One day, hopefully soon, when diagnosed with the cancer, smiling doctor will prescribe us a proper dosage of THORPEMIN and tell us not worry because it will blow over like any other flu.
I wish to be still around when that day will be here.
3 Peregrine Baci/AntiPS Abstracts: #1244/Apr8 – “PS-Targeting Antibody Reactivates Tumor Immunity & Destroys Tumor Vasculature In Mice” [UTSW] #2850/Apr9 – “Predicting Anti-Tumor Responses to PS-Targeting Antibodies Using Tumor Imaging” [PPHM, UCI] #4326/Apr9 – “PS-Targeting ‘Betabodies’ for the Treatment of Cancer” [UTSW]
Peregrine’s Anti-PS Mabs: • PGN635 is Fully-Human Bavituximab=1N11=AT004 (B2GPI-depen.) – see http://tinyurl.com/cparur & http://tinyurl.com/6ql5nf • PGN632 is the Duke-PPHM-HIV candidate=11.31=AT005 (B2GPI-indep.) – see http://tinyurl.com/7x4l3k5 & http://tinyurl.com/cxkcb4 • PGN650 is a human F(ab’)2 fragment that targets PS expression (1st ref’d in AACR’13 #2452) – see http://tinyurl.com/76nqqkm . 124I-PGN650 is Peregrine’s PS-Imaging candidate, whose IND clinical filing was announced 4-3-12. Note: PGN632 (Duke/HIV preclin’s) binds to PS indep. of B2-glycoprotein I (B2GPI), unlike Bavi & FH-Bavituximab(PGN635) which depend on B2GPI as a binding intermediary.
= = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = 4-8-13/Mon Poster #1244: “Phosphatidylserine-Targeting Antibody Reactivates Tumor Immunity & Destroys Tumor Vasculature In Mice” Yi Yin, Xianming Huang, Dan Ye, Philip Thorpe - UTSW-MC/Dallas Session: Cytokines, Modification of the Tumor Microenvironment, and Intervention ABSTRACT: The immunosuppressive lipid, phosphatidylserine (PS), becomes exposed on tumor blood vessels and tumor cells responding to therapy. The exposed PS contributes to the immunosuppressed tumor microenvironment. Bavituximab is a phosphatidylserine (PS)-targeting antibody that is being combined with chemotherapy in clinical trials in cancer patients. Here, we tested the hypothesis that innate immunity against cancer can be elicited by combining chemotherapy with a monoclonal antibody that indirectly binds exposed phosphatidylserine (PS). We used a murine version of bavituximab, 2aG4, plus docetaxel to treat prostate tumors in mice. Combination treatment markedly retarded tumor growth, prolonged survival times and delayed progression to androgen-independent disease. Antibody treatment reduced the presence of myeloid-derived suppressor cells (MDSCs) in the tumors and caused macrophages to repolarize from the immunosuppressive, proangiogenic M2-like state into a tumoricidal M1-like state. The reactivated macrophages destroyed antibody-coated tumor vasculature and tumor cells. Addition of 2aG4 to MDSCs in vitro caused them to differentiate into M1-like macrophages and DCs. Thus, PS-targeting antibodies appear to reactivate innate immunity in tumors resulting in tumor growth inhibition. - - - - - - - - - - - PPHM 4-10-13 PRESS RELEASE COMMENTS RE: #1244: ”Additional data presented from a series of preclinical studies(3) demonstrate that PS-targeting antibodies mediate immuno-stimulatory changes in tumors resulting in an increase of tumor-fighting (M1) macrophages, immune cells strongly associated with survival benefits in patients with NSCLC(1). Peregrine recently reported promising data from a randomized, double-blind, placebo-controlled Phase II second-line NSCLC clinical trial demonstrating a 60% improvement in median overall survival (OS) in patients receiving 3 mg/kg bavituximab plus docetaxel compared to the control arm. The company plans to meet with the U.S. FDA in the 2nd Qtr of calendar year 2013 with the goal of initiating a Phase III trial by calendar year-end.” http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=755519 PDF of AACR’13 Poster #1244: http://www.peregrineinc.com/images/stories/pdfs/yi_2013.pdf
= = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = 4-9-13/Tue Poster #2850: “Predicting Anti-Tumor Responses to Phosphatidylserine-Targeting Antibodies Using Tumor Imaging” Jian Gong 1, Richard Archer 1, Van Nguyen 1, Christopher C.W. Hughes 2, Jeff Hutchins 1, Bruce Freimark 1 1 Peregrine Pharmaceuticals; 2 Univ. of California/ Irvine Session: Immune Therapeutics & Monoclonal Antibodies 1 ABSTRACT: Phosphatidylserine (PS) is a phospholipid normally residing in the inner leaflet of the plasma membrane and becomes exposed on tumor vascular endothelial cells and tumor cells in response to chemotherapy, irradiation and oxidative stresses in the tumor microenvironment. Binding of antibodies targeting PS on the tumor endothelial cells and tumors induces the recruitment of immune cells and engages the immune system to destroy tumor vasculature. The antibodies also enhance anti-tumor immunity by blocking the immunosuppressive action of PS. A chimeric PS-targeting antibody, bavituximab, is being used in combination with chemotherapy to treat patients with solid tumors in Phase II trials. Fully human antibody PGN635 binds PS through the interaction of beta-2-glycoprotein 1 (B2GP1) in the same manner as bavituximab. Using human PC-3 prostate tumor xenografts in SCID mice, we demonstrate that targeting of PS in tumors by PGN635 is enhanced by chemotherapy. Combination of PGN635 with docetaxel inhibited tumor growth compared to the control IgG plus docetaxel group (p<0.05). Near-infrared optical imaging of PS in tumors with PGN650, an F(ab')2 antibody fragment of PGN635, showed tumor growth inhibition in mice treated with docetaxel correlates with PS expression levels in the tumors. Maximal uptake of the PS imaging was observed when chemotherapy was given 24 hours before the imaging probe. - - - - - - - - - - - PPHM 4-10-13 PRESS RELEASE COMMENTS RE: #2850: Data presented from imaging studies(2) demonstrate that the chemotherapeutic drug docetaxel, a commonly prescribed second-line treatment for patients with advanced NSCLC, increases the exposure of bavituximab's target molecule, phosphatidylserine (PS), on tumor blood vessel cells and tumor cells. Results also showed that PS exposure in tumors is correlated with tumor burden and response to docetaxel treatment, supporting exposed PS as a promising biomarker of cancer and response to therapy. Peregrine's PS-targeting imaging agent I-124-PGN650 is currently being evaluated in a clinical trial [ http://clinicaltrials.gov/ct2/show/NCT01632696 ] to assess its safety and potential to image multiple tumor types in patients with cancer.” http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=755519 PDF of AACR’13 Poster #2850: http://www.peregrineinc.com/images/stories/pdfs/jian_2013.pdf
= = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = 4-9-13/Tue Poster #4326: “Phosphatidylserine-Targeting ‘Betabodies’ for the Treatment of Cancer” Xianming Huang 1, Dan Ye 1, Troy Luster 2, E. Sally Ward 1, Philip Thorpe1 1 UTSW-MC/Dallas; 2 Human Genome Science, Maryland, MD Session: Antibody Therapeutics & Novel Delivery Technologies ABSTRACT: Bavituximab is a chimeric monoclonal antibody that is being combined with chemotherapy to treat patients with lung or pancreatic cancer in randomized Phase II clinical trials. Bavituximab targets the immunosuppressive lipid, phosphatidylserine (PS), which becomes exposed on the outer membrane surface of tumor blood vessels and tumor cells in tumors responding to therapy. The antibody acts by destroying tumor vasculature and by reactivating tumor immunity. Here, we generated new PS-targeting therapeutics by fusing domains of the PS-binding plasma protein, mouse B2-glycoprotein I (B2GP1), to the Fc region of mouse IgG2a. Such ‘betabodies’ potentially have the following advantages: they bind directly to PS, and do not require a cofactor protein (B2GP1) for binding; they