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Why is Ampersand hiding info to maximize shareholder value with Avid CDMO?
CGI required for Merck Keytruda approval and Ampersand now controlling much IP asset data via other subsidiaries that are going to be exposed and there is lots more...now you all know why Ampersand likes Interpace Diagnostics that likes CGI and other subsidiaries come into play..
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Panna Sharm CEO CGI
https://ir.cancergenetics.com/press-releases/detail/1168/cancer-genetics-inc-listed-by-merck-as-a-national-reference-laboratory-for-keytruda-pembrolizumab-companion-diagnostic-testing
Cancer Genetics, Inc. Listed by Merck as a National Reference Laboratory for KEYTRUDA® (pembrolizumab) Companion Diagnostic Testing
Reinforces CGIs Position as a Leader in Immuno-Oncology & Companion Diagnostics For PD-L1 Testing & Monitoring
Company Expects Significant Growth in Comprehensive Molecular & Immune Profiling for Lung Cancer as KEYTRUDA Enters First-Line Treatment
RUTHERFORD, N.J. & LOS ANGELES, Dec. 05, 2016 (GLOBE NEWSWIRE) -- Cancer Genetics, Inc. (Nasdaq:CGIX), an emerging leader in enabling precision medicine for oncology through the use of molecular markers and information, announced today that it is on Mercks list of national reference laboratories offering the PD-L1 22C3 pharmDx immunohistochemistry (IHC) assay, the first U.S. Food and Drug Administration (FDA)-approved companion diagnostic test for pembrolizumab, KEYTRUDA®, for PD-L1 testing in non-small cell lung cancer (NSCLC). The company first started offering the DAKO PD-L1 IHC 22C3 pharmDx test in early 2016, and was recently listed as a national reference laboratory.
In October, the FDA approved pembrolizumab (KEYTRUDA®, Merck & Co., Inc.) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 as determined by an FDA-approved test, becoming the first FDA approval of a checkpoint inhibitor for first-line treatment of lung cancer. The approval also expanded the indication in second-line treatment of lung cancer to include all patients with PD-L1-expressing NSCLC. The approval was based on results of two randomized, controlled trials that demonstrated statistically significant improvements in survival for patients randomized to pembrolizumab compared with chemotherapy.
Cancer Genetics now offers all the available FDA approved companion diagnostics for PD-L1 testing across several cancer indications, and is providing these tests for both patient management in the clinical setting as well as for immuno-oncology trials sponsored by leading pharmaceutical companies. Cancer Genetics is now supporting over 100 clinical studies and trials, and over 30 with a component for immuno-oncology testing and monitoring.
Dr. Jorge Nieva, Associate Professor of Clinical Medicine at Keck School of Medicine of USC and a global thought leader in developing multidisciplinary lung cancer programs stated, "PD-L1 testing is critically important for my lung cancer patients. Having a high-quality provider that understands the intricacies of PD-L1 scoring and getting those results in a rapid timeframe means that patients don't have to wait. Consistent, high-quality molecular testing results translate into improved outcomes, reduced waiting times for patients, and a real change in personalizing therapy."
Clinical awareness of validated biomarker testing and education of clinicians and pathologists about the guidelines for PD-L1, including 22C3, is critical to making breakthrough therapies like KEYTRUDA® more available for patients. Merck and CGI will both carry out activities to educate the clinical marketplace about the utility of PD-L1 IHC 22C3, one of the most important diagnostic markers for such novel immuno-oncology therapies. CGI believes that these educational and awareness activities targeted at clinicians and cancer care facilities will drive higher volume of compliant PD-L1 testing along with an increased demand for comprehensive lung cancer profiling using CGIâ??s tests and technologies.
CGI and leading cancer experts believe that the synergistic effect of integrating immuno-oncology and targeted therapies will result in personalized cancer treatment with higher efficacies and improved outcomes. CGI has actively developed and validated PD-L1 markers for a wide range of cancers, including: melanoma, NSCLC, head and neck, breast, gastric, colon, bladder, pancreatic, renal, prostate, and ovarian cancers, urothelial carcinoma, mesothelioma, and B-cell lymphomas. CGI believes that it has validated, under a compliant and CLIA regulated setting, PD-L1 testing across more cancer indications than any other commercial cancer laboratory. Because of this, the company expects to have significant continued acceleration in the number of immuno-oncology studies and clinical trials that it is providing testing and information for in the coming quarters in both PD-L1 and other key immune markers.
â??KEYTRUDA's approval as a first-line treatment will make PD-L1 expression testing more common for both squamous and nonsquamous lung cancers, and will mark an accelerated era of IO awareness and testing for cancer treatment. We are very excited to be on Merckâ??s list as we have demonstrated again that CGI is at the forefront of enabling precision diagnostics in immuno-oncology, and then bringing these advances into a large-scale clinical setting so that patients can ultimately benefit,â? said CGI President and CEO, Panna Sharma.
Pembrolizumab is a programmed death receptor-1 (PD-1)-blocking antibody that is being studied in a broad range of solid tumors and hematological malignancies. It has been granted Breakthrough Therapy Designation status by the FDA four times for the treatment of patients with melanoma, NSCLC, colorectal cancer, and classical Hodgkin lymphoma. Pembrolizumab (KEYTRUDA®) is now indicated for the treatment of patients with NSCLC, melanoma, and head and neck cancer. KEYTRUDA® sales were already growing rapidly, but following KEYTRUDA's first-line approval analysts have adjusted peak sale estimates. For example, Bernstein analysts have increased their KEYTRUDA® outlook for 2017 by $1 billion and they now expect KEYTRUDA® sales of $7.8 billion in 2025 which will require a significantly higher number of patients to be tested and diagnosed.
ABOUT CANCER GENETICS
Cancer Genetics Inc. is a leader in enabling precision medicine in oncology from bench to bedside through the use of oncology biomarkers and molecular testing. CGI is developing a global footprint with locations in the US, India and China. We have established strong clinical research collaborations with major cancer centers such as Memorial Sloan Kettering, The Cleveland Clinic, Mayo Clinic, Keck School of Medicine of USC and the National Cancer Institute.
The Company offers a comprehensive range of laboratory services that provide critical genomic and biomarker information. Its state-of-the-art reference labs are CLIA-certified and CAP-accredited in the US and have licensure from several states including New York State.
For more information, please visit or follow CGI at:
Internet: www.cancergenetics.com
Twitter: @Cancer_Genetics
Facebook: www.facebook.com/CancerGenetics
Forward-Looking Statements:
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements pertaining to Cancer Genetics Inc.â??s expectations regarding future financial and/or operating results and potential for our tests and services, and future revenues or growth in this press release constitute forward-looking statements.
Any statements that are not historical fact (including, but not limited to, statements that contain words such as "will," "believes," "plans," "anticipates," "expects," "estimates") should also be considered to be forward-looking statements. Forward-looking statements involve risks and uncertainties, including, without limitation, risks inherent in the development and/or commercialization of potential products, risks of cancellation of customer contracts or discontinuance of trials, risks that anticipated benefits from acquisitions will not be realized, uncertainty in the results of clinical trials or regulatory approvals, need and ability to obtain future capital, maintenance of intellectual property rights and other risks discussed in the Cancer Genetics, Inc. Form 10-K for the year ended December 31, 2015 and the Form 10-Q for the Quarter ended September 30, 2016 along with other filings with the Securities and Exchange Commission. These forward-looking statements speak only as of the date hereof. Cancer Genetics, Inc. disclaims any obligation to update these forward-looking statements.
Eb, thanks for the updates ...greatly appreciated. I wonder how Eli Lilly is doing with Loxo Oncology as they are only the 2nd behind Merck for FDA approval based upon tissue etc not location of tumor
Lots of PS Targeting research involved as CGI Cancer Genetics Inc ( that aided Keytruda) has ties in Loxo
Cancer Genetics Inc and HTG Molecular deal as CGI scooped up by Interpace Diagnostics ...which was scooped up by Ampersand
Ampersand was brought in for Avid CDMO as Biomarkers were KEY...much more interest from new IIS that will not settle
There are many Subcutaneous BLAs pending ...Avid CDMO stands to pick up and lock in the manufacturing ....and those smart enough to lock in (as some already have will have PRIORITY when PS Targeting gets approval ) stand to be able to have the advantage to get even quicker FDA approvals based on PS Targeting
Extracellular vesicles as a novel source of biomarkers in liquid biopsies for monitoring cancer progression and drug resistance
M. Helena Vasconcelos abc
Hugo R. Caires ab
Arturs Abols d
Cristina P.R. Xavier ab
Aija Line de
a
i3S- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
b
Cancer Drug Resistance Group, IPATIMUP – Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
c
Department of Biological Sciences, FFUP – Faculty of Pharmacy of the University of Porto, Porto, Portugal
d
Latvian Biomedical Research and Study Centre, Riga, Latvia
e
Faculty of Biology, University of Latvia, Riga, Latvia
Received 16 September 2019, Revised 9 October 2019, Accepted 11 October 2019, Available online 15 October 2019.
