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2 Peregrine Posters at SITC/Wash Nov7-10 - both on the blockage of PS-mediated immunosuppressive checkpoints by PS-Targeting antibodies. Abstracts below…

Nov7-10 2013 “28th Annual Meeting of the Society for Immunotherapy of Cancer (SITC)”, WashDC
“The yearly SITC Annual Meeting & Associated Programs serve as the primary SITC organized events and the premier destination for scientific exchange, education, and networking in the cancer immunotherapy community… By bringing together over 800 domestic & intl. basic, clinical, and translational scientists from academia, gov’t, and the biotech/pharmaceutical industry, in an interactive, educational environment, SITC's scientific programming helps bridge the "bench to bedside" gap between translational research, development, and clinical practice.”
http://www.sitcancer.org/2013
Schd: SITC: http://www.sitcancer.org/2013/annual-meeting/schedule
Abstracts: http://www.immunotherapyofcancer.org/supplements/1/S1/all
... Journal for ImmunoTherapy of Cancer 2013, (Suppl1 (7Nov2013)
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Peregrine’s 2 Posters:
#P151 “Targeting of Phosphatidylserine by Monoclonal Antibodies Reverses an Immunosuppressive Checkpoint Inducing Innate and Specific Anti-Tumor Responses”
Jian Gong, Rich Archer, Van Nguyen, Jeff Hutchins, Bruce Freimark (Peregrine)
ABSTRACT: Phosphatidylserine (PS) is a phospholipid normally residing in the inner leaflet of the plasma membrane and becomes exposed on tumor vascular endothelial cells (ECs) and tumor cells, and exposure is enhanced in response to chemotherapy, irradiation and oxidative stresses in the tumor microenvironment. PS exposure in tumors promotes an immunosuppressive microenvironment which includes the recruitment of myeloid derived suppressor cells (MDSCs) and M2-like macrophages as well as the production of anti-inflammatory cytokines. Binding of PS targeting antibodies on tumor endothelial cells, tumors and their secreted microparticles triggers a Fc-FcR mediated pro-inflammatory cellular and cytokine response that reverses this immunosuppressive, PS meditated checkpoint thereby enhancing anti-tumor immunity. A chimeric anti-PS antibody, bavituximab, is being used in combination with chemotherapy to treat patients with solid tumors in multiple late-stage clinical trials. Using syngeneic tumors and human tumor xenografts in mice, we demonstrate PS targeting antibodies specifically localize to PS exposed on membranes of tumor blood vessels, tumors, tumor-infiltrating inflammatory cells and microparticles. Analysis of blood, spleens and tumor tissue demonstrates that 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 the PS-mediated immunosuppressive checkpoint, and reactivation of M1 macrophages, dendritic cell maturation 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.
http://www.immunotherapyofcancer.org/content/1/S1/P151

#P154 "Phosphatidylserine-targeting Antibody Induces M1 Macrophage Polarization, Promotes Myeloid Derived Suppressor Cell Differentiation And Boosts Tumor-Specific Immunity”
Xianming Huang, Yi Yin, Dan Ye, Rolf Brekken, Philip Thorpe (UTSW)
ABSTRACT: Phosphatidylserine (PS) is a potent immunosuppressive lipid typically segregated to the inner leaflet of the plasma membrane. PS is externalized on tumor vasculature, tumor-derived exosomes, and tumor cells in the tumor microenvironment and externalization is markedly enhanced by therapy (e.g., radiation, chemotherapy, and/or androgen deprivation). Externalized PS interacts with immune cells where it actively promotes immunosuppression and tumor progression by expansion of myeloid derived suppressor cells (MDSCs) and M2-like tumor associated macrophages (TAMs). Bavituximab is a PS-targeting antibody that is being evaluated in multiple late-stage clinical trials in cancer patients. Here we show that treatment of PC3 tumor-bearing mice with 2aG4, a murine-version of bavituximab, significantly depleted M2-likeTAMs and MDSCs and increased the presence of M1-like TAMs and mature dendritic cells. In addition, PS blockade markedly altered the cytokine balance in the tumor microenvironment from immunosuppressive to immunostimulatory. Furthermore, in the immune-competent TRAMP mouse prostate tumor model, combination treatment of anti-PS antibody with castration induced strong tumor-specific T-cell immunity that resulted in significantly improved tumor free long-term survival and apparent cures in 35% of the animals, compared to no long-term survivors in groups treated with either single agent. In vitro studies confirmed that anti-PS re-polarized TAMs from an M2 to M1-like phenotype and drove MDSCs to differentiate into M1-like macrophages and functional dendritic cells. These data suggest that PS expression on the external cell surface defines an upstream immune checkpoint that is primarily responsible for expansion of MDSCs and M2-like TAMs in tumors. The results further support that blockade of the PS signal by bavituximab treatment can reverse this immune checkpoint suppression and promote therapeutically effective anti-tumor immunity.
http://www.immunotherapyofcancer.org/content/1/S1/P154

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NOTE: Peregrine presented at the 27th annual SITC mtg. in Oct.2012:
Track: Therapeutic Monoclonal Antibodies In Cancer
#176 “Targeting of Phosphatidylserine by Monoclonal Antibodies Induces Innate & 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, Univ. of Texas, SW Medical Center, Dallas, TX
3 Molecular Biology & Biochemistry, Univ. of California, Irvine, CA
2012: http://www.peregrineinc.com/images/stories/pdfs/sitc_2012.pdf