Avid Bioservices Inc (CDMO)

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5-11-16/BC-Res. article, Freimark-et-al, “PS-Targeting/Anti-PD1/Triple-MBC” - our observations demonstrate that including PS-targeting antibodies such as bavituximab can enhance the anti-tumor activity of anti-PD-1/PD-L1 treatments, not only by increasing TIL responses but also by inhibiting cytokines stimulated by single-agent anti-PD-1 therapy that serve to suppress the immune response & promote tumor progression.

5-11-16/Breast Cancer Research: “Phosphatidylserine-targeting Antibodies Augment the Anti-Tumorigenic Activity of Anti-PD-1 Therapy by Enhancing Immune Activation & Downregulating Pro-Oncogenic Factors Induced by T-Cell Checkpoint Inhibition in Murine Triple-Negative Breast Cancers”
http://breast-cancer-research.biomedcentral.com/articles/10.1186/s13058-016-0708-2
Michael J. Gray, Jian Gong, Michaela M. S. Hatch, Van Nguyen, Christopher C. W. Hughes, Jeff T. Hutchins, Bruce D. Freimark
Rec. 1-27-16, Acc. 4-22-16, Pub. 5-11-16
BACKGROUND: The purpose of this study was to investigate the potential of antibody-directed immunotherapy targeting the aminophospholipid phosphatidylserine, which promotes immunosuppression when exposed in the tumor microenvironment, alone and in combination with antibody treatment towards the T-cell checkpoint inhibitor PD-1 in breast carcinomas, including triple-negative breast cancers. . . .
CONCLUSIONS(Abstract): Our data suggest that antibody therapy targeting phosphatidylserine-associated immunosuppression, which has activity as a single agent, can significantly enhance immunotherapies targeting the PD-1 pathway in murine breast neoplasms, including triple-negative breast cancers.
CONCLUSIONS(Article): In summary, our observations demonstrate that including PS-targeting antibodies such as bavituximab can enhance the anti-tumor activity of anti-PD-1/PD-L1 treatments, not only by increasing TIL responses but also by inhibiting cytokines stimulated by single-agent anti-PD-1 therapy that serve to suppress the immune response and promote tumor progression.
COMPETING INTERESTS: Christopher C. W. Hughes is Professor & Chair, Dept of Molecular Biology & Biochemistry, Univ. of California, Irvine, and is a consultant to Peregrine Pharmaceuticals. Michaela M. S. Hatch is a research scientist working in the lab of CCWH. All other authors are employees of Peregrine Pharmaceuticals.
FULL ARTICLE: http://breast-cancer-research.biomedcentral.com/articles/10.1186/s13058-016-0708-2

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4-20-16/AACR'16 & 4-4-16/Cancer-Immunology-Res.(AACR) article, both describing preclin. data showing that Bavi combination I-O treatment (w/anti-PD-1 & anti-CTLA-4) “induces a shift in the tumor microenvironment from immunosuppressive to immune active” in Triple- Breast Cancer & Melanoma. 4-20-16 PR references a “planned clinical trial of bavituximab in combination with AstraZeneca's durvalumab under a clinical collaboration”. The AACR'16 poster #5116 (PPHM/U.Cal-Irvine) PDF now on Peregrine's website: http://www.peregrineinc.com/images/stories/pdfs/aacr-2016-gray.pdf

4-20-16/AACR'16 PR: Preclinical Data Presented at American Association for Cancer Research (AACR) Annual Meeting Demonstrate Enhanced Therapeutic Benefit of Combining a PS-Targeting Antibody With Anti-PD-1 Therapy in Models of Triple Negative Breast Cancer (TNBC)
* Statistically Significant Improvement in Overall Survival for Combination as Compared to Anti-PD-1 Therapy Alone in TNBC Models; Combination Also Protects Against Re-Challenge With TNBC Tumor Cells
* Novel Genetic Analysis Technology Further Validates Immune Modulating Mechanism of Bavituximab and Anti-PD-1 Combination; Supports Clinical Evaluation of Bavituximab and I-O Agent Combinations
http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=965932

TUSTIN, April 20, 2016: Peregrine Pharmaceuticals, Inc. (NASDAQ: PPHM, PPHMP), a biopharmaceutical company focused on developing therapeutics to stimulate the body's immune system to fight cancer, today announced the presentation of preclinical study data demonstrating enhanced anti-tumor activity and immune activation for a combination of the preclinical bavituximab equivalent (ch1N11) and anti-PD-1 therapy in models of breast cancer including triple negative breast cancer (TNBC). Additionally, new analysis conducted using the nCounter ® PanCancer Immune Profiling Panel from NanoString Technologies ® further validated previously reported findings showing that the combination treatment induced a shift in the tumor microenvironment from immunosuppressive to immune active. This was evidenced by a distinct change in immune cell phenotypes, as well as an increase in immune activating cytokines and decrease in immunosuppressive cytokines. These study results, which were presented at the 2016 American Association for Cancer Research (AACR 2016) Annual Meeting, provide further support for Peregrine's strategy of evaluating bavituximab in combination with a range of novel immuno-oncology (I-O) agents for the treatment of various cancers.

