What is Tarvacin™ and Peregrine Pharmaceuticals

[Preciouslife1]

HUGE PATENT ISSUED TODAY... From TYP on RB board:

http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2 FPTO%2Fsearch-bool.html&r=1&f=G&l=50&co1=AND&d=PTXT&s1=%22Thorpe ,+Philip%22.INNM.&OS=IN/"Thorpe,+Philip"&RS=IN/"Thorpe,+Philip"

Patent #7,067,109

Cancer treatment kits comprising therapeutic conjugates that bind to aminophospholipids


Abstract
Disclosed is the surprising discovery that aminophospholipids, such as phosphatidylserine and phosphatidylethanolamine, are specific, accessible and stable markers of the luminal surface of tumor blood vessels. The present invention thus provides aminophospholipid-targeted diagnostic and therapeutic constructs for use in tumor intervention. Antibody-therapeutic agent conjugates and constructs that bind to aminophospholipids are particularly provided, as are methods of specifically delivering therapeutic agents, including toxins and coagulants, to the stably-expressed aminophospholipids of tumor blood vessels, thereby inducing thrombosis, necrosis and tumor regression.



CS

[Preciouslife1]

http://cancerres.aacrjournals.org/cgi/abstract/66/10/5371

.....and the lipids covered are very broad also, the lipids themselves, as well as any potential complexes with proteins, (obviously including but not limited to bavi's mechanism of binding beta2GPI with PS).

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from the patent:

The "binding ligands" of the present invention are thus "aminophospholipid binding ligands", "therapeutic aminophospholipid binding ligand constructs", "aminophospholipid-targeted therapeutic agents", "aminophospholipid-targeted therapeutics", "aminophospholipid-targeted therapeutic agent constructs", or "therapeutic agent-aminophospholipid targeting agent constructs". For simplicity, these agents are referred to herein as "binding ligands" or "therapeutic agent-targeting agent constructs", with the understanding that such terms are used as a succinct way of referring to a conjugate or other operative association of a selected therapeutic agent and a targeting agent, antibody, binding protein or active fragment thereof, that binds to an aminophospholipid, preferably phosphatidylserine or phosphatidylethanolamine, expressed on the luminal surface of tumor or intratumoral vascular endothelial cells.

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The prominent aminophospholipids found in mammalian biological systems are the negatively-charged phosphatidylserine ("PS") and the neutral or zwitterionic phosphatidylethanolamine ("PE"), which are therefore preferred aminophospholipids for targeting by the present invention. However, the invention is by no means limited to the targeting of phosphatidylserines and phosphatidylethanolamines, and any other aminophospholipid target may be employed (White et al., 1978; incorporated herein by reference) so long as it is expressed, accessible or complexed on the luminal surface of tumor vascular endothelial cells.

All aminophospholipid-, phosphatidylserine- and phosphatidylethanolamine-based components are encompassed as targets of the invention irrespective of the type of fatty acid chains involved, including those with short, intermediate or long chain fatty acids, and those with saturated, unsaturated and polyunsaturated fatty acids. Preferred compositions for raising antibodies for use in the present invention may be aminophospholipids with fatty acids of C18, with C18:1 being more preferred (Levy et al., 1990; incorporated herein by reference). To the extent that they are accessible on tumor vascular endothelial cells, aminophospholipid degradation products having only one fatty acid (lyso derivatives), rather than two, may also be targeted (Qamar et al., 1990; incorporated herein by reference).

Another group of potential aminophospholipid targets include, for example, phosphatidal derivatives (plasmalogens), such as phosphatidalserine and phosphatidalethanolamine (having an ether linkage giving an alkenyl group, rather than an ester linkage giving an acyl group). Indeed, the targets for therapeutic intervention by the present invention include any substantially lipid-based component that comprises a nitrogenous base and that is present, expressed, translocated, presented or otherwise complexed in a targetable form on the luminal surface of tumor vascular endothelial cells, not excluding phosphatidylcholine ("PC"). Lipids not containing glycerol may also form appropriate targets, such as the sphingolipids based upon sphingosine and derivatives.

The biological basis for including a range of lipids in the group of targetable components lies, in part, with the observed biological phenomena of lipids and proteins combining in membranous environments to form unique lipid-protein complexes. Such lipid-protein complexes extend to antigenic and immunogenic forms of lipids such as phosphatidylserine, phosphatidylethanolamine and phosphatidylcholine with, e.g., proteins such as .beta..sub.2-glycoprotein I, prothrombin, kininogens and prekallikrein. Therefore, as proteins and polypeptides can have one or more free primary amino groups, it is contemplated that a range of effective "aminophospholipid targets" may be formed in vivo from lipid components that are not aminophospholipids in the strictest sense. Nonetheless, all such targetable complexes that comprise lipids and primary amino groups constitute an "aminophospholipid" within the scope of the present invention.