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https://doi.org/10.1016/j.drup.2019.100647
Get rights and content
Abstract
Cancer-derived extracellular vesicles (EVs) have been detected in the bloodstream and other biofluids of cancer patients. They carry various tumor-derived molecules such as mutated DNA and RNA fragments, oncoproteins as well as miRNA and protein signatures associated with various phenotypes. The molecular cargo of EVs partially reflects the intracellular status of their cellular origin, however various sorting mechanisms lead to the enrichment or depletion of EVs in specific nucleic acids, proteins or lipids. It is becoming increasingly clear that cancer-derived EVs act in a paracrine and systemic manner to promote cancer progression by transferring aggressive phenotypic traits and drug-resistant phenotypes to other cancer cells, modulating the anti-tumor immune response, as well as contributing to remodeling the tumor microenvironment and formation of pre-metastatic niches. These findings have raised the idea that cancer-derived EVs may serve as analytes in liquid biopsies for real-time monitoring of tumor burden and drug resistance. In this review, we have summarized recent longitudinal clinical studies describing promising EV-associated biomarkers for cancer progression and tracking cancer evolution as well as pre-clinical and clinical evidence on the relevance of EVs for monitoring the emergence or progression of drug resistance. Furthermore, we outlined the state-of-the-art in the development and commercialization of EV-based biomarkers and discussed the scientific and technological challenges that need to be met in order to translate EV research into clinically applicable tools for precision medicine.
Very interesting and I wonder if some realize the war going on for shares ...IIS pitted vs IIS
Craig-Hallum maybe starts to make some other IIS think twice on how fast shares will be scooped up before them
NEW IIS maybe not as new as those that picked up shares the very first trading days of July
Nov 15 the time line where we see more info...buy with Craig Hallum stepping forward this morning I think more is revealed sooner than some think
I doubt Craig Hallum stepped forward without shares ....and many don't see that yet
Distribution, dynamics and functional roles of phosphatidylserine within the cell
October 15, 2019
Jason G. Kay & Gregory D. Fairn
Abstract
Phosphatidylserine (PtdSer), an essential constituent of eukaryotic membranes, is the most abundant anionic phospholipid in the eukaryotic cell accounting for up to 10% of the total cellular lipid. Much of what is known about PtdSer is the role exofacial PtdSer plays in apoptosis and blood clotting. However, PtdSer is generally not externally exposed in healthy cells and plays a vital role in several intracellular signaling pathways, though relatively little is known about the precise subcellular localization, transmembrane topology and intracellular dynamics of PtdSer within the cell. The recent development of new, genetically-encoded probes able to detect phosphatidylserine is leading to a more in-depth understanding of the biology of this phospholipid. This review aims to give an overview of recent developments in our understanding of the role of PtdSer in intracellular signaling events derived from the use of these recently developed methods of phosphatidylserine detection.
Background
The ability to produce phosphatidylserine (PtdSer) is essential for mammalian survival [1], while the lack of PtdSer production in yeast leads to growth defects and an increase in other negatively charged lipids in an attempt at compensation [2, 3]. In addition, over production of PtdSer leads to the congenital disease Lenz-Majewski syndrome, characterized by the combination of sclerosing bone dysplasia, intellectual disability and distinct craniofacial, dental, cutaneous and distal-limb anomalies [4].
PtdSer has important roles in apoptosis and blood clotting, and most of what is known about PtdSer applies to these roles. However, in homeostasis PtdSer is not generally externally exposed, yet it clearly plays a vital role in healthy cells. The function of PtdSer, as with all lipids, is determined by both its concentration and sidedness in individual organellar membranes. Mitochondria associated membranes (MAMs) of the endoplasmic reticulum (ER) have high rates of PtdSer synthesis and serve as a conduit for the transfer of lipids between the ER and adjacent mitochondria [5, 6]. The bulk subcellular distribution of PtdSer results from the coordinated actions of metabolic enzymes in conjunction with vesicular and nonvesicular transport pathways, while the topology of PtdSer results from the actions of transmembrane enzymes capable of moving PtdSer between lipid bilayers; PtdSer flippases, floppases, and scramblases [7, 8]. Until relatively recently, PtdSer distribution and topology studies depended solely on the fractionation and subsequent chemical analysis of cellular organelles. These early studies highlighted PtdSer distribution throughout the cell is unbalanced (Fig. 1a), being more concentrated in the plasma membrane (PM) (~?10–15% total lipid) with lower levels in the ER (~?4%) and mitochondria (~?1%), the latter of which uses PtdSer as a source of phosphatidylethanolamine (PtdEtn) (reviewed in [7, 9, 10]). The PtdSer content of less abundant organelles, including the endosomal system, has generally been less well defined because of the difficulty inherent in purifying them to homogeneity.
In addition to difference of PtdSer content amongst organelles, the unequal bilayer distribution of PtdSer at the PM has long been appreciated [11], as has the importance of movement of PtdSer from the cytoplasmic to exofacial face of the PM being involved in critical signaling events including blood clotting [12] and apoptotic cell recognition and removal by macrophages [13]. Furthermore, the PM has a net-negative charge on its cytoplasmic face [14], and consequently has an essential role in charge-based signaling events [15]. However, the contribution by PtdSer to this charge, as well as precise localization and the dynamics of PtdSer, or indeed other organelles, within whole and live cells, remains an area of active research which has recently been aided by new tools for the detection and visualization of PtdSer. In this review, we will highlight recent contributions to the understanding of PtdSer distribution and its roles within a normal cell.
Distribution and dynamics of phosphatidylserine
The development of the PtdSer-specific LactC2 probe, based on the PtdSer-specific calcium independent discoidin-type C2 binding domain of lactadherin (also known as Milk fat globule-EGF factor 8 (MFGE8)) [16] has enabled the visualization of PtdSer in live cells (Fig. 1b-c). Indeed, the initial study using this probe showed for the first time the cytoplasmic-facing distribution of PtdSer in live cells. This initial LactC2 study underscored the importance of PtdSer in providing the negative charge of the PM, finding that cationic probes track the presence of LactC2-identified PtdSer, including in the absence of polyphosphoinositides [16]. The study also highlighted the presence of PtdSer in, and its ability to recruit charge-based protein probes to, endosomal compartments, while not being detectable in the cytoplasmic-facing cis-Golgi, ER or mitochondria. While it is possible the LactC2 probe does not have high enough sensitivity to detect the relatively low levels of PtdSer present in these organelles [9, 10], it is also possible that, like in the PM, PtdSer leaflet distribution in intracellular organelle membranes is asymmetrical [17]. Indeed, there existed significant evidence prior to the development of the LactC2 probe suggesting this is the case, at least in the ER [18,19,20,21]. This evidence has since been strengthened with additional data that does not require the biochemical isolation, and potential disruption of, this intricate tubular organelle. Using a combined light microscopy and on-section staining electron microscopy (EM) approach, the LactC2 probe was able to detect PtdSer on the luminal but not cytoplasmic facing ER membrane [22]. A modified ER-targeted LactC2 probe has also been used to successfully detect PtdSer in the ER lumen of live cells [23].
The ability of PtdSer to change membrane leaflets faces a high energy barrier, with spontaneous translocation estimated to only occur in the order of hours per single molecular translocation event [24, 25]. Three categories of proteins have been characterized that enable the trans-leaflet movement of lipids: flippases that transfer lipids to the cytosolic leaflet from the PM extracellular or organellar luminal leaflet, floppases that transfer in the opposite direction (out of the cytosolic facing leaflet), and scramblases that are bidirectional [26,27,28]. As the cytoplasmic leaflet of the ER is where the active site of glycerophospholipid enzymes reside [29], it has generally been thought that most glycerophospholipids in the ER are scrambled equally between leaflets to allow for proper ER membrane expansion and leaflet coupling [30, 31]. How this can be compliant with PtdSer having a polarized distribution in the lumen of the ER is unclear. However, expression of gain-of-function PtdSer synthase 1 identified from Lenz-Majewski syndrome patients does result in the appearance of cytosolic PtdSer in the ER, demonstrating that the normal mechanism(s) that restrict PtdSer to the luminal leaflet are saturable [32]. One possibility is that PtdSer, once in the luminal leaflet, is kept there through interactions with luminal proteins and/or Ca2+ [33]. Other non-mutually exclusive possibilities are that movement PtdSer from the cytoplasmic-facing leaflet occurs at the MAM into the mitochondria where it is used for the production of PtdEth [34], or PtdSer is removed from the cytoplasmic leaflet through non-vesicular transport by lipid transfer proteins (LTPs).
