeking funding for its production of monoclonal antibodies targeting the identified conversed epitope sites on both the HIV-1 and the SAR...
March 22, 2021 08:00:00 am | ACCESSWIRE |
Enzolytics Finalizes Documentation with International Medical Partners, Ltd for Clinical Trials and Initial Production of ITV-1 Company Also Provides Update on Year End Reporting
COLLEGE STATION, TX / ACCESSWIRE / March 16, 2021 / Enzolytics, Inc. (OTC Markets "ENZC" or the "Company") today announced the formalization of corporate legal documents pursuant to Articles of Association forming International Medical Partners ("IMPL") a Bulgarian Limited Liability Company ...
March 16, 2021 09:00:00 am | ACCESSWIRE |
Enzolytics Is Surrounded By Controversy And Could Be Worthless
The company recently merged with BioClonetics and plans to develop treatments for HIV and COVID-19. However, there are no revenues and its Bulgarian partner denies that Enzolytics has a stake in it. Enzolytics has a valuation of $982.1 million but I don’t think the business...
March 15, 2021 11:32:52 am | SeekingAlpha |
Enzolytics Announces the Discovery and Patenting of 8 Newly Identified Conserved Target Sites on the HIV-1 Virus
Production of monoclonal antibodies targeting these sites is in process. U.S. patent protection has been filed claiming these sites. COLLEGE STATION,TX / ACCESSWIRE / March 8, 2021 / Enzolytics, Inc. (OTC PINK:ENZC) (the "Company") today announced it has filed for patent protection on t...
March 08, 2021 09:00:00 am | ACCESSWIRE |
Hot Reddit Penny Stocks For Your Watch List In March 2021
Reddit Penny Stocks Continue Surging But Are They Worth The Risk? The stock market continues selling off today and many penny stocks weren’t immune to this drop either. Even some of the sectors that tend to perform well in environments like this were seen pulling back during Frid...
March 05, 2021 12:40:15 pm | PennyStocks.com |
Enzolytics Announces the Discovery and Patenting of Eleven Newly Identified Conserved Target Sites on the SARS-CoV-2 Virus (Coronavirus)
Production of Monoclonal Antibodies Targeting These Sites Is in Process in the Company's Texas Lab COLLEGE STATION, TX / ACCESSWIRE / February 22, 2021 / Enzolytics, Inc. (OTC Markets "ENZC" or the "Company") today announced it has identified eleven conserved, expectedly immutable sites...
February 22, 2021 10:30:00 am | ACCESSWIRE |
Enzolytics Updates Permitting Progress in Europe on Its Planned Clinical Trials of Its Patented ITV-1 Anti-HIV and Other Developments
COLLEGE STATION, TX / ACCESSWIRE / February 22, 2021 / Enzolytics, Inc. (OTC Markets "ENZC" or the "Company") today announced the execution of Articles of Association to form International Medical Partners ("IMPL") a Bulgarian Limited Liability Company of which the Company is 50% owner. The ...
February 22, 2021 09:15:00 am | ACCESSWIRE |
Enzolytics Inc. Reports Test Results of its Patented ITV-1 Conducted at the National Centre of Infectious and Parasitic Diseases
COLLEGE STATION, TX / ACCESSWIRE / February 16, 2021 / Enzolytics, Inc. (OTC PINK:ENZC) (the "Company") announced today the results of an in vitro study of the Company's ITV-1/IPF peptide treatment that demonstrated the broad efficacy with low toxicity. The Company's ITV-1 peptide was test...
February 16, 2021 09:00:00 am | ACCESSWIRE |
Enzolytics Announces The Discovery Of Seven Newly Identified Conserved Target Sites On The HIV Virus
Company begins process of identifying conserved/immutable target sites on SARS-CoV-2 (the CoronaVirus) and other developments COLLEGE STATION, TX / ACCESSWIRE / February 1, 2021 / Enzolytics, Inc. (OTC PINK:ENZC)(the "Company") today announced it has identified seven additional conserve...
Enzolytics, Inc. Engages PCAOB Auditor for December 31, 2020 Year End Audit
COLLEGE STATION, TX / ACCESSWIRE / January 11, 2021 / Enzolytics, Inc. (OTC Markets "ENZC" or the "Company") today, announced it has accepted a proposal from a Houston based PCAOB Audit firm to Audit the Company's year-end financial statements, subject to the receipt and acceptance of the en...