[Preciouslife1]

Clinical Research 6: New Targets and Methodologies for Immunotherapy
Abstract #1986

Development of targeted tissue factor as vascular targeting agent coaguligand

Richard H. Archer, Jeanette R. Doerr, Rinal Shah, Steven W. King and Ronald T. Aimes

Peregrine Pharmaceuticals, Inc., Tustin, CA

Neovascularization is required for solid tumors to grow beyond a certain critical volume. Intensive efforts in recent years have focused on understanding and ultimately developing methodologies to interfere with tumor angiogenesis, thereby denying tumors sufficient blood supply. While these efforts have been successful in slowing tumor progression, data suggest that they may fall short on effecting the established vascular bed in larger tumors. Other modalities are needed to target the established vasculature of larger tumors. Peregrine is developing a series of coaguligands, a class of biologic drugs that target the tumor vasculature and exploit the normal haemostatic machinery, causing occlusions within the tumor associated blood vessels and subsequently causing hypoxia, necrosis, and ultimately leading to tumor death. Two new coaguligand molecules were developed in order to induce thrombosis of tumor blood vessels: NHS76:tTF and HuTarv:tTF. NHS76:tTF, fuses a human antibody targeting histone/DNA complexes to the extracellular domain of tissue factor (tTF). HuTarv:tTF is a fusion of a humanized anti-phosphatidylserine (PS) antibody to tTF. These fusion proteins were stably expressed in Chinese hamster ovary (CHO) cells and purified via protein A affinity. In addition, a C-terminal poly-histidine tagged tTF (tTF:H6) was stably expressed and purified via nickel-affinity chromatography. ELISA analyses showed that purified NHS76:tTF was able to bind to DNA/histone complexes and HuTarv:tTF bound PS in vitro similar to the parental antibodies NHS76 and humanized Tarvacin, respectively. A coupled ELISA demonstrated that the binding of the fusion proteins to their respective targets could be detected with an anti-tissue factor antibody, indicating the fusion proteins were intact. In a coupled enzymatic assay the target-bound fusion proteins supported the hydrolysis of Spectrozyme Xa, a chromagenic substrate for Factor Xa, in a Factor VIIa-dependent manner, indicating that both aspects of the fusion proteins were functional. Neither purified tTF:H6 nor NHS76 alone were able to bind to DNA/histone complexes and support cleavage of Spectrozyme Xa; similar results were obtained for HuTarv and tTF:H6 on PS coated plates. In addition, both fusion proteins were able to induce clotting in citrated whole blood. In contrast, neither parental antibody showed any ability to induce clotting in neither whole blood nor plasma. In vivo studies are underway to test both coaguligands in multiple animal models for specificity and for the ability to induce coagulation in tumor vasculature.

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An Anti-Phosphatidylserine (PS) Antibody, TarvacinTM That Targets Tumor Blood Vessels Does Not Affect Platelet Function In Vitro.


Anna M. Dyszkiewicz-Korpanty, MD, PhD1,*, Ravindra Sarode, MD2, Philip E. Thorpe, PhD3,* and Eugene P. Frenkel, MD1

1 Department of Internal Medicine, UT Southwestern Medical Center at Dallas, Dallas, TX, USA; 2 Department of Pathology, UT Southwestern Medical Center at Dallas, Dallas, TX, USA and 3 Department of Pharmacology, UT Southwestern Medical Center at Dallas, Dallas, TX, USA.

Abstract

TarvacinTM is a chimeric anti-PS antibody that is currently in Phase I clinical trials in cancer patients. It acts by targeting PS that becomes exposed on vascular endothelium in tumors in response to oxidative stress in the tumor microenvironment. TarvacinTM recognizes a complex of PS and the PS-binding protein, ß2 glycoprotein I. Host leukocytes are induced to bind to the complex in tumor vessels and destroy tumor vessels by antibody-dependent cellular cytotoxity. However, antibodies directed against PS-associated proteins are also known to elicit anti-phospholipid syndromes (APS). Anti-PS antibodies possibly cause APS by displacing anticoagulant proteins from PS on activated cell or by enhancing the binding of prothrombin; another explanation might be a direct activation of endothelial cells and platelets. The aim of the study was to determine whether Tarvacin TM induces or interferes with platelet activation caused by ADP, collagen type I or calcimycin in vitro. Blood was drawn from 3 healthy volunteers, aged 31–54, who have not taken any antiplatelet medication for 14 days prior to the study. Dual channel whole blood aggregometer (Chronolog, Havertown, PA, USA) was employed for platelet aggregation studies in whole blood (WB/impedance method) and platelet rich plasma (PRP/optical method). Platelet count in PRP was adjusted to 200 K/µL. Platelet agonists (PS exposure triggers) used in the experiments were as follows: collagen (0.5, 1, 2 µg/mL), ADP (1.25, 2.5, 5, 10 µM), Calcimycin (10, 20, 30 µM) and Calcium ions (1, 2 mmol/L). TarvacinTM was provided by Peregrine Pharmaceuticals Inc, Tustin, CA. The Anti-CD 20 antibody, Rituxan TM and physiologic saline were used as controls. Specimens (WB diluted with saline in 1:1 ratio or PRP) with the addition of TarvacinTM (100 µg/mL) or Rituxan TM (100 µg/mL) or saline were first incubated on a gentle mixer for 10 minutes; incubation was then continued at 37 ° in the aggregometer well for another 5 minutes. Agonist-induced platelet aggregation was subsequently examined. Platelet aggregation studies in both WB and PRP showed that TarvacinTM neither induced platelet activation, nor inhibited platelet activation in response to ADP, collagen or calcimycin in vitro. In conclusion, TarvacinTM does not affect platelet function in the present in vitro assays. Possibly, the epitope on the PS -ß2 glycoprotein I complex does not orientate the antibody in a manner that interferes with platelet activation. Alternatively, activated endothelial cells or other factors may be critical to support platelet activation.

Thanx Jazz,

[Preciouslife1]

Peregrine's Final HCV Phase 1a Study Results Accepted for Oral Presentation at AASLD Annual Meeting

- Study Results for First-in-Class Agent Bavituximab Will Be Presented at The Liver Meeting(R), the Leading Scientific Meeting on Liver Disease -

TUSTIN, Calif., Aug. 16 /PRNewswire-FirstCall/ -- Peregrine Pharmaceuticals, Inc. (Nasdaq: PPHM), a biopharmaceutical company with a portfolio of innovative, clinical stage products for the treatment of hepatitis C virus (HCV) infection and cancer, today announced that data from its Phase la study of bavituximab in patients with chronic hepatitis C viral (HCV) infection have been accepted for oral presentation at The Liver Meeting(R) 2006, the premier event in the science and practice of hepatology hosted by the American Association for the Study of Liver Diseases (AASLD).