LTPs, along with vesicular trafficking, are how lipids move between cellular membranes [9, 33, 35]. Recent studies have highlighted the ability of specific LTPs, oxysterol-binding homology (Osh) proteins 6 and 7 in yeast [36, 37] and oxysterol-binding protein (OSBP)-related proteins (ORPs) 5 and 8 in mammalian cells [36, 38], to move PtdSer between membranes. The existence of these PtdSer-specific LTPs thus provide a potential mechanism for the generation and/or maintenance of the PtdSer cellular membrane gradient present in cells. Indeed, recent studies have shown that LTP-mediated transfer of PtdSer against its concentration gradient is possible through exchange with phosphatidylinositol 4-phosphate (PtdIns4P) down its concentration gradient from the PM to the ER, where the phosphatase Sac1 converts PtdIns4P to PtdIns [38, 39]. However, recent evidence suggests this exchange may be principally used to fine tune the PM levels of PtdIns4P and PtdIns(4,5)P2 rather than be responsible for bulk movement of PtdSer into the PM [39, 40]. There is also compelling evidence for the importance of vesicular trafficking in being the major route for PtdSer trafficking and concentration within the PM. For example, in yeast with temperature-sensitive mutations in secretory proteins Sec6 and Sec1, the polarization of PtdSer in the PM normally seen at a forming bud is inhibited and PtdSer instead accumulates on the vesicle that are prevented from fusing with the PM [2]. Additionally, endosomal recycling is important in the maintenance of high PtdSer levels, with inhibition causing a redistribution of PtdSer throughout the endosomal system in yeast [41]. Similarly, disrupting LTP function in mammalian cells has been found to result in slightly altered, but not disrupted, cellular membrane PtdSer distribution [38, 39]. Furthermore, Snx4, a member of the sorting nexin family of proteins involved in endosomal cargo sorting and recycling [42] that is specifically involved in recycling of Snc1 in yeast [43] and transferrin receptor in mammalian cells [44] has recently been implicated in leading to the modification of endosomal PtdSer levels [41].
Thus, while nonvesicular lipid transport, mediated by LTPs, play an important role, vesicular trafficking appears to be a significant contributor for maintaining the inter-membrane PtdSer gradient within the cell. Though the full molecular mechanisms of how PtdSer is segregated from other lipids remains to be fully elucidated, biochemical studies indicate a significant fraction of PtdSer in mammalian cells is enriched in PM-derived detergent-resistant, cholesterol-enriched “lipid-rafts” [45]. This biochemical data is supported by both electron microscopy analysis showing PtdSer is not homogenously distributed throughout the PM [22] and the finding that cholesterol and PtdSer co-segregate throughout subcellular compartments, being most concentrated in the PM and early endosomal compartments and relatively absent from the ER [22, 46, 47]. Further, acute changes in either affect the distribution of the other; cholesterol is required for the normal distribution of PtdSer [2, 48] and acute changes in PM levels of PtdSer alter the distribution of cholesterol [46]. Evidence is also building for the likelihood that plasma membrane outer leaflet rafts, dependent on glycersphingolipids and cholesterol [49], are coupled to inner leaflet rafts [50, 51]. The importance of PtdSer in this coupling, in both the PM and endosomal membranes, is the subject of a recent excellent review [52] so will not be further covered here.
Roles of intracellular phosphatidylserine
As described in Background, PtdSer is essential in mammalian cells [1], while yeast lacking PtdSer are viable but have greatly reduced growth kinetics [2, 3]. As well, as PtdSer-mediated extracellular signaling, such as during blood clotting and apoptosis, has recently been reviewed [53,54,55], we will focus here on information regarding the roles of PtdSer within healthy non-apoptotic cells (Fig. 2).
Fig. 2
figure2
Current knowledge of roles and intracellular transport of PtdSer. PtdSer is produced in the ER, from where it is distributed throughout the cell. PtdSer can be transferred to the mitochondria through mitochondria associated membranes (MAMs) (1), where it is mostly converted to PtdEtn. Distribution to the PM and endosomal system can occur via traditional vesicle-mediated trafficking as well as via direct movement via PtdSer-specific lipid transfer proteins (2). The relative importance of both trafficking methods is currently unclear. At the PM (3), PtdSer is kept in the cytoplasmic-facing leaflet and is important for generating a high net-negative charge. A number of important signaling molecules are recruited to the PM through charge and/or direct PtdSer recognition binding, with PtdSer thus playing essential roles in many signaling cascades and protein localization. PtdSer also plays important roles in endocytosis (4), including through its curvature-inducing headgroup interactions as well as interactions with proteins required for caveolae formation. PtdSer may also play a role in Golgi function (5), related to cargo sorting and budding from the trans-Golgi. PtdSer also appears to be important for recycling of cargo and interaction with the recycling machinery (e.g. Evectin2, EHD1, Snx4) at the recycling endosome (6). These interactions with the recycling machinery also likely helps to ensure PtdSer returns to, and maintains its enrichment on, the PM while causing reduced PtdSer levels on the late endosomes and lysosomes. Mito – mitochondria, ER – endoplasmic reticulum, PM – plasma membrane, EV – exocytic vesicle, EE – endocytic vesicle, RE – recycling endosome, Lys – lysosome
Full size image
As described, at steady state in a healthy cell PtdSer makes up to ~?15?mol% of the total lipid in the PM. Furthermore, as it is nearly exclusively in the inner (cytoplasmic-facing) leaflet it can therefore make up to ~?30?mol% of the lipid on this leaflet. As the major lipid with a net-negative charge, PtdSer is therefore responsible for providing much of the inner leaflet’s charge density. A significant role of PtdSer then is interacting with proteins in a non-specific charge-based manner to permit their appropriate localization within the cell (Table 1). For example, the protein kinase Src and Ras GTPase family members Rac1 and K-Ras are proteins whose membrane targeting requires a polycationic stretch in addition to lipid modifications [56, 57]. The polycationic stretch of K-Ras4B has a net charge of +?8, resulting in its localization almost exclusively at the PM. If PtdSer is removed [58], or if the net charge of this stretch is varied the resulting mutants are directed additionally to other membranes; constructs of intermediate charge (e.g., +?5) localize to endosomal membranes [16]. Similarly, Src has a polycationic stretch next to its myristoylated residue at the N-terminus with a net charge of +?5, and the kinase was found to associate not only with the PM but also extensively with PtdSer-enriched endosomal membranes [16].
Table 1 Examples of Intracellular Proteins Binding or Influenced by PtdSer
Full size table
Further evidence of the importance for PtdSer in charge-based protein distributions has been observed with the phagocytic process. When pathogens cause a depletion of PtdSer from phagosomes, Src is also lost [59]. In other instances, such charged motifs are not sufficient to direct proteins to a membrane but nonetheless influence their targeting, likely playing a complementary role [56, 60]. Evidence that this is the case comes from studies in yeast where polarized PtdSer is required for the recruitment of the signaling and polarity-regulating molecule Cdc42 to the forming bud neck; without PtdSer Cdc42 remains Golgi-associated and buds are very inefficiently formed, leading to poor growth [2]. Similarly, Cdc42 and Rho1 are dependent on PtdSer polarization for their proper localization and function in Schizosaccharomyces pombe [61]. In yet another example, the plant GTPase Rho of Plants (ROP) family member ROP6 doesn’t appear to require PtdSer for its PM association, but does require PtdSer to be stabilized into nanodomains within the membrane upon activation that allows proper signal transduction [62]. Whether PtdSer is required for, or can modulate, signaling of other ROP family members, all of which contain a polybasic stretch of amino acids at their C-terminus [62], remains to be seen.