"These presented study results, particularly the significant increase in overall survival and immunity to tumor re-challenge seen with the treatment combination as compared to anti-PD-1 therapy alone, continue to strengthen our collection of translational and preclinical data supporting the potential for bavituximab to enhance the therapeutic impact of I-O agents in the treatment of cancer. In doing so, these data provide further rationale for our clinical strategy focused on studying bavituximab in combination with I-O agents targeting the PD-1/PD-L1 pathway in a range of cancers," stated Jeff T. Hutchins, Ph.D., Peregrine's VP, Preclinical Research. "With a wealth of supportive research in hand, we look forward to the continued advancement of our clinical collaborations with AstraZeneca, the National Comprehensive Cancer Network [NCCN] and Memorial Sloan Kettering Cancer Center, to further evaluate the therapeutic potential of bavituximab with novel I-O agent combinations."

Bavituximab is an investigational immunotherapy designed to assist the body's immune system by targeting and modulating the activity of phosphatidylserine (PS), a highly immune-suppressive signaling molecule expressed broadly on the surface of cells in the tumor microenvironment. Peregrine's PS signaling pathway inhibitor candidates, including bavituximab, reverse the immunosuppressive environment that many tumors establish in order to proliferate, while also activating immune cells that target and fight cancer. The preclinical equivalent of bavituximab, ch1N11, is used in animal model studies as a guide for clinical development.

As part of the study that was presented at AACR [Poster #5116 PPHM/Friemark, U.Cal-Irvine/CW-Hughes http://www.peregrineinc.com/images/stories/pdfs/aacr-2016-gray.pdf ], researchers evaluated the combination of ch1N11 and anti-PD-1 therapy versus anti-PD-1 stand-alone therapy in two well-characterized murine models of TNBC (EMT-6 and E0771). Study data showed that the combination therapy significantly enhanced overall survival (p=0.0155) and was capable of mediating complete tumor regressions in a greater number of subjects compared to single agent treatments (60% vs. 20%). Data also demonstrated that animals receiving combination treatment had significant increases in tumor associated indicators of immune system activation, including CD45+, CD8+ and CD3+ T-cells. Importantly, the combination treatment led to a prolonged anti-tumor immune response which protected the animals that achieved a complete tumor regression against a re-challenge with the same E0771 TNBC model tumor cells. This sustained anti-tumor response demonstrates the ability of the combination treatment to trigger immune system memory and support adaptive immune responses against reemerging disease in this TNBC model. All study animals experienced no signs of adverse effects or weight loss following repeated doses of all therapeutic agents.

About Bavituximab: A Targeted Investigational Immunotherapy
Bavituximab is an investigational chimeric monoclonal antibody that targets phosphatidylserine (PS). Signals from PS inhibit the ability of immune cells to recognize and fight tumors. Bavituximab is believed to override PS mediated immunosuppressive signaling by blocking the engagement of PS with its receptors as well as by sending an alternate immune activating signal. PS targeting antibodies have been shown to shift the functions of immune cells in tumors, resulting in multiple signs of immune activation and anti-tumor immune responses.

About Peregrine Pharmaceuticals, Inc.
Peregrine Pharmaceuticals, Inc. is a biopharmaceutical company developing therapeutics to stimulate the body's immune system to fight cancer. The company is focused on evaluating its lead immunotherapy candidate, bavituximab, in combination with a range of novel immuno-oncology (I-O) agents for the treatment of various cancers. One specific component of this I-O combination strategy includes a planned clinical trial of bavituximab in combination with durvalumab, AstraZeneca's investigational anti-PD-L1 immune checkpoint inhibitor, under a clinical collaboration.

