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Dr. Philip Thorpe’s 46min. 5-1-12 NYAS Anti-PS Symposium talk Replay & Slides – see below. He was the last of these 5 speakers at the NYAS “Phosphatidylserine (PS) Asymmetry - Therapeutic Applications in Cancer & Infectious Disease Symposium. If you have the time to listen to all 5 of these talks, you will learn an immense amount about the moa of Peregrine’s PS-targeting antibody therapeutic, Bavituximab.

TALK REPLAYS (5-1-12) – see direct links below:
. . .(if the direct links don’t work for you, you can get them via http://www.nyas.org/PSasymmetry - click Related-Content/”eBriefing PS-Asymmetry”, then MEDIA)’…
Intro: George Zavoico (MLV & Co.) => http://www.nyas.org/MediaPlayer.aspx?mid=8163b627-7c47-45c6-9f15-2b9e1609d476

I. Alan Schroit (UTSW): “Regulation of PS Asymmetry & Physiologic Consequences of Its Loss”
=> (40min.) http://www.nyas.org/MediaPlayer.aspx?mid=dc3ec7ed-1e0a-47fd-a5ca-96dd9e6c73bb

II. David Ucker (Univ. of Illinois/Chicago): “Innate Apoptotic Immunity and Glycolytic Enzyme Externalization”
=> (39 min) http://www.nyas.org/MediaPlayer.aspx?mid=ae50efa0-1bb1-42a2-9574-5eac7053e7b8

III. Ari Helenius (ETH/Zurich): “Phopshatidylserine Asymmetry & Cell Survival”
=> (38min.) http://www.nyas.org/MediaPlayer.aspx?mid=ff0a5576-dba1-4e33-8e73-c4280291495b

IV. Chris Reutelingsperger (Univ. of Maastricht/Netherlands): “PS Targeting with Annexin A5 to Diagnose & Treat Human Disease”
=> (35min.) http://www.nyas.org/MediaPlayer.aspx?mid=325f01c4-5209-4ceb-9870-a0860eaf330f
http://www.nyas.org/MediaPlayer.aspx?mid=325f01c4-5209-4ceb-9870-a0860eaf330f

V. Philip Thorpe (UTSW): “Targeting Tumor Vasculature & Reactivating Tumor Immunity with Bavituximab”
=> (46min.) http://www.nyas.org/MediaPlayer.aspx?mid=25e51622-c908-46ef-bba1-95ca6a814eed ***See Dr. Thorpe’s 30 SLIDES Below***

Dr. Thorpe’s talk is A MUST, but the other 4 are excellent as well.

Of note is PPHM SAB’r Dr. Alan Schroit’s [MDA, adjunct prof. at UTSW/Dallas] talk, “Regulation of PS Asymmetry & Physiologic Consequences of Its Loss” Dr. Schroit is the best in the world with targeting phospholipids and knowledge of cellular membrane expression of altered phospholipids in cancer cells. His work at MDA is critical to Peregrine’s PS-targeting patent estate – see http://tinyurl.com/3cwtdy => 7-9-07: Peregrine Licenses MDA’s “Clipped B2GP1” (inventor: Dr. Schroit)… “Peregrine, Schroit, and MDA will collab. to conduct preclinical studies designed to advance B2GP1 toward human trials.” Dr. Schroit’s MDA bio states this: “Dr. Schroit's lab has concentrated on the chemistry, biology and pathology of phosphatidylserine exposure in the outer leaflet of cells. He is an expert on targeting phospholipids and the knowledge of cellular membrane expression of altered phospholipids in cancer cells. These studies have led to the development of new methods to treat cancer by inducing production of anti-PS antibodies in patients.”

