Wednesday, October 31, 2012 11:50:11 AM
10-31-12: Anti-PS Mabs Stimulate Cancer-Fighting Immune Responses & Specifically Target Tumors (10-25-12 SITC Poster and 10-10-12 Nuclear Medicine & Biology Paper)
PR 10-31-12: ”New Data Support Ability of PS-Targeting Antibodies to Specifically Target Tumors and Stimulate Cancer-Fighting Immune Responses”
• Presentation at the 27th Annual Meeting of the Society for Immunotherapy of Cancer Highlights Ability of PS-Targeting Antibodies to Induce Innate and Adaptive Immune Responses
• Published Article in Nuclear Medicine & Biology Supports Potential of Peregrine's PS-Targeting Antibody PGN635 to Detect Tumor Response to Therapy
http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=717438
TUSTIN, 10/31/12: Peregrine Pharmaceuticals (NASDAQ: PPHM), a biopharmaceutical company developing first-in-class monoclonal antibodies focused on the treatment and diagnosis of cancer, today announced the presentation of preclinical data showing specific localization and enhancement of anti-tumor functions of immune cells inside tumors following administration of phosphatidylserine (PS)-targeting antibodies. These data show that by specifically targeting PS exposed on tumor blood vessels, Peregrine's antibodies mediate beneficial changes in the local tumor environment including the increase of signaling chemicals associated with anti-tumor immune responses, a reduction of signaling chemicals associated with immune suppression, as well as increasing the prevalence of tumor-destroying immune cells. The antibody-induced effects are localized to the tumor environment, and therefore do not appear to cause systemic side effects. Peregrine's lead PS-targeting antibody, bavituximab, is currently being evaluated in 8 clinical trials in multiple oncology indications.
"We believe these results build on previous findings showing the potential of PS-targeted agents for diagnosis, therapy and to monitor the effectiveness of anti-tumor agents," said Jeff T. Hutchins, Ph.D., Peregrine's VP of Preclinical Research. "While several new promising cancer immunotherapies are successful in amplifying the anti-tumor behavior of specific cell types, they carry the risk of side-effects associated with systemic immune activation. To date, data from our collective preclinical studies and clinical trials shows that exposed PS produces a dominant immunosuppressive signal favoring tumor survival and growth. By specifically targeting and blocking PS with our antibodies, we see potent anti-tumor effects through a shift of multiple immune cells and their associated signaling chemokines. These new data further support our continued enthusiasm for the broad-spectrum cancer-fighting potential of bavituximab as we look forward to data from several clinical trials in the coming months."
The immune modulation of anti-tumor responses data were presented at the 27th Annual Meeting of the Society for Immunotherapy of Cancer (1) held in Bethesda, Maryland from October 24-28, 2012. Separately, data were published in the peer-reviewed journal Nuclear Medicine and Biology highlighting results from a study investigating the company's fully human phosphatidylserine (PS)-targeting antibody PGN635 [Note: PGN635 is Fully-Human Bavituximab=1N11=AT004 (B2GPI-depen.) – see http://tinyurl.com/cparur & http://tinyurl.com/6ql5nf ] utilized as a radiolabeled tumor imaging probe (2). Data from the study showed that in animals pre-treated with the chemotherapeutic agent paclitaxel, a high accumulation of the radiolabeled antibody (89Zr-PGN635) [ Note: Genentech working with 89Zr-PGN635/Imaging – see http://tinyurl.com/8wvem9y ] was observed in the treated tumors, reaching tumor to blood ratios of up to 13-fold. These results demonstrate the potential breadth of applicability of the company's PS-targeting antibodies to clearly image solid tumors regardless of cancer type, and provide a potential method to rapidly assess the anti-tumor efficacy of chemotherapies and other approved and experimental cancer treatments.
1. Targeting of Phosphatidylserine by Monoclonal Antibodies Induces Innate and Specific Anti-tumor Responses
Bruce Freimark 1, Jian Gong 1, Richard Archer 1, Van Nguyen 1, Christopher Hughes 2, Xianming Huang3 , Yi Yin 3, Philip Thorpe 3
1. Peregrine Pharmaceuticals, Inc., Tustin, CA; 2. Molecular Biology & Biochemistry, University of California, Irvine, CA; 3. Pharmacology, University of Texas SW Medical Center, Dallas, TX
[ http://www.sitcancer.org/2012/annualmeeting ]
[ Poster now on website: http://www.peregrineinc.com/images/stories/pdfs/sitc_2012.pdf ]
2. ImmunoPET Imaging of Phosphatidylserine in Pro-Apoptotic Therapy Treated Tumor Models
Annie Ogasawara, Jeff N. Tinianow, Alexander N. Vanderbilt, Herman S. Gill, Sharon Yee, Judith E. Flores, Simon-Peter Williams, Avi Ashkenazi, Jan Marik, Nuclear Medicine & Biology, doi: 10.1016/j.nucmedbio.2012.09.001.
[ pub. Online 10-10-12 http://www.sciencedirect.com/science/journal/aip/09698051 ]
ABOUT BAVITUXIMAB
Bavituximab is a first-in-class phosphatidylserine (PS)-targeting monoclonal antibody that represents a new approach to treating cancer. Bavituximab is the lead drug candidate from the company's PS technology platform and is currently being tested in eight clinical trials including three randomized Phase II trials in front-line and second-line non-small cell lung cancer, front-line pancreatic cancer and five investigator-sponsored trials (ISTs) in additional oncology indications. PS is a highly immunosuppressive molecule usually located inside the membrane of healthy cells, but "flips" and becomes exposed on the outside of cells that line tumor blood vessels, creating a specific target for anti-cancer treatments. PS-targeting antibodies target and bind to PS and block this immunosuppressive signal, thereby enabling the immune system to recognize and fight the tumor.
ABOUT PEREGRINE PHARMACEUTICALS, INC.
Peregrine Pharmaceuticals, Inc. is a biopharmaceutical company with a portfolio of innovative monoclonal antibodies in clinical trials focused on the treatment and diagnosis of cancer. The company is pursuing multiple clinical programs in cancer with its lead product candidate bavituximab and novel brain cancer agent Cotara®. Peregrine also has in-house cGMP manufacturing capabilities through its wholly-owned subsidiary Avid Bioservices, Inc. ( http://www.avidbio.com ), which provides development and biomanufacturing services for both Peregrine and outside customers. Additional information about Peregrine can be found at http://www.peregrineinc.com .
Safe Harbor*snip*
Contact: Christopher Keenan or Jay Carlson
Peregrine Pharmaceuticals, Inc. (800) 987-8256 info@peregrineinc.com
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Oct24-28 2012 “27th Annual Meeting of the Society for Immunotherapy of Cancer”, Bethesda
“The SITC Annual Meeting (Oct24-28 2012) & Associated Programs serve as the premier destination for scientific exchange, education and networking in the cancer immunotherapy community. Basic researchers, clinicians, students, postdoctoral fellows, and allied health professionals dedicated to improving cancer patient outcomes come together at the SITC Annual Meeting & Associated Programs to experience cutting edge research, education and training that serves as the catalyst to advance the field.”
http://www.sitcancer.org/2012/annualmeeting
10-25-12: “SITC’s Primer on Tumor Immunology & Cancer Immunotherapy”
http://www.sitcancer.org/2012/primer/schedule
Pgm: http://www.sitcancer.org/UserFiles/am12-final-program_v8_loFINAL_v1.pdf
Track: Therapeutic Monoclonal Antibodies In Cancer
#176 “Targeting of Phosphatidylserine by Monoclonal Antibodies Induces Innate and Specific Anti-Tumor Responses”
Bruce Freimark 1, Jian Gong 1, Rich Archer 1, Van Nguyen 1, Christopher Hughes 3, Xianming Huang 2, Yi Yin 2, Philip Thorpe 2
1 Preclinical Development, Peregrine Pharmaceuticals, Tustin, CA
2 Pharmacology, University of Texas, SW Medical Center, Dallas, TX
3 Molecular Biology & Biochemistry, Univ. of California, Irvine, CA
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From the SITC poster (per FTM’s iHub #100922 http://tinyurl.com/cltbrsd ):
=> http://www.peregrineinc.com/images/stories/pdfs/sitc_2012.pdf
ABSTRACT: Phosphatidylserine (PS) is a phospholipid normally residing in the inner leaflet of the plasma membrane. PS becomes exposed on tumor vascular endothelial cells and tumor cells in response to chemotherapy, irradiation and oxidative stresses in the tumor microenvironment. Binding of antibodies to PS on tumor endothelial cells and tumor cells recruits immune cells and engages the immune system to destroy tumor vasculature. The antibodies also enhance anti-tumor immunity by blocking the immunosuppressive action of PS. A chimeric PS-targeting antibody, bavituximab, is being used in combination with chemotherapy to treat patients with solid tumors in Phase II trials. Using syngeneic tumors and human tumor xenografts in mice, we have demonstrated PS targeting antibodies can specifically localize to tumors and antibody uptake by tumors is enhanced by chemotherapy and irradiation. In addition, PS targeting antibodies are capable of suppressing tumor growth in multiple tumor types by several mechanisms including destruction of tumor blood vessels by ADCC mechanisms, blockage of PS-mediated immunosuppression, and reactivation of macrophage and T-cell cellular anti-tumor responses. The combination of these mechanisms promotes strong localized anti-tumor responses without the side-effects of systemic immune activation.
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IMAGING APPLICATIONS Of PS-TARGETING MABS:
10-12-12: Genentech studying Imaging using PGN635(Fhu-Bavi) for the potential "detection of tumor response to therapy". http://tinyurl.com/8wvem9y
…Nuclear Medicine & Biology, Genentech's Jan Marik, "ImmunoPET Imaging of PS in Pro-Apoptotic Therapy Treated Tumor Models"
4-3-12: Peregrine Launches PS-Targeting Clinical Imaging Program (AACR'12 #2452) http://tinyurl.com/7p7jovt & http://tinyurl.com/7yrwqm7
…PPHM "recently filed an IND" with FDA for an Imaging trial using 124I-PGN650, ~12pts.
...6-28-12: Trial added to trials.gov: http://clinicaltrials.gov/ct2/show/NCT01632696 - see CANCER TRIALS ABOVE for more details.
12-2011: Thorpe Article on FH-Bavi/Optical-Imaging in Translational Oncology http://tinyurl.com/7vcnbz2
11-14-11: Dr. Bruce Freimark presents PS IMAGING poster at AACR-NCI-EORTC Conf./SanFran http://tinyurl.com/89hpydn
9-12-11: Drs. Thorpe & Freimark present PS IMAGING posters at World Imaging Congress/S.Diego http://tinyurl.com/3uv5rgr
9-9-11: PS IMAGING potential discussed in Qtly. Conf. Call: http://tinyurl.com/3q7hzjh
…more on PS Imaging in iBox here: http://investorshub.advfn.com/boards/show_ibox.aspx?boardid=2076
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MUST LISTEN: Dr. Philip Thorpe’s 46min. 5-1-12 NYAS Anti-PS Symposium talk Replay & Slides
Dr. Thorpe was the last of 5 speakers (Alan Schroit, Chris Reutlingsperger, David Ucker, Ari Helenius, Philip Thorpe) at the NYAS “Phosphatidylserine (PS) Asymmetry - Therapeutic Applications in Cancer & Infectious Disease Symposium". If you have the time to listen to all 5 of these talks, you will learn an immense amount about the moa of Peregrine’s PS-targeting antibody therapeutic, Bavituximab.
For anybody looking for the replay links, they’re here: http://investorshub.advfn.com/boards/read_msg.aspx?message_id=79851320
Dr. Thorpe’s talk is A MUST, but the other 4 are excellent as well.
