Avid Bioservices Inc (CDMO)

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Peregrine at AACR’14 Apr6-9 – 3 posters about Bavi as an “Upstream PS Checkpoint Inhibitor”; notably, “when combined with downstream immune checkpoint inhibitors such as anti-CTLA-4 and anti-PD-1, PS targeting mediates an improved protective tumor-specific immunity following tumor rechallenge”, and, “combination of bavituximab with the anti-PD-1 checkpoint blockade should synergistically induce potent long-lasting antitumor immunity.”…

Apr5-9 2014: AACR 104nd Annual Meeting, SanDiego http://www.aacr.org/AACR2014
Program: http://www.aacr.org/home/scientists/meetings--workshops/aacr-annual-meeting-2014/program.aspx
3 PEREGRINE/UTSW(PS-Targeting/Bavituximab) posters (#639, #LB262, #4978)…

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Abstract #639 - Poster time: Sun. Apr 6, 2014, 1:00-5:00pm
“Antibody-Mediated Blockade of Phosphatidylserine Combined With Radiation Improves Survival & Tumor Eradication in a Rat Model of NSCLC”
Olivier Belzile, Zhang Zhang, Xianming Huang, Debabrata Saha, Rolf A. Brekken UTSW-MC/Dallas
FULL ABSTRACT of #639 (O.Belzile/R.Brekken - UTSW):
“Stereotactic body radiation therapy (SBRT) uses image guidance to deliver very high doses of radiation, in no more than 5 fractions, to tumors. SBRT has shown remarkable benefit in patients with peripheral lung tumors but can cause severe toxicity to central organs when the tumor is proximally located if full potency doses are used (18 Gy x 3 fractions, for example). Bavituximab, a therapeutic monoclonal antibody that is headed to Phase III clinical trials, recognizes the immunosuppressive lipid, phosphatidylserine (PS), which becomes exposed on both tumor blood vessels and tumor cells subjected to SBRT. We hypothesized that treatment with the antibody 2aG4 (a murine version of bavituximab) would synergize with SBRT and allow tolerable doses of radiation to be used to treat centrally-located NSCLC without sacrificing efficacy. Nude rats bearing established orthotopic A549-luc NSCLC were treated with 3x12 Gy of radiation alone or combined with 2aG4 (4mg/kg) injected twice per week. Tumor growth was followed by bioluminescence. Rats treated with radiation and 2aG4 had a 100% survival rate 106 days after implantation and tumors were completely eradicated in 44% of these animals. In contrast, rats treated with radiation had a survival rate of 17% while only 11% of untreated rats survived. A toxicity study was conducted in which 3x12 Gy of radiation was delivered to central organs of tumor-free rats. This treatment does not appear to cause severe toxicity. These results suggest that bavituximab with radiation may result in improved clinical outcome in patients with centrally-located Non-Small Cell Lung Cancer (NSCLC).”
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ADDL. INFO. ON #639 FROM PEREGRINES’S 4-7-14 PR:
“Data Presented at AACR Support Potential of Combining Peregrine's PS-Targeting Immunotherapy Agent Bavituximab With Irradiation in Lung Cancer”
• Combination of PS-Targeting Antibody and Radiation Resulted in 100% Survival at 6 Months Compared to 43% With Irradiation Alone in Preclinical Lung Cancer Model
TUSTIN, 4/7/14: Peregrine Pharmaceuticals, a biopharmaceutical company developing first-in-class monoclonal antibodies focused on the treatment and diagnosis of cancer, today announced data from studies demonstrating that an equivalent antibody to Peregrine's lead immunotherapeutic antibody candidate bavituximab administered with stereotactic body radiation therapy (SBRT) showed a 100% improvement in survival and favorable tumor eradication in a model of non-small cell lung cancer (NSCLC) compared to irradiation alone. These data were presented yesterday at the 105th Annual Meeting of the American Association for Cancer Research (AACR) being held in San Diego, California from April 5-9, 2014. Bavituximab is an investigational immunotherapy currently being evaluated in NSCLC as part of the SUNRISE pivotal Phase III clinical trial.
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"Data from these studies show a very impressive survival improvement and tumor burden reduction when administering an animal equivalent of bavituximab with radiation therapy compared to radiation alone," said Jeff T. Hutchins, Ph.D., VP of Preclinical Research at Peregrine. "Importantly, the use of lower doses of stereotactic body radiation, a highly targeted therapeutic irradiation technique, demonstrates considerable therapeutic value in combination with bavituximab activity. Based on these results, we believe there is potential for more effective and less toxic combinations of stereotactic body radiation and investigational immunotherapies like bavituximab to work together as a potential treatment modality for patients with lung cancer."
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These studies utilized rats bearing established orthotopic A549-luc NSCLC tumors, which were staged and monitored by bioluminescence imaging. Animals were treated with 3x12 Gy of radiation alone or combined with 2aG4 (mouse equivalent antibody to bavituximab) injected twice weekly. Rats treated with radiation and 2aG4 had a 100% survival rate 184 days after implantation and tumors were completely eradicated in 67% of these animals. In contrast, rats treated with radiation had a survival rate of 43% while only 12.5% of untreated rats survived. A toxicity study was conducted in which 3x12 Gy of radiation was delivered to central organs of tumor-free rats. This treatment does not appear to cause severe toxicity. These results suggest that bavituximab with radiation may result in improved clinical outcome in patients with centrally-located NSCLC…
A copy of this poster is available in the Technology section of Peregrine's website located at http://www.peregrineinc.com/technology/bavituximab-oncology/recent-data.html .