January 11, 2021 10:00:00 am | ACCESSWIRE |
Enzolytics, Inc. 2020 Year End Update
COLLEGE STATION, TX / ACCESSWIRE / December 30, 2020 / Enzolytics, Inc. (OTC Markets "ENZC" or the "Company") today shared the following update provided by Enzolytics' CEO Charles Cotropia. The full content of the update is presented below. "December 30, 2020 To Our Shareholders, On Septe...
December 30, 2020 12:30:00 pm | ACCESSWIRE |
Enzolytics, Inc. Engages BTS Research to Conduct Toxicity Study
PLANO, TX / ACCESSWIRE / December 14, 2020 / Enzolytics, Inc. (OTC PINK:ENZC or the "Company") has engaged SAMM SOLUTIONS, INC. (DBA BTS Research), through a Master Service Agreement ("MSA"), to conduct a toxicity study on the Company's Flagship compound ITV-1. The Company has previously tes...
December 14, 2020 10:40:00 am | ACCESSWIRE |
Enzolytics, Inc. Files Provisional Patent for Treatment of Multiple Sclerosis
PLANO, TX / ACCESSWIRE / December 10, 2020 / Enzolytics, Inc. (OTC PINK:ENZC or the "Company") today announced the filing of a provisional patent with the U.S. Patent Office on December 9, 2020 for a treatment of Multiple Sclerosis developed by Harry Zhabilov, titled NUCLEAR PROTEINS ISOLAT...
December 10, 2020 01:30:00 pm | ACCESSWIRE |
Enzolytics, Inc. Completes Merger with BioClonetics Immunotherapeutics, Inc.
PLANO, TX / ACCESSWIRE / December 1, 2020 / Enzolytics, Inc. (OTC Markets "ENZC" or the "Company") announced the execution of the definitive business combination agreement successfully merging the biotech companies Enzolytics, Inc. and BioClonetics Immunotherapeutics, Inc. on World AIDS Day....
December 01, 2020 10:15:00 am | ACCESSWIRE |
Enzolytics Inc. Shares Current BioClonetics Immunotherapeutics, Inc. Update
PLANO, TX / ACCESSWIRE / November 13, 2020 / Enzolytics Inc. (OTC PINK:ENZC) or the "Company" today shared the following update provided by ENZC's Merger target BioClonetics Immunotherapeutics, Inc. ("BCLS" or "BioClonetics"), resulting from the application of proceeds from the initial fundi...
November 13, 2020 09:00:00 am | ACCESSWIRE |
Enzolytics, Inc. Appoints Ronald Moss, M.D. to Its Medical Advisory Board
Offers Update on OTC Disclosure Filings and Initial Funding PLANO, TX / ACCESSWIRE / November 10, 2020 / Enzolytics, Inc. (OTC PINK:ENZC) or the "Company" announced the appointment of Ronald Moss, M.D., to the Medical Advisory Board of the Company. Dr. Moss has an extensive 25-year bac...
November 10, 2020 09:00:00 am | ACCESSWIRE |
Enzolytics, Inc. Announces Appointment of Charles Cotropia as CEO of ENZC and Harry Zhabilov as Its CSO
Enzolytics announces the procurement of funding for initial operations of merging entity PLANO, TX / ACCESSWIRE / October 22, 2020 / Enzolytics, Inc. (OTC PINK:ENZC) (or the "Company") announced the appointment, by the Board of Directors of the Company, on October 20 of Charles Cotropia...
October 22, 2020 09:00:00 am | ACCESSWIRE |
Enzolytics, Inc. Shares BioClonetics Immunotherapeutics, Inc. Company Update
Enzolytics provides guidance on engagement of manufacturer and OTC Markets Membership PLANO, TX / ACCESSWIRE / October 19, 2020 / Enzolytics, Inc. (OTC PINK:ENZC)( "ENZC" or the "Company") today shared the update provided by ENZC's Merger target BioClonetics Immunotherapeutics, Inc. ("B...
October 19, 2020 09:00:00 am | ACCESSWIRE |
Enzolytics, Inc. Announces Execution of Binding Letter of Intent for Merger with BioClonetics Immunotherapeutics, Inc.