Traditionally, the interactions between polycationic stretches in proteins and anionic phospholipid headgroups have been thought to be strictly charge based with little specificity. However, recent evidence challenges this assumption. For instance, K-Ras4B which contains six lysine residues adjacent to a farnesylated cysteine residue, has recently been shown to interact with PtdSer preferentially [63]. The tail region of K-Ras4B adopts a series on conformations, disordered, ordered and intermediate, with the disordered being the preferred conformation. This conformation is also able to H-bond PtdSer more effectively than the other two confirmations [63]. Conversely, other proteins such as K-RasG12V and Rac1 show no preference for PtdSer [63,64,65]. While these are only initial studies, the results suggest that some polybasic proteins may have a preference for PtdSer or other anionic lipids beyond simple electrostatically driven interactions.
There are also multiple lines of evidence indicating the charge of PtdSer contributes to PM curvature and is important for the formation of some forms of endocytic vesicles. For example, caveolae are bulb-shaped nanodomains (50–100?nm) of the PM that have been linked with many physiological functions, including mechanosensing and endocytic transport [66]. While caveolae have been known to be enriched for cholesterol and specific glycerosphingolipids, including GM3 [67], PtdSer has recently been identified as being required for their formation and maintenance [68]. This is likely at least partly due to the charge-based PtdSer binding of the cavin1 protein [69] which, along with caveolin1, is required for in vivo caveola formation [70]. PtdSer is also capable of causing membrane curvature and induce endocytosis upon the acute removal of cholesterol, again a consequence of the charged headgroup of PtdSer [48]. It is likely that cholesterol, which makes up ~?40?mol% of PM lipids [10], helps to keep the PtdSer headgroup charge density on the inner leaflet low enough to not induce spontaneous curvature. However, once cholesterol is removed the distance between phospholipid headgroups is decreased, resulting in high spontaneous curvature capable of forming endocytic tubules [48, 71]. Indeed, increasing PtdSer levels on the inner leaflet of the PM above homeostatic levels (and therefore charge density) without concomitant cholesterol removal is also sufficient to increase formation of endocytic vesicles [48]. It is tempting to speculate that the cavin and caveolin proteins are taking advantage of this curvature-inducing property of PtdSer to induce caveolae. Thus, while cholesterol appears important for PtdSer cellular localization, it also appears to be important for modulation of PtdSer spacing and membrane curvature induction. This intimate relationship with cholesterol likely plays important roles in other PtdSer function as well, as suggested by PtdSer dynamics and interactions with caveolae [68] and signaling proteins [2, 59, 62].
The understanding of the role of PtdSer in internal membranes remains even less clear than the roles at the PM. Similar to the plasma membrane, recycling endosomes are rich in PtdSer [72] and recent work has demonstrated that PtdSer supports a variety of functions in these endosomes. The endosomal protein Evectin-2 contains a pleckstrin homology domain that binds to PtdSer rather than phosphoinositides [72]. Depletion of Evectin-2 or decreasing the availability of PtdSer prevents the movement of cholera toxin from the recycling endosome to the Golgi. Similarly, depletion of Evectin-2 and a reduction of PtdSer levels results in an inability of Golgi proteins (e.g. TGN38) to be retrieved from endosomes [72, 73]. In addition to the presence of PtdSer on the cytosolic leaflet of recycling endosomes, PtdSer flippases (e.g., ATP8A1, ATP8A2) are also required to support trafficking events. One critical effector downstream of flipped PtdSer is the Eps15 homology domain-containing protein-1 (EHD1), an ATPase with dynamin-like activity and a role in membrane remodeling required for the retrograde transport of Shiga toxin to the Golgi [74, 75]. Curiously, PtdSer, Evectin-2 and ATP8A1 have all recently been implicated as regulators of Yes-associated protein (YAP) signaling and cell proliferation [76]. ATP8A1 knockdown results in the activation of Lats, which in turn phosphorylates YAP and prevents its translocation into the nucleus. Silencing of Evectin-2 results in a decrease of Nedd4-mediated ubiquitination of Lats1, resulting in increased levels that also result in increased phosphorylation and inactivation of YAP. These studies raise several questions regarding how PtdSer and its flipping in recycling endosomes are controlling these effectors. Additionally, since recycling endosomes receive a lot of incoming membrane from the asymmetric plasma membrane, it is unclear where the luminal leaflet PtdSer is coming from to serve as a substrate for the flippases. Much is still to be learned regarding the cell physiology of PtdSer and we anticipate that the same biophysical properties PtdSer imposes on the plasma membrane will hold in endosomes and the trans-Golgi.
Conclusions
It is becoming clear through recent studies that the essential phospholipid PtdSer is important for many intracellular processes in addition to its well-characterized roles in apoptosis and blood clotting. This advancement of our understanding of the intracellular roles for PtdSer has been fueled in part by the recent development of new probes to detect PtdSer. However, as described, our knowledge of the normal roles for PtdSer in both signaling and cellular trafficking within the normal cell is still developing and many details remain to be discovered.
https://biosignaling.biomedcentral.com/articles/10.1186/s12964-019-0438-z
Let's go Chair Joseph Carleone, has Danaher been in the loop for what is going on with PS Targeting ..
3DP for tissue regeneration, biomechanics of Ebola adhesion, and more take center stage in Philadelphia
Oct 16-19
Disseminating new knowledge
...
...
Biomechanical Characterization of the Adhesion Between Enveloped Virus and Phosphatidylserine-Binding Proteins:
Wenpeng Cao, Chuqian Xiong, Zhibo Zhang, Anand Jagota, X. Frank Zhang
https://www.eurekalert.org/pub_releases/2019-10/lu-ltp101119.php
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Report on Avid published this morning
The stakes are high when Avid CDMO has $100M potential contracts looming ...maybe that is why new NEW IIS are ready
As for losses ...paper losses mean little, especially when I hear some shorts must cover soon and I guess that was the reason for some posts
The shorts that need to cover might want to look into what Mirati is a whispering about ...
PS Targeting pipelines are out there and CDMO licenses are coming, Dr Rolf Brekken knows Mirati and Xencor ties over at Mirati as Merck ...( Well we shall see what Merck needs to do...)
I imagine a 3rd party that tests MOAs of certain drugs will shake things up and PS Targeting is required
October 11, 2019
A Chlamydia pneumoniae adhesin induces phosphatidylserine exposure on host cells
Oct 11, 2019
Jan N. Galle, Tim Fechtner, Thorsten Eierhoff, Winfried Römer & Johannes H. Hegemann
Abstract
In mammalian cells, the internal and external leaflets of the plasma membrane (PM) possess different phospholipids. Phosphatidylserine (PS) is normally confined to the inner (cytoplasmic) membrane leaflet. Here we report that the adhesin CPn0473 of the human pathogenic bacterium Chlamydia pneumoniae (Cpn) binds to the PM of human cells and induces PS externalization but unexpectedly not apoptosis. PS externalization is increased in human cells exposed to infectious Cpn cells expressing increased CPn0473 and reduced in exposure to Cpn expressing decreased CPn0473. CPn0473 binds specifically to synthetic membranes carrying PS and stimulates pore formation. Asymmetric giant unilamellar vesicles (GUVs) in which PS is restricted to the inner leaflet reveal that CPn0473 induces PS externalization in the absence of other proteins. Thus our identification of CPn0473 as a bacterial PS translocator capable of specific and apoptosis-independent PS externalization during infection extends the spectrum of mechanisms intracellular pathogens use to enter host cells.
...
...
Results
CPn0473 associates with negatively charged PLs
To investigate the protein’s function further, we screened for interaction partners and found that recombinant rCPn0473 binds strongly to liposomes in pull-down experiments (Fig. 1a). Assays performed with nitrocellulose strips spotted with different lipids indicated that rCPn0473 binds to various negatively charged PLs
..
...
https://www.nature.com/articles/s41467-019-12419-8
________
So pneumoniae and that flipping PS ...John Springs Stafford is going to look mighty conflicting of interest bad it seems, because now PS Targeting will be in all of Big Pharma pipelines and Thermofisher I agree, would be a perfect place for Avid Bioservices to rise under their wings
___
Speaking of Thermofisher and Jason Stafford that left Thorpe's lab to wind up there .....
MRI Global with MUCH DTRA / BARDA contracts and using PS Targeting with Rich Richieri via Rubicon ....has a good relationship with Thermofisher : )
The puzzle pieces are coming alive and it was always about the IP assets
More to come....but new "NEW" IIS don't like any spoilers
Avid CDMO IP assets known well by Martin Hynes III works for MAPP and Eli Lilly Research Labs ...ties DTRA / BARDA via Ronald T Aimes ( ex Peregrine and VERY well aware of PS Targeting ) and MRIGlobal did much of the contract work via you guessed it, Rubicon --where Massag Parseghian and Rich Richieri landed after leaving Peregrine and are they aware of PS Targeting ? HELL YES and much more....