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BAVI MOA: 5-1-12 Dr. Phil Thorpe's 46min talk at NYAS PS-Targeting Symposium http://tinyurl.com/9792gl5
. . .Symposium title: "Phosphatidylserine (PS) Asymmetry - Therapeutic Apps. in Cancer & Infectious Disease Symposium"
. . .Replays of 5 speakers: Alan Schroit, Chris Reutlingsperger, David Ucker, Ari Helenius, Philip Thorpe
BAVI MOA: 5-26-11 Dr.Thorpe's keynoter at Recombinant-Mabs/Barcelona http://tinyurl.com/3klpodc & http://tinyurl.com/3m33h33
BAVI MOA: 4-2010 Thrombosis Research article (Dr.Thorpe) http://tinyurl.com/9reso7s
BAVI MOA: See http://www.peregrineinc.com/technology/bavituximab-oncology/recent-data.html
Dr. Philip E. Thorpe – UTSW-MC/Dallas [PPHM SAB, inventor of Bavituximab]
• Bavituximab is the chimeric version of murine mab 3G4
• 2aG4 is a mouse IgG2a version of murine mab 3G4
• PGN635 is fully-human bavituximab (aka 1N11, AT004)
10-20-12 FTM on Bavi MOA (#100242):
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=80729530
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=80730708
10-20-12 FTM on PGN635 vs. PGN650: http://investorshub.advfn.com/boards/read_msg.aspx?message_id=80733008
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The foundation of the PS-Targeting approach is built on the fact that PS is immunosuppressive…
Suggest this prep. reading:
2-2005: “Interaction between Phosphatidylserine and the Phosphatidylserine Receptor Inhibits Immune Responses In Vivo”
Peter Henson, et al, Journal of Immunology, Feb.2005, p.1393–1404 – FULL PDF: http://www.jimmunol.org/cgi/content/full/174/3/1393
. . .The Cliff Notes 7-word synopsis => “Evolution has favored pathogenesis that resembles apoptosis.”
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12-5-12: IBC’S “IMMUNOMODULATORY ANTIBODIES” CONF. SESSION OVERVIEW
“Dr. Thorpe will give an update on the mechanism of anti-tumor action of Bavituximab, an immunostimulatory chimeric monoclonal antibody that is showing promising activity in clinical trials in patients with various types of cancer. Bavituximab targets the immunosuppressive lipid phosphatidylserine (PS) that becomes exposed on tumor blood vessels and tumor cells. Tumors externalize PS and secrete PS-expressing exosomes that impose quiescence on immune cells, thereby creating a tumor microenvironment that supports tumor growth. Bavituximab causes myeloid-derived suppressor cells in tumors to differentiate into tumoricidal M1 macrophages that destroy tumor vasculature and tumor cells by antibody-dependent cell-mediated cytotoxicity. It also causes immature dendritic cells in tumors to mature and present tumor antigens that result in the generation of tumor-specific cytotoxic T cells. Thus, bavituximab reactivates innate & adaptive tumor immunity, and induces an immune cell-mediated shutdown of tumor vasculature.”
http://tinyurl.com/8phzs5w
12-5-12: DR. PHILIP THORPE, IBC’S “IMMUNOMODULATORY ANTIBODIES” CONF. – “OVERCOMING IMMUNE SUPPRESSION IN TUMORS WITH BAVITUXIMAB”
“Bavituximab is a monoclonal antibody that is proving safe & effective as a 2nd-Line therapy in advanced lung cancer patients. It targets the immunosuppressive lipid, phosphatidylserine [PS], which becomes exposed on tumor blood vessels & tumor cells. Bavituximab causes MDSCs to differentiate into tumoricidal M1 macrophages that destroy the tumor vasculature and tumor cells by ADCC. It also causes immature dendritic cells in tumors to mature and present tumor antigens, resulting in the generation of tumor-specific cytotoxic T-cells.”
http://tinyurl.com/8phzs5w
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8-15-12, PEREGRINE’S CEO STEVE KING, WEDBUSH/NYC
“Bavituximab has a very novel MOA - it turns out that PS is not simply a marker of disease, but is actually involved in controlling the immune response to disease. By blocking that immunosuppressive signal, we actually allow the immune system to turn on and fight the disease. The concept is, Phosphatidylserine (PS) itself is a normal component of cellular membranes, present in every cell of the body, only very-tightly regulated to internal side of the cell. So, essentially, if you inject PS-finding agents, such as is done in our Imaging pgm, the agents simply float around and eventually clear the body if there’s no sign of disease. What our scientists discovered, is that as cancer develops, you get a very unique environment, you have poor blood flow, reactive oxygen species, hypoxia – as a result of all these insults, the mechanisms that keep PS inside of cells become disrupted, and the PS becomes exposed on the outside of the cell. It turns out that this exposed PS in the tumor microenvironment is very important in controlling the immune response. The only normal time which you have PS exposure is when cells undergo normal programmed cell death, or apoptosis. So, as cells die, you see the same phenomenon of PS becoming expressed or exposed on the outside of the cell. What happens then is, as the immune system is undergoing its daily routine of removing dead & dying cells, those macrophages & dendritic cells, whose responsibility it is to remove the cells, interact with the dead & dying cells, and actually have a PS-receptor on their surface. As the exposed PS binds to the receptor on the immune cells, it actually sends specific signals to down-regulate the immune response, because when you’re removing dead & dying cells you don’t need a robust immune response, obviously. It turns out that cancer, as well as a number of other diseases, have taken advantage of this fact, and by simply causing PS-exposure during the tumor microenvironment, you now do not get an adequate immune-response to the disease, allowing the tumors to outgrow the poor immune-response that’s being given. Bavituximab is injected, it goes to the site of the disease, so it accumulates on the PS inside the tumor environment, blocks the PS that’s exposed in that environment, and now those immune cells - you can actually detect a significant change in there phenotypes, as they go from a non-inflammatory to a pro-inflammatory state and really begin the fight the disease. And over time, you see development of a full adaptive immune response. As at fully adaptive immune response happens, you then have this full immune response, which includes ADCC, mediated by the antibody itself, normal cell-killing, mediated by the antibody, as well as activation and down-stream effects of the immune response.”
http://tinyurl.com/8mhrtld
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5-1-12, DR. PHILIP THORPE, NYAS PS-TARGETING SYMPOSIUM
• Bavituximab, an antibody drug in development by Peregrine Pharmaceuticals, targets PS in tumor blood vessels and can reactivate immunity to cancer cells.
• This antibody can serve as both an imaging agent and as an adjuvant treatment with other therapies.
• Bavituximab can induce tumor-specific T-cell immunity in some situations.
TARGETING TUMOR VASCULATURE: Taking advantage of the externalization of PS on tumor cells could provide new treatment strategies for cancer treatments. Philip Thorpe of UT Southwestern Medical Center described preclinical and clinical studies of bavituximab, an antibody drug developed by Peregrine Pharmaceuticals that targets PS in the vasculature of tumors. As tumors develop, they create a stressful, hypoxic cellular environment that results in the formation of reactive oxygen species and the release of inflammatory cytokines. In this environment, the asymmetry of lipid distribution in the membrane of the endothelial cells that line tumor blood vessels breaks down, leading to the externalization of PS. In addition, PS is often exposed on the surface of tumor cells. As a strategy for targeting PS externalization, Peregrine Pharmaceuticals initially developed a mouse monoclonal antibody that targets PS by binding to two molecules of B2-glycoprotein-I that in turn bind to PS on the surface of cells. With only a single molecule of the protein, binding to the surface of cells is relatively weak, but the affinity increases by a factor of 30,000 with the addition of a 2nd molecule of B2-glycoprotein-I. The researchers have constructed a series of antibodies that targets the tumor vasculature. Two are mouse antibodies, 3G4 & 2aG4. Bavituximab is a chimeric antibody with mouse PS binding regions fused to human IgG. The fully human antibody is known as PGN635. These antibodies localize specifically to the blood vessels in tumors, which makes them useful as imaging agents. Studies with normal tissues and various tumor types reveal that these antibodies show affinity for a range of tumor types but minimal binding to a variety of normal tissues.
BAVITUXIMAB AS AN ANTI-TUMOR AGENT: In rodent studies, antibodies alone inhibit tumor growth by 30%–90%. That variation most likely reflects the differences in PS expression on blood vessels in different tumors. However, combining the antibody treatment with other treatments, including chemotherapy, radiation, or androgen deprivation, improved these results. In studies of prostate tumors in mice, the combination of the mouse antibody 2aG4 and docetaxel slowed tumor growth by 98% compared with 90% for docetaxel alone and 80% for antibody alone. The PS-targeting antibody in combination with intense radiation can shrink lung cancer tumors that are resistant to radiation alone.
How does the antibody work?
1. As one proposed mechanism of action, these PS-targeting antibodies damage tumor vessels by a process known as antibody-dependent cellular cytotoxicity (ADCC). As poor blood flow and hypoxia lead cells in the tumor vasculature to expose PS on their surfaces, bavituximab targets those cells and shuts down blood flow, which starves those tumor cells of nutrients.
2. As a 2nd mechanism, bavituximab can overcome the immunosuppressive processes observed with cells that externalize PS. In tumors the expression of PS on cell surfaces keeps macrophages in their M2 state, an activation state that suppresses inflammation and supports angiogenesis. It also prevents myeloid-derived suppressor cells (MDSCs) from differentiating into macrophages and dendritic cells (DCs). In addition, PS inhibits the maturation of DCs, which prevents the presentation of antigens to T cells. Bavituximab repolarizes macrophages to their M1 state, which allows them to kill cells that express PS, including the tumor vascular endothelium. It also leads to differentiation of the MDSCs and prompts DCs to mature and to present tumor antigens to T cells.
TUMOR-SPECIFIC IMMUNITY: Bavituximab can also prompt the development of tumor-specific immunity. In experiments with rats with treatment-resistant glioma tumors, 15% of the animals treated both with radiation and with antibody therapies did not die from those tumors. When the researchers reintroduced glioma tumor cells into these surviving rats, the rats were immune to the cancer. The team determined that spleen cells from these animals could kill gliomas, which indicated the antibody treatment had induced T cell immunity.
• Dr. Thorpe’s 5-1-12 46min. talk replay: http://www.nyas.org/MediaPlayer.aspx?mid=25e51622-c908-46ef-bba1-95ca6a814eed
• Replays of all 5 speakers: Alan Schroit, Chris Reutlingsperger, David Ucker, Ari Helenius, Philip Thorpe => http://tinyurl.com/9o4ddse
The 30 slides (PDF) from Dr. Thorpe’s 5-1-12 NYAS presentation are here: http://www.peregrineinc.com/images/stories/pdfs/nyasweb.pdf
Bavi MOA diagram (5-1-12 Thorpe/NYAS):
DIRECT LINKS to Host’s Intro and All 5 Scientists Talks at NYAS 5-1-12:
Intro: George Zavoico (MLV & Co.) => http://www.nyas.org/MediaPlayer.aspx?mid=8163b627-7c47-45c6-9f15-2b9e1609d476
I. Alan Schroit (UTSW): “Regulation of PS Asymmetry & Physiologic Consequences of Its Loss”
=> (40min.) http://www.nyas.org/MediaPlayer.aspx?mid=dc3ec7ed-1e0a-47fd-a5ca-96dd9e6c73bb
II. David Ucker (Univ. of Illinois/Chicago): “Innate Apoptotic Immunity and Glycolytic Enzyme Externalization”
=> (39 min) http://www.nyas.org/MediaPlayer.aspx?mid=ae50efa0-1bb1-42a2-9574-5eac7053e7b8
III. Ari Helenius (ETH/Zurich): “Phopshatidylserine Asymmetry & Cell Survival”
=> (38min.) http://www.nyas.org/MediaPlayer.aspx?mid=ff0a5576-dba1-4e33-8e73-c4280291495b
IV. Chris Reutelingsperger (Univ. of Maastricht/Netherlands): “PS Targeting with Annexin A5 to Diagnose & Treat Human Disease”
=> (35min.) http://www.nyas.org/MediaPlayer.aspx?mid=325f01c4-5209-4ceb-9870-a0860eaf330f
V. Philip Thorpe (UTSW): “Targeting Tumor Vasculature & Reactivating Tumor Immunity with Bavituximab”
=> (46min.) http://www.nyas.org/MediaPlayer.aspx?mid=8163b627-7c47-45c6-9f15-2b9e1609d476
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4-3-12: DR. PHILIP THORPE, AACR/2010, #5495
“Cure of Castration-Resistant Prostate Cancer in TRAMP Mice By Reactivating Tumor Immunity with a Phosphatidylserine-Targeting Antibody [PGN635]”
“Androgen deprivation therapy (ADT) is initially effective against prostate cancer, but many patients eventually relapse and die from the outgrowth of castration-resistant disease. Here, we tested the hypothesis that tumor immunity against castration-resistant prostate cancer can be elicited by combining ADT with treatment with a monoclonal antibody that binds exposed phosphatidylserine (PS). The rationale was that PS is an immunosuppressive lipid that becomes exposed on tumor blood vessels and malignant cells in prostate tumors responding to ADT, and inhibits immune responses to prostate tumor antigens. To validate this hypothesis, we castrated TRAMP mice after they had developed prostatic adenocarcinomas and treated them with the PS-targeting antibody, mch1N11 [PGN635 is Fully-Human Bavituximab=1N11=AT004 (B2GPI-depen.) – see http://tinyurl.com/cparur & http://tinyurl.com/6ql5nf ] . We first demonstrated that PS exposure was induced on tumor vascular endothelium and tumor cells by castration. PS exposure on vessels coincided with regions of hypoxia generated in the tumor microenvironment. Next, we demonstrated that castration combined with treatment with mch1N11 inhibited tumor growth and progression. About half of the treated TRAMP mice did not develop castration-resistant tumors, and eventually died of old age. Immunohistochemical studies revealed that the mch1N11 treatment combined with castration generated T-cell immune responses against TRAMP tumor antigens that kept the tumor in check. Extensive disruption of tumor vasculature and abundant infiltration of immune cells, including CD8 positive T lymphocytes, Natural killer (NK) cells and dendritic cells were observed. Splenocytes from mice treated with mch1N11 plus castration were able to kill TRAMP-C2 specifically in vitro, whereas splenocytes from mice in the other groups could not. These results demonstrate that PS, which becomes exposed on prostate cancer cells and tumor vasculature after ADT, inhibits immunity to TRAMP tumor antigens. Treatment with the PS-targeting antibody mch1N11 reactivates tumor immunity, which can permanently hold new tumor development in check.