can be made fully human; they are smaller in size (100 KDa); and they have slower blood clearance rates. A construct was generated that bound strongly to PS-expressing cells and plates, localized to tumor vascular endothelium in vivo, and had a B-phase blood half-life of approximately 5 days after intravenous injection into mice as compared with one day for a murine version of bavituximab, 2aG4. Betabodies could potentially be the next generation of PS-targeting cancer therapeutics. - - - - - - - - - - - PPHM 4-10-13 PRESS RELEASE COMMENTS RE: #4326: ” Researchers also presented details of new PS-binding constructs(4). Termed "betabodies," the molecules consist of the PS-binding domain of the serum protein B2-glycoprotein I (B2GPI), fused to the constant region of an antibody. Betabodies bind to PS directly, are smaller in size and have a longer serum half-life than natural antibodies. Early studies indicate that betabodies hold potential as next-generation PS-binding agents that have the potential to be used for a broad number of applications including antibody-drug conjugates and next generation therapeutics for oncology and infectious diseases." http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=755519 PDF of AACR’13 Poster #4326: http://www.peregrineinc.com/images/stories/pdfs/xianming_2013.pdf
= = = = = = = = = = = = = = = = PR 4-10-13: Data Presented at AACR Annual Meeting Support Targeted Immune Reactivation Mechanism and Potential of Peregrine's Bavituximab in Solid Tumor Therapy • Imaging Studies Show Docetaxel Strongly Upregulates Bavituximab's PS Target in Tumors, Further Supporting Lead Clinical Indication in Second Line Non-Small Cell Lung Cancer • Preclinical Studies Support Potential of Bavituximab to Induce Cancer-Fighting Changes in Immune Response to Tumors That Have Been Associated With Prolonged Survival in Lung Cancer Patients http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=755519
TUSTIN, CA 4/10/13: Peregrine Pharmaceuticals, Inc. (NASDAQ: PPHM), a biopharmaceutical company developing first-in-class monoclonal antibodies focused on the treatment and diagnosis of cancer, today highlighted data presented at the Annual Meeting of the American Association for Cancer Research (AACR). Data was presented this week from preclinical studies investigating the immune-stimulating mechanism of action of Peregrine's lead phosphatidylserine (PS)-targeting oncology clinical candidate bavituximab and the anti-tumor and imaging potential of other PS-targeting molecules. Bavituximab is currently being evaluated in several oncology clinical trials including the lead indication of second-line non-small cell lung cancer (NSCLC), which is anticipated to advance into a pivotal Phase III trial later this year.
"These studies yield important insights into the fundamental role that exposed PS plays in tumor immune evasion, and further support our lead clinical candidate bavituximab's ability to reactivate tumor immunity. This is now clearly evidenced by several specific measurements of both the immune-stimulating and anti-tumor mechanisms mediated by PS-targeting antibodies as well as imaging studies demonstrating that tumor growth inhibition is correlated with PS expression levels in tumors," said Jeff T. Hutchins, Ph.D., VP of Preclinical Research at Peregrine Pharmaceuticals. "Included in these presentations was a compelling finding of a pronounced antibody-mediated increase in tumor-fighting immune cells that is independently correlated with an impressive survival benefit in patients with NSCLC based on a published retrospective study of clinical data(1). When taken together, these results support PS as a promising oncology drug target and provide additional rationale for the impressive Phase II survival data we have seen in bavituximab's lead indication of second-line NSCLC."