PLANO, TX / ACCESSWIRE / October 14, 2020 / Enzolytics, Inc. (OTC PINK:ENZC) (or the "Company") today announced the execution of a binding letter of intent (the "LOI") to merge with BioClonetics Immunotherapeutics, Inc. ("BCLS" or "BioClonetics") a biotech company located in Dallas Texas, re...
October 14, 2020 09:00:00 am | ACCESSWIRE
Enzolytics, Inc. Announces Execution of Binding Letter of Intent for Merger with BioClonetics Immunotherapeutics, Inc.
PLANO, TX / ACCESSWIRE / October 14, 2020 / Enzolytics, Inc. (OTC PINK:ENZC) (or the "Company") today announced the execution of a binding letter of intent (the "LOI") to merge with BioClonetics Immunotherapeutics, Inc. ("BCLS" or "BioClonetics") a biotech company located in Dallas Texas, re...
October 14, 2020 09:00:00 am | ACCESSWIRE |
Enzolytics, Inc. Announces New Board Member, Charles Cotropia, CEO of BioClonetics Immunotherapeutics, Inc. Harry Zhabilov CEO of Enzolytics to Join Board of BioClonetics
PLANO, TX / ACCESSWIRE / October 1, 2020 / Enzolytics, Inc. (OTC PINK:ENZC) or (the "Company") today announced the addition of Charles Cotropia to the Company's Board of Directors. ENZC entered into a Letter of Intent (the "LOI") to merge with BioClonetics Immunotherapeutics, Inc. ("BCLS" or...
October 01, 2020 09:00:00 am | ACCESSWIRE |
Enzolytics, Inc. Announces Execution of Letter of Intent with BioClonetics Immunotherapeutics, Inc. (With Additional Update on 2020 Initiatives)
PLANO, TX / ACCESSWIRE / September 16, 2020 / Enzolytics, Inc. (OTC PINK:ENZC or the "Company") today announced the execution of a non-binding letter of intent (the "LOI") to merge with BioClonetics Immunotherapeutics, Inc. ("BCLS" or "BioClonetics") a biotech company located in Dallas Texas...
September 16, 2020 09:00:00 am | ACCESSWIRE |
Enzolytics Update
PLANO, TX / ACCESSWIRE / April 16, 2020 / Enzolytics- (OTC PINK:ENZC) is pleased to update shareholders on the current corporate initiatives. The company has retained SEC counsel for the purpose of updating all corporate information, financials and to bring the company current from a public ...
Enzolytics Comments on Recent Market Activity and Shareholder Update
DALLAS, TX / ACCESSWIRE / February 6, 2020 / Enzolytics- (OTC Pink Sheet-ENZC) was notified by FINRA that an unauthorized press release titled, "Enzolytics Inc., Launches Coronavirus Prevention Kit" was distributed to the public. Enzolytics and its management had no knowledge of this press r...
April 16, 2020 09:00:00 am | ACCESSWIRE
LINK to ENZC Press Releases
https://marketwirenews.com/stock/enzc/news/
BioClonetics Immunotherapeutics
OUR TECHNOLOGY HAS BEEN VALIDATED
In Vitro Testing Has Demonstrated the Neutralizing Capability of Our Monoclonal Antibody Clone 3
The ability of HIV to mutate renders anti-retroviral therapies ineffective against HIV in many cases. Because the Company's monoclonal antibody therapies target a portion of the virus that does not change, such mutations are not expected to affect the monoclonal antibody therapy.
Significant testing demonstrates the basis for this expectation. Specifically, in in vitro tests conducted in five independent laboratories, CLONE 3 has been tested against 43 clinical HIV isolates (strains) of the virus. CLONE 3 has demonstrated that it successfully neutralizes 41 of them (100% effective against over 95% of the HIV strain against which it was tested).
Presently, CLONE 3 is the only human monoclonal antibody found to neutralize the Clade C isolate found in Africa, China and India. CLONE 3 also neutralizes the Clade B isolate that is predominate in North America and Europe. In view of these test results, the Company is moving forward with animal and human trials to establish CLONE 3 as a significant means for treatment of those that have HIV/AIDS and to produce a vaccine against HIV.