- - - - PPHM 4-4-12 PRESS RELEASE COMMENTS RE: #4395:
“ In this presentation, researchers presented data showing robust anti-tumor responses in a challenging preclinical prostate cancer model when an animal version of bavituximab was combined with androgen deprivation therapy (ADT). Using the TRAMP model of prostate cancer in which mice are genetically engineered to continually generate prostate cancer, the combination regimen of bavituximab with ADT remarkably resulted in complete inhibition of cancer in roughly 40% of the animals, preventing tumor growth until the animals died of old age. These results support PS as a fundamentally immunosuppressive molecule, the blocking of which with PS-targeting antibodies can help facilitate robust immune responses to cancer."
http://tinyurl.com/7yrwqm7
Poster PDF: http://www.peregrineinc.com/images/stories/pdfs/aacr_2012_prostate_cure.pdf
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5-26-11: DR. PHILIP THORPE, KEYNOTE PRESENTATION AT INFORMA LIFE SCIENCES RECOMBINANT ANTIBODIES CONF. IN BARCELONA
”Targeting Tumor Vasculature & Reactivating Tumor Immunity with Bavituximab
"Our research shows that exposed PS in the tumor environment plays a fundamental immunosuppressive role that prevents the immune system from recognizing cancer cells as 'foreign,' resulting in cancer patients not being able to reject their tumors. We show that highly immunosuppressive cells called myeloid-derived suppressor cells, or MDSCs, accumulate in tumors and fail to mature into functional immune cells. What is especially exciting is that administration of PS-targeting antibodies like bavituximab breaks the grip of the tumor on the immune system. In treated animals, we see the disappearance of MDSCs and the appearance of functional immune cells, especially macrophages. The entire tumor environment shifts from being immunosuppressive to being immune responsive. These results have important implications for cancer therapy."
- - PPHM’s PR: “Data presented today show that PS-targeting antibodies overcome the immunosuppression in tumors that prevents immune responses to tumor cells. Antibody treatment of tumor-bearing mice caused the differentiation of highly immunosuppressive myeloid-derived suppressor cells (MDSCs) into functional immune cells, notably M1 macrophages and dendritic cells. This was accompanied by a decrease in the immunosuppressive cytokines and markers IL-10, CD206, and CD301 by more than 60%, and an increase in the proinflammatory cytokines TNF-alpha, IL-12, and IL-6 by more than 500% compared to mice treated with the control antibody. The reactivated M1 macrophages were shown to home in on PS-expressing tumor blood vessels and destroy them, resulting in marked inhibition of tumor growth. PS-targeting antibody treatment also enhanced the ability of dendritic cells to generate cytotoxic T-cells against cancer cells, resulting in a 4-fold increase of tumor-specific T-cells. These results support PS as a fundamental immunosuppressive molecule exploited by tumors, and bavituximab as an agent capable of overcoming PS-mediated immune suppression.”
http://tinyurl.com/3klpodc
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4-5-11: DR. PHILIP THORPE, AACR/2011, #3651
”Phosphatidylserine-Targeting Antibody Induces Differentiation of Myeloid-Derived Suppressor Cells into M1-like Macrophages”
“Data from several studies suggest PS-targeting antibodies prompt a reactivation of innate immune functions inside tumors. New studies demonstrated that an animal equivalent of bavituximab alters immune cells' production of signaling chemicals from an immunosuppressive (IL-10-dominated) response generally associated with fostering growth, to a pro-inflammatory (IL-12 and TNFa -dominated) response associated with tumor destruction. This immune shift was demonstrated by a doubling of the ratio of tumor-fighting (M1) to tumor-tolerating (M2) macrophages inside tumors as compared to animals treated with a control antibody. "We have now measured several important immune response changes induced by the PS-targeting action of bavituximab," said Philip E. Thorpe, Ph.D., professor of pharmacology at UT Southwestern Medical Center, scientific adviser to Peregrine and inventor of the company's PS-targeting antibody technology. "When taken together, the data support bavituximab initiating a fundamental shift inside tumors, overcoming what is now increasingly understood to be PS-mediated immune tolerance of tumors. Based on the consistent anti-tumor data we have observed in our prior studies, we had suspected that PS-targeting antibodies were facilitating immune reactivation in tumors. These new data strengthen our hypothesis and potentially have broad implications for the future of cancer immunotherapy."
POSTER – SEE http://www.peregrineinc.com/images/stories/pdfs/aacr_moa.pdf
The phosphatidylserine (PS)-targeting antibody, bavituximab, is currently in Phase II clinical trials in patients with NSCLC and Pancreatic Cancer. Bavituximab, and its murine counterpart, 2aG4, induce the attack of monocytes & macrophages on PS-expressing tumor vascular endothelium & tumor cells and inhibit the immunosuppressive effects of PS in the tumor microenvironment. Myeloid-derived suppressor cells (MDSC) are one of the major cells responsible for the immunosuppressed state in tumors. In this study, we tested the influence of 2aG4 on the differentiation of MDSC into M1-like tumor associated macrophages (TAMs). Taken together, our results suggest that 2aG4 causes the differentiation of MDSCs into macrophages having an M1-like phenotype.
SUMMARY:
1. 2aG4 treatment of MDSCs induces their differentiation towards macrophages with an M1-like phenotype with higher expression of iNOS and lower CD206.
2. 2aG4 treated MDSCs produce more proinflammatory cytokines and less immunosuppressive cytokines.
3. 2aG4 treatment of PC3 tumor-bearing mice significantly decreases the number of tumor-infiltrating and splenic MDSC, and increases the ratio of M1 to M2 macrophages in the tumor.
4. 2aG4 treatment switches tumor associated macrophages towards M1-like macrophages.
http://tinyurl.com/68p9zs4
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4-25-10: DR. PHILIP THORPE, THROMBOSIS RESEARCH
”Targeting Anionic Phospholipids on Tumor Blood Vessels & Tumor Cells”
“Bavituximab’s MOA:
(i) Anti-vascular activity: 3G4 & 2aG4 [Bavituximab is chimeric 3G4]have a strong vascular targeting action. Histologic examination of tumors from treated mice reveals a marked reduction in the vascular density and plasma content of tumors (Fig. 3). Time course studies show the sequence of events to be: (1) Antibodies localize to tumor vasculature within 1 hour; (2) Monocytes arrive in tumor vessels within 1–2 days; (3) Vascular collapse occurs between 2 and 6 days. Collagen IV positive ‘ghosts’ of de-endothelialized vessels remain; (4) Macrophages having tumoricidal M1 phenotype infiltrate into the tumors in large numbers by 4–5 days. (5) Central necrosis develops throughout the entire core of the tumor with survival of a peripheral rim of tumor cells, characteristic of the action of a VTA. The destruction of tumor endothelium is dependent on the Fc piece of the antibody, and appears to be caused by monocytes and macrophages, the predominant cell types that localize to tumor vessels in nu/nu and SCID mice [15]. Mouse macrophages can be demonstrated in vitro to kill 2aG4-coated PS-expressing mouse endothelial cells. All these facts are consistent with the primary mechanism of anti-vascular action being ADCC-mediated destruction of the tumor endothelium by cells of the innate immune system.
(ii) Induction of pro-inflammatory responses: PS suppresses the production of pro-inflammatory cytokines by monocytes and macrophages. Normally, apoptotic cells are silently engulfed by macrophages without their raising a pro-inflammatory response [23]. PS on apoptotic cells binds to PS receptors on the macrophages, which signals the macrophages to secrete antiinflammatory cytokines, such as TGFb and IL-10 [23]. When PS is masked by 2aG4, the suppression of proinflammatory signals is blocked and the cells switch to the production of pro-inflammatory cytokines, such as TNFa and IL-1b. These cytokines then recruit large numbers of macrophages into the tumor interstitium (Fig. 4). The macrophages have the M1 phenotype, characteristic of tumoricidal macrophages, as opposed to M2 phenotype, characteristic of proangiogenic macrophages.
(iii) Induction of immunity to tumor cells: A third mechanism of action is seen in immunocompetent animals. It is known that PS can suppress immune responses by preventing dendritic cell maturation and antigen presentation [24]. We found in rats implanted with non-immunogenic F98 intracranial gliomas that 10 Gy whole brain irradiation plus 2aG4 can produce curative CTL responses against the surviving glioma cells [18]. Curative CTL responses were also generated by 2aG4 in mice with irradiated syngeneic 4T1 breast tumors [25]. When dendritic cells were co-cultured with 2aG4-coated irradiated F98 glioma cells, they were able to present the F98 cell antigens to T-cells to generate cytotoxic T-cells that were specifically cytotoxic to F98 cells in vitro (Fig. 4). The induction of T-cell immunity in vitro was PS-dependent and required the Fc piece of 2aG4 for maximal effect. Thus, we have compelling evidence that PS on irradiated tumor cells imposes host cell tolerance towards tumor cells and that the antibodies block the immunosuppressive effects of PS, leading to the induction of T-cell immunity to tumor cells. For this reason, the antibodies are actually better anti-tumor agents in immunocompetent animals than they are in immunodeficient animals whose adaptive immune mechanisms are compromised.”
http://tinyurl.com/9reso7s
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4-19-10: DR. PHILIP THORPE, AACR/2010, #1919
“Phosphatidylserine on Dying Tumor Cells Suppresses Dendritic Cell Activation & Inhibits Tumor Immunity: Reversal With PS-Targeting Antibody”
“We recently showed that PS on the surface of apoptotic cancer cells can suppress recognition of tumor antigens by the immune system. It appears from work in several laboratories that dendritic cells (DC) that ingest PS-expressing tumor cells fail to mature in response to external maturation signals. In the present study, we investigated whether masking PS on apoptotic tumor cells with anti-PS antibody (2aG4) [NOTE: “2aG4” is a mouse IgG2a version of murine mab 3G4; bavituximab is chimeric 3G4] can reverse the inhibitory effect of PS on DC. Mouse bone marrow derived DC were co-cultured with irradiated (PS-expressing) 4T1 breast tumor cells in the presence or absence of 2aG4. We found that:
(i) Masking tumor cell PS with 2aG4 increases their phagocytosis by DCs;
(ii) Masking tumor cell PS with 2aG4 allows DCs to mature and express immunostimulatory molecules (CD40, CD80, CD86 and MHC II);
(iii) Masking PS with 2aG4 decreases the production of anti-inflammatory cytokines (TGFB and IL-10) and increases the production of inflammatory cytokines (TNFa, CCL5, IL-1B and IL-6), indicating that PS-blockade polarizes DC towards the immunostimulatory type I phenotype;
(iv) Immunizing mice with 2aG4-treated irradiated 4T1 cells enhances the immunogenicity of the tumor cells, rendering them resistant to rechallenge with syngeneic viable 4T1 tumor cells.