"We believe that bavituximab represents a potentially valuable new approach for the treatment of chronic HCV infection. Given the novel nature of this approach, we are very pleased that AASLD has selected our clinical data for an oral presentation," said Steven W. King, president and CEO of Peregrine. "The next phase of the HCV clinical program is already underway with patient enrollment in the Phase 1b repeat dose study proceeding well and on track for completion by year-end. The presentation at The Liver Meeting gives us an excellent opportunity to raise awareness of the potential promise of the bavituximab HCV program as we continue clinical development."

Over 5,000 hepatologists and hepatology health professionals from around the world will meet at the 57th Annual Meeting & Postgraduate Course of AASLD -- The Liver Meeting at the John B. Hynes Convention Center in Boston, Massachusetts from October 27-31, 2006. The bavituximab presentation is scheduled for October 30, 2006 at 3:00 pm EST.

About Bavituximab

Bavituximab is the first investigational agent in a new class of anti-phosphatidylserine (anti-PS) immunotherapeutics that targets and binds to cellular components not normally present on the outside of cells, but which become exposed on certain virally infected cells and on the surface of enveloped viruses. Bavituximab helps stimulate the body's immune defenses to destroy both the virus particles and the infected cells. Bavituximab is currently in clinical trials for the treatment of chronic hepatitis C virus infection. Preliminary results from an ascending single dose Phase la trial in HCV patients reported earlier this year indicated that bavituximab was well tolerated, and it showed promising signs of anti-viral activity. A repeat dose Phase 1b HCV trial is ongoing and is expected to be completed by year-end. Similar to their proposed anti-viral mechanism, anti-PS immunotherapeutics also bind to phospholipids exposed on tumor blood vessels in all solid cancers tested to date. Bavituximab is currently in Phase 1 clinical trials for the treatment of advanced refractory solid tumor cancers.

About Peregrine Pharmaceuticals

Peregrine Pharmaceuticals, Inc. is a biopharmaceutical company with a portfolio of innovative product candidates in clinical trials for the treatment of cancer and hepatitis C virus (HCV) infection. The company is pursuing three separate clinical trials in cancer and HCV infection with its lead product candidate bavituximab (formerly Tarvacin) and Cotara(R). Peregrine also has in-house manufacturing capabilities through its wholly owned subsidiary Avid Bioservices, Inc. (www.avidbio.com), which provides development and bio-manufacturing services for both Peregrine and outside customers. Additional information about Peregrine can be found at www.peregrineinc.com.

Thank you...Thank you very much!

[Preciouslife1]

Peregrine to Initiate Bavituximab Combination Therapy Trial in India With Multiple Cancer Chemotherapy Regimens


- Clinical Trial to be Conducted With Experienced Indian Contract Research Organization and Top Cancer Centers - - Data is Expected to Expedite Ongoing Development Efforts in the U.S. -TUSTIN, Calif., Sept. 11 /PRNewswire-FirstCall/ -- Peregrine Pharmaceuticals, Inc. (Nasdaq: PPHM), a biopharmaceutical company with a portfolio of innovative, clinical stage products for the treatment of hepatitis C virus infection and cancer, today announced that it is completing plans to initiate a clinical trial in India of bavituximab in combination with chemotherapy. The trial is primarily designed to test the safety and tolerability of bavituximab with several standard chemotherapy regimens commonly used for treating major cancer types, including breast, lung and pancreatic cancer. The company is collaborating with an experienced Indian contract research organization with recent success in managing a registration clinical trial for a novel monoclonal antibody therapeutic. The new cancer trial will be conducted according to internationally accepted ICH GCP guidelines. Peregrine expects that results from this study, along with data from its ongoing U.S. Phase I cancer trial, will help support advancing bavituximab into Phase II cancer trials in 2007.
"Preclinical studies have repeatedly demonstrated the exciting potential of bavituximab plus chemotherapy for the treatment of solid cancers," said Steven W. King, president and CEO of Peregrine. "This new study, which complements our ongoing Phase l cancer trial in the U.S., will be an important milestone enabling us to accelerate the clinical assessment of bavituximab's anti-cancer potential."
Mr. King continued, "In recent years global pharmaceutical firms including Pfizer, GlaxoSmithKline, Roche and Eli Lilly have been conducting an increasing number of major clinical trials in India, taking advantage of the country's world-class clinical research facilities that leverage India's large cadre of Western-trained medical personnel and enormous pool of patients eager to participate in clinical trials. We look forward to working with our Indian collaborators to advance the bavituximab cancer program that we believe has significant potential for patients."
Bavituximab is currently being studied in Phase l clinical trials in the U.S. for the treatment of solid tumors and chronic hepatitis C infection. Clinical data collected to date has shown that bavituximab is safe and well-tolerated, and the company has reported promising signs of anti-viral activity in the hepatitis C trial. The new multi-center cancer trial is a pilot safety and pharmacokinetic study, with patients scheduled to receive bavituximab along with docetaxel, gemcitabine or carboplatin/paclitaxel for eight weeks. These chemotherapies are part of the current standard-of-care for a number of solid tumor types including breast, lung and pancreatic cancers. Study endpoints include safety and drug pharmacokinetics, and patients will be evaluated for tumor response according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Peregrine has completed an investigator meeting in India to prepare for trial initiation, and the trial has already been cleared to proceed at one of the three sites. Clearance from the other sites is on schedule and expected shortly.
Numerous preclinical studies have confirmed that bavituximab acts synergistically when administered in combination with chemotherapy. In the past 12 to 18 months, researchers associated with Peregrine have presented and published multiple studies demonstrating the promising anti-cancer potential of bavituximab and chemotherapy in major tumor types. Preclinical studies presented at the AACR annual meeting showed the potential of a bavituximab alent plus chemotherapy or radiation to increase survival in resistant breast and brain cancer, a very positive result in these models of advanced disease. A study published in the International Journal of Cancer demonstrated that a bavituximab given in combination with gemcitabine showed encouraging efficacy in animal models of pancreatic cancer, including reductions in the static disease that actually kills most victims. And an article in Cancer Research reported that a bavituximab plus docetaxel inhibited tumor growth by 93% in a model of advanced breast cancer.
"A growing body of research suggests that bavituximab acts synergistically with chemotherapy to kill cancer cells and possibly eliminate stases far more effectively than either agent alone," said Dr. Philip Thorpe, an inventor of the bavituximab technology and scientific advisor to Peregrine. "We believe the excellent preclinical activity we have seen in a variety of tumor types reflects in part the fact that chemotherapy and radiation up-regulate bavituximab's phospholipid target. I am very pleased that this new trial in India will soon get underway and thereby speed up the timeline for the clinical development of bavituximab as a potentially major new cancer therapy."
About Peregrine Pharmaceuticals
Peregrine Pharmaceuticals, Inc. is a biopharmaceutical company with a portfolio of innovative product candidates in clinical trials for the treatment of cancer and hepatitis C virus (HCV) infection. The company is pursuing three separate clinical trials in cancer and HCV infection with its lead product candidates bavituximab and Cotara(R). Peregrine also has in-house manufacturing capabilities through its wholly owned subsidiary Avid Bioservices, Inc. (www.avidbio.com), which provides development and bio-manufacturing services for both Peregrine and outside customers. Additional information about Peregrine can be found at www.peregrineinc.com.