I will say this, if there is no competing bid as there was no competing bid back on the shift of the IP assets to Oncologie, then Roche is in on the sandbox game with the rest of them
Well we know now why all the Eli Lilly backed folks at Omeros published the PS Targeting significance back on Sept 10 2019 as it is well known that the blockade of flipped PS is vital for ALL solid tumors and ALL non responders etc etc
_____
Rubicon (directly from there website)
A modified Annexin A5 created in Dr. Reutelingspergerâ??s lab is being adapted by the Rubicon team for targeting of extracellularly-exposed PS in the tumor microenvironment. A direct PS-binder, Annexin A5 holds great promise as an immunotherapeutic agent.
http://www.rubiconbio.com/about/
(Once one sees all the PS Targeting related research Rich Richieri was in the midst of ....and now, Avid the pure play CDMO wants Richieri ? I guess the BOD did not want to be questioned about all this ...but hey, if contracts come in all is fine as they say
______
Now it gets better ...but some IIS now have all this info and more and the bottom line is that is where Eli Lilly folks come into the picture and hell, I can understand dual technology for military and civilian but when John Springs Stafford gets hired on to lie to shareholders it seems...and that is where the line is crossed
Actually the line was crossed with the death of PS Targeting inventor of Bavi etc the late Dr Phil Thorpe
_____
Martin Hynes III
Experience
Mapp Biopharmaceutical
Vice President
Mapp Biopharmaceutical
Oct 2014 - Present 5 years 1 month
San Diego , CA
Six Sigma Champion
Senior Director of Product Research and Development
Six Sigma Champion
Jan 2006 - Present 13 years 10 months
Led deployment of Six Sigma program in Product Research and Development organization of ~1500 employees
Executed over 300 Six Sigma projects that have resulted in significant cost and cycle time reductions
Lead major cross-functional drug development cycle time improvement efforts
Lead a group of 20 black belts selected for their upward potential and leadership ability
Led deployment of Six Sigma program in Product Research and Development organization of ~1500 employees
Executed over 300 Six Sigma projects that have resulted in significant cost and cycle time reductions
Lead major cross-functional drug development cycle time improvement efforts
Lead a group of 20 black belts selected for their upward potential and leadership ability
Lilly Research Laboratories
Senior Director, Six Sigma Champion
Lilly Research Laboratories
Jan 1979 to Present 40 years 10 months
Eli Lilly
Senior Director
Eli Lilly
2009 - Sep 2014 5 years
Senior Director
Product Research and Development
Six Sigma Champion
Senior Director
Product Research and Development
Six Sigma Champion
Eli Lilly
Director of Quality and Operations
Eli Lilly
Feb 2002 -Dec 2005 3 years 11 months
Quality
Led the development of a training, procedures and records management organization that provides a competitive advantage by reducing regulatory risk and meeting FDA Quality System expectations
Developed and delivered annual Quality updates on Good Manufacturing Practices and Good Laboratory Practices regulatory changes
Lead Quality oversight committee
Receipt of Quality Advocate Award
Supervised a staff of approximately 50
Operations
Formed project management group to manage molecule-enabling projects
Developed functional capacity management system, business process and computer system to support development of all molecule and molecule-enabling projects
Supervised a staff of approximately 10
Quality
Led the development of a training, procedures and records management organization that provides a competitive advantage by reducing regulatory risk and meeting FDA Quality System expectations
Developed and delivered annual Quality updates on Good Manufacturing Practices and Good Laboratory Practices regulatory changes
Lead Quality oversight committee
Receipt of Quality Advocate Award
Supervised a staff of approximately 50
Operations
Formed project management group to manage molecule-enabling projects
Developed functional capacity management system, business process and computer system to support development of all molecule and molecule-enabling projects
Supervised a staff of approximately 10
Sh
Lilly Research Laboratories
Director of Global Business Integration Project Implementation
Lilly Research Laboratories
Jun 2000 - Feb 2002 1 year 9 months
Led the implementation of the SAP enterprise system in the global Lilly Research Laboratories organization
Including Human Resources, Financial, Clinical Grants and Project Systems Management functionality
Developed a global communication and change management strategy for Lilly Research Laboratories employees in more than 50 countries
Delivered project on time and within approved scope to over 10,000 global research employees
Largest implementation of SAP Project Systems time entry system ever undertaken
Making Lilly the first major pharmaceutical company to be able to integrate drug development project timelines and costs within an enterprise system
This system is being utilized successfully for both project management and capacity management in Lilly's global research organization
Approximately 25 direct reports
Director of Projects Management
Led the implementation of the SAP enterprise system in the global Lilly Research Laboratories organization
Including Human Resources, Financial, Clinical Grants and Project Systems Management functionality
Developed a global communication and change management strategy for Lilly Research Laboratories employees in more than 50 countries
Delivered project on time and within approved scope to over 10,000 global research employees
Largest implementation of SAP Project Systems time entry system ever undertaken
Making Lilly the first major pharmaceutical company to be able to integrate drug development project timelines and costs within an enterprise system
This system is being utilized successfully for both project management and capacity management in Lilly's global research organization
Approximately 25 direct reports
Director of Projects Management
Sh
Eli Lilly
16 years
Director of Project Management
1994 - 2001 7 years
Director of Project Management for Neuroscience
Director of Project Management for Neuroscience
Director of Projects Management
Jan 1995 - Jan 1997 2 years 1 month
Had line management responsibility for Neuroscience and Endocrine project managers and their associates (approximately 30 people)
Played a key role in the reengineering of Lilly Drug Development Process (Quality Speed Values (QSV))
Developed projects management core competency model with Human Resource component
Utilized in professional titles process, individual development plans, and collection of team feedback
Seen as "one of the most comprehensive and effective competency models in industry today" (Kerzner, 2000, 2003)
Established project management workbench
Led the team to develop a web site for Drug Development Information
Team received the 1999 President's Award for this contribution
Several major companies offered to purchase this tool
Led the development of Milestone reporting
Led the development of the milestone tracking system and database
Central source of all key milestones and project history
Provided monthly status reports to government committees
Updated cross-functional drug development process maps
Led the development of the facilitated planning process for drug development teams that led to improved development plans as evidenced by improved on-time delivery
A radical redesign of our planning process
Seen as "best in class" within the industry
Had line management responsibility for Neuroscience and Endocrine project managers and their associates (approximately 30 people)
Played a key role in the reengineering of Lilly Drug Development Process (Quality Speed Values (QSV))
Developed projects management core competency model with Human Resource component
Utilized in professional titles process, individual development plans, and collection of team feedback
Seen as "one of the most comprehensive and effective competency models in industry today" (Kerzner, 2000, 2003)
Established project management workbench
Led the team to develop a web site for Drug Development Information
Team received the 1999 President's Award for this contribution
Several major companies offered to purchase this tool
Led the development of Milestone reporting
Led the development of the milestone tracking system and database
Central source of all key milestones and project history
Provided monthly status reports to government committees
Updated cross-functional drug development process maps
Led the development of the facilitated planning process for drug development teams that led to improved development plans as evidenced by improved on-time delivery
A radical redesign of our planning process
Seen as "best in class" within the industry
Show less
Director Of Quality Assurance
1990 â?? 19944 years
Director Of Quality Assurance for Research and Development
Director Of Quality Assurance for Research and Development
Director of Clinical Research
Jan 1987 â?? Jan 19903 years 1 month
Director of Clinical Research
1987 â?? 19903 years
Lilly Japan, Kobe Japan
Lilly Japan, Kobe Japan
Director of Clinical Research
Jan 1985 â?? Jan 19872 years 1 month
the Kobe affiliate from 3 to 48 people
Led the newly-formed clinic
Nice update and biomarkers / protein pathways are key to FDA approval
I received a couple messages that the PS Targeting - New England Peptide company video if it does not auto play or signed in ...just do a search for "Sam Massoni exosomes"
Answers must be given to shareholders ...it is and always was about the IP assets and since flipped PS exists on all stressed cells leading to inflammation leading to diseased cells leading to cancer, then that is the Targeting of CDMO IP assets
Ampersand Capital that now controls Avid CDMO BOD, it seems....is not being truthful and if they are aligned with John Springs Stafford, one better learn to complain loud and clear
______
October 8, 2019
Wellesley equity firm buys majority of Gardner biotech
Sam Massoni, president and CEO of New England Peptide
By Sam Bonacci
Gardner biomanufacturer New England Peptide has received a majority recapitalization from Wellesley private equity firm Ampersand Capital Partners, as the company sets its sights on continued expansion.