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Late-Breaking Abstract #LB-262 – Poster time: Tue. Apr 8, 2014, 1:00-5:00pm
“Phosphatidylserine-Targeting Antibody Synergizes with Anti-PD-1 Antibody To Inhibit Tumor Growth in K1735 Mouse Melanoma Model”
Xianming Huang, Dan Ye, Rolf Brekken, Yi Yin* UTSW-MC/Dallas
*Note: Yi Yin is a member of the UTSW “Raj Lab” (Ganesh V. Raj, MD/PhD) http://www.utsouthwestern.edu/labs/raj/about/meet-the-pi.html
FULL ABSTRACT of #LB-262 (X.Huang/Y.Yin - UTSW):
“A large body of evidence indicates that PS is a major player in tumor-associated immunosuppression, including the induction and expansion of immune suppressor cells, such as MDSCs & M2 macrophages, and the production of immunosuppressive cytokines, such as TGF-beta and IL-10. Furthermore, PS also inhibits DCs maturation and antigen presentation. Thus, PS is a critical target for cancer immunotherapy. We have previously shown that anti-PS antibody can override PS-driven immunosuppression and re-program the tumor microenvironment from immunosuppressive to immunosupportive, breaks tumor immune tolerance and elicits potent de novo antitumor T-cell immunity. In the present study, we examined the combination of anti-PD-1 with anti-PS antibody in K1735 mouse melanoma model. Tumor-bearing mice were treated with each antibody alone or the combination at 2.5 mg/kg, twice a week. The combination treatment showed significantly superior tumor growth inhibition than with either antibody alone, animals treated with the combination survived significantly longer than with either antibody alone. Flow cytometry analysis showed the combination has the highest ratio of tumor-infiltrating immune effector to suppressor cells. Finally, no toxicity was observed in all treatment groups following multiple treatment doses. These data suggest that combination of PS blockade with immune checkpoint blockade represents a promising combinatorial strategy for cancer immunotherapy.”
[NOTE: Examples of anti-PD-1 drugs in development: 1. Merck’s pembrolizumab (aka MK-3475, former name=labrolizumab); 2. BMY’s nivolumab (aka BMS-936558); 3. CureTech’s pidilizumab (aka CT-011) - Teva/partner term. 1-2013]
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ADDL. INFO. ON #LB-262 FROM PEREGRINES’S 4-9-14 PR:
“Data Presented at AACR Support Potential of Peregrine's PS-Targeting Immunotherapy Bavituximab to Enhance Anti-Tumor and Immune-Stimulating Effects of Anti-CTLA-4 and Anti-PD-1 Treatments in Models of Melanoma and Colon Cancer”
• Combination Treatment With Upstream PS Checkpoint Inhibitor and Downstream CTLA-4 or PD-1 Inhibitors Provides Superior Protection Against Tumor Re-Challenge
• Data Presented Show Significant Increases in Functional Tumor Specific T Cells and Increases in Inflammatory Cytokines Following PS and PD1 Inhibitor Combination Therapy
TUSTIN, 4/9/14: Peregrine Pharmaceuticals today announced data from studies validating the immune-stimulatory mechanism of action of bavituximab and demonstrating that the combination of a preclinical phosphatidylserine (PS)-targeting antibody with the immune checkpoint inhibitors anti-CTLA-4 or anti-PD-1 antibodies yielded superior anti-tumor immune responses in animal models of melanoma and colon cancer compared to anti-CTLA-4 and PD-1 antibodies alone…
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"Data from these combination studies are compelling as they provide further evidence that support the immune-stimulatory effects of bavituximab in reducing the prevalence of key immunosuppressive checkpoints in the tumor environment, reducing tumor-suppressive factors, reducing immune suppressor cells and providing increased tumor-specific immunity," said Jeff T. Hutchins, PhD, VP of Preclinical Research at Peregrine. "These data also show that when combined with downstream immune checkpoint inhibitors such as anti-CTLA-4 and anti-PD-1, PS targeting mediates an improved protective tumor-specific immunity following tumor rechallenge. While these new downstream checkpoint inhibitors have been shown to strengthen the tumor-killing activity of T-cells and thus extend survival in some patients, there remains a need to increase the number of responders that mount anti-tumor T-cell responses in order to maximize the effects of these downstream checkpoint inhibitors. We believe a PS-targeting antibody, such as bavituximab, plays a key role in reducing tumor suppression and driving a more inclusive immune-mediated response. Insights from these data will influence our future clinical development plans including the soon to be opened investigator-sponsored trial assessing the potential of bavituximab and an anti-CTLA-4 antibody in patients with advanced melanoma."
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In a poster [LB-262] titled: "Phosphatidylserine-Targeting Antibody Synergizes with anti-PD-1 Antibody to Inhibit Tumor Growth in K1735 Mouse Melanoma Model," researchers from the UTSW-MC summarized their findings that PS-targeting antibodies block PS-mediated tumor immunosuppression while reactivating tumor immunity at multiple levels. Specifically, results showed that a PS-targeting antibody repolarized tumor-associated macrophages (TAM) from an M2 to a M1-phenotype, decreased the presence of myeloid-derived suppressor cells (MDSC), promoted dendritic cell maturation into cells having the phenotype of functional antigen presenting cells and elicited antitumor T cell immunity. In addition, statistically signifcant differences were seen in T-cell mediating markers IL-2 and gamma-interferon with the ch-1N11 and PD-1 combination. Researchers concluded that the combination of bavituximab with the anti-PD-1 checkpoint blockade should synergistically induce potent long-lasting antitumor immunity.