[Preciouslife1]

Peregrine's Anti-Phospholipid Technology Platform Broadened by Newly Validated Anti-Cancer Target


Friday September 15, 9:30 am ET
- Data Presented at 2nd European Conference on Tumor Angiogenesis and Antiangiogenic Therapy Demonstrate Anti-Cancer Potential of New Phospholipid Target -
- Data Also Suggest This Target Can Be Addressed With Peptide or Small Molecule Agents -

TUSTIN, Calif., Sept. 15 /PRNewswire-FirstCall/ -- Peregrine Pharmaceuticals, Inc. (Nasdaq: PPHM - News), a biopharmaceutical company with a portfolio of innovative, clinical stage products for the treatment of cancer and hepatitis C virus infection, today reported new research that validates a second phospholipid drug target in Peregrine's proprietary anti-phospholipid platform. The data indicated that the new target, known as PE (or phosphatidylethanolamine), can be specifically targeted on tumor blood vessels for anti-cancer applications, similar to the activity of PS (or phosphatidylserine), the target for Peregrine's bavituximab program. The data were presented today by Dr. Philip Thorpe, an inventor of the anti-phospholipid technology, at the 2nd European Conference on Tumor Angiogenesis and Antiangiogenic Therapy in Munich, Germany.


"A growing body of preclinical and clinical data indicates that therapies targeting PS have significant potential as novel immunotherapeutics to treat cancer and viral infections," said Dr. Thorpe, professor of pharmacology at UT Southwestern Medical Center and a member of the Peregrine Scientific Resource Board. "These new data confirm that certain other aminophospholipids share these properties, providing us with the opportunity to develop a variety of anti-phospholipid agents designed to target specific disease states. We look forward to continuing these studies and to assessing how we can apply these findings to develop important new drugs."

Data presented at the conference supported that the new target appears to exhibit many of the same qualities that make PS an attractive drug target. The data showed that therapeutic compounds targeting PE were able to specifically localize to tumor blood vessels, signal the immune system and exert anti-tumor effects against a model of the cancer fibrosarcoma, as had been previously demonstrated by antibodies that bind to PS. However, the new research showed that the new PE target could be addressed using a non-antibody drug candidate, unlike the previous PS studies, which all used monoclonal antibodies for targeting. These results open the door to the possibility that orally available agents such as peptides and potentially even small molecule drugs could eventually become second-generation drug candidates using Peregrine's technology.

"As our lead anti-PS agent bavituximab advances in clinical studies for the treatment of cancer and hepatitis C infection, we are increasingly enthusiastic about the clinical potential of its unique mechanism," said Steven W. King, president and CEO of Peregrine. "These exciting new data show that our anti-PS approach represents a technology platform rather than a single target, and the new target already is included in our anti-phospholipid intellectual property portfolio. We will work with Dr. Thorpe and his colleagues in continuing to explore the potential of these findings for our drug discovery and development efforts."

Peregrine's proprietary anti-phospholipid immunotherapeutic technology uses monoclonal antibodies to target and bind to specific phospholipids that are present on the inner surface of normal cell membranes, but which become exposed for binding on the external surface of cells that line the blood vessels associated with tumors, as well as on certain viruses and the cells they infect. After binding, these agents help stimulate the body's immune defenses to destroy cells that exhibit the specific phospholipid component on their surface.