These results were the product of testing in 5 independent laboratories. In tests conducted at the University of California at San Francisco (by Jay Levy, M.D.), CLONE 3 Antibody was shown to have in vitro neutralization effect against geographically distinct clinical HIV (primary) isolates. Research conducted at four additional international institutes has confirmed these results of in vitro neutralization. In total, the neutralizing capabilities of CLONE 3 have been verified at the following 5 laboratories:
1. University of California, San Francisco, CA, USA (Jay Levy, M.D.)
2. University of South Florida, Tampa, FL, USA (Kenneth Ugen, Ph.D.)
3. Polymun Scientific, GmbH, Vienna, AUSTRIA, (Hermann Katinger, Ph.D.)
4. Duke University, Durham, NC, USA (David Montefiori, Ph.D.)
5. Dana Farber Cancer Institute (DFCI), Harvard Medical School, Boston, MA, USA, (Ruth Ruprecht, M.D., Ph.D.)
In these tests, Clone 3 neutralized [at IC90] 41 of 43 (>95%) of the clinical HIV-1 group M, N, and O isolates. Clone 3 neutralized 3 of 3 group O HIV isolates tested at 10 µg/ml in PBMC-based assay. In another study of Clone 3 tested against one group N primary HIV-1 isolate, results indicated that the IC90 for Clone 3 versus the HIV primary isolate YBF30 was 3.72 µg/ml. Further, Clone 3 has also been demonstrated to effectively neutralize 4 of 4 virulent pediatric South African clade C isolates [ZA349, ZA562, ZA600, ZA737]; and at 10 µg/ml, neutralize [IC99] a pediatric Zambian clade C HIV-1157, as well as the simian immunodeficiency virus construct SHIV-1157ip. Therefore, of the 43 HIV isolates against which Clone 3 has been tested, it neutralized 41 (over 95%).
Clinical Evidence of Effectiveness of Clone 3
Other laboratory evidence also supports the Company's conclusion that the Clone 3 antibody will neutralize HIV-1 in humans. This evidence includes the following five (5) laboratory findings in the publications listed:
- P.A. Broliden et al. reported that, in a group of HIV-infected infants born to HIV+ mothers, infants who lacked anti-KLIC (Clone 3) antibodies had a rapid progression to symptomatic AIDS.
Vanini et al. reported that deCreasing concentration of anti-KLIC (Clone 3) antibodies directly correlated with HIV disease progression.
- Loomis-Price et al., demonstrated that high antibody reactivity to the peptide containing the (Clone 3) immunogen epitope [KLIC] is associated with slow progression to AIDS.
- Dietrich et al. further validated the significance of the (Clone 3) epitope by reporting the presence of anti-KLlC antibodies identified in HIV+ blood plasma obtained from LTNPs who had normal T?cell counts, no opportunistic infections and were not taking any prescribed adjunct chemotherapeutics or anti-retroviral drugs.
- Cano et al. cited the BioClonetics publications on (Clone 3) mAb, noting that the human monoclonal anti-gp41 antibody was a neutralizing anti-HIV antibody that binds preferentially to a linear peptide in the immunodominant region. The authors found "a correlation between the presence of anti-linear peptide antibodies and endurance of infection".
The National Institute of Health (NlH) studies, conducted by Anthony Fauci et al., head of the NIH, and published in Nature Medicine November 2001, provide further validation of the efficacy of this linear amino acid epitope, KLIC, as a protective active vaccine immunogen.
As background for understanding how tests conducted by Dr. Fauci demonstrate that Clone 3 will be effective in humans, one must understand how Clone 3 actually neutralizes the HIV virus. Through collaboration with the Karolinska Institute in Stockholm, Sweden (Britta Wahren, M.D., Professor of Microbiology), the Company identified the linear minimal essential core epitope on the virus to which Clone 3 binds. As published in the Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology in 1996 (reference 3 in Appendix), this minimal core epitope is defined as the amino acid sequence KLIC, located on the portion of the virus designated as glycoprotein (gp) 41.