In addition to its drug development programs, 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 third-party customers. For more information, please visit http://www.peregrineinc.com .
Safe Harbor *snip*
Jay Carlson, Peregrine Pharmaceuticals, Inc., 800-987-8256 [e-mail]
Stephanie Diaz (Investors), Vida Strategic Partners, 415-675-7401 [e-mail]
Tim Brons (Media), Vida Strategic Partners, 415-675-7402 [e-mail]

Apr17-20 2016: AACR 2016, New Orleans
http://www.aacr.org/Meetings/Pages/MeetingDetail.aspx?EventItemID=63
Abstracts: http://www.aacr.org/Meetings/Pages/MeetingDetail.aspx?EventItemID=63&DetailItemID=363
4-20-16/Wed. 7:30-11am, Session: IMMUNOMODULATION & IMMUNOTHERAPY
#5116: “Phosphatidylserine-Targeting Antibodies Augment Anti-Tumor Activity of PD-1 Antibodies and Alter Immuno-Profiles in Murine Triple Negative Breast Cancers”
Michael J. Gray 1, Jian Gong 1, Ryan N. Parks 1, Michaela M.S. Hatch 2, Van Nguyen 1, Christopher C.W. Hughes 2, Jeff T. Hutchins 1, Bruce D. Freimark 1
1=Peregrine Pharmaceuticals; 2=Univ. of Calif./Irvine
ABSTRACT: Current treatments for triple negative breast cancers rely primarily upon surgical intervention and chemotherapy. Unfortunately, chemotherapies have the propensity to help establish an immunosuppressive condition in part though exposure of phosphatidylserine (PS) in the tumor microenvironment. We demonstrate that treatment of the murine triple negative breast cancer E0771 using a PS-targeting antibody inhibits in vivo growth, and significantly enhances the anti-tumor activity of antibodies directed to the checkpoint inhibitor PD-1. Combinational treatment by antibodies targeting PS & PD-1 increased the number of tumor infiltrating lymphocytes (TILs) to a greater extent than observed with single-arm therapies. Furthermore, combination of PS & PD-1 targeting antibodies provides a distinct survival advantage over treatment by either agent alone, which correlates with an increase in complete tumor regression and the onset of a durable immune mediated response capable of rejecting a secondary challenge by the same tumor. Finally, immune-profiling analysis of tumor RNA using Nanostring revealed that the combination antibody therapy enhanced immune regulatory pathways including MHC class I/II expression, antigen processing and presentation, and leukocyte and macrophage functions. Combined, our data suggest that in triple negative breast cancers antibody therapy blocking PS-associated immunosuppression may further enhance immunotherapies directed at immune checkpoint inhibitors, including those targeting the PDL-1/PD-1 axis.
Poster #5116 PDF: http://www.peregrineinc.com/images/stories/pdfs/aacr-2016-gray.pdf
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Peregrine Exhibiting at Booth #2318 (across from MDAnderson #2312)
http://www.aacr.org/Documents/16AM_Exhibits_ListasofApr4.pdf (see rt.side bottom)



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4-4-16/Cancer-Immunology-Res.(AACR) article, “PS Blockade Enhances Antitumor Responses to CTLA-4 & PD-1 Antibodies in Melanoma” - Xianming Huang(UTSW/Brekken Lab), Bruce Freimark, Rolf Brekken(UTSW), 9 others…