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Abstract #4978 - Poster time: Wed. Apr 9, 2014, 8am-12pm
“Targeting of Phosphatidylserine by Monoclonal Antibodies Enhances Activity of Immune Checkpoint Inhibitors in Tumors”
Jian Gong, Van Nguyen, Shen Yin, Rich Archer, Jeff Hutchins, Bruce Freimark Peregrine Pharmaceuticals, Tustin, CA
FULL ABSTRACT of #4978 (J.Gong/B.Freimark - Peregrine):
“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. PS exposure becomesenhanced 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), immature dendritic cells, and M2-like macrophages as well as the production of anti-inflammatory cytokines. Binding of PS targeting antibodies on tumor endothelial cells, tumor cells and their secreted microparticles triggers an Fc-FcR mediated pro-inflammatory cellular and cytokine response that reverses the immunosuppressive PS meditated checkpoint, thereby enhancing anti-tumor immunity. A chimeric PS-targeting antibody, bavituximab, is being used in combination with chemotherapy to treat patients with solid tumors in multiple late-stage clinical trials. Using multiple syngeneic tumors in immune competent mice, we demonstrate PS targeting antibodies enhance the anti-tumor activity of anti-CTLA-4 and anti-PD-1 antibodies. Tumor growth inhibition correlates with infiltration of immune cells in tumors and induction of adaptive immunity. The combination of these mechanisms promotes strong, localized, anti-tumor responses without the side-effects of systemic immune activation.”
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ADDL. INFO. ON #4978 FROM PEREGRINES’S 4-9-14 PR:
In a poster [ #4978] titled, "Targeting of Phosphatidylserine by Monoclonal Antibodies Enhances Activity of Immune Checkpoint Inhibitors in Tumors," scientists from Peregrine Pharmaceuticals, led by Bruce Freimark, Ph.D., Director of Pre-Clinical Research Oncology, reported that animals treated with the PS-targeting antibody ch1N11, the preclinical equivalent to bavituximab, in combination with anti-CTLA-4 or anti-PD-1 in melanoma and colon cancer tumor models demonstrated greater delayed tumor growth and suppression than anti-CTLA-4 or anti-PD-1 alone. Results also showed that the combination with anti-CTLA-4 reduced M2 macrophages in the melanoma tumor model, an important cell type responsible for facilitating tumor growth and proliferation. In addition, in the preclinical melanoma model, the combination of ch1N11 with anti-CTLA-4 or anti-PD-1 antibody developed protective tumor-specific immunity to tumor re-challenge than either the anti-CTLA-4 or anti-PD-1 antibody alone. Lastly, results showed that the combination treatment of ch1N11 and anti-PD-1 led to a proportional increase in tumor infiltrating cytotoxic T-cells, while decreasing PD-L1 expression on tumor derived CD45 cells such as tumor, endothelial and stromal cells as compared to anti-PD-1 alone.
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"We now have compelling evidence from these preclinical studies in multiple tumor models that PS-targeting antibodies mediate a fundamental immune-stimulatory shift in the tumor environment, facilitating increased antigen presenting cells as well as tumor-specific cytotoxic T-cells," said Peregrine's Dr. Bruce Freimark. "With the use of immunohistochemical staining, we have seen that tumors from animals treated with ch1N11 in combination with anti-PD-1 antibody showed faster and more complete T-cell and macrophage tumor infiltration rates, which correlate with decreased tumor cells, than anti-PD-1 alone. We look forward to further exploring the potential of the bavituximab with other immune checkpoint inhibitors."
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Copies of these posters are available on the front page of Peregrine's website.
[ http://www.peregrineinc.com => http://www.peregrineinc.com/technology/bavituximab-oncology/recent-data.html ]
AACR’14 #639(Bavi+Rad/NSCLC): http://www.peregrineinc.com/images/stories/pdfs/aacr_brekken.pdf
AACR’14 #LB262(Bavi+AntiPD1/Melanoma): http://www.peregrineinc.com/images/stories/pdfs/aacr_xianming.pdf
AACR’14 #4978(Bavi+Downstream): http://www.peregrineinc.com/images/stories/pdfs/aacr_freimark_2014.pdf