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May1 2012 1-5pm: “New York Academy of Sciences Symposium”, 7WTC/NYC
Symposium Name: “Phosphatidylserine (PS) Asymmetry - Therapeutic Applications in Cancer & Infectious Disease”
• Academy Event by the Cancer & Signaling Discussion Group
• Sponsors: N.Y. Academy of Sciences & Peregrine Pharmaceuticals
”This symposium will highlight recent developments in the understanding of PS exposure, its biological consequences, and its exploitation to create novel agents for the detection and treatment of cancer & viral diseases”
Event: http://www.nyas.org/PSasymmetry
NYAS: http://www.nyas.org/WhatWeDo/Default.aspx

SYMPOSIUM DESC:
Phosphatidylserine (PS) is a membrane lipid that regulates multiple biological processes. It is normally positioned in the inner leaflet of the plasma membrane but translocates to the outer, extracellular-facing surface to signal clearance of apoptotic cells, to quell unwanted inflammatory reactions and immunity, and to stimulate hemostasis and complement activation at sites of injury. PS exposure can be subverted by cells that become malignant or infected by viruses as a ploy to escape host defenses. This symposium will highlight recent developments in the understanding of PS regulation and its exploitation to create novel therapeutics for cancer & viral diseases.

SPEAKERS:
• ALAN SCHROIT (UTSW [PPHM SAB]) will introduce the topic and discuss how PS asymmetry is regulated in resting cells and the physiologic and pathologic consequences of its loss.
• DAVID UCKER (Univ. of Illinois at Chicago) will describe how PS exposure suppresses inflammatory and immune responses to cells undergoing apoptosis at the end of their natural lifespan.
• ARI HELENIUS (ETH Honggerberg/Switz) will discuss how viruses use macropinocytosis and apoptotic mimcry to enter host cells.
• CHRIS REUTELINGSPERGER (Univ. of Maastricht/Netherlands) will discuss the use of annexin A5 to image apoptosis for detecting cardiopulmonary lesions and monitoring tumor responses to therapy. He will also discuss the use of annexin A5 for drug delivery.
• PHILIP THORPE (UTSW [PPHM SAB, inventor of Bavituximab]) will discuss clinical trials with bavituximab, an antibody that targets PS-expressing tumor vasculature and reactivates host immunity.

Website: http://www.nyas.org/PSasymmetry
Click “E-Briefing” for these tabs:
• Meeting Report (textual summaries)
• Media (replays, with slides) **See Below for Dr. Thorpe’s 30 Slides**
• Resources (speaker pubs)
• Speakers (bios)
• Sponsors: N.Y. Academy of Sciences & Peregrine Pharmaceuticals

NYAS 5-1-12 Meeting Report - Speaker: Philip Thorpe, UTSW-MC/Dallas
HIGHLIGHTS
• Bavituximab, an antibody drug in development by Peregrine Pharm., targets PS in tumor blood vessels and can reactivate immunity to cancer cells.
• This antibody can serve as both an imaging agent and as an adjuvant treatment with other therapies.
• Bavituximab can induce tumor-specific T-cell immunity in some situations.

TARGETING TUMOR VASCULATURE
Taking advantage of the externalization of PS on tumor cells could provide new treatment strategies for cancer treatments. Philip Thorpe of UT Southwestern MC (Dallas) described preclinical & clinical studies of bavituximab, an antibody drug developed by Peregrine Pharmaceuticals that targets PS in the vasculature of tumors. As tumors develop, they create a stressful, hypoxic cellular environment that results in the formation of reactive oxygen species and the release of inflammatory cytokines. In this environment, the asymmetry of lipid distribution in the membrane of the endothelial cells that line tumor blood vessels breaks down, leading to the externalization of PS. In addition, PS is often exposed on the surface of tumor cells. As a strategy for targeting PS externalization, Peregrine Pharm. initially developed a mouse monoclonal antibody that targets PS by binding to 2 molecules of B2-glycoprotein-I that in turn bind to PS on the surface of cells. With only a single molecule of the protein, binding to the surface of cells is relatively weak, but the affinity increases by a factor of 30,000 with the addition of a second molecule of B2-glycoprotein-I. The researchers have constructed a series of antibodies that targets the tumor vasculature. Two are mouse antibodies, 3G4 & 2aG4. Bavituximab is a chimeric antibody with mouse PS binding regions fused to human IgG. The fully human antibody is known as PGN635. These antibodies localize specifically to the blood vessels in tumors, which makes them useful as imaging agents. Studies with normal tissues and various tumor types reveal that these antibodies show affinity for a range of tumor types but minimal binding to a variety of normal tissues.