In Dr. Fauci's primate phage-display peptide vaccine studies, primates were vaccinated with a peptide immunogen represented as the linear KLVC rather than KLIC. (Fauci et al., Nature Medicine, Volume 7, Number 11, November 2001, pp. 1225-1231). KLVC is a linear peptide having a conservative amino-acid substitution of valine (V) for isoleucine (I). KLIC occurs in the native HIV-1 gp41 amino acid sequence and is essentially seen as the same immunogen.
The vaccinated primates produced an antibody [anti-KLVC] that is cross-reactive with linear peptide KLIC?an amino acid sequence on HIV gp41 (and SHIV gp41). When the primates were challenged with the SHIV virus [having the gp41 amino acid sequence KLIC], the vaccinated primates'although infected with SHIV were infected at a lower SHIV viral set point than the SHIV challenged non-vaccinated control primate. Moreover, the vaccinated primates retained normal T4 cell counts while the non-vaccinated control primate's T4 cell counts decreased and progressed to AIDS and death within 6 months of SHIV challenge. The KLVC vaccinated primates' health status were that of a Long-Term Non-Progressor (LTNP).
These tests demonstrate that the Clone 3 active vaccine component prevented progression to AIDS-like illness, and also supports the conclusion that the peptide of the Clone 3 epitope (KLIC) will be effective as an active vaccine against HIV/AIDS.
Additional evidence allows the company to project that its antibody will neutralize over 98% of the HIV viral strains (clades) worldwide based upon information confirmed by the U.S. Government?s National Laboratory HIV clinical isolate database at Los Alamos, NM. Specifically, to date, Los Alamos has currently reported 4,556 clinical HIV-1 variants or subtypes (February 2015). The company has determined that the site on the virus to which Clone 3 binds in the neutralization step (its epitope) is highly conserved in 98% of the HIV-1 viral strains. Based on this knowledge and other independent in vivo clinical-correlate evidence from five (5) additional independent research institutions, the company's proprietary antibody is expected to provide a safe immunotherapeutic long-term remission for people living with HIV/AIDS and an effective active vaccine that protects uninfected individuals from HIV infection.
http://bioclonetics.com/validation.html
IND Filing means an Investigational New Drug Application (as more fully defined in Title 21 CFR 312.22 and 312.23) and all amendments and supplements thereto filed with the FDA.
Introduction
Current Federal law requires that a drug be the subject of an approved marketing application before it is transported or distributed across state lines. Because a sponsor will probably want to ship the investigational drug to clinical investigators in many states, it must seek an exemption from that legal requirement. The IND is the means through which the sponsor technically obtains this exemption from the FDA.
During a new drug's early preclinical development, the sponsor's primary goal is to determine if the product is reasonably safe for initial use in humans, and if the compound exhibits pharmacological activity that justifies commercial development. When a product is identified as a viable candidate for further development, the sponsor then focuses on collecting the data and information necessary to establish that the product will not expose humans to unreasonable risks when used in limited, early-stage clinical studies.
FDA's role in the development of a new drug begins when the drug's sponsor (usually the manufacturer or potential marketer), having screened the new molecule for pharmacological activity and acute toxicity potential in animals, wants to test its diagnostic or therapeutic potential in humans. At that point, the molecule changes in legal status under the Federal Food, Drug, and Cosmetic Act and becomes a new drug subject to specific requirements of the drug regulatory system.
There are three IND types:
An Investigator IND is submitted by a physician who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed. A physician might submit a research IND to propose studying an unapproved drug, or an approved product for a new indication or in a new patient population.
Emergency Use IND allows the FDA to authorize use of an experimental drug in an emergency situation that does not allow time for submission of an IND in accordance with 21CFR , Sec. 312.23 or Sec. 312.20. It is also used for patients who do not meet the criteria of an existing study protocol, or if an approved study protocol does not exist.
Treatment IND is submitted for experimental drugs showing promise in clinical testing for serious or immediately life-threatening conditions while the final clinical work is conducted and the FDA review takes place.
There are two IND categories:
Commercial
Research (non-commercial)
The IND application must contain information in three broad areas:
Animal Pharmacology and Toxicology Studies - Preclinical data to permit an assessment as to whether the product is reasonably safe for initial testing in humans. Also included are any previous experience with the drug in humans (often foreign use).
Manufacturing Information - Information pertaining to the composition, manufacturer, stability, and controls used for manufacturing the drug substance and the drug product. This information is assessed to ensure that the company can adequately produce and supply consistent batches of the drug.