Data presented from imaging studies(2) demonstrate that the chemotherapeutic drug docetaxel, a commonly prescribed second-line treatment for patients with advanced NSCLC, increases the exposure of bavituximab's target molecule, phosphatidylserine (PS), on tumor blood vessel cells and tumor cells. Results also showed that PS exposure in tumors is correlated with tumor burden and response to docetaxel treatment, supporting exposed PS as a promising biomarker of cancer and response to therapy. Peregrine's PS-targeting imaging agent I-124-PGN650 is currently being evaluated in a clinical trial to assess its safety and potential to image multiple tumor types in patients with cancer.
Additional data presented from a series of preclinical studies(3) demonstrate that PS-targeting antibodies mediate immuno-stimulatory changes in tumors resulting in an increase of tumor-fighting (M1) macrophages, immune cells strongly associated with survival benefits in patients with NSCLC(1). Peregrine recently reported promising data from a randomized, double-blind, placebo-controlled Phase II second-line NSCLC clinical trial demonstrating a 60% improvement in median overall survival (OS) in patients receiving 3 mg/kg bavituximab plus docetaxel compared to the control arm. The company plans to meet with the U.S. Food and Drug Administration (FDA) in the second quarter of calendar year 2013 with the goal of initiating a Phase III trial by calendar year-end.
Researchers also presented details of new PS-binding constructs(4). Termed "betabodies," the molecules consist of the PS-binding domain of the serum protein B2-glycoprotein I (B2GPI), fused to the constant region of an antibody. Betabodies bind to PS directly, are smaller in size and have a longer serum half-life than natural antibodies. Early studies indicate that betabodies hold potential as next-generation PS-binding agents that have the potential to be used for a broad number of applications including antibody-drug conjugates and next generation therapeutics for oncology and infectious diseases.
(1) ”The M1 form of tumor-associated macrophages in non-small cell lung cancer is positively associated with survival time” Ma et al. BMC Cancer 2010, 10:112. Open access research article:http://www.biomedcentral.com/content/pdf/1471-2407-10-112.pdf
PRESENTATION DETAILS:
(2) Jian Gong(1), Richard Archer(1), Van Nguyen(1), Christopher C.W. Hughes(2), Jeff Hutchins(1), Bruce Freimark(1). 1. Peregrine Pharmaceuticals, Inc., Tustin, CA; 2. University of California, Irvine, Irvine, CA. “Predicting Anti-Tumor Responses to Phosphatidylserine Targeting Antibodies Using Tumor Imaging” In Proceedings of the 104th Annual Meeting of the American Association for Cancer Research (AACR); 2013 Apr 6-10; Washington, D.C. Abstract 2850 [ PDF of AACR’13 Poster #2850: http://www.peregrineinc.com/images/stories/pdfs/jian_2013.pdf ]
(3) Yi Yin, Xianming Huang, Dan Ye, Philip Thorpe. UT Southwestern Medical Ctr., Dallas, TX “Phosphatidylserine-Targeting Antibody Reactivates Tumor Immunity and Destroys Tumor Vasculature in Mice” In Proceedings of the 104th Annual Meeting of the American Association for Cancer Research (AACR); 2013 Apr 6-10; Washington, D.C. Abstract 1244 [ PDF of AACR’13 Poster #1244: http://www.peregrineinc.com/images/stories/pdfs/yi_2013.pdf ]
(4) Xianming Huang(1), Dan Ye(1), Troy Luster(2), E. Sally Ward(1), Philip Thorpe(1). 1. UT Southwestern Medical Ctr., Dallas, TX; 2. Human Genome Science, Maryland ”Phosphatidylserine-Targeting 'Betabodies' for the Treatment of Cancer” In Proceedings of the 104th Annual Meeting of the American Association for Cancer Research (AACR); 2013 Apr 6-10; Washington, D.C. Abstract 4326 [ PDF of AACR’13 Poster #4326: http://www.peregrineinc.com/images/stories/pdfs/xianming_2013.pdf ]
ABOUT BAVITUXIMAB Bavituximab is a first-in-class phosphatidylserine (PS)-targeting monoclonal antibody that represents a new approach to treating cancer. Bavituximab is the lead drug candidate from the company's PS technology platform and is currently being tested in eight clinical trials, including three randomized Phase II trials in front-line and second-line non-small cell lung cancer and front-line pancreatic cancer, and five investigator-sponsored trials (ISTs) in additional oncology indications. PS is a highly immunosuppressive molecule usually located inside the membrane of healthy cells, but "flips" and becomes exposed on the outside of cells that line tumor blood vessels, creating a specific target for anti-cancer treatments. PS-targeting antibodies target and bind to PS and block this immunosuppressive signal, thereby enabling the immune system to recognize and fight the tumor.