New England Peptide designs and manufactures peptide and antibody solutions for drug, vaccine and diagnostic development organizations worldwide. The investment will be used to support the company's worldwide growth initiatives, according to Ampersand, including expanding peptide synthesis capabilities.
The amount of Ampersand's investment was not disclosed.
Ampersand is a middle market private equity firm focused on growth-oriented investments in the healthcare sector with offices in Greater Boston and Amsterdam, Netherlands.
As part of the transaction, José de Chastonay will become the executive chairman of the company's board of directors. He has served in a number of senior management and advisory roles within various research chemical manufacturing organizations, most recently as chief marketing officer and Member of the corporate executive committee at Swiss technology company Bachem Holding AG.
New England Peptide CEO and Founder Sam Massoni said in a statement he was excited to partner with de Chastonay and move forward with assistance from Ampersand.
https://www.wbjournal.com/article/wellesley-equity-firm-buys-majority-of-gardner-biotech
Good question and knowing manufacturing the demand of an approved BLA / FDA approval etc is required by FDA...does Avid and Oncologie meet for each BP customer on timelines of an approval. Some info they do not want public now, so they will certainly shift away to answer
Omeros CLEARLY stated PS Targeting is pending within their pipeline and the manufacturing is 100% a requirement ...now with all the ex Eli Lilly ties among Omeros and Oncologie Inc, a Manhattan Project way forward for PS Targeting was in play
That is false, there are big milestone payments and Omeros has Breakthru Designation given already from FDA for PS Targeting and BLA filed : )
Hold those shares of Avid CDMO because new IIS have other information that you may not be privy to
_____
Sept 10, 2019
Omeros Corporate Presentation
Pg6 (read all ...just highlighting)
"Phosphatidylserine(PS) is a newly discovered GPR174 agonist."
"Represents a new axis in cancer Immunotherapy for all solid tumors"
"Could address non-responders to all current therapies"
READ all 51 pages of Corportate Presentation and PS is STRESSED as high importance and BLA filed / Breakthru Designation already accepted ....says NO MORE patients required / BLA data significant
https://investor.omeros.com/static-files/32f2f111-fc8f-47ec-b3ec-4a8a3ef931ac
___________
Omeros, FDA Agree On Endpoint For Pivotal Trial Of Small Blood Vessel Damage Treatment
Omeros announced Thursday ahead of the market open that it has reached an agreement with the FDA on the response-based primary endpoint of its pivotal trial to support the biologic license application for narsoplimab.
Narosoplimab, codenamed OMS721, is Omeros' lead human monoclonal antibody candidate for the treatment of hematopoietic stem cell transplant-associated thrombotic microangiopathy, or HSCT-TMA.
HSCT-TMA is a severe complication of HSCT, affecting about 20-30% of recipients. TMA is a condition where small blood vessels are damaged due to an endothelial injury, which in turn affects key organs such as the brain, kidney and heart.
Why It's Important
HSCT-TMA has no approved treatment, and narsoplimab is the only drug in development for the condition. The investigational asset has been granted Breakthrough Therapy Designation.
Omeros expressed confidence that the study will meet the primary endpoint.
What's Next
Omeros said it will now complete the ongoing data collection from medical records of patients already treated with narosplimab either in the clinical trial or under compassionate use for inclusion in the clinical sections of the BLA.
It also plans to meet with the European Medicines Agency's rapporteurs this summer to pave the way for European approval.
The company hopes to complete and submit the BLA, as well as the MAA for European approval.
Omeros has the leeway to make a rolling submission to the FDA, which allows it to submit the completed portions without having to wait for all the sections to be completed.
https://m.benzinga.com/article/14060738
____________
Narsoplimab (OMS721)
Narsoplimab is a human monoclonal antibody targeting mannan-binding lectin-associated serine protease-2 (MASP-2), the effector enzyme of the lectin pathway of the complement system. The lectin pathway is one of the principal pathways of complement and is activated primarily by tissue damage and microbial infection. Importantly, inhibition of MASP-2 does not appear to interfere with the classical complement pathway, a critical component of the acquired immune response to infection. This novel, proprietary drug is designed to prevent complement-mediated inflammation and endothelial damage while leaving intact the respective functions of the other pathways of innate immunity.
HEMOTOPOIETIC STEM CELL TRANSPLANT-ASSOCIATED THROMBOTIC MICROANGIOPATHY (HSCT-TMA)
Narsoplimab has been granted FDA Breakthrough Therapy designation in patients who have high-risk HSCT-TMA, as well as Orphan Drug designation for the prevention of complement-mediated TMAs and for the treatment of HSCT-TMA. In the European Union, narsoplimab has been designated an Orphan Medicinal Product for treatment in hematopoietic stem cell transplantation.
In a late-stage clinical trial compared to an historical control, narsoplimab improved the estimated median overall survival in high-risk HSCT-TMA patients by an order of magnitude and improved 100-day survival by approximately six-fold.
With the FDA’s only Breakthrough Therapy designation awarded for this disorder, as well as Orphan Drug designations from both the FDA and the European Medicines Agency, we currently are preparing marketing applications for the approval of narsoplimab in both the US and Europe to treat HSCT-TMA.
IgA NEPHROPATHY
Narsoplimab has also received FDA Breakthrough Therapy and Orphan Drug designations for the treatment of IgA nephropathy and Orphan Medicinal Product designation for IgA nephropathy in the European Union.
In a Phase 2 clinical trial, narsoplimab reduced proteinuria in IgA nephropathy patients by 50%-90% and stabilized or increased glomerular filtration rates – effects unmatched by any other drug in development for IgA nepropathy.
With the FDA’s only Breakthrough Therapy designation awarded for this disorder, as well as Orphan Drug designations from both the FDA and the European Medicines Agency, narsoplimab is advancing through a Phase 3 clinical program to treat IgA nephropathy.
ATYPICAL HEMOLYTIC UREMIC SYNDROME (aHUS)
Narsoplimab has received FDA Fast Track designation for the treatment of aHUS. Phase 2 clinical results are positive and a Phase 3 clinical program is underway.
________________
Now there is ample evidence that flipped PS to increases and exists in IgA nepropathy as Omeros has discovered / along with other oncology indications / with one example seen below detailing other research
......
_________________
Increased phosphatidylserine-exposing microparticles and their originating cells are associated with the coagulation process in patients with IgA nephropathy.
He Z, et al. Nephrol Dial Transplant. 2016.
Authors
He Z1, Zhang Y2, Cao M2, Ma R2, Meng H3, Yao Z2, Zhao L2, Liu Y2, Wu X2, Deng R2, Dong Z4, Bi Y4, Kou J3, Novakovic V5, Shi J2, Hao L1.
Author information
1
Department of Nephropathy and Hemodialysis, First Hospital, Harbin Medical University, Harbin, China.
2
Department of Hematology, First Hospital, Harbin Medical University, Harbin, China.
3
Department of Cardiology, Second Hospital, Harbin Medical University, Harbin, China.
4
Department of Cardiology, First Hospital, Harbin Medical University, Harbin, China.
5
Research Department, VA Boston Healthcare System, Boston, MA, USA.
Citation
Nephrol Dial Transplant. 2016 May;31(5):747-59. doi: 10.1093/ndt/gfv403. Epub 2015 Dec 15.
Abstract
BACKGROUND: Relatively little information is available about phosphatidylserine positive (PS(+)) microparticles (MPs) and their originating cells in IgA nephropathy (IgAN) despite well-established intraglomerular coagulation. Our objectives were to detect PS exposure on MP membranes and MP-origin cells and to evaluate its role in procoagulant activity (PCA) and fibrin formation and their association with pathological lesions in the disease.
METHODS: Patients with IgAN and healthy controls were studied. Lactadherin was used to quantify PS exposure on MPs and MP-origin cells. PCA of MPs and MP-origin cells was evaluated by clotting time and purified coagulation complex assays. Fibrin production was determined by turbidity. PS exposure, fibrin strands and FVa/Xa binding were observed on MPs/cells using confocal microscopy.