4-4-16: “Antibody-Mediated Phosphatidylserine Blockade Enhances the Antitumor Responses to CTLA-4 & PD-1 Antibodies in Melanoma”
Cancer Research Institute Journal (AACR) – Rec.10-2-15, Rev.12-29-15, Acc.1-20-16, PubOnline=4-4-16
http://cancerimmunolres.aacrjournals.org/content/early/2016/04/02/2326-6066.CIR-15-0250.abstract
FULL(32pgs): http://cancerimmunolres.aacrjournals.org/content/early/2016/04/02/2326-6066.CIR-15-0250.full.pdf
Bruce D Freimark 1, Jian Gong 1, Dan Ye 2, Michael J. Gray 3, Van Nguyen 1, Shen Yin 1, Michaela M.S. Hatch 4, Christopher C W Hughes(PPHM SAB) 4, Alan J Schroit(PPHM SAB) 5, Jeff T Hutchins 1, Rolf A Brekken(PPHM SAB) 2, Xianming Huang 2
1 Preclinical Research, Peregrine Pharmaceuticals, Inc.
2 Hamon Ctr for Therapeutic Oncology Res., Depts of Surgery/Pharmacology, UTSW-MC/Dallas
3 Preclinical Research, Peregrine Pharmaceuticals
4 Molecular Biology & Biochemistry, Univ. of California, Irvine
5 Simmons Cancer Center, UTSW/Dallas
ABSTRACT
In tumor bearing animals, the membrane phospholipid phosphatidylserine (PS) suppresses immune responses, suggesting that PS signaling could counteract the antitumor effect of antibody-driven immune checkpoint blockade. Here we show that treating melanoma-bearing mice with a PS-targeting antibody enhances the antitumor activity of downstream checkpoint inhibition. Combining PS-targeting antibodies with CTLA-4 or PD-1 blockade resulted in significantly greater inhibition of tumor growth than did single agent therapy. Moreover, combination therapy enhanced CD4+ and CD8+ tumor-infiltrating lymphocyte numbers; elevated the fraction of cells expressing the pro-inflammatory cytokines IL2, IFNy, and TNFa; and increased the ratio of CD8 T cells to myeloid-derived suppressor cells and regulatory T cells in tumors. Similar changes in immune cell profiles were observed in splenocytes. Taken together, these data show that antibody-mediated PS blockade enhances the antitumor efficacy of immune checkpoint inhibition.
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IN SUMMARY(Pg.17): In summary, we have shown that PS-targeting antibodies improve the efficacy of anti-CTLA-4 or anti-PD-1 therapy in murine models of melanoma, suggesting that these combinations have the potential to improve outcome in patients with advanced stage melanoma. Bavituximab, a chimeric PS-targeting antibody, is currently being evaluated in late-stage clinical trials for the treatment of cancer patients with solid tumors (46,54) and strong antitumor activity has been demonstrated in melanoma clinical trials using checkpoint inhibitor antibodies targeting CTLA-4 (10), PD-1 (12,13), and PD-L1 (55). It is increasingly apparent that successful immunotherapy requires tumor cell killing, induction of pro-inflammatory immune responses and concomitant reduction of immunosuppressive signals leading to increased tumor infiltration by activated T cells. Based on the distinct mechanism of action and multiple points of blockade, PS-targeting antibodies such as bavituximab may enhance the anti-tumor responses of immune checkpoint inhibitors by further blocking suppressive signals in the tumor microenvironment.

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BAVI MOA 1-18-16: CEO Steve King explains PPHM's direct PS-Targeting advantage vs. the “individual-receptors” PS-binding approach of others like: Axl Mer TIM-3 RAGE Tyro3 GAS6 CD300a BAI1 MFG-E8 etc. http://tinyurl.com/h2h87mc

2-2016: Rutgers' Dr. Raymond Birge's relationship with Peregrine & UTSW's Dr. Rolf Brekken and his 2-26-16 article, ”Phosphatidylserine is a Global Immunosuppressive Signal in Efferocytosis, Infectious Disease, and Cancer” http://tinyurl.com/z5d9qt9

11-9-15 SITC'15: New Bavi+Checkpoint Inhibitors preclin. data (UTSW/DUKE's Herbert K. Lyerly) http://tinyurl.com/pbof95w
...Also, collab. with Dr. Bernard Fox (Immunotherapist/Earle A. Chiles Res.Inst.) on new Immuno-Profiling Clinical Test (Opal 6-plex quantitative IF Assay), PPHM roundtable with Raymond Birge (Rutgers), Douglas Graham (Emory), Dmitry Gabrilovich (Wistar), Rolf Brekken (UTSW), Maria Karasarides (AstraZeneca) - ”Combining Bavi w/anti-PD-1 significantly enhanced O/S… significant incr. CD45+, CD8+ and CD3+ T-cells… led a prolonged anti-tumor immune response which protected the animals against a re-challenge w/same tumor.”
BAVI MOA 8-26-15: Jeff Hutchins(VP/PreClin-Res) ImVacS’15 Talk – 29pg. Slideshow http://tinyurl.com/qz64pzg
…“Expansion & Activation of T Cells via the Targeting of the Immunosuppressive Ligand PS: Combination Strategy with Conventional, Targeted, and Checkpoint Inhibitor Therapy”

5-31-15: ASCO’15 Roundtable (webcast), “Raising the Immuno-Oncology Bar” - 7 panel members, incl. 3 Sloan Kettering researchers http://tinyurl.com/qxu4w2x

BAVI MOA 3-25-15: PPHM/VP Dr. Jeff Hutchins’ presentation at "Immune Checkpoint Inhibitors Conf.", Boston - PDF(34 Slides): http://tinyurl.com/ooxkhq7

BAVI MOA 2-9-15: PPHM's Dr. Bruce Freimark’s presentation at KEYSTONE "Tumor Immunology Meeting", Banff/CN – PR & Slides: http://tinyurl.com/q6cx4w6

BAVI MOA 12-12-14 San Antomio Breast Cancer Symposium, Dr. Bruce Freimark, Bavi+anti-PD-1 vs. Breast Cancer http://tinyurl.com/p5ng6vs