Clinical Protocols and Investigator Information - Detailed protocols for proposed clinical studies to assess whether the initial-phase trials will expose subjects to unnecessary risks. Also, information on the qualifications of clinical investigators--professionals (generally physicians) who oversee the administration of the experimental compound--to assess whether they are qualified to fulfill their clinical trial duties. Finally, commitments to obtain informed consent from the research subjects, to obtain review of the study by an institutional review board (IRB), and to adhere to the investigational new drug regulations.
Once the IND is submitted, the sponsor must wait 30 calendar days before initiating any clinical trials. During this time, FDA has an opportunity to review the IND for safety to assure that research subjects will not be subjected to unreasonable risk.
https://www.fda.gov/drugs/types-applications/investigational-new-drug-ind-application
2020 has started off strong in the world of biopharma partnerships. Already, Nurix have struck a $2.6 billion deal with Sanofi for a proprietary drug discovery platform, and Astex Pharmaceuticals and Taiho Pharmaceuticals announced a $2.6 billion deal with MSD (Merck & Co.) for exclusive worldwide rights to therapies being developed for oncological indications. But as much as we enjoy speculating about the deal trends for this new year, let’s first take a look at how the 2019 deal landscape closed off.
Top deals and highlights in 2019
2019 was an eventful year in the world of biotech and pharma deals, comprising strategic and unexpected transactions that have contributed to the consistently dynamic industry landscape. Looking at the top transactions from the past year, the top 10 M&A deals (see table 1) achieved an aggregated value of around $245 billion. At the same time, the top 10 partnership deals (see table 2) totaled at an aggregated value of approx. $49 billion. Compared to 2018, we can confidently say that 2019 was a year of high value deals. As a matter of fact, the aggregate values of both deal types yielded a year-over-year increase of $129 billion and $14.5 billion, respectively.
Celgene and Bristol-Myers Squibb (BMS) kicked down the doors of 2019 with the announcement of the second largest pharmaceutical acquisition deal in history; only $16 billion less than Pfizer’s acquisition of Warner-Lambert for $90 billion back in 1999. The second largest acquisition of 2019, valued at $63 billion and also considered one of the top 10 valued acquisitions of all time, is AbbVie’s acquisition of Allergan. This strategic move allowed AbbVie to diversify and expand its revenue base and leadership in immunology, hematologic oncology, medical aesthetics, neuroscience, women’s health, eye care and virology.
Beyond the deal value size, our analysis indicated that eight of the top ten valued acquisitions in 2019 included portfolios of marketed therapies and pipeline candidates within neuroscience, rare diseases, and of course, oncology. Other exciting news included Takeda’s foreign takeover of Shire, securing Takeda’s spot in the list of top 20 global pharmaceutical companies by market cap. Takeda is, however, not the only Japanese pharmaceutical company on the list after Astellas making their second largest deal ever by acquiring Audentes, expanding their territory in the world of gene therapies.
Shifting our focus towards partnership deals, the top 10 largest deals have values ranging from $2-14 billion. Chinese companies have made it to the list on both the licensee and licensor side, aligning with earlier predictions of how the 2019 licensing landscape would evolve on that side of the globe. We can also see Big Pharma strategically in-licensing both precision healthcare as well as gene therapy assets and expertise.
The top 2019 partnership deal spot is won by the marketed therapy Otezla®, in-licensed by Amgen from Celgene for a total of $13.4 billion. Otezla® is used in the treatment of inflammatory diseases such as psoriatic arthritis and plaque psoriasis. Market exclusivity for the product is set to expire in 2023, but the therapy is being developed for several additional indications. Japanese pharma Takeda hasn’t exclusively been playing the acquisition game, but has also made an appearance on the top partnership deals list by out-licensing Xiidra® to Novartis for a potential $5.3 billion. Another noteworthy company in the space is Gilead, with two appearances in the list of top 10 partnership deals by size, with deals struck in oncology and rare diseases.
Outlook of 2020
There are several emerging factors that have potential to pave the way for industry growth in 2020.