RESULTS: Using flow cytometry, we found that IgAN patients had high levels of PS(+) MPs derived from lymphocytes, monocytes, neutrophils, platelets, erythrocytes and endothelial cells (ECs). The PS exposure on MP-origin cells also increased in these patients. MPs and MP-origin cells (leukocytes, platelets and erythrocytes) isolated from IgAN patients and ECs cultured with IgAN serum had a significantly shorter median coagulation time (P < 0.001), higher median intrinsic FXa (P < 0.001) and higher thrombin (P < 0.001) generation than controls. These coagulation functional assays were associated with the glomerular lesions. The lesions were also correlated with glomerular fibrin deposition (all P < 0.05). In the presence of patient MPs or their related cells, fibrin formation peaked faster with a higher maximum turbidity when compared with healthy controls. Blocking PS with lactadherin in the IgAN group prolonged coagulation time to control levels, inhibited the PCA up to 80% and markedly reduced fibrin formation. More importantly, we observed that fibrin strands formed on MPs and ECs in the same regions that bound lactadherin, similar to the FVa/Xa costaining.
CONCLUSIONS: We find that high levels of PS(+) MPs and the MP-origin cells are associated with the coagulation process in IgAN, and this may provide a previously unrecognized contribution to intraglomerular coagulation.
https://www.ncbi.nlm.nih.gov/m/pubmed/26673909/
_________________
Omeros publishing "minimum" info regarding PS Targeting IP is important (if one listened closely, Omeros has much more info being held for confidentiality...and for any IIS contact I don't trust because I had no idea who he/she really was and again, will not listen to any to nicely request to stop mentioning certain puzzle pieces because Avid Bioservices BOD have failed to update their website and Stafford failed 100% for taking up the job to manipulate markets due to not getting all the information and playing dumb
_______
I wonder how far Roche will go, because Anita Kavlie had much info with her workings and NEW knowledge behind the late Dr Phil Thorpe that stirred up Big Pharma with his research and findings. Kyle also now at Halozyme
______
Patents by Inventor Anita Kavlie
Anita Kavlie has filed for patents to protect the following inventions.
This listing includes patent applications that are pending as well as patents that have already been granted by the United States Patent and Trademark Office (USPTO).
Compositions for Inhibiting MASP-2 Dependent Complement Activation
Publication number: 20190119402
Abstract: The present invention relates to anti-MASP-2 inhibitory antibodies and compositions comprising such antibodies for use in inhibiting the adverse effects of MASP-2 dependent complement activation.
Type: Application
Filed: July 13, 2018
Publication date: April 25, 2019
Inventors: Thomas Dudler, Wayne R. Gombotz, James Brian Parent, Clark E. Tedford, Anita Kavlie, Urs Beat Hagemann, Herald Reiersen, Sergej Kiprijanov
ANTIBODIES AGAINST HUMAN ANGIOPOIETIN 2
Publication number: 20180282404
Abstract: The present invention relates to antibodies against human Angiopoietin 2 (anti-ANG-2 antibodies), methods for their production, pharmaceutical compositions containing said antibodies, and uses thereof.
Type: Application
Filed: February 28, 2018
Publication date: October 4, 2018
Applicant: Hoffmann-La Roche Inc.
Inventors: Ulrich Brinkmann, Remko Albert Griep, Klaus Kaluza, Anita Kavlie, Christian Klein, Joerg Thomas Regula, Werner Scheuer
Compositions for inhibiting MASP-2 dependent complement activation
Patent number: 10047165
Abstract: The present invention relates to anti-MASP-2 inhibitory antibodies and compositions comprising such antibodies for use in inhibiting the adverse effects of MASP-2 dependent complement activation.
Type: Grant
Filed: September 13, 2016
Date of Patent: August 14, 2018
Assignee: Omeros Corporation
Inventors: Thomas Dudler, Wayne R. Gombotz, James Brian Parent, Clark E. Tedford, Anita Kavlie, Urs Beat Hagemann, Herald Reiersen, Sergej Kiprijanov
BISPECIFIC ANTI-VEGF/ANTI-ANG-2 ANTIBODIES
Publication number: 20170369566
Abstract: The present invention relates to bispecific antibodies against human VEGF and against human ANG-2, methods for their production, pharmaceutical compositions containing said antibodies, and uses thereof.
Type: Application
Filed: May 23, 2017
Publication date: December 28, 2017
Applicant: Hoffmann-La Roche Inc.
Inventors: Monika Baehner, Ulrich Brinkmann, Guy Georges, Remko Albert Griep, Sabine Imhof-Jung, Anita Kavlie, Hubert Kettenberger, Christian Klein, Joerg Thomas Regula, Wolfgang Schaefer, Juergen Michael Schanzer, Werner Scheuer, Stefan Seeber, Markus Thomas
BISPECIFIC, BIVALENT ANTI-VEGF/ANTI-ANG-2 ANTIBODIES
Publication number: 20170240626
Abstract: The present invention relates to bispecific, bivalent antibodies against human vascular endothelial growth factor (VEGF/VEGF-A) and against human angiopoietin-2 (ANG-2), methods for their production, pharmaceutical compositions containing said antibodies, and uses thereof.
Type: Application
Filed: October 4, 2016
Publication date: August 24, 2017
Applicant: Hoffmann-La Roche Inc.
Inventors: Monika Baehner, Sabine Imhof-Jung, Anita Kavlie, Hubert Kettenberger, Christian Klein, Joerg Thomas Regula, Wolfgang Schaefer, Juergen Michael Schanzer, Werner Scheuer, Kay-Gunnar Stubenrauch, Markus Thomas
...
...
...
https://patents.justia.com/inventor/anita-kavlie
_________
Patents Assigned to Affitech AS
ANTIBODIES
Publication number: 20160244527
Abstract: The present invention provides antibodies which bind to CXC chemokine receptor 4 (CXCR4) and which do not induce significant apoptosis of CXCR4 expressing cells. Also provided are inter alia immunoconjugates and compositions comprising such antibodies and methods and uses involving such antibodies, particularly in the medical and diagnostic fields.
Type: Application
Filed: May 11, 2016
Publication date: August 25, 2016
Applicant: AFFITECH RESEARCH AS
Inventors: Anita KAVLIE, Sergej Michailovic KIPRIJANOV
Anti-VEGF antibody compositions and methods
Patent number: 9421256
Abstract: Disclosed are human antibodies that specifically inhibit VEGF binding to only one (VEGFR2) of the two primary VEGF receptors. The antibodies effectively inhibit angiogenesis and induce tumor regression, and yet have improved safety due to their specificity. The present invention thus provides new human antibody-based compositions, methods and combined protocols for treating cancer and other angiogenic diseases. Advantageous immunoconjugate compositions and methods using the new VEGF-specific human antibodies are also provided.
Type: Grant
Filed: February 15, 2013
Date of Patent: August 23, 2016
Assignees: Affitech Research AS, Peregrine Pharmaceuticals, Inc.
Inventors: Anita Kavlie, Kyle Schlunegger
https://patents.justia.com/assignee/affitech-as
_________________
Anita Kavlie
Oslo University Hospital · Department of Pathology
Top co-authorsView all
Christian Klein
Head Oncology Programs & Department Head Cancer Immunotherapy Discovery at Roche Pharmaceutical Research and Early Development,
Ulrich Brinkmann
Roche
Markus Thomas
Philip E Thorpe
University of Texas Southwester
https://www.researchgate.net/profile/Anita_Kavlie/amp
_____________
Kyle, ex Peregrine sits over at Halozyme and there is much still to this day being well hidden from Peregrine shareholders and for the latest request that was sent on where Omeros came from...well, Peregrine collaborators and Roche
____________
Pharmexa announces further information about Affitech AS and Pharmexa A/S prior to the planned Extraordinary General Assembly in Pharmexa
April 7, 2009
...
...
An Alzheimer Disease vaccine (PX106) - licensed to the Danish pharmaceutical
company H. Lundbeck A/S. H. Lundbeck holds an exclusive global license for
PX106 for the treatment of Alzheimer's disease.
The strengths of the combined company
Affitech's proprietary antibody technology platform has been used successfully
to discover antibodies for several of its collaboration partners which included
Roche, Peregrine, Xoma, NatImmune, Viventia and Omeros. These technologies
include the Molecule-Based Antibody Screening or MBAS and Cell-Based Antibody
Selection or CBAS™ systems. Management believes that the CBAS system not gives
significant opportunities for the discovery of novel antibodies against cell
surface targets such as G-Protein-Coupled Receptors (GPCRs) but also against
cancer stem cell targets. With the recent consolidation in the antibody
discovery industry, the combined company is one of few remaining independent
players in the field.
...