BAVITUXIMAB AS AN ANTI-TUMOR AGENT
In rodent studies, antibodies alone inhibit tumor growth by 30%–90%. That variation most likely reflects the differences in PS expression on blood vessels in different tumors. However, combining the antibody treatment with other treatments, including chemotherapy, radiation, or androgen deprivation, improved these results. In studies of prostate tumors in mice, the combination of the mouse antibody 2aG4+docetaxel slowed tumor growth by 98% compared with 90% for docetaxel alone and 80% for antibody alone. The PS-targeting antibody in combination with intense radiation can shrink lung cancer tumors that are resistant to radiation alone.
How does the antibody work?
As one proposed mechanism of action, these PS-targeting antibodies damage tumor vessels by a process known as Antibody-Dependent Cellular Cytotoxicity (ADCC). As poor blood flow and hypoxia lead cells in the tumor vasculature to expose PS on their surfaces, bavituximab targets those cells and shuts down blood flow, which starves those tumor cells of nutrients.
As a 2nd mechanism, bavituximab can overcome the immunosuppressive processes observed with cells that externalize PS. In tumors the expression of PS on cell surfaces keeps macrophages in their M2 state, an activation state that suppresses inflammation and supports angiogenesis. It also prevents myeloid-derived suppressor cells (MDSCs) from differentiating into macrophages and dendritic cells (DCs). In addition, PS inhibits the maturation of DCs, which prevents the presentation of antigens to T cells. Bavituximab repolarizes macrophages to their M1 state, which allows them to kill cells that express PS, including the tumor vascular endothelium. It also leads to differentiation of the MDSCs and prompts DCs to mature and to present tumor antigens to T cells.

TUMOR-SPECIFIC IMMUNITY & CLINICAL TRIALS
Bavituximab can also prompt the development of tumor-specific immunity. In experiments with rats with treatment-resistant glioma tumors, 15% of the animals treated both with radiation and with antibody therapies did not die from those tumors. When the researchers reintroduced glioma tumor cells into these surviving rats, the rats were immune to the cancer. The team determined that spleen cells from these animals could kill gliomas, which indicated the antibody treatment had induced T cell immunity. Bavituximab is currently being tested clinically. More than 400 people have been treated with the drug, which is well tolerated and appears not to show combined toxicity when used with chemotherapy, Thorpe said. A variety of single-arm, early Phase II studies have been completed as a 2nd-Line or 1st-Liine treatment in people with advanced breast cancer and as a Frontline treatment for NSCLC. Randomized Phase II studies in NSCLC and pancreatic cancer are also underway.
JPG of Dr. Thorpe’s “Report”:

Graph only:

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The 30 Slides (PDF) from Dr. Thorpe’s 5-1-12 NYAS presentation are here: http://www.peregrineinc.com/images/stories/pdfs/nyasweb.pdf
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And, I copied them in here:
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The 30 Slides Dr. Philip Thorpe presented 5-1-2012 at the NYAS PS-Targeting Symposium:
…Note that Dr. Thorpe’s describes Bavi’s MOA in several parts:
• Mechanism #1: Tumor Vessel Damage by ADCC
• Mechanism #2: Blockade of PS-Mediated Immunosuppression in Tumors
• Macrophage Polarization M2 to M1 Switch
• Generation of Tumor-Specific Cytotoxic T Cells
• Proposed Mechanism: PS Blocks MDSC, Macrophage, and DC (Dendritic Cells) Differentiation
• Proposed Mechanism: Bavi Reactivates Innate & Adaptive Immunity



















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=> “Evolution has favored pathogenesis that resembles apoptosis.”