Regulatory changes
It will be important to keep an eye on the U.S. FDA’s organizational changes as well as its new leadership. Earlier announcements have for example unveiled plans of establishing a new office to improve review processes of new drugs. More specifically, the FDA ex-commissioner Scott Gottlieb revealed that the agency will focus on creating more structured approaches to the evaluation of biomarkers, while developing a standardized approach to using personalized medicine and digital data. This is an essential step towards enabling the growing landscape of personalized medicine and will hopefully reduce the current regulatory uncertainty. Together with the rise of digital technologies in healthcare, these regulatory improvements will most likely lead to an increase in deals within the precision medicine space. In particular, we expect to see precision oncology companies continuing to be acquired by Big Pharma, as we have seen with recent acquisitions of Array Biopharma and Loxo Oncology.
Growing gene and cell therapy space
Oncology remains the top therapeutic area in terms of deal activity levels. A position taken from hypertension in 2010 and held ever since. We can only speculate which area that will be the next contender, however, we would argue that the gene and cell therapy market might get interesting. 2019 saw the market launch of four gene and cell therapies that resulted in a collective total sales of $2 billion after a decade of several launched and withdrawn advanced therapy medicinal products (ATMP). This means that the gene and cell therapy market is starting to establish itself with the most deal growth expected within cardiovascular, muscular, and neurological disorders.
Pressed drug pricing
In line with 2019, drug pricing is also an important issue on the radar for 2020. Legislative proposals have been made to address how to lower prescription drug costs in the US, among which is a proposal to establish a US federal agency that would oversee drug pricing. The coming elections could have a huge impact in how these legislative proposals will proceed. Looking at the current administration, Bernstein analyst Ronny Gal believes that the current administration will take minimal action on drug costs this year. Despite taking this news into consideration, the long-term fate of healthcare pricing reduction is still unknown. And taking things a step further, the resulting impact of pricing reduction is also a bit of a brain teaser. On one hand, pricing reduction will most likely have a negative impact on valuations, likely causing deal volume and/or deal sizes to decrease. However, lower drug pricing may also affect the buying power of licensees/acquirers due to negatively impacted cash flow. Simplifying a bit, the resulting deal landscape will in the end be dependent on the ratio of licensor/acquired valuation decrease to licensee/acquirer cash flow decrease.
Expanding biosimilar market
Beyond 2020, the decade might see an expanding biosimilar market caused by a row of biologic patent expirations. It is unclear how this expanding market will impact global deal making. On the one hand, this expansion could impact the pricing of biologics via the classical post-exclusivity market takeover route; on the other, opinions on whether biosimilars are on par with leading biologics in terms of safety and efficacy still remain discordant. This particularity gives originators significant pricing power, illustrated by Humira®’s country-specific discounts from 2019. It will be curious to see this dynamic play out in the launch of other biosimilars, and their influence on the attractiveness of new biologics. Global deal frequency, especially in regions such as Latin America, may grow, however deal sizes might decrease. Building upon previous predictions from 2019, we also expect to see China continuing their growth as a key player within the pharmaceutical industry in the coming decade, partially driven by reformed priority review and approval process that allows domestic drug developers to compete with multinational counterparts. With these changes we expect a more levelled global playing field in the world of biopharma deals, with an increase in both frequency and size of deals that involve Chinese companies.
ENZC is now developing monoclonal antibodies for treating the CoronaVirus.
CEOCFO: Mr. Cotropia, what is the concept behind Enzolytics, Inc?
Mr. Cotropia: Enzolytics, Inc. is a drug development company with two separate but complementary therapy platforms for treating infectious diseases, including treatment for HIV. One technology, invented by Harry Zhabilov, the CSO of our company, includes a patented antiviral peptide that has been tested in clinical studies at the National Center of Infectious and Parasitic Diseases in Bulgaria. In these trials, this therapeutic, known as ITV-1, demonstrated effectiveness in the treatment of HIV patients in various stages of the disease. In trials conducted in 31 patients, the therapeutic showed efficacy; specifically, in 68% of those individuals tested, there was an increase in CD4 + T lymphocytes. This increase was accompanied by an increase in the CD4/CD8 index and CD4% in over 50% of those tested. The increase in these parameters demonstrated statistical significance compared to the control group. The absolute number and the relative percent of CD8 + T lymphocytes decreased. And the viral load in 80.5% of those tested was below the threshold of detection.