These results have important implications for our understanding of the immunosuppressive effects of PS in cancer and could lead to the development of a novel whole cell cancer vaccine strategy in which PS-blocking is used to enhance immunogenicity.”
http://tinyurl.com/y266azk
FULL PDF: http://www.peregrineinc.com/images/stories/pdfs/2010_AACR_Poster_PS_Reversal.pdf
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1-24-2011: PPHM HAS EXEC. INFO. REPORT (EIO) PREPARED BY CRYSTAL RESEARCH (JEFFERY KRAWS)
Phosphatidylserine (PS)-Targeting Therapy
“In the human body, there are certain phospholipids that are typically located on the interior of the cell membrane; thus, they are not exposed on the cell surface. However, these aminophospholipids can move to the surface of cells that line tumor blood vessels or that are infected with an enveloped virus. Bavituximab targets a specific aminophospholipid, called phosphatidylserine (PS), which is exposed on cells lining tumor blood vessels, virally infected cells, and on the surface of enveloped viruses. It is important to note that bavituximab does not target healthy cells, as these cells do not expose PS, nor does bavituximab signal the immune system against healthy cells. Peregrine believes that this feature of targeting tumor blood vessels or virus-infected cells may enable bavituximab to be a safer treatment with fewer side effects than many current options. Furthermore, exposed PS on tumor blood vessels may represent a new target for diagnostic products. To Peregrine’s knowledge, it is the only company studying PS-targeting MAbs in clinical trials as therapy for solid tumors or enveloped virus infections. As bavituximab is believed to employ a novel mechanism of action that is not yet represented among other anticancer or antiviral antibody approaches, it may have the potential to be combined with existing standard-of-care treatments, thereby improving efficacy without creating overlapping toxicities. Peregrine is developing two clinical programs - oncology and antiviral - based on its PS-targeting platform technology. Its lead antibody, bavituximab, helps stimulate and direct the body’s immune defenses to attack PS-expressing cells on tumor vasculature, enveloped viruses, and cells infected with an enveloped virus.”
http://tinyurl.com/2dja6uo
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4-1-2011: LIFETECH-CAPITAL UPDATE (STEVE DUNN)
Bavituximab for Cancer (chimeric anti-phosphatidylserine monoclonal antibody)
“Bavituximab is a chimeric (mouse/human) monoclonal antibody that preferentially binds to a specific phospholipid called phosphatidylserine [PS]. PS is a phospholipid normally found on the inner (or cytosolic) side of the cell membrane. When a cell undergoes programmed cell death (apoptosis) or encounters certain stresses the PS will translocate, via enzymes called flippases, to the outside (or extracellular) side of the lipid bilayer. There is much evidence to suggest that this translocation is a natural process that suppresses the immune system in situations where an aggressive immune response is not necessary or required. Research has demonstrated that exposed or extracellular PS can act as a fundamental initiator of an anti-inflammatory as well as anti-immunogenic immune responses, as reported in The Journal of Biological Chemistry [10-2006 http://www.jbc.org/content/281/50/38376.full ] and The Journal of Apoptosis [2-2007: http://www.springerlink.com/content/r7nht3231334v117 ]. It is believed that exposed PS is perceived by the immune system as a sign of a dying cell of the same overall organism, i.e. as friend not foe. The immune response that clears native cellular debris is mild, rather than the aggressive immune attack that would be invoked against a foreign intruder. Tumors have been shown to exploit the immunomodulatory effects of exposed PS for their own survival and proliferation within the body. Physical and physiological stresses in the tumor environment, micro and macro, cause PS exposure in the endothelial cells lining the tumor vasculature. The exposed PS shields the tumor from immune response and creates an environment favorable to further tumor growth. In addition to the exposed PS found on the tumor vasculature, PS-exposing microvesicles shed from tumor cells exhibit multiple immunosuppressive mechanisms further shielding the tumor from detection. There is also evidence that the process of new blood vessel formation, or angiogenesis, is partially dependant on PS exposure of apoptotic cells. The exposure of PS in solid tumor vasculature creates a potential anti-cancer target that Peregrine’s Bavituximab exploits. The monoclonal antibody, Bavituximab, selectively binds to exposed PS in existing tumor vasculature and in essence, alerts the immune system to the presence of “foe not friend” evoking a much more aggressive immune response. The immune response is specific to cells exhibiting PS exposure, which potentially destroys the tumors blood supply while minimizing unwanted or off-target side effects in healthy tissue. Destruction of the tumor vasculature inhibits growth and development of multiple solid tumor types as demonstrated by PS is a phospholipid found on the cytosolic side of the cell membrane in healthy cells. In certain environments, such as in solid tumor vasculature… PS will translocate to the outside of the lipid bilayer. Bavituximab specifically binds to these exposed phospholipids. The bound monoclonal antibodies alert the immune system to the cancerous cells found in the tumor vasculature. The immune system then destroys the vasculature cutting off the flow of oxygen and nutrients to the tumor cells, resulting in tumor cell death and tumor shrinkage.”
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2-8-2010: MLV ANALYST GEORGE ZAVOICO
BAVITUXIMAB
“Bavituximab is Peregrine’s leading drug candidate and principal value driver. It is a human-mouse chimeric monoclonal antibody that targets a cell membrane phospholipid called phosphatidylserine (PS). Cellular membranes are composed of four major types of phospholipids: phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), and PS. Other important membrane components are cholesterol and sphingomyelin, but they will not be considered further in this discussion. Structurally, cell membranes are bilayers, composed of a hydrophobic, or water excluding, center and hydrophilic, or water attracting, surfaces. Phospholipids are polar molecules with a long fatty, hydrophobic tails, and a more compact, hydrophilic head group (Exhibit 2). In the bilayer, the fatty hydrophobic tails point inward, exposing the hydrophilic head groups to the aqueous environment of the cytoplasm inside the cell and the extracellular fluids outside the cell. What is remarkable about the structure of cell membranes is the asymmetric distribution of its component phospholipids in the outer and inner leaflets of the bilayer. Cells expend a tremendous amount of energy maintaining the asymmetry. PE and PS are enriched in the inner, or cytoplasmic, side of the bilayer, while PC is enriched in the outer side of the bilayer. Remarkably, in normal cells PS is practically absent from the outer side of the bilayer. However, in tumor cells, in vascular endothelial cells infiltrating and providing blood flow to solid tumors, cells infected by viruses, and certain membrane enveloped viruses, the asymmetry is lost, with PS becoming exposed on the outer surface of the cell membrane. Since this property appears to be unique to these cells, drugs that target exposed PS could be selective anti-cancer or anti-viral agents.
Bavituximab is a human-mouse chimeric monoclonal antibody that binds to PS indirectly through a plasma protein called B-2-glycoprotein 1 (B2GP1), as shown in Exhibit 2. B2GP1 consists of 5 domains, the last of which, domain V, binds very weakly to PS. Bavituximab, and an equivalent mouse antibody called 3G4, bind to domain II of B2GP1, and cross-link two molecules of the protein. Interestingly, this increases the binding affinity of B2GP1 for PS by about 1000-fold. Once bound to the cell surface bavituximab induces an inflammatory and immune response that leads to the death of the cell it is bound to. Bavituximab is believed to cause the collapse and loss of integrity of the tumor vasculature, depriving the tumor of blood flow and the delivery of oxygen and nutrients and removal of cellular waste, leading to the death of the tumor cells. Bavituximab binding to virally infected cells also leads to their death, preferably before the viruses can replicate in the infected cell and be released to infect other cells. Since PS is thought to be a specific marker for tumor vasculature and virally-infected cells, Peregrine is developing bavituximab as an anti-cancer and anti-viral agent.”
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BAVI’S ANTI-TUMOR MOA DESCRIBED ON PEREGRINE’S WEBSITE (9-2012):
“Bavituximab is a first-in-class phosphatidylserine (PS)-targeting monoclonal antibody that represents a new approach to treating cancer. PS is a highly immunosuppressive molecule usually located inside the membrane of healthy cells, but "flips" and becomes exposed on the outside of cells that line tumor blood vessels, creating a specific target for anti-cancer treatments. PS-targeting antibodies target and bind to PS and block this immunosuppressive signal, thereby enabling the immune system to recognize and fight the tumor. Research has shown that chemotherapy and radiation increase the exposure of PS on the surface of the tumor blood vessels, increasing the availability of bavituximab's target molecule, and potentially enhancing bavituximab's anti-tumor activity.”
• PS (in green) is a molecule normally located inside all cells where it's kept inactive
• The cancer microenvironment causes PS to flip to the outside of cells lining tumor blood vessels.
• Chemotherapy further increases exposed PS in the tumor environment
• Exposed PS is a highly immunosuppressive molecule that mimics "apoptosis", muting immune responses
• Bavituximab (yellow) overrides PS-mediated immunosuppressive signals...
• Allowing immune reactivation to attack the tumor
• Activated immune system causes tumor blood flow shut down and adaptive immune response to the tumor
http://www.peregrineinc.com/technology/bavituximab-oncology/mechanism-of-action.html
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The 30 Slides Dr. Philip Thorpe presented 5-1-2012 at the NYAS PS-Targeting Symposium:
…Note that Dr. Thorpe’s describes Bavi’s MOA in several parts:
• Mechanism #1: Tumor Vessel Damage by ADCC
• Mechanism #2: Blockade of PS-Mediated Immunosuppression in Tumors
• Macrophage Polarization M2 to M1 Switch
• Generation of Tumor-Specific Cytotoxic T Cells
• Proposed Mechanism: PS Blocks MDSC, Macrophage, and DC (Dendritic Cells) Differentiation
• Proposed Mechanism: Bavi Reactivates Innate & Adaptive Immunity
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A few of the more illustrative slides from Dr. Phillip Thorpe’s 53-pg. Keynote Presentation
on 5-26-11 at the ‘Recombinant Antibodies’ Conf. in Barcelona… [ http://tinyurl.com/3klpodc & http://tinyurl.com/3m33h33 ]
“Keynote Presentation at Leading European Antibody Conference Highlights Immune Reactivation Mechanisms of Bavituximab”
Slide 5: Note: “1N11” (Fully Human Bavituximab), aka: AT004, PGN635…
Slide 41:
COMMENTARY ON SLIDE 41 BY IHUB’S “FIRE FOX”, 5-27-11 #64371
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=63661054
“RRDog-- Your Ode to Dr. Thorpe is well sung. I agree completely. The market doesn't appreciate the MOA "tour de force" Thorpe has pulled off here. However, for the FDA, the analysts and the medical community considering Bavi trials, Thorpe's presentation in Barcelona will be hugely compelling for years to come. I bet many aspiring PhD candidates are already making plans to replicate new versions of this break-through Phil Thorpe accomplishment. An immunology maven I spoke with emphasized the importance of Slide #41, which tells the whole story in one picture. Everyone who owns stock in PPHM should print Slide 41 and keep it by their bedside. If Bavi indeed triggers either of these MOA mechanisms, it's the launch of huge new therapeutic platform - certainly in cancer and perhaps in viral therapy as well. But if both of these mechanisms of action are operating, the effects of Bavi as an immunotherapy will be nothing short of sensational. The fact that Thorpe has nailed down these TWO separate ways that Bavi "breaks the grip of tumor on the immune system", indicates huge promise for Bavi !!!”
Slide 52:
DR. THORPE’S COMMENTS ON BAVI’S MOA FROM THE 5-26-11 PR:
"Our research shows that exposed PS in the tumor environment plays a fundamental immunosuppressive role that prevents the immune system from recognizing cancer cells as 'foreign,' resulting in cancer patients not being able to reject their tumors," said Philip E. Thorpe, Ph.D., professor of pharmacology in the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center, scientific adviser to Peregrine and inventor of the company's PS-targeting antibody technology. "We show that highly immunosuppressive cells called myeloid-derived suppressor cells, or MDSCs, accumulate in tumors and fail to mature into functional immune cells. What is especially exciting is that administration of PS-targeting antibodies like bavituximab breaks the grip of the tumor on the immune system. In treated animals, we see the disappearance of MDSCs and the appearance of functional immune cells, especially macrophages. The entire tumor environment shifts from being immunosuppressive to being immune responsive. These results have important implications for cancer therapy."