Peregrine's lead anti-phospholipid agent bavituximab is currently being studied in Phase l clinical trials in the U.S. for the treatment of solid tumors and chronic hepatitis C infection. Clinical data collected to date have shown that bavituximab is safe and well tolerated, and the company has reported promising signs of anti-viral activity in the hepatitis C trial. A solid cancer trial in India combining bavituximab and chemotherapy regimens is expected to start shortly.

[Preciouslife1]

Researchers Report Peregrine's Phospholipid-Targeted Antibodies Fused With Cytokines Reduce Tumor Growth in Animals by Over 90%


- Data Demonstrates Potential of New Class of Targeted Fusion Therapies -

- Combines Peregrine's Proprietary Vascular Targeting Agent (VTA) and
Anti-Phospholipid Technology Platforms -

TUSTIN, Calif., Sept. 19 /PRNewswire-FirstCall/ -- Peregrine Pharmaceuticals, Inc. (Nasdaq: PPHM), a biopharmaceutical company with a portfolio of innovative, clinical stage products for the treatment of cancer and hepatitis C virus (HCV) infection, today reported new research showing that a fusion protein approach that combines two proprietary Peregrine technology platforms -- its Vascular Targeting Agent (VTA) and anti- phospholipid (anti-PS) technologies -- has demonstrated significant anti-tumor potential. In a presentation at the Angiogenesis and Vascular Targeting Agents Conference, researchers presented data showing that a fusion protein combining an antibody from Peregrine's anti-phospholipid therapy program with immunostimulatory cytokines such as interferon or interleukin reduced tumor growth in animal cancer models by more than 90%, with no discernable increase in toxicity. These studies represent an important validation of a new class of compounds in Peregrine's proprietary VTA platform, which uses agents targeted to tumor blood vessels to kill tumors by depriving them of the nutrients and oxygen needed for continued growth.

"We have long thought that our anti-phospholipid platform would be ideal for the delivery of cytokines for cancer therapy, and the data presented today strongly supports the concept of using a cytokine fusion protein to 'supercharge' the ability of anti-phospholipid antibodies to stimulate the immune system," said Steven W. King, president and CEO of Peregrine. "The potential power of this approach is evident from the fact that our collaborators were able to reduce tumors in these animals by more than 90%, with no evidence of cytokine-induced toxicity. Based on this promising data and its good fit with our ongoing development efforts, we plan on working with our collaborators to conduct the studies needed to advance this technology toward human clinical studies."

In the research presented today by Dr. Xianming Huang, assistant professor of pharmacology at UT Southwestern Medical Center, interleukin 2 and interferon alpha proteins fused with an anti-phosphatidylserine monoclonal antibody were tested. The fusion proteins retained full antibody binding and cytokine activity, and combinations of the anti-PS antibody linked to the different cytokines had better anti-tumor effects than either agent alone, inhibiting tumor growth by over 90% in some B-cell lymphoma and melanoma tumor models.

"The anti-tumor efficacy of interferons in clinical trials has been limited by their very short half-life and significant systemic toxicity," said Dr. Huang. "To overcome these obstacles, we engineered immunocytokine fusion proteins combining an anti-PS antibody with various interferons. The resulting fusion proteins were able to target tumor blood vessels and displayed potent anti-cancer effects in tumor models without causing any observable toxicity. These studies demonstrate that this approach could have significant potential for targeted immunotherapy of solid tumors."

The new class of fusion protein agents falls under Peregrine's VTA technology platform that includes over 200 patents and patent applications covering broad concepts of tumor therapy using agents that target tumor blood vessels. Because interferon is currently part of standard-of-care therapy for hepatitis C virus infection, Peregrine also intends to assess the utility of the new class as a second-generation treatment for HCV infection.

Peregrine's lead anti-phospholipid agent bavituximab is currently being studied in Phase l clinical trials in the U.S. for the treatment of solid tumors and chronic hepatitis C infection. Clinical data collected to date have shown that bavituximab is safe and well tolerated, and the company has reported promising signs of anti-viral activity in the hepatitis C trial. A solid cancer trial in India combining bavituximab and chemotherapy regimens is expected to start shortly.

The presentation, "Targeting Inside-Out Phosphatidylserine (PS) on Tumor Vascular Endothelium," was presented today at 2:45 pm EDT by Dr. Xianming Huang of UT Southwestern Medical Center at the 4th Annual Angiogenesis and Vascular Targeting Agents Conference in Boston, MA.

[Preciouslife1]

Abstract:

TITLE: Phase I single-dose study of bavituximab, a chimeric anti-phosphatidylserine monoclonal antibody, in subjects with chronic hepatitis C

AUTHORS (FIRST NAME, LAST NAME): Eliot W. Godofsky1, Joseph S. Shan2
INSTITUTIONS (ALL): 1. Bach and Godofsky Infectious Diseases, Bradenton, FL, USA.
2. Peregrine Pharmaceuticals, Tustin, CA, USA.