ABOUT PEREGRINE PHARMACEUTICALS, INC. Peregrine Pharmaceuticals, Inc. is a biopharmaceutical company with a portfolio of innovative monoclonal antibodies in clinical trials focused on the treatment and diagnosis of cancer. The company is pursuing multiple clinical programs in cancer with its lead product candidate bavituximab and novel brain cancer agent Cotara®. Peregrine also has in-house cGMP manufacturing capabilities through its wholly-owned subsidiary Avid Bioservices, Inc. ( http://www.avidbio.com ), which provides development and biomanufacturing services for both Peregrine and third-party customers. Additional information about Peregrine can be found at http://www.peregrineinc.com . Safe Harbor *snip* Contact: Christopher Keenan or Jay Carlson Peregrine Pharmaceuticals, Inc. (800) 987-8256
AACR’13 4-8-13/Mon Poster #1244: “Phosphatidylserine-Targeting Antibody Reactivates Tumor Immunity & Destroys Tumor Vasculature In Mice” Yi Yin, Xianming Huang, Dan Ye, Philip Thorpe - UTSW-MC/Dallas Session: Cytokines, Modification of the Tumor Microenvironment, and Intervention
AACR’13 4-9-13/Tue Poster #2850: “Predicting Anti-Tumor Responses to Phosphatidylserine-Targeting Antibodies Using Tumor Imaging” Jian Gong 1, Richard Archer 1, Van Nguyen 1, Christopher C.W. Hughes 2, Jeff Hutchins 1, Bruce Freimark 1 1 Peregrine Pharmaceuticals; 2 Univ. of California/ Irvine Session: Immune Therapeutics & Monoclonal Antibodies 1
AACR’13 4-9-13/Tue Poster #4326: “Phosphatidylserine-Targeting ‘Betabodies’ for the Treatment of Cancer” Xianming Huang 1, Dan Ye 1, Troy Luster 2, E. Sally Ward 1, Philip Thorpe1 1 UTSW-MC/Dallas; 2 Human Genome Science, Maryland, MD Session: Antibody Therapeutics & Novel Delivery Technologies . . . = = = = = = = = = = = = = = = = = “In Memoriam Philip E. Thorpe, Ph.D. 1951-2013 Founder, scientist, and friend” http://www.peregrineinc.com
“Phil will be sorely missed as a colleague and friend. At Peregrine, each of us is pursuing Phil's dream of bringing important drugs to patients who need them based on his basic research. We are more motivated than ever to see this dream through.”
The entire UT Southwestern Medical Center community mourns Dr. Thorpe's passing. His achievements in drug targeting, angiogenesis, and antibody-based therapeutics had global impact, and his loss will be felt deeply on our campus and well beyond. Dr. Thorpe’s research focused on the development of novel drugs targeting tumor blood vessels. His laboratory made the remarkable discovery that a fatty lipid molecule, phosphatidylserine, is preferentially expressed on cancer blood vessels, where it can serve as a target to increase the specificity of drugs to the tumor.
Private services were held. A memorial service will take place on campus at a later date.