PR 10-31-12: ”New Data Support Ability of PS-Targeting Antibodies to Specifically Target Tumors and Stimulate Cancer-Fighting Immune Responses”
• Presentation at the 27th Annual Meeting of the Society for Immunotherapy of Cancer Highlights Ability of PS-Targeting Antibodies to Induce Innate and Adaptive Immune Responses
• Published Article in Nuclear Medicine & Biology Supports Potential of Peregrine's PS-Targeting Antibody PGN635 to Detect Tumor Response to Therapy
http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=717438
TUSTIN, 10/31/12: Peregrine Pharmaceuticals (NASDAQ: PPHM), a biopharmaceutical company developing first-in-class monoclonal antibodies focused on the treatment and diagnosis of cancer, today announced the presentation of preclinical data showing specific localization and enhancement of anti-tumor functions of immune cells inside tumors following administration of phosphatidylserine (PS)-targeting antibodies. These data show that by specifically targeting PS exposed on tumor blood vessels, Peregrine's antibodies mediate beneficial changes in the local tumor environment including the increase of signaling chemicals associated with anti-tumor immune responses, a reduction of signaling chemicals associated with immune suppression, as well as increasing the prevalence of tumor-destroying immune cells. The antibody-induced effects are localized to the tumor environment, and therefore do not appear to cause systemic side effects. Peregrine's lead PS-targeting antibody, bavituximab, is currently being evaluated in 8 clinical trials in multiple oncology indications.
"We believe these results build on previous findings showing the potential of PS-targeted agents for diagnosis, therapy and to monitor the effectiveness of anti-tumor agents," said Jeff T. Hutchins, Ph.D., Peregrine's VP of Preclinical Research. "While several new promising cancer immunotherapies are successful in amplifying the anti-tumor behavior of specific cell types, they carry the risk of side-effects associated with systemic immune activation. To date, data from our collective preclinical studies and clinical trials shows that exposed PS produces a dominant immunosuppressive signal favoring tumor survival and growth. By specifically targeting and blocking PS with our antibodies, we see potent anti-tumor effects through a shift of multiple immune cells and their associated signaling chemokines. These new data further support our continued enthusiasm for the broad-spectrum cancer-fighting potential of bavituximab as we look forward to data from several clinical trials in the coming months."
The immune modulation of anti-tumor responses data were presented at the 27th Annual Meeting of the Society for Immunotherapy of Cancer (1) held in Bethesda, Maryland from October 24-28, 2012. Separately, data were published in the peer-reviewed journal Nuclear Medicine and Biology highlighting results from a study investigating the company's fully human phosphatidylserine (PS)-targeting antibody PGN635 [Note: PGN635 is Fully-Human Bavituximab=1N11=AT004 (B2GPI-depen.) – see http://tinyurl.com/cparur & http://tinyurl.com/6ql5nf ] utilized as a radiolabeled tumor imaging probe (2). Data from the study showed that in animals pre-treated with the chemotherapeutic agent paclitaxel, a high accumulation of the radiolabeled antibody (89Zr-PGN635) [ Note: Genentech working with 89Zr-PGN635/Imaging – see http://tinyurl.com/8wvem9y ] was observed in the treated tumors, reaching tumor to blood ratios of up to 13-fold. These results demonstrate the potential breadth of applicability of the company's PS-targeting antibodies to clearly image solid tumors regardless of cancer type, and provide a potential method to rapidly assess the anti-tumor efficacy of chemotherapies and other approved and experimental cancer treatments.
1. Targeting of Phosphatidylserine by Monoclonal Antibodies Induces Innate and Specific Anti-tumor Responses
Bruce Freimark 1, Jian Gong 1, Richard Archer 1, Van Nguyen 1, Christopher Hughes 2, Xianming Huang3 , Yi Yin 3, Philip Thorpe 3
1. Peregrine Pharmaceuticals, Inc., Tustin, CA; 2. Molecular Biology & Biochemistry, University of California, Irvine, CA; 3. Pharmacology, University of Texas SW Medical Center, Dallas, TX
[ http://www.sitcancer.org/2012/annualmeeting ]
[ Poster now on website: http://www.peregrineinc.com/images/stories/pdfs/sitc_2012.pdf ]
2. ImmunoPET Imaging of Phosphatidylserine in Pro-Apoptotic Therapy Treated Tumor Models
Annie Ogasawara, Jeff N. Tinianow, Alexander N. Vanderbilt, Herman S. Gill, Sharon Yee, Judith E. Flores, Simon-Peter Williams, Avi Ashkenazi, Jan Marik, Nuclear Medicine & Biology, doi: 10.1016/j.nucmedbio.2012.09.001.
[ pub. Online 10-10-12 http://www.sciencedirect.com/science/journal/aip/09698051 ]
ABOUT BAVITUXIMAB
Bavituximab is a first-in-class phosphatidylserine (PS)-targeting monoclonal antibody that represents a new approach to treating cancer. Bavituximab is the lead drug candidate from the company's PS technology platform and is currently being tested in eight clinical trials including three randomized Phase II trials in front-line and second-line non-small cell lung cancer, front-line pancreatic cancer and five investigator-sponsored trials (ISTs) in additional oncology indications. PS is a highly immunosuppressive molecule usually located inside the membrane of healthy cells, but "flips" and becomes exposed on the outside of cells that line tumor blood vessels, creating a specific target for anti-cancer treatments. PS-targeting antibodies target and bind to PS and block this immunosuppressive signal, thereby enabling the immune system to recognize and fight the tumor.
ABOUT PEREGRINE PHARMACEUTICALS, INC.
Peregrine Pharmaceuticals, Inc. is a biopharmaceutical company with a portfolio of innovative monoclonal antibodies in clinical trials focused on the treatment and diagnosis of cancer. The company is pursuing multiple clinical programs in cancer with its lead product candidate bavituximab and novel brain cancer agent Cotara®. Peregrine also has in-house cGMP manufacturing capabilities through its wholly-owned subsidiary Avid Bioservices, Inc. ( http://www.avidbio.com ), which provides development and biomanufacturing services for both Peregrine and outside customers. Additional information about Peregrine can be found at http://www.peregrineinc.com .
Safe Harbor*snip*
Contact: Christopher Keenan or Jay Carlson
Peregrine Pharmaceuticals, Inc. (800) 987-8256 info@peregrineinc.com
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Oct24-28 2012 “27th Annual Meeting of the Society for Immunotherapy of Cancer”, Bethesda
“The SITC Annual Meeting (Oct24-28 2012) & Associated Programs serve as the premier destination for scientific exchange, education and networking in the cancer immunotherapy community. Basic researchers, clinicians, students, postdoctoral fellows, and allied health professionals dedicated to improving cancer patient outcomes come together at the SITC Annual Meeting & Associated Programs to experience cutting edge research, education and training that serves as the catalyst to advance the field.”
http://www.sitcancer.org/2012/annualmeeting
10-25-12: “SITC’s Primer on Tumor Immunology & Cancer Immunotherapy”
http://www.sitcancer.org/2012/primer/schedule
Pgm: http://www.sitcancer.org/UserFiles/am12-final-program_v8_loFINAL_v1.pdf
Track: Therapeutic Monoclonal Antibodies In Cancer
#176 “Targeting of Phosphatidylserine by Monoclonal Antibodies Induces Innate and Specific Anti-Tumor Responses”
Bruce Freimark 1, Jian Gong 1, Rich Archer 1, Van Nguyen 1, Christopher Hughes 3, Xianming Huang 2, Yi Yin 2, Philip Thorpe 2
1 Preclinical Development, Peregrine Pharmaceuticals, Tustin, CA
2 Pharmacology, University of Texas, SW Medical Center, Dallas, TX
3 Molecular Biology & Biochemistry, Univ. of California, Irvine, CA
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From the SITC poster (per FTM’s iHub #100922 http://tinyurl.com/cltbrsd ):
=> http://www.peregrineinc.com/images/stories/pdfs/sitc_2012.pdf
ABSTRACT: Phosphatidylserine (PS) is a phospholipid normally residing in the inner leaflet of the plasma membrane. PS becomes exposed on tumor vascular endothelial cells and tumor cells in response to chemotherapy, irradiation and oxidative stresses in the tumor microenvironment. Binding of antibodies to PS on tumor endothelial cells and tumor cells recruits immune cells and engages the immune system to destroy tumor vasculature. The antibodies also enhance anti-tumor immunity by blocking the immunosuppressive action of PS. A chimeric PS-targeting antibody, bavituximab, is being used in combination with chemotherapy to treat patients with solid tumors in Phase II trials. Using syngeneic tumors and human tumor xenografts in mice, we have demonstrated PS targeting antibodies can specifically localize to tumors and antibody uptake by tumors is enhanced by chemotherapy and irradiation. In addition, PS targeting antibodies are capable of suppressing tumor growth in multiple tumor types by several mechanisms including destruction of tumor blood vessels by ADCC mechanisms, blockage of PS-mediated immunosuppression, and reactivation of macrophage and T-cell cellular anti-tumor responses. The combination of these mechanisms promotes strong localized anti-tumor responses without the side-effects of systemic immune activation.
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IMAGING APPLICATIONS Of PS-TARGETING MABS:
10-12-12: Genentech studying Imaging using PGN635(Fhu-Bavi) for the potential "detection of tumor response to therapy". http://tinyurl.com/8wvem9y
…Nuclear Medicine & Biology, Genentech's Jan Marik, "ImmunoPET Imaging of PS in Pro-Apoptotic Therapy Treated Tumor Models"
4-3-12: Peregrine Launches PS-Targeting Clinical Imaging Program (AACR'12 #2452) http://tinyurl.com/7p7jovt & http://tinyurl.com/7yrwqm7
…PPHM "recently filed an IND" with FDA for an Imaging trial using 124I-PGN650, ~12pts.
...6-28-12: Trial added to trials.gov: http://clinicaltrials.gov/ct2/show/NCT01632696 - see CANCER TRIALS ABOVE for more details.
12-2011: Thorpe Article on FH-Bavi/Optical-Imaging in Translational Oncology http://tinyurl.com/7vcnbz2
11-14-11: Dr. Bruce Freimark presents PS IMAGING poster at AACR-NCI-EORTC Conf./SanFran http://tinyurl.com/89hpydn
9-12-11: Drs. Thorpe & Freimark present PS IMAGING posters at World Imaging Congress/S.Diego http://tinyurl.com/3uv5rgr
9-9-11: PS IMAGING potential discussed in Qtly. Conf. Call: http://tinyurl.com/3q7hzjh
…more on PS Imaging in iBox here: http://investorshub.advfn.com/boards/show_ibox.aspx?boardid=2076
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MUST LISTEN: Dr. Philip Thorpe’s 46min. 5-1-12 NYAS Anti-PS Symposium talk Replay & Slides
Dr. Thorpe was the last of 5 speakers (Alan Schroit, Chris Reutlingsperger, David Ucker, Ari Helenius, Philip Thorpe) at the NYAS “Phosphatidylserine (PS) Asymmetry - Therapeutic Applications in Cancer & Infectious Disease Symposium". If you have the time to listen to all 5 of these talks, you will learn an immense amount about the moa of Peregrine’s PS-targeting antibody therapeutic, Bavituximab.
For anybody looking for the replay links, they’re here: http://investorshub.advfn.com/boards/read_msg.aspx?message_id=79851320
Dr. Thorpe’s talk is A MUST, but the other 4 are excellent as well.