ABSTRACT BODY: Background: Bavituximab is a novel monoclonal antibody that specifically targets phosphatidylserine (PS) on the outer surface of the plasma membrane of virally infected cells and enveloped viruses. Once bound, it is believed to direct the host’s immune system to clear virally infected cells and viruses. Its antiviral activity has been previously demonstrated in animal models of murine cytomegalovirus and pichinde virus.
Aim: To determine the safety, tolerability and pharmacokinetics of a single intravenous (IV) infusion of bavituximab in a phase I, open-label, dose-escalation study in subjects with chronic HCV infection who failed to respond to or relapsed after pegylated interferon plus ribavirin combination therapy.
Methods: Sequential cohorts of 6 subjects were given a single 90 min IV infusion of bavituximab at 0.1, 0.3, 1, 3 or 6 mg/kg and were followed for 12 weeks. Vital signs, physical exams, safety laboratory parameters, serum bavituximab levels were monitored and serum HCV RNA levels were measured by NGI SuperQuant.
Results: The infusion was safe and well tolerated by all subjects. All adverse events were mild or moderate in severity, except for 1 report of severe headache at 1 mg/kg and 1 of severe vertigo at 3mg/kg, both unrelated to study drug. The majority of AEs were considered not related to study drug, with the most common being injection site bruises, nausea, rhinitis, and headache. There were no laboratory AEs except for expected subclinical transient prolongation of aPTT for the 3 and 6 mg/kg dose groups on day 1 postdose. After IV infusion, bavituximab reaches Cmax at 1h postdose with a mean elimination half-life of ~31h. There was a trend towards a bimodal decrease in mean serum HCV RNA levels. The first decrease was seen within 24 hours postdose and the second began around day 4 and appeared sustained up to several weeks in some subjects. Serum cytokine analyses are ongoing.
Conclusions: Single IV doses of bavituximab up to 6 mg/kg were safe and well tolerated. It has a predictable pharmacokinetic profile. The transient reductions in serum viral load were consistent with the proposed mechanism of immune stimulation. Unlike conventional therapy, bavituximab is a unique therapeutic that targets viruses and virally infected cells by channeling host’s defense against them. Since it does not target viral proteins, bavituximab is unlikely to elicit traditional viral resistance.

I'm concerned about the discussion about PTT levels over at I HUB. Any thoughts? Especially this statement by an MD (at least that's what he claims).

"#2. The reading (lab test) is elevated artifactually. There are additional tests to see if this is the case. I would think they would have done these tests so in all likelyhood the prolongation is real. 2-3 times prolongation is not mild. Medically someone is felt to be fully anticoagulated at that level. The transient nature of this is also puzzling. What constitites transient? An hour, a day, a week?"

[Preciouslife1]

Unregistered, I personally am not concerned about the Activated Partial Thromboplastin Time or aPTT test because I am hearing nothing but very good things from trials in both HCV and Solid refractory tumors. Here is some info on aPTT:

The Test

How is it used?
The aPTT test is used when someone has unexplained bleeding or clotting. Along with the PT test (which evaluates the extrinsic and common pathways of the coagulation cascade), the aPTT is often used as a starting place when investigating the cause of a bleeding or thrombotic episode. It is often used with recurrent miscarriages that often are associated with anticardiolipin and phospholipid antibodies. The aPTT and PT tests are also sometimes used as pre-surgical screens for bleeding tendencies, although numerous studies have shown that they are not useful for this purpose. The aPTT is also used to monitor heparin anticoagulant therapy as well as other therapeutic anticoagulants such as hirudin or argatroban. These are substitute drugs that may be used when a patient has heparin-induced thrombocytopenia, which is a decreased platelet count.
If the aPTT is prolonged, and the cause is not due to heparin contamination or to other pre-analytical problems such as an insufficient or clotted blood sample, then the aPTT is followed by mixing studies to check for possible factor deficiencies or inhibitors. Mixing is a procedure where the patient’s plasma is mixed with pooled normal plasma (a combination of blood from different donors that has normal amounts of all of the clotting factors in it). If the patient has a factor deficiency, mixing it with the pooled normal plasma should provide enough of the missing factor(s) for the aPTT to “correct” – to clot within the normal time frame. If it does correct, further coagulation factor testing is done to determine those factors that are deficient. If it does not correct, then the prolonged aPTT may be due to a specific or nonspecific inhibitor. Further testing may then be done to check for antibodies to specific factors and to identify nonspecific antibodies such as lupus and anticardiolipin antibodies.


When is it ordered?
The aPTT may be ordered, along with other tests such as a PT test, when a patient presents with unexplained bleeding or bruising, a thromboembolism, an acute condition such as disseminated intravascular coagulation (DIC) that may cause both bleeding and clotting as factors are used up at a rapid rate, or with a chronic condition such as liver disease. When the patient has had a thrombotic episode or recurrent miscarriages, the aPTT may be ordered as part of an evaluation for lupus or anticardiolipin antibodies. It may be ordered as part of a pre-surgical evaluation for bleeding tendencies, especially if the surgery carries an increased risk of blood loss and/or if the patient has a clinical history of bleeding – such as nosebleeds and bruising that may indicate the presence of an inherited or acquired factor deficiency or of an acquired inhibitor.
When a patient is on intravenous (IV) or injection heparin therapy, the aPTT is ordered at regular intervals to monitor the degree of anticoagulation. When a person is switched from heparin therapy to longer-term warfarin (Coumadin) therapy, the two are overlapped and both the aPTT and PT are monitored until the patient has stabilized.