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PR 4-1-14: “Peregrine Pharmaceuticals Announces Three Abstracts Accepted for Presentation at AACR 2014 Annual Meeting”
http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=836976

TUSTIN, 4/1/14: Peregrine Pharmaceuticals, Inc. (NASDAQ: PPHM) (NASDAQ: PPHMP), a biopharmaceutical company developing first-in-class monoclonal antibodies focused on the treatment and diagnosis of cancer, today announced the acceptance of 3 preclinical abstracts scheduled for poster presentations at the 105th Annual Meeting of the American Association for Cancer Research (AACR), to be held April 5-9, 2014 in San Diego, California. Data to be presented include studies investigating the therapeutic potential of Peregrine's phosphatidylserine (PS)-targeting antibodies when administered in combination treatment regimens with irradiation as well as with approved and developmental cancer immunotherapies.

ABSTRACT DETAILS:

Abstract Number: 639
Presentation Title: Antibody-mediated blockade of phosphatidylserine combined with radiation improves survival and tumor eradication in a rat model of non-small cell lung cancer
Presentation Time: Sunday, April 6, 2014, 1:00 PM - 5:00 PM
Location: Hall A-E, Poster Section 27, Poster Board Number: 14
Author Block: Olivier Belzile, Zhang Zhang, Xianming Huang, Debabrata Saha, Rolf A. Brekken. University of Texas Southwestern Medical Center, Dallas, Texas

Late-Breaking Abstract Number: LB-262
Presentation Title: Phosphatidylserine-targeting antibody synergizes with anti-PD-1 antibody to inhibit tumor growth in K1735 mouse melanoma model
Presentation Time: Tuesday, April 8, 2014, 1:00 PM - 5:00 PM
Location: Hall A-E, Poster Section 41
Author Block: Xianming Huang, Dan Ye, Rolf Brekken, Yi Yin. UT Southwestern Medical Center, Dallas, Texas

Abstract Number 4978
Presentation Title: Targeting of phosphatidylserine by monoclonal antibodies enhances activity of immune checkpoint inhibitors in tumors
Presentation Time: Wednesday, April 9, 2014, 8:00 AM -12:00 PM
Location: Hall A-E, Poster Section 7, Poster Board: 2
Author Block: Jian Gong, Van Nguyen, Shen Yin, Rich Archer, Jeff Hutchins, Bruce Freimark. Peregrine Pharmaceuticals, Inc., Tustin, CA

About Peregrine Pharmaceuticals, Inc.
Peregrine Pharmaceuticals, Inc. is a biopharmaceutical company with a pipeline of novel drug candidates in clinical trials for the treatment and diagnosis of cancer. The company is developing multiple clinical programs in cancer with its lead immunotherapy candidate bavituximab while seeking a partner to further advance its novel brain cancer agent Cotara®. Peregrine also has in-house cGMP manufacturing capabilities through its wholly-owned subsidiary Avid Bioservices, Inc. ( http://www.avidbio.com ), which provides development and biomanufacturing services for both Peregrine and third-party customers. Additional information about Peregrine can be found at http://www.peregrineinc.com.
Contact: Christopher Keenan or Jay Carlson
Peregrine Pharmaceuticals, 800-987-8256, [e-mail]