***** The goal of the Thorpe laboratory is to take novel concepts in drug design and try to create them into successful drugs. We focus mainly on drugs for treating cancer, but also work on imaging agents and novel antivirals. Over the years, 5 drugs developed wholly or partially in our laboratory have entered clinical trials. To do this work, we have assembled a multidisciplinary team of 12-14 researchers from around the world.
Our expertise covers everything from protein engineering, synthetic chemistry, pharmacological testing, cell biology, immunology and animal testing. We are supported in this work by grants from the National Institutes of Health, the Dept. of Defense, the Cancer Prevention & Research Institute of Texas, and several foundations. However, to develop drugs for clinical use requires more than grant support. It requires the cooperation of a pharmaceutical company for manufacture, toxicology, and providing the infrastructure for interfacing with hospitals and the FDA.
Our commercial partner is Peregrine Pharmaceuticals, based in Tustin, Calif., with whom we have worked closely for 15 years. Between the Thorpe lab and the company, we have the expertise to design new drugs, and take them through all stages of preclinical and clinical testing to the community. . . = = = = = = = = = = = = = = = = =PEREGRINE: “In Memoriam Philip E. Thorpe, Ph.D. 1951-2013 Founder, scientist, and friend” http://www.peregrineinc.com
Peregrine Pharmaceuticals today mourns the loss of Dr. Philip E. Thorpe, scientific advisor to the company and inventor of our phosphatidylserine (PS)-targeting technology on which our lead drug candidate bavituximab is based. Phil was a Professor of Pharmacology at the University of Texas Southwestern Medical Center, was associated with the Harold C. Simmons Comprehensive Cancer Center and held The Serena S. Simmons Distinguished Chair in Cancer Immunopharmacology. Phil’s achievements were numerous and included advances in drug targeting, angiogenesis, and antibody-based therapeutics which had a global impact. His loss will be felt deeply by all of us.
Phil’s research focused on the development of novel drugs targeting tumor blood vessels. It was his laboratory that made the remarkable discovery that a fatty lipid molecule, phosphatidylserine, is preferentially expressed on cancer blood vessels, where it can serve as a target to increase the specificity of drugs to the tumor.
Phil was firmly dedicated to the translation of his novel concepts in drug design into practical drug therapies for cancer, imaging agents, and anti-virals. His expertise covered a wide range of fields including protein engineering, synthetic chemistry, pharmacological testing, cell biology, and immunology. Five drugs developed wholly or partially in Phil’s laboratory have entered clinical trials and he is included in over 200 issued and pending worldwide patents, including dozens in the U.S. He is the author of more than 200 publications including articles in the fields of drug targeting, angiogenesis, and antibody-based therapeutics.
Phil was a tireless advocate as a scientific advisor to Peregrine for over 15 years.
Among other honors, Phil was one of the first recipients of the Pierce Immunotoxin Award, presented every two years for outstanding contributions to immunotoxin research, in 1998, and he received the Texas State Legislature Award for Research Excellence in 1997 as well as the American Cancer Society Award of Excellence in 1999.
Phil graduated summa cum laude with a Bachelor of Science in Pharmacology from the University of Liverpool in 1972, and he received a Ph.D. in Immunology from the Clinical Research Centre in London in 1976. He served as a Medical Research Council Fellow at Chester Beatty Research Institute in London (now The Institute of Cancer Research) until 1981, then as Director of the Drug Targeting Laboratory, Imperial Cancer Research Fund in London until 1991, when he first joined UT Southwestern as Professor of Pharmacology. Phil also served as Associate Director of the Center for Molecular Medicine at Maine Medical Center Research Institute from 1998-1999.
Phil will be sorely missed as a colleague and friend. At Peregrine, each of us is pursuing Phil's dream of bringing important drugs to patients who need them based on his basic research. We are more motivated than ever to see this dream through. . . - - - - - - - - - - - - - From a Colleague: ”We are all fortunate to have interacted with such a brilliant, fun-loving and positive spirit. May the lives that he touched continue to strive, like him, to change the world for the better.”
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