What does the test result mean?
Normal aPTTs may reflect normal clotting function but moderate single factor deficiencies may still exist. They will not be reflected in the aPTT until they have decreased to 30 to 40% of normal. Also some lupus antibodies may be present that will not be prolonged with the usual aPTT result. If the lupus antibody (LA) is suspected, an LA-sensitive aPTT can be used to test for it. A prolonged aPTT means that clotting is taking longer to occur than expected and may be caused by a variety of factors (see the list below). Often, this suggests that there may be a coagulation factor deficiency or a specific or nonspecific inhibitor affecting the body’s clotting ability. Coagulation factor deficiencies may be acquired or inherited. Several factors are Vitamin K dependent. If a person has liver disease, for instance, or more rarely a Vitamin K deficiency, he may have one or more factor deficiencies. Inherited factor deficiencies may involve the quantity and/or function of the factor produced.
Inhibitors may be antibodies that specifically target certain coagulation factors, such as Factor VIII antibodies, or they may be non specific inhibitors, such as lupus antibodies and anticardiolipin antibodies that bind to chemicals called phospholipids found on the surface of platelets. Since phospholipids assist in the clotting process, and since the aPTT test reagents (chemicals used to run the tests) contain phospholipids, such antibodies may prolong the aPTT even though they are usually associated with thrombosis instead of bleeding.
The administration of Heparin will also prolong an aPTT, either as part of anticoagulation therapy or as a contaminant. Heparin is a drug that is given intravenously (IV) or by injection to prevent and to treat thromboemboli (blood clots that block blood vessels). When it is given in therapeutic doses it must be monitored – too much and the patient will bleed excessively, too little and the patient may continue to clot. The aPTT is used to monitor heparin therapy and occasionally to monitor other therapeutic anticoagulants such as hirudin, or argatroban.
A decreased aPTT may result when coagulation Factor VIII is elevated. This may occur during an acute phase reaction - a condition causing acute tissue inflammation or trauma. This is usually a temporary change that is not monitored with the aPTT. When the condition causing the acute phase reaction is resolved, the aPTT will return to normal levels.
Prolonged aPTT tests may be due to:

1. Pre-analytical problems. These may include:
   • Insufficient sample - there must be enough blood collected. The anticoagulant to blood ratio must be 9:1
   • Patients with high or low hematocrit levels may have altered aPTTs.
   • Heparin contamination. This is the most common problem – especially when blood is collected from intravenous lines that are being kept “open” with heparin washes.
   • Clotted blood samples - the clotting process uses up some of the factors
2. Inherited or acquired factor deficiencies. Some factor deficiencies cause bleeding, others - contact factors - prolong the aPTT in vitro but do not cause bleeding and have little clinical significance. Prolonged aPTTs due to factor deficiencies usually “correct” after being mixed with pooled normal plasma.
3. A nonspecific inhibitor such as the lupus anticoagulant (LA). If the LA does prolong the aPTT or LA sensitive aPTT, it will not correct with normal plasma mixing but it will usually correct if an excess of phospholipid is added to the sample.
4. A specific inhibitor. Although these are relatively rare, these are antibodies that attack a particular factor. They may develop in someone with a bleeding disorder who is receiving factor replacements (such as Factor VIII which is used to treat hemophilia A) or spontaneously as an autoantibody. The specific inhibitor will prolong the aPTT and it will not correct with mixing.
5. Heparin anticoagulant therapy (the target aPTT is often about 1.5 to 2.5 times higher than a patient’s pretreatment level).
6. Warfarin (Coumadin) anticoagulation therapy. The aPTT is not used to monitor warfarin therapy but it may be affected by it.
7. Increased PTT levels may also be seen with leukemia and with Von Willebrand’s disease.

Is there anything else I should know?
Once heparin is started, the laboratory work-up of an abnormal aPTT is difficult. Often when a patient presents with unexplained bleeding or clotting, an aPTT will be ordered along with other bleeding and hypercoaguability tests before treatment is begun. If this is not feasible, some investigational testing may have to wait until the current acute condition has been resolved.

[Preciouslife1]

Common Questions
1. Is the aPTT always used to monitor heparin therapy?
2. Should everyone have their aPTT checked?
3. How can I change my aPTT?


1. Is the aPTT always used to monitor heparin therapy?
In a couple of situations it is not. 1) When very high doses of heparin are used, as may occur during open heart surgery, the aPTT loses its sensitivity – it will not clot. At this intense level of anticoagulation the Activated Clotting Time (ACT) is used as a monitoring tool instead of aPTT. 2) LMWH (low molecular weight heparin), which is a fast acting form of heparin used in other treatment applications (such as deep vein thrombosis prevention), does not usually require monitoring.

2. Should everyone have their aPTT checked?
This is not usually necessary. The aPTT is not used as a routine general screening test. It is ordered when someone has symptoms of abnormal bleeding or clotting. Asymptomatic patients are usually only screened prior to a surgery – an then only if their doctor believes it is necessary to evaluate their risk of excessive bleeding during the procedure....

[Preciouslife1]

Plasma Protein -2-Glycoprotein 1 Mediates Interaction between the Anti-tumor Monoclonal Antibody 3G4 and Anionic Phospholipids on Endothelial Cells*
Troy A. Luster, Jin He, Xianming Huang, Sourindra N. Maiti, Alan J. Schroit, Philip G. de Groot¶, and Philip E. Thorpe1

From the Simmons Comprehensive Cancer Center, Hamon Center for Therapeutic Oncology Research, the Department of Pharmacology and the Department of Radiation Oncology, the University of Texas Southwestern Medical Center, Dallas, Texas 75390, the Department of Cancer Biology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, and the Department of Hematology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands

A promising target on tumor vasculature is phosphatidylserine (PS), an anionic phospholipid that resides exclusively on the inner leaflet of the plasma membrane of resting mammalian cells. We have shown previously that PS becomes exposed on the surface of endothelial cells (EC) in solid tumors. To target PS on tumor vasculature, the murine monoclonal antibody 3G4 was developed. 3G4 localizes to tumor vasculature, inhibits tumor growth, and enhances anti-tumor chemotherapies without toxicity in mice. A chimeric version of 3G4 is in clinical trials. In this study, we investigated the basis for the interaction between 3G4 and EC with surface-exposed PS. We demonstrate that antibody binding to PS is dependent on plasma protein -2-glycoprotein 1 (2GP1). 2GP1 is a 50-kDa glycoprotein that binds weakly to anionic phospholipids under physiological conditions. We show that 3G4 enhances binding of 2GP1 to EC induced to expose PS. We also show that divalent 3G4-2GP1 complexes are required for enhanced binding, since 3G4 Fab' fragments do not bind EC with exposed PS. Finally, we demonstrate that an artificial dimeric 2GP1 construct binds to EC with exposed PS in the absence of 3G4, confirming that antibody binding is mediated by dimerization of 2GP1. Together, these data indicate that 3G4 targets tumor EC by increasing the avidity of 2GP1 for anionic phospholipids through formation of multivalent 3G4-2GP1 complexes.