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BAVI MOA: 5-1-12 Dr. Phil Thorpe's 46min talk at NYAS PS-Targeting Symposium http://tinyurl.com/9792gl5
. . .Symposium title: "Phosphatidylserine (PS) Asymmetry - Therapeutic Apps. in Cancer & Infectious Disease Symposium"
. . .Replays of 5 speakers: Alan Schroit, Chris Reutlingsperger, David Ucker, Ari Helenius, Philip Thorpe
BAVI MOA: 5-26-11 Dr.Thorpe's keynoter at Recombinant-Mabs/Barcelona http://tinyurl.com/3klpodc & http://tinyurl.com/3m33h33
BAVI MOA: 4-2010 Thrombosis Research article (Dr.Thorpe) http://tinyurl.com/9reso7s
BAVI MOA: See http://www.peregrineinc.com/technology/bavituximab-oncology/recent-data.html
Dr. Philip E. Thorpe – UTSW-MC/Dallas [PPHM SAB, inventor of Bavituximab]
• Bavituximab is the chimeric version of murine mab 3G4
• 2aG4 is a mouse IgG2a version of murine mab 3G4
• PGN635 is fully-human bavituximab (aka 1N11, AT004)
10-20-12 FTM on Bavi MOA (#100242):
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=80729530
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=80730708
10-20-12 FTM on PGN635 vs. PGN650: http://investorshub.advfn.com/boards/read_msg.aspx?message_id=80733008
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The foundation of the PS-Targeting approach is built on the fact that PS is immunosuppressive…
Suggest this prep. reading:
2-2005: “Interaction between Phosphatidylserine and the Phosphatidylserine Receptor Inhibits Immune Responses In Vivo”
Peter Henson, et al, Journal of Immunology, Feb.2005, p.1393–1404 – FULL PDF: http://www.jimmunol.org/cgi/content/full/174/3/1393
. . .The Cliff Notes 7-word synopsis => “Evolution has favored pathogenesis that resembles apoptosis.”
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12-5-12: IBC’S “IMMUNOMODULATORY ANTIBODIES” CONF. SESSION OVERVIEW
“Dr. Thorpe will give an update on the mechanism of anti-tumor action of Bavituximab, an immunostimulatory chimeric monoclonal antibody that is showing promising activity in clinical trials in patients with various types of cancer. Bavituximab targets the immunosuppressive lipid phosphatidylserine (PS) that becomes exposed on tumor blood vessels and tumor cells. Tumors externalize PS and secrete PS-expressing exosomes that impose quiescence on immune cells, thereby creating a tumor microenvironment that supports tumor growth. Bavituximab causes myeloid-derived suppressor cells in tumors to differentiate into tumoricidal M1 macrophages that destroy tumor vasculature and tumor cells by antibody-dependent cell-mediated cytotoxicity. It also causes immature dendritic cells in tumors to mature and present tumor antigens that result in the generation of tumor-specific cytotoxic T cells. Thus, bavituximab reactivates innate & adaptive tumor immunity, and induces an immune cell-mediated shutdown of tumor vasculature.”
http://tinyurl.com/8phzs5w
12-5-12: DR. PHILIP THORPE, IBC’S “IMMUNOMODULATORY ANTIBODIES” CONF. – “OVERCOMING IMMUNE SUPPRESSION IN TUMORS WITH BAVITUXIMAB”
“Bavituximab is a monoclonal antibody that is proving safe & effective as a 2nd-Line therapy in advanced lung cancer patients. It targets the immunosuppressive lipid, phosphatidylserine [PS], which becomes exposed on tumor blood vessels & tumor cells. Bavituximab causes MDSCs to differentiate into tumoricidal M1 macrophages that destroy the tumor vasculature and tumor cells by ADCC. It also causes immature dendritic cells in tumors to mature and present tumor antigens, resulting in the generation of tumor-specific cytotoxic T-cells.”
http://tinyurl.com/8phzs5w
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8-15-12, PEREGRINE’S CEO STEVE KING, WEDBUSH/NYC
“Bavituximab has a very novel MOA - it turns out that PS is not simply a marker of disease, but is actually involved in controlling the immune response to disease. By blocking that immunosuppressive signal, we actually allow the immune system to turn on and fight the disease. The concept is, Phosphatidylserine (PS) itself is a normal component of cellular membranes, present in every cell of the body, only very-tightly regulated to internal side of the cell. So, essentially, if you inject PS-finding agents, such as is done in our Imaging pgm, the agents simply float around and eventually clear the body if there’s no sign of disease. What our scientists discovered, is that as cancer develops, you get a very unique environment, you have poor blood flow, reactive oxygen species, hypoxia – as a result of all these insults, the mechanisms that keep PS inside of cells become disrupted, and the PS becomes exposed on the outside of the cell. It turns out that this exposed PS in the tumor microenvironment is very important in controlling the immune response. The only normal time which you have PS exposure is when cells undergo normal programmed cell death, or apoptosis. So, as cells die, you see the same phenomenon of PS becoming expressed or exposed on the outside of the cell. What happens then is, as the immune system is undergoing its daily routine of removing dead & dying cells, those macrophages & dendritic cells, whose responsibility it is to remove the cells, interact with the dead & dying cells, and actually have a PS-receptor on their surface. As the exposed PS binds to the receptor on the immune cells, it actually sends specific signals to down-regulate the immune response, because when you’re removing dead & dying cells you don’t need a robust immune response, obviously. It turns out that cancer, as well as a number of other diseases, have taken advantage of this fact, and by simply causing PS-exposure during the tumor microenvironment, you now do not get an adequate immune-response to the disease, allowing the tumors to outgrow the poor immune-response that’s being given. Bavituximab is injected, it goes to the site of the disease, so it accumulates on the PS inside the tumor environment, blocks the PS that’s exposed in that environment, and now those immune cells - you can actually detect a significant change in there phenotypes, as they go from a non-inflammatory to a pro-inflammatory state and really begin the fight the disease. And over time, you see development of a full adaptive immune response. As at fully adaptive immune response happens, you then have this full immune response, which includes ADCC, mediated by the antibody itself, normal cell-killing, mediated by the antibody, as well as activation and down-stream effects of the immune response.”
http://tinyurl.com/8mhrtld
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5-1-12, DR. PHILIP THORPE, NYAS PS-TARGETING SYMPOSIUM
• Bavituximab, an antibody drug in development by Peregrine Pharmaceuticals, targets PS in tumor blood vessels and can reactivate immunity to cancer cells.
• This antibody can serve as both an imaging agent and as an adjuvant treatment with other therapies.
• Bavituximab can induce tumor-specific T-cell immunity in some situations.
TARGETING TUMOR VASCULATURE: Taking advantage of the externalization of PS on tumor cells could provide new treatment strategies for cancer treatments. Philip Thorpe of UT Southwestern Medical Center described preclinical and clinical studies of bavituximab, an antibody drug developed by Peregrine Pharmaceuticals that targets PS in the vasculature of tumors. As tumors develop, they create a stressful, hypoxic cellular environment that results in the formation of reactive oxygen species and the release of inflammatory cytokines. In this environment, the asymmetry of lipid distribution in the membrane of the endothelial cells that line tumor blood vessels breaks down, leading to the externalization of PS. In addition, PS is often exposed on the surface of tumor cells. As a strategy for targeting PS externalization, Peregrine Pharmaceuticals initially developed a mouse monoclonal antibody that targets PS by binding to two molecules of B2-glycoprotein-I that in turn bind to PS on the surface of cells. With only a single molecule of the protein, binding to the surface of cells is relatively weak, but the affinity increases by a factor of 30,000 with the addition of a 2nd molecule of B2-glycoprotein-I. The researchers have constructed a series of antibodies that targets the tumor vasculature. Two are mouse antibodies, 3G4 & 2aG4. Bavituximab is a chimeric antibody with mouse PS binding regions fused to human IgG. The fully human antibody is known as PGN635. These antibodies localize specifically to the blood vessels in tumors, which makes them useful as imaging agents. Studies with normal tissues and various tumor types reveal that these antibodies show affinity for a range of tumor types but minimal binding to a variety of normal tissues.
BAVITUXIMAB AS AN ANTI-TUMOR AGENT: In rodent studies, antibodies alone inhibit tumor growth by 30%–90%. That variation most likely reflects the differences in PS expression on blood vessels in different tumors. However, combining the antibody treatment with other treatments, including chemotherapy, radiation, or androgen deprivation, improved these results. In studies of prostate tumors in mice, the combination of the mouse antibody 2aG4 and docetaxel slowed tumor growth by 98% compared with 90% for docetaxel alone and 80% for antibody alone. The PS-targeting antibody in combination with intense radiation can shrink lung cancer tumors that are resistant to radiation alone.
How does the antibody work?
1. As one proposed mechanism of action, these PS-targeting antibodies damage tumor vessels by a process known as antibody-dependent cellular cytotoxicity (ADCC). As poor blood flow and hypoxia lead cells in the tumor vasculature to expose PS on their surfaces, bavituximab targets those cells and shuts down blood flow, which starves those tumor cells of nutrients.
2. As a 2nd mechanism, bavituximab can overcome the immunosuppressive processes observed with cells that externalize PS. In tumors the expression of PS on cell surfaces keeps macrophages in their M2 state, an activation state that suppresses inflammation and supports angiogenesis. It also prevents myeloid-derived suppressor cells (MDSCs) from differentiating into macrophages and dendritic cells (DCs). In addition, PS inhibits the maturation of DCs, which prevents the presentation of antigens to T cells. Bavituximab repolarizes macrophages to their M1 state, which allows them to kill cells that express PS, including the tumor vascular endothelium. It also leads to differentiation of the MDSCs and prompts DCs to mature and to present tumor antigens to T cells.
TUMOR-SPECIFIC IMMUNITY: Bavituximab can also prompt the development of tumor-specific immunity. In experiments with rats with treatment-resistant glioma tumors, 15% of the animals treated both with radiation and with antibody therapies did not die from those tumors. When the researchers reintroduced glioma tumor cells into these surviving rats, the rats were immune to the cancer. The team determined that spleen cells from these animals could kill gliomas, which indicated the antibody treatment had induced T cell immunity.
• Dr. Thorpe’s 5-1-12 46min. talk replay: http://www.nyas.org/MediaPlayer.aspx?mid=25e51622-c908-46ef-bba1-95ca6a814eed
• Replays of all 5 speakers: Alan Schroit, Chris Reutlingsperger, David Ucker, Ari Helenius, Philip Thorpe => http://tinyurl.com/9o4ddse
The 30 slides (PDF) from Dr. Thorpe’s 5-1-12 NYAS presentation are here: http://www.peregrineinc.com/images/stories/pdfs/nyasweb.pdf
Bavi MOA diagram (5-1-12 Thorpe/NYAS):
DIRECT LINKS to Host’s Intro and All 5 Scientists Talks at NYAS 5-1-12:
Intro: George Zavoico (MLV & Co.) => http://www.nyas.org/MediaPlayer.aspx?mid=8163b627-7c47-45c6-9f15-2b9e1609d476
I. Alan Schroit (UTSW): “Regulation of PS Asymmetry & Physiologic Consequences of Its Loss”
=> (40min.) http://www.nyas.org/MediaPlayer.aspx?mid=dc3ec7ed-1e0a-47fd-a5ca-96dd9e6c73bb
II. David Ucker (Univ. of Illinois/Chicago): “Innate Apoptotic Immunity and Glycolytic Enzyme Externalization”
=> (39 min) http://www.nyas.org/MediaPlayer.aspx?mid=ae50efa0-1bb1-42a2-9574-5eac7053e7b8
III. Ari Helenius (ETH/Zurich): “Phopshatidylserine Asymmetry & Cell Survival”
=> (38min.) http://www.nyas.org/MediaPlayer.aspx?mid=ff0a5576-dba1-4e33-8e73-c4280291495b
IV. Chris Reutelingsperger (Univ. of Maastricht/Netherlands): “PS Targeting with Annexin A5 to Diagnose & Treat Human Disease”
=> (35min.) http://www.nyas.org/MediaPlayer.aspx?mid=325f01c4-5209-4ceb-9870-a0860eaf330f
V. Philip Thorpe (UTSW): “Targeting Tumor Vasculature & Reactivating Tumor Immunity with Bavituximab”
=> (46min.) http://www.nyas.org/MediaPlayer.aspx?mid=8163b627-7c47-45c6-9f15-2b9e1609d476
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4-3-12: DR. PHILIP THORPE, AACR/2010, #5495
“Cure of Castration-Resistant Prostate Cancer in TRAMP Mice By Reactivating Tumor Immunity with a Phosphatidylserine-Targeting Antibody [PGN635]”
“Androgen deprivation therapy (ADT) is initially effective against prostate cancer, but many patients eventually relapse and die from the outgrowth of castration-resistant disease. Here, we tested the hypothesis that tumor immunity against castration-resistant prostate cancer can be elicited by combining ADT with treatment with a monoclonal antibody that binds exposed phosphatidylserine (PS). The rationale was that PS is an immunosuppressive lipid that becomes exposed on tumor blood vessels and malignant cells in prostate tumors responding to ADT, and inhibits immune responses to prostate tumor antigens. To validate this hypothesis, we castrated TRAMP mice after they had developed prostatic adenocarcinomas and treated them with the PS-targeting antibody, mch1N11 [PGN635 is Fully-Human Bavituximab=1N11=AT004 (B2GPI-depen.) – see http://tinyurl.com/cparur & http://tinyurl.com/6ql5nf ] . We first demonstrated that PS exposure was induced on tumor vascular endothelium and tumor cells by castration. PS exposure on vessels coincided with regions of hypoxia generated in the tumor microenvironment. Next, we demonstrated that castration combined with treatment with mch1N11 inhibited tumor growth and progression. About half of the treated TRAMP mice did not develop castration-resistant tumors, and eventually died of old age. Immunohistochemical studies revealed that the mch1N11 treatment combined with castration generated T-cell immune responses against TRAMP tumor antigens that kept the tumor in check. Extensive disruption of tumor vasculature and abundant infiltration of immune cells, including CD8 positive T lymphocytes, Natural killer (NK) cells and dendritic cells were observed. Splenocytes from mice treated with mch1N11 plus castration were able to kill TRAMP-C2 specifically in vitro, whereas splenocytes from mice in the other groups could not. These results demonstrate that PS, which becomes exposed on prostate cancer cells and tumor vasculature after ADT, inhibits immunity to TRAMP tumor antigens. Treatment with the PS-targeting antibody mch1N11 reactivates tumor immunity, which can permanently hold new tumor development in check.