...
https://www.globenewswire.com/news-release/2009/04/07/7764/0/en/Pharmexa-announces-further-information-about-Affitech-AS-and-Pharmexa-A-S-prior-to-the-planned-Extraordinary-General-Assembly-in-Pharmexa.html
Exciting times ahead for Avid IP assets, though the Avid Bioservices have made a clear attempt to cut off shareholders and their requests to make it onto the homepage and further, let shareholders know what protection they have in place re: Oncologie Inc restricting access to PS Targeting collaborations
I doubt some IIS knew how close RTW and Perceptive and others are to Merck
How many trials are active right now ..publically .. with PS Targeting?
How many are not known to Avid shareholders ...and worse, Avid BOD playing dumb
_____
Brekken Lab(before it was merged with Dr. Thorpes Lab)
Juliet Carbon
Jason Toombs
Shanna Arnold
Lee Rivera
Marie Burdine
Laura Sullivan
Kristi Lynn
Amanda Kirane
Mike Dellinger
Puja Gupta
Christina Roland
Sean Dineen
Collaborators:
Jason Fleming – MDACC
Thomas Wilkie
John Minna
Joan Schiller
Philip Thorpe
Roderich Schwarz
Adi Gazdar
Hiromi Yanagisawa
Tom Kodadek- Scripps
Joyant Pharmaceuticals
https://www.pancan.org/section_facing_pancreatic_cancer/learn_about_pan_cancer/educational_events/past_symposia_presentions/dallas10/Research%20in%20Pancreatic%20Cancer_Brekken.pdf
_____
Immunovant is merging with Health Sciences Acquisitions Corporation, a $115 million blank check company sponsored by RTW Investments and backed by Adage Capital, Cormorant, Eventide and Perceptive Advisors. In addition to around $100 million confirmed to be in the bank, RTW and Roivant, alongside BVF Partners, have put together a $35 million private “bridge financing.”
“We believe IMVT-1401 is a uniquely compelling asset within the FcRn drug class, which we expect will become a cornerstone therapy for treating many auto-antibody driven diseases,” said Roderick Wong, the chief investment officer of RTW, who took charge of HSAC, in a statement.
Wong will now step aside from the helm to make room for Immunovant CEO Pete Salzmann to run the combined entity, of which current Immunovant shareholders will retain 77%. They may be awarded more shares if the price goes up.
The neonatal Fc receptor (FcRn) target is believed to be implicated in a range of IgG-mediated autoimmune diseases. Immunovant was founded last year after licensing its lead compound — a subcutaneous injection — from South Korea’s HanAll Biopharma.
Salzmann, an Eli Lilly vet, has steered the drug through a Phase I program and kicked off Phase IIa trials for Graves’ ophthalmopathy and myasthenia gravis, both of which will be funded by the transaction. A third IND is planned for warm autoimmune hemolytic anemia.
Immunovant is the fourth public company among Roivant’s subsidiaries, a group that has grown to 20 — though only 16 have been disclosed, with the latest introduction of Cytovant. Ramaswamy, who’s built his Vant empire on a web of deals, has managed to secure sizable IPOs for Axovant, Myovant and Urovant, though all their shares have slide substantially since respective public debuts.
Execs had originally pencilled in a $100 million IPO for Dermavant, but after postponing that plan once they officially withdrew the application on the same day Roivant announced a sweeping $3 billion deal with Sumitomo Dainippon Pharma that gives the Japanese pharma rights to at most 11 Vants (Dermavant was not explicitly named).
https://endpts.com/vivek-ramaswamy-engineers-new-deal-with-rtw-to-take-pete-salzmanns-immunovant-public/
Cheynew, green days ahead for sure with Avid CDMO
Question to the board, with the pressure coming down on Big Pharma MDs and researchers and 'understanding ..' the legal aspect an MD takes...would criminal charges be far fetched to those MDs that helped in the delay or possibly halting of PS Targeting due to being somewhat bribed by BP $$$$ ?
As MDs that abuse in oaths re: opioid cases...shall it be debated in the Millions of lives that also were affected by shorting / delaying / etc etc a drug ( PS Targeting ) drug that is required? Non disclosures mean nothing in lawsuits
Martin Edelman knew
Jedd Wolchok knew
Scott Antonia knew
David Carbone knew
Dmitry Gabrilovich knew
The list goes on and on and on markers can now unequivacally PROVE the protein pathways that are bad and good
Jerome Galon and many others or even Omeros ...can make a further statement and stop Big Pharma in one more delay
Cor, you seem to have amassed a rather large amount of pointless posts of non material information
Who told you the IP surrounding PS Targeting was not of value and who ever said Avid CDMO future revenues are not hitched to the IP?
Maybe Lanny Breuer that left DOJ for safety to Covington Burling failed to disclose info as the DOJ knows right now the value of the IP surrounding PS Targeting has been inching its way to China by way of Ronin Capital John Springs Stafford
I have been told 100% different ...from your opinion and by the way...let's assume IIS are at HIGHEST levels ever for just CDMO and not IP, why are they about to increase again : )
Be prepared ...IIS know things you may not and the IP surrounding PS Targeting will be seen by all
The DOJ had been pressured and Lanny is not there to just turn a blind eye on Big Pharma cancer cures via PS Targeting
Merck is hiding info behind Avid Bioservices shareholders
Ann O'Connell Adams ex clerk in Fargo ND and ex Covington & Burling (Merck legal advised...) and now DOJ criminal division KNOWS and she knows ex Covington & Burling legal now working for Merck = Jennifer Zachary
All better start making noise because Merck is hiding info and PS Targeting IP was held back again ...by John Springs Stafford
I guess it is true, that certain IIS on accumulation path have a requirement to wait in order....till the first trading days of 3rd quarter
It does match the prior pattern of first trading days of 2nd qtr
Hold those shares as it is all about accumulation
I wonder if a whistleblower gets made public for the FDA and IO drugs which was all due to immune systems primed with a PS Trgeting drug prior in Sunrise phase III
So in Feb 2019 we have some others trying to fight cancer and trying to figure out how to best improve fendiline. Since Omeros and others knowing that there are two brakes on the immune system, we now see just in Aug 2019 that researchers below FOUND a way to battle cancer in a more efficacious way.
Betabodies is Bavituximab 2.0 and it is amazing how patents become new again with a slight change to the targeting of flipped PS, equaling more license fees and royalties to CDMO
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I like the Bavituximab mention 13 times in the Corning patent
I noticed no diabetics allowed in many earlier Bavi trials
Uncontrolled disease - diabetes
https://clinicaltrials.gov/ct2/show/NCT00669565
Unlike Sunrise Phase III that accepted diabetics
Sunrise Phase III exclusions ...diabetics no longer on exclusion list
https://clinicaltrials.gov/ct2/show/NCT01999673
...and as for the very new Corning patent that names Bavituximab as anti-diabetic
Yes I was told that and now some other IIS are prepared
John Springs Stafford seemed to have completely misled some investors and although the slow bleed started years ago... some interesting facts coming out now that will make John Stafford look bad
500 Patents with Bavituximab is quite relevant when we are talking 15% of net profits
Dana Darber / Gordon Freeman had this one and most importantly, reduction in off target toxicities
John Springs Stafford would look really bad and will look really bad once the website is updated
It will be updated but many more emails must be sent into the company and Mackey new BOD never was shown the shareholder letters that all sent in?
Pressure needs to be put on... or more 200k share transfers going to be triggered after hours
The new IIS are aware
Avid Bioservices CDMO will receive much licensing fees from their IP assets and the question remains what incentives John Springs Stafford received for his role
Thanks for the update on all patents mentioning Bavituximab etc because it has DOUBLED since I last checked and I was only researching all the top Big Pharma patents that would require licenses
A third party test, to test MANY drugs to verify which BPs have PS Targeting drugs would be coming and that will surprise all
Some more reminders how Omeros poachinh from Merck
In the end, it is BP vs BP and all will require PS Targeting and hedge fund vs hedge fund as all hedge funds will require CDMO as they have Apple
More IIS will be getting this information
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Danielle Aldredge
Sr Scientist II at Omeros Corporation
Seattle, Washington
Biotechnology76
Experience
Sr Scientist II
Omeros Corporation
March 2019 – Present 7 months
Senior Scientist
Merck
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Sara Goldstein ties to Univ of PA knowledge of PS Targeting also now at Omeros and Univ Of PA knows well of PS Targeting Biomarkers
I understand but what of Omeros? No one is mentioning they just published Sept 10, 2019 that there are two brakes and PS Targeting required
PS Regulates Tumor Immunity
If one reads that post again, I don't see Omeros publishing how important PS Targeting is on Sept 10, 2019
More importantly, they (Omeros) have MORE unpublished data that is being held back as they say it will be presented at a future conference