This Enzolytics anti-HIV treatment is now being advanced through the certification stage to thereafter be made available for patient therapy.
The Company is now combining this technology with recently acquired technology, created by BioClonetics Immunotherapeutics, for creating fully human anti-monoclonal antibodies for treating HIV. Using this technology, the Company has produced a fully human anti-monoclonal antibody that has been tested in 5 international labs where it neutralized over 95% of all strains of the HIV virus against which it was tested. Additional neutralizing antibodies are being produced.
The therapies of Enzolytics’ two technologies, that produced by Enzolytics and that created by BioClonetics, are expected to be synergistic. Additionally, because the HIV virus and the CoronaVirus have correlative structures and with our knowledge of how our monoclonal antibodies neutralize HIV, we are now developing monoclonal antibodies for treating the CoronaVirus.
You can read the entire interview at:
https://www.ceocfointerviews.com/enzolytics20.html
I received an email from ETrade the other day about them paying me to borrow my "hard to borrow" shares (obviously I'd be a fool to let them borrow, so they can use them against me). The funny part is that I specifically created my ET account to purchase ENZC 1 year ago, because Fidelity would not allow me to buy it. In other words, ENZC is the only stock in my ET account.
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=162526676&txt2find=etrade|borrow
Somebody also recently received an email from their broker wanting to borrow their ENZC shares.
While ENZC 1.5 BILLION UNRESTRICTED SHARES GET DUMPED TIME AND TIME AGAIN THE STOCK PRICE CONTINUES TO RISE!
YOU GOTTA LOVE IT
ENZC ENZC ENZC
How do you know ENZC hasn't taken their complaint to the SEC and are preparing for a lawsuit?
Cotropia is very well versed in the law and has been very straight forward, precise, direct, factual and focused as tge CEO of ENZC.
Management never BLAMED social media for the fall of the PPS.
They SPECIFICALLY stated:
Recently, we have become aware of commentators on our technology who, rather than fairly and validly analyzing our technology and our findings, instead propound, for what we perceive as some self-serving reasons, erroneous and irrelevant assertions to mislead those interested in knowing the fundamental truth about our discoveries. For example, one "red flag" raised by one commentator has been to criticize our AI team - not on the basis of the technology and substance of its findings - but by focusing on the date of incorporation of the partner. Obviously, the date an entity is incorporated is irrelevant when those on the research team have decades of experience with the knowledge, skill and capability to analyze the amino acid sequences (containing thousands in number) of each of over 50,000 different Coronavirus isolates. It is from this sophisticated analysis and resulting findings that the Achilles' heels of the Coronavirus are revealed, namely those epitopes that must be and that can be targeted by monoclonal antibodies to effectively treat the virus not only today but into the future. We question the motive behind these grossly misdirected comments, made for what we perceived as self-serving reasons and not to provide an honest, fair and truthful dialogue about a most serious medical crisis. While we perceive such irrelevant and misleading comments as intending to divert attention from the problem at hand and the solutions that are possible, we stand resolved to focus on the science and applying our capabilities to achieve success for all who will confront this virus - a virus that has and will do societal damage around the world, not only today but in the future".
WHERE DO THEY BLAME SOCIAL MEDIA FOR THE FALL OF THE PPS?
The BULLSHIT you are trying to create is just what they are talking about.
ENZC is a straight shooter and they don't play games:
Here is where ENZC publicly stated THIS IS NOT FROM OUR COMPANY!!!
DALLAS, TX / ACCESSWIRE / February 6, 2020 / Enzolytics- (OTC Pink Sheet-ENZC) was notified by FINRA that an unauthorized press release titled, "Enzolytics Inc., Launches Coronavirus Prevention Kit" was distributed to the public. Enzolytics and its management had no knowledge of this press release in any manner, and disavows any information contained in this press release. The company does not have a "Coronavirus Prevention Kit" and finds the claim reckless and fraudulent.
Hi Free Nebula,
Gald to see you are still around on the ENZC board.
Hopefully we see that white candle.
darron427,
You have traders, flippers and use to be longs.
If people are buying than someone is selling.
It doesn't matter how valuable a company may or may not become, traders/flippers hit the target whether it be 10, 20 or 30 persent and move on.
Not everyone is a long.
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