- - - - PPHM 4-4-12 PRESS RELEASE COMMENTS RE: #4395:
“ In this presentation, researchers presented data showing robust anti-tumor responses in a challenging preclinical prostate cancer model when an animal version of bavituximab was combined with androgen deprivation therapy (ADT). Using the TRAMP model of prostate cancer in which mice are genetically engineered to continually generate prostate cancer, the combination regimen of bavituximab with ADT remarkably resulted in complete inhibition of cancer in roughly 40% of the animals, preventing tumor growth until the animals died of old age. These results support PS as a fundamentally immunosuppressive molecule, the blocking of which with PS-targeting antibodies can help facilitate robust immune responses to cancer."
http://tinyurl.com/7yrwqm7
Poster PDF: http://www.peregrineinc.com/images/stories/pdfs/aacr_2012_prostate_cure.pdf
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5-26-11: DR. PHILIP THORPE, KEYNOTE PRESENTATION AT INFORMA LIFE SCIENCES RECOMBINANT ANTIBODIES CONF. IN BARCELONA
”Targeting Tumor Vasculature & Reactivating Tumor Immunity with Bavituximab
"Our research shows that exposed PS in the tumor environment plays a fundamental immunosuppressive role that prevents the immune system from recognizing cancer cells as 'foreign,' resulting in cancer patients not being able to reject their tumors. We show that highly immunosuppressive cells called myeloid-derived suppressor cells, or MDSCs, accumulate in tumors and fail to mature into functional immune cells. What is especially exciting is that administration of PS-targeting antibodies like bavituximab breaks the grip of the tumor on the immune system. In treated animals, we see the disappearance of MDSCs and the appearance of functional immune cells, especially macrophages. The entire tumor environment shifts from being immunosuppressive to being immune responsive. These results have important implications for cancer therapy."
- - PPHM’s PR: “Data presented today show that PS-targeting antibodies overcome the immunosuppression in tumors that prevents immune responses to tumor cells. Antibody treatment of tumor-bearing mice caused the differentiation of highly immunosuppressive myeloid-derived suppressor cells (MDSCs) into functional immune cells, notably M1 macrophages and dendritic cells. This was accompanied by a decrease in the immunosuppressive cytokines and markers IL-10, CD206, and CD301 by more than 60%, and an increase in the proinflammatory cytokines TNF-alpha, IL-12, and IL-6 by more than 500% compared to mice treated with the control antibody. The reactivated M1 macrophages were shown to home in on PS-expressing tumor blood vessels and destroy them, resulting in marked inhibition of tumor growth. PS-targeting antibody treatment also enhanced the ability of dendritic cells to generate cytotoxic T-cells against cancer cells, resulting in a 4-fold increase of tumor-specific T-cells. These results support PS as a fundamental immunosuppressive molecule exploited by tumors, and bavituximab as an agent capable of overcoming PS-mediated immune suppression.”
http://tinyurl.com/3klpodc
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4-5-11: DR. PHILIP THORPE, AACR/2011, #3651
”Phosphatidylserine-Targeting Antibody Induces Differentiation of Myeloid-Derived Suppressor Cells into M1-like Macrophages”
“Data from several studies suggest PS-targeting antibodies prompt a reactivation of innate immune functions inside tumors. New studies demonstrated that an animal equivalent of bavituximab alters immune cells' production of signaling chemicals from an immunosuppressive (IL-10-dominated) response generally associated with fostering growth, to a pro-inflammatory (IL-12 and TNFa -dominated) response associated with tumor destruction. This immune shift was demonstrated by a doubling of the ratio of tumor-fighting (M1) to tumor-tolerating (M2) macrophages inside tumors as compared to animals treated with a control antibody. "We have now measured several important immune response changes induced by the PS-targeting action of bavituximab," said Philip E. Thorpe, Ph.D., professor of pharmacology at UT Southwestern Medical Center, scientific adviser to Peregrine and inventor of the company's PS-targeting antibody technology. "When taken together, the data support bavituximab initiating a fundamental shift inside tumors, overcoming what is now increasingly understood to be PS-mediated immune tolerance of tumors. Based on the consistent anti-tumor data we have observed in our prior studies, we had suspected that PS-targeting antibodies were facilitating immune reactivation in tumors. These new data strengthen our hypothesis and potentially have broad implications for the future of cancer immunotherapy."
POSTER – SEE http://www.peregrineinc.com/images/stories/pdfs/aacr_moa.pdf
The phosphatidylserine (PS)-targeting antibody, bavituximab, is currently in Phase II clinical trials in patients with NSCLC and Pancreatic Cancer. Bavituximab, and its murine counterpart, 2aG4, induce the attack of monocytes & macrophages on PS-expressing tumor vascular endothelium & tumor cells and inhibit the immunosuppressive effects of PS in the tumor microenvironment. Myeloid-derived suppressor cells (MDSC) are one of the major cells responsible for the immunosuppressed state in tumors. In this study, we tested the influence of 2aG4 on the differentiation of MDSC into M1-like tumor associated macrophages (TAMs). Taken together, our results suggest that 2aG4 causes the differentiation of MDSCs into macrophages having an M1-like phenotype.
SUMMARY:
1. 2aG4 treatment of MDSCs induces their differentiation towards macrophages with an M1-like phenotype with higher expression of iNOS and lower CD206.
2. 2aG4 treated MDSCs produce more proinflammatory cytokines and less immunosuppressive cytokines.
3. 2aG4 treatment of PC3 tumor-bearing mice significantly decreases the number of tumor-infiltrating and splenic MDSC, and increases the ratio of M1 to M2 macrophages in the tumor.
4. 2aG4 treatment switches tumor associated macrophages towards M1-like macrophages.
http://tinyurl.com/68p9zs4
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4-25-10: DR. PHILIP THORPE, THROMBOSIS RESEARCH
”Targeting Anionic Phospholipids on Tumor Blood Vessels & Tumor Cells”
“Bavituximab’s MOA:
(i) Anti-vascular activity: 3G4 & 2aG4 [Bavituximab is chimeric 3G4]have a strong vascular targeting action. Histologic examination of tumors from treated mice reveals a marked reduction in the vascular density and plasma content of tumors (Fig. 3). Time course studies show the sequence of events to be: (1) Antibodies localize to tumor vasculature within 1 hour; (2) Monocytes arrive in tumor vessels within 1–2 days; (3) Vascular collapse occurs between 2 and 6 days. Collagen IV positive ‘ghosts’ of de-endothelialized vessels remain; (4) Macrophages having tumoricidal M1 phenotype infiltrate into the tumors in large numbers by 4–5 days. (5) Central necrosis develops throughout the entire core of the tumor with survival of a peripheral rim of tumor cells, characteristic of the action of a VTA. The destruction of tumor endothelium is dependent on the Fc piece of the antibody, and appears to be caused by monocytes and macrophages, the predominant cell types that localize to tumor vessels in nu/nu and SCID mice [15]. Mouse macrophages can be demonstrated in vitro to kill 2aG4-coated PS-expressing mouse endothelial cells. All these facts are consistent with the primary mechanism of anti-vascular action being ADCC-mediated destruction of the tumor endothelium by cells of the innate immune system.
(ii) Induction of pro-inflammatory responses: PS suppresses the production of pro-inflammatory cytokines by monocytes and macrophages. Normally, apoptotic cells are silently engulfed by macrophages without their raising a pro-inflammatory response [23]. PS on apoptotic cells binds to PS receptors on the macrophages, which signals the macrophages to secrete antiinflammatory cytokines, such as TGFb and IL-10 [23]. When PS is masked by 2aG4, the suppression of proinflammatory signals is blocked and the cells switch to the production of pro-inflammatory cytokines, such as TNFa and IL-1b. These cytokines then recruit large numbers of macrophages into the tumor interstitium (Fig. 4). The macrophages have the M1 phenotype, characteristic of tumoricidal macrophages, as opposed to M2 phenotype, characteristic of proangiogenic macrophages.
(iii) Induction of immunity to tumor cells: A third mechanism of action is seen in immunocompetent animals. It is known that PS can suppress immune responses by preventing dendritic cell maturation and antigen presentation [24]. We found in rats implanted with non-immunogenic F98 intracranial gliomas that 10 Gy whole brain irradiation plus 2aG4 can produce curative CTL responses against the surviving glioma cells [18]. Curative CTL responses were also generated by 2aG4 in mice with irradiated syngeneic 4T1 breast tumors [25]. When dendritic cells were co-cultured with 2aG4-coated irradiated F98 glioma cells, they were able to present the F98 cell antigens to T-cells to generate cytotoxic T-cells that were specifically cytotoxic to F98 cells in vitro (Fig. 4). The induction of T-cell immunity in vitro was PS-dependent and required the Fc piece of 2aG4 for maximal effect. Thus, we have compelling evidence that PS on irradiated tumor cells imposes host cell tolerance towards tumor cells and that the antibodies block the immunosuppressive effects of PS, leading to the induction of T-cell immunity to tumor cells. For this reason, the antibodies are actually better anti-tumor agents in immunocompetent animals than they are in immunodeficient animals whose adaptive immune mechanisms are compromised.”
http://tinyurl.com/9reso7s
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4-19-10: DR. PHILIP THORPE, AACR/2010, #1919
“Phosphatidylserine on Dying Tumor Cells Suppresses Dendritic Cell Activation & Inhibits Tumor Immunity: Reversal With PS-Targeting Antibody”
“We recently showed that PS on the surface of apoptotic cancer cells can suppress recognition of tumor antigens by the immune system. It appears from work in several laboratories that dendritic cells (DC) that ingest PS-expressing tumor cells fail to mature in response to external maturation signals. In the present study, we investigated whether masking PS on apoptotic tumor cells with anti-PS antibody (2aG4) [NOTE: “2aG4” is a mouse IgG2a version of murine mab 3G4; bavituximab is chimeric 3G4] can reverse the inhibitory effect of PS on DC. Mouse bone marrow derived DC were co-cultured with irradiated (PS-expressing) 4T1 breast tumor cells in the presence or absence of 2aG4. We found that:
(i) Masking tumor cell PS with 2aG4 increases their phagocytosis by DCs;
(ii) Masking tumor cell PS with 2aG4 allows DCs to mature and express immunostimulatory molecules (CD40, CD80, CD86 and MHC II);
(iii) Masking PS with 2aG4 decreases the production of anti-inflammatory cytokines (TGFB and IL-10) and increases the production of inflammatory cytokines (TNFa, CCL5, IL-1B and IL-6), indicating that PS-blockade polarizes DC towards the immunostimulatory type I phenotype;
(iv) Immunizing mice with 2aG4-treated irradiated 4T1 cells enhances the immunogenicity of the tumor cells, rendering them resistant to rechallenge with syngeneic viable 4T1 tumor cells.