The Inventor of the Anti-PS mab '3G4/bavituximab' is Dr. Philip E. Thorpe of UTSW-MC/Dallas.
BIO: http://www.utsouthwestern.edu/findfac/research/0,2357,17308,00.html
...also: http://www.researchgate.net/profile/Philip_Thorpe
Dr. Thorpe's LAB TEAM: http://tinyurl.com/yuxemu
DR. THORPE'S PATENTS: GRANTED: http://tinyurl.com/m232k PENDING: http://tinyurl.com/845p2
DR. THORPE'S ARTICLES: http://tinyurl.com/csjsl Also see: http://www.researchgate.net/profile/Philip_Thorpe

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4-26-12 PR: Peregrine's Novel PS-Targeting Technology Platform to Be Highlighted at The New York Academy of Sciences Symposium on May 1, 2012
• Global Experts Convene to Discuss Innovative Science and Applications of Targeting Phosphatidylserine; Philip Thorpe, PhD, to Discuss Peregrine's Lead Drug Candidate, Bavituximab
http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=667635
TUSTIN, 4/26/12: Peregrine Pharmaceuticals, Inc. (NASDAQ: PPHM) today announced that its phosphatidylserine (PS)-targeting technology platform and its lead drug candidate, bavituximab, will be highlighted at a symposium hosted by The New York Academy of Sciences. The event entitled "Phosphatidylserine Asymmetry and Cell Survival: Therapeutic Applications in Cancer and Infectious Disease" will be held on Tuesday, May 1, 2012 at 1:00pm EDT at The New York Academy of Sciences in New York. The symposium featuring a panel of global scientific experts will examine the role that PS plays in regulating immune response, how cancer and viral diseases exploit PS exposure for their own survival and proliferation in the body, and the latest research and clinical data on therapeutic PS-targeting agents, including Peregrine's bavituximab.

As part of the expert panel, Philip Thorpe, Ph.D., scientific advisor to Peregrine and inventor of the company's PS-targeting antibody technology, will review bavituximab's dual mechanism of action in targeting the vasculature of a tumor, as well as stimulating a lasting immune response in preclinical models of multiple cancers. Peregrine's bavituximab is currently being studied in 7 clinical trials spanning multiple oncology indications. Peregrine anticipates announcing preliminary data from its Phase II clinical trial of 2nd-Line NSCLC patients evaluating bavituximab in combination with docetaxel vs. placebo plus docetaxel in the 2nd quarter…

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By: Freethemice 8-15-12 iHub #87095
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=78580873
I listened to Dr. Thorpe’s 5-1-12 NYAS Anti-PS Symposium talk yet again [ http://tinyurl.com/9qlt6ug ], and came up with this. The minutes 22:30-25:30 tell us about how the MOA has been updated to include exosomes. These very small vesicles are released by the tumor and have PS on their surface. This PS is sensed by the macrophages and dendritic cells which have PS receptors (TIM-3, TIM-4). This then causes an immunosuppresive signal in those immune cells. When bavi is added it binds to the PS on the exosomes and the Fc-gamma receptors on the immune effector cells. This send a immunostimulatory signal to those immune cells. It is then the combination of the two signals which determines what the immune response will be. The immunostimulatory signal over-rides the immunosuppressive signal and the tumor microenvironment is changed to be immunostimulatory.
I drew this figure to show what is happening. This was the first time I have heard Thorpe talk about exosomes in such detail. You can replace "exosome" with "tumor cell" also.


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http://www.peregrineinc.com
http://www.peregrineinc.com/about-us/medical-and-scientific-advisors.html
http://www.peregrineinc.com/technology/bavituximab-oncology.html
http://www.peregrineinc.com/pipeline/bavituximab-oncology.html
http://www.peregrineinc.com/technology/ps-imaging.html