These results have important implications for our understanding of the immunosuppressive effects of PS in cancer and could lead to the development of a novel whole cell cancer vaccine strategy in which PS-blocking is used to enhance immunogenicity.”
http://tinyurl.com/y266azk
FULL PDF: http://www.peregrineinc.com/images/stories/pdfs/2010_AACR_Poster_PS_Reversal.pdf
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1-24-2011: PPHM HAS EXEC. INFO. REPORT (EIO) PREPARED BY CRYSTAL RESEARCH (JEFFERY KRAWS)
Phosphatidylserine (PS)-Targeting Therapy
“In the human body, there are certain phospholipids that are typically located on the interior of the cell membrane; thus, they are not exposed on the cell surface. However, these aminophospholipids can move to the surface of cells that line tumor blood vessels or that are infected with an enveloped virus. Bavituximab targets a specific aminophospholipid, called phosphatidylserine (PS), which is exposed on cells lining tumor blood vessels, virally infected cells, and on the surface of enveloped viruses. It is important to note that bavituximab does not target healthy cells, as these cells do not expose PS, nor does bavituximab signal the immune system against healthy cells. Peregrine believes that this feature of targeting tumor blood vessels or virus-infected cells may enable bavituximab to be a safer treatment with fewer side effects than many current options. Furthermore, exposed PS on tumor blood vessels may represent a new target for diagnostic products. To Peregrine’s knowledge, it is the only company studying PS-targeting MAbs in clinical trials as therapy for solid tumors or enveloped virus infections. As bavituximab is believed to employ a novel mechanism of action that is not yet represented among other anticancer or antiviral antibody approaches, it may have the potential to be combined with existing standard-of-care treatments, thereby improving efficacy without creating overlapping toxicities. Peregrine is developing two clinical programs - oncology and antiviral - based on its PS-targeting platform technology. Its lead antibody, bavituximab, helps stimulate and direct the body’s immune defenses to attack PS-expressing cells on tumor vasculature, enveloped viruses, and cells infected with an enveloped virus.”
http://tinyurl.com/2dja6uo
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4-1-2011: LIFETECH-CAPITAL UPDATE (STEVE DUNN)
Bavituximab for Cancer (chimeric anti-phosphatidylserine monoclonal antibody)
“Bavituximab is a chimeric (mouse/human) monoclonal antibody that preferentially binds to a specific phospholipid called phosphatidylserine [PS]. PS is a phospholipid normally found on the inner (or cytosolic) side of the cell membrane. When a cell undergoes programmed cell death (apoptosis) or encounters certain stresses the PS will translocate, via enzymes called flippases, to the outside (or extracellular) side of the lipid bilayer. There is much evidence to suggest that this translocation is a natural process that suppresses the immune system in situations where an aggressive immune response is not necessary or required. Research has demonstrated that exposed or extracellular PS can act as a fundamental initiator of an anti-inflammatory as well as anti-immunogenic immune responses, as reported in The Journal of Biological Chemistry [10-2006 http://www.jbc.org/content/281/50/38376.full ] and The Journal of Apoptosis [2-2007: http://www.springerlink.com/content/r7nht3231334v117 ]. It is believed that exposed PS is perceived by the immune system as a sign of a dying cell of the same overall organism, i.e. as friend not foe. The immune response that clears native cellular debris is mild, rather than the aggressive immune attack that would be invoked against a foreign intruder. Tumors have been shown to exploit the immunomodulatory effects of exposed PS for their own survival and proliferation within the body. Physical and physiological stresses in the tumor environment, micro and macro, cause PS exposure in the endothelial cells lining the tumor vasculature. The exposed PS shields the tumor from immune response and creates an environment favorable to further tumor growth. In addition to the exposed PS found on the tumor vasculature, PS-exposing microvesicles shed from tumor cells exhibit multiple immunosuppressive mechanisms further shielding the tumor from detection. There is also evidence that the process of new blood vessel formation, or angiogenesis, is partially dependant on PS exposure of apoptotic cells. The exposure of PS in solid tumor vasculature creates a potential anti-cancer target that Peregrine’s Bavituximab exploits. The monoclonal antibody, Bavituximab, selectively binds to exposed PS in existing tumor vasculature and in essence, alerts the immune system to the presence of “foe not friend” evoking a much more aggressive immune response. The immune response is specific to cells exhibiting PS exposure, which potentially destroys the tumors blood supply while minimizing unwanted or off-target side effects in healthy tissue. Destruction of the tumor vasculature inhibits growth and development of multiple solid tumor types as demonstrated by PS is a phospholipid found on the cytosolic side of the cell membrane in healthy cells. In certain environments, such as in solid tumor vasculature… PS will translocate to the outside of the lipid bilayer. Bavituximab specifically binds to these exposed phospholipids. The bound monoclonal antibodies alert the immune system to the cancerous cells found in the tumor vasculature. The immune system then destroys the vasculature cutting off the flow of oxygen and nutrients to the tumor cells, resulting in tumor cell death and tumor shrinkage.”
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2-8-2010: MLV ANALYST GEORGE ZAVOICO
BAVITUXIMAB
“Bavituximab is Peregrine’s leading drug candidate and principal value driver. It is a human-mouse chimeric monoclonal antibody that targets a cell membrane phospholipid called phosphatidylserine (PS). Cellular membranes are composed of four major types of phospholipids: phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), and PS. Other important membrane components are cholesterol and sphingomyelin, but they will not be considered further in this discussion. Structurally, cell membranes are bilayers, composed of a hydrophobic, or water excluding, center and hydrophilic, or water attracting, surfaces. Phospholipids are polar molecules with a long fatty, hydrophobic tails, and a more compact, hydrophilic head group (Exhibit 2). In the bilayer, the fatty hydrophobic tails point inward, exposing the hydrophilic head groups to the aqueous environment of the cytoplasm inside the cell and the extracellular fluids outside the cell. What is remarkable about the structure of cell membranes is the asymmetric distribution of its component phospholipids in the outer and inner leaflets of the bilayer. Cells expend a tremendous amount of energy maintaining the asymmetry. PE and PS are enriched in the inner, or cytoplasmic, side of the bilayer, while PC is enriched in the outer side of the bilayer. Remarkably, in normal cells PS is practically absent from the outer side of the bilayer. However, in tumor cells, in vascular endothelial cells infiltrating and providing blood flow to solid tumors, cells infected by viruses, and certain membrane enveloped viruses, the asymmetry is lost, with PS becoming exposed on the outer surface of the cell membrane. Since this property appears to be unique to these cells, drugs that target exposed PS could be selective anti-cancer or anti-viral agents.
Bavituximab is a human-mouse chimeric monoclonal antibody that binds to PS indirectly through a plasma protein called B-2-glycoprotein 1 (B2GP1), as shown in Exhibit 2. B2GP1 consists of 5 domains, the last of which, domain V, binds very weakly to PS. Bavituximab, and an equivalent mouse antibody called 3G4, bind to domain II of B2GP1, and cross-link two molecules of the protein. Interestingly, this increases the binding affinity of B2GP1 for PS by about 1000-fold. Once bound to the cell surface bavituximab induces an inflammatory and immune response that leads to the death of the cell it is bound to. Bavituximab is believed to cause the collapse and loss of integrity of the tumor vasculature, depriving the tumor of blood flow and the delivery of oxygen and nutrients and removal of cellular waste, leading to the death of the tumor cells. Bavituximab binding to virally infected cells also leads to their death, preferably before the viruses can replicate in the infected cell and be released to infect other cells. Since PS is thought to be a specific marker for tumor vasculature and virally-infected cells, Peregrine is developing bavituximab as an anti-cancer and anti-viral agent.”
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BAVI’S ANTI-TUMOR MOA DESCRIBED ON PEREGRINE’S WEBSITE (9-2012):
“Bavituximab is a first-in-class phosphatidylserine (PS)-targeting monoclonal antibody that represents a new approach to treating cancer. PS is a highly immunosuppressive molecule usually located inside the membrane of healthy cells, but "flips" and becomes exposed on the outside of cells that line tumor blood vessels, creating a specific target for anti-cancer treatments. PS-targeting antibodies target and bind to PS and block this immunosuppressive signal, thereby enabling the immune system to recognize and fight the tumor. Research has shown that chemotherapy and radiation increase the exposure of PS on the surface of the tumor blood vessels, increasing the availability of bavituximab's target molecule, and potentially enhancing bavituximab's anti-tumor activity.”
• PS (in green) is a molecule normally located inside all cells where it's kept inactive
• The cancer microenvironment causes PS to flip to the outside of cells lining tumor blood vessels.
• Chemotherapy further increases exposed PS in the tumor environment
• Exposed PS is a highly immunosuppressive molecule that mimics "apoptosis", muting immune responses
• Bavituximab (yellow) overrides PS-mediated immunosuppressive signals...
• Allowing immune reactivation to attack the tumor
• Activated immune system causes tumor blood flow shut down and adaptive immune response to the tumor
http://www.peregrineinc.com/technology/bavituximab-oncology/mechanism-of-action.html
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The 30 Slides Dr. Philip Thorpe presented 5-1-2012 at the NYAS PS-Targeting Symposium:
…Note that Dr. Thorpe’s describes Bavi’s MOA in several parts:
• Mechanism #1: Tumor Vessel Damage by ADCC
• Mechanism #2: Blockade of PS-Mediated Immunosuppression in Tumors
• Macrophage Polarization M2 to M1 Switch
• Generation of Tumor-Specific Cytotoxic T Cells
• Proposed Mechanism: PS Blocks MDSC, Macrophage, and DC (Dendritic Cells) Differentiation
• Proposed Mechanism: Bavi Reactivates Innate & Adaptive Immunity
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A few of the more illustrative slides from Dr. Phillip Thorpe’s 53-pg. Keynote Presentation
on 5-26-11 at the ‘Recombinant Antibodies’ Conf. in Barcelona… [ http://tinyurl.com/3klpodc & http://tinyurl.com/3m33h33 ]
“Keynote Presentation at Leading European Antibody Conference Highlights Immune Reactivation Mechanisms of Bavituximab”
Slide 5: Note: “1N11” (Fully Human Bavituximab), aka: AT004, PGN635…
Slide 41:
COMMENTARY ON SLIDE 41 BY IHUB’S “FIRE FOX”, 5-27-11 #64371
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=63661054
“RRDog-- Your Ode to Dr. Thorpe is well sung. I agree completely. The market doesn't appreciate the MOA "tour de force" Thorpe has pulled off here. However, for the FDA, the analysts and the medical community considering Bavi trials, Thorpe's presentation in Barcelona will be hugely compelling for years to come. I bet many aspiring PhD candidates are already making plans to replicate new versions of this break-through Phil Thorpe accomplishment. An immunology maven I spoke with emphasized the importance of Slide #41, which tells the whole story in one picture. Everyone who owns stock in PPHM should print Slide 41 and keep it by their bedside. If Bavi indeed triggers either of these MOA mechanisms, it's the launch of huge new therapeutic platform - certainly in cancer and perhaps in viral therapy as well. But if both of these mechanisms of action are operating, the effects of Bavi as an immunotherapy will be nothing short of sensational. The fact that Thorpe has nailed down these TWO separate ways that Bavi "breaks the grip of tumor on the immune system", indicates huge promise for Bavi !!!”
Slide 52:
DR. THORPE’S COMMENTS ON BAVI’S MOA FROM THE 5-26-11 PR:
"Our research shows that exposed PS in the tumor environment plays a fundamental immunosuppressive role that prevents the immune system from recognizing cancer cells as 'foreign,' resulting in cancer patients not being able to reject their tumors," said Philip E. Thorpe, Ph.D., professor of pharmacology in the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center, scientific adviser to Peregrine and inventor of the company's PS-targeting antibody technology. "We show that highly immunosuppressive cells called myeloid-derived suppressor cells, or MDSCs, accumulate in tumors and fail to mature into functional immune cells. What is especially exciting is that administration of PS-targeting antibodies like bavituximab breaks the grip of the tumor on the immune system. In treated animals, we see the disappearance of MDSCs and the appearance of functional immune cells, especially macrophages. The entire tumor environment shifts from being immunosuppressive to being immune responsive. These results have important implications for cancer therapy."
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