************************************************** *

Received for publication, June 1, 2006 , and in revised form, July 20, 2006.

* This work was supported by a Sponsored Research Agreement with Peregrine Pharmaceuticals Inc., the Gillson Longenbaugh Foundation, and a postdoctoral fellowship from the American Cancer Society (to T. A. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 To whom correspondence should be addressed: Dept. of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9041. Tel.: 214-648-1499; Fax: 214-648-1613; E-mail: philip.thorpe@utsouthwestern.edu.

[Preciouslife1]

Peregrine Pharmaceuticals Announces Annual Meeting Webcast 08:00 a.m.

10/23/2006 Provided by- Company to Webcast Portions of Its Annual Stockholders' Meeting on October 24, 2006 -TUSTIN, Calif., Oct 23, 2006 /PRNewswire-FirstCall via COMTEX/ -- Peregrine Pharmaceuticals, Inc. (PPHM), a biopharmaceutical company developing targeted therapeutics for the treatment of cancer and hepatitis C virus infection, today announced it will webcast part of its Annual Meeting of Stockholders to be held on October 24, 2006. The webcast will begin at 10:30 am PDT.The webcast will begin with the voting results of the Annual Meeting and will be followed by a presentation from Mr. Steven King, Peregrine's president and CEO, who will review the company's recent progress. Peregrine collaborator and inventor of its Anti-Phospholipid Immunotherapy platform, Dr. Philip Thorpe, will then provide a review of the extensive body of preclinical data supporting the utility of Peregrine's lead anti-viral and anti-cancer drug candidate bavituximab.To access the webcast, please visit the Investor Relations section of the company website ( www.peregrineinc.com ) and click on the Annual Meeting webcast icon. The webcast will be archived on Peregrine's website for approximately 30 days.About PeregrinePeregrine Pharmaceuticals, Inc. is a biopharmaceutical company with a portfolio of innovative product candidates in clinical trials for the treatment of cancer and hepatitis C virus (HCV) infection. The company is pursuing five separate clinical trials in cancer and HCV infection with its lead product candidates bavituximab and Cotara(R) in the U.S. and India. Peregrine also has in-house manufacturing capabilities through its wholly owned subsidiary Avid Bioservices, Inc. ( www.avidbio.com ), which provides development and bio-manufacturing services for both Peregrine and outside customers. Additional information about Peregrine can be found at www.peregrineinc.com .

Contacts:
GendeLLindheim BioCom Partners
Investors Media
info@peregrineinc.com Barbara Lindheim
(800) 987-8256 (212) 918-4650


GendeLLindheim BioCom Partners, Investors, +1-800-987-8256, info@peregrineinc.com, or
Media, Barbara Lindheim, +1-212-918-4650, for Peregrine Pharmaceuticals, Inc.

[Preciouslife1]

Dr Godofsky Abstract:

ID# 127
Location: Memorial Auditorium (Hynes Convention Center)
Time of
Presentation:
Oct 30 3:00 PM - 3:15 PM
Category:
P06. HCV Therapy: Preclinical and Early Clinical Development
Phase I single-dose study of bavituximab, a chimeric antiphosphatidylserine monoclonal antibody, in subjects with chronic
hepatitis C.
E. W. Godofsky1; J. S. Shan2
1. Bach and Godofsky Infectious Diseases, Bradenton, FL, USA.
2. Peregrine Pharmaceuticals, Tustin, CA, USA.
Background: Bavituximab is a novel monoclonal antibody that specifically targets phosphatidylserine (PS) on the outer surface of the plasma membrane of virally infected cells and enveloped viruses. Once bound, it is believed to direct the host’s immune system to clear virally infected cells and viruses. Its antiviral activity has been previously demonstrated in animal models of murine cytomegalovirus and pichinde virus.
Aim: To determine the safety, tolerability and pharmacokinetics of a single intravenous (IV) infusion of bavituximab in a phase I, open-label, dose-escalation study in subjects with chronic HCV infection who failed to respond to or relapsed after pegylated interferon plus ribavirin combination therapy.
Methods: Sequential cohorts of 6 subjects were given a single 90 min IV infusion of bavituximab at 0.1, 0.3, 1, 3 or 6 mg/kg and were followed for 12 weeks. Vital signs, physical exams, safety laboratory parameters, serum bavituximab levels were monitored and serum HCV RNA levels were measured by NGI SuperQuant.
Results: The infusion was safe and well tolerated by all subjects. All adverse events were mild or moderate in severity, except for 1 report of severe headache at 1 mg/kg and 1 of severe vertigo at 3mg/kg, both unrelated to study drug. The majority of AEs were considered not related to study drug, with the most common being injection site bruises, nausea, rhinitis, and headache. There were no laboratory AEs except for expected subclinical transient prolongation of aPTT for the 3 and 6 mg/kg dose groups on day 1 postdose. After IV infusion, bavituximab reaches Cmax at 1h postdose with a mean elimination half-life of ~31h. There was a trend towards a bimodal decrease in mean serum HCV RNA levels. The first decrease was seen within 24 hours postdose and the second began around day 4 and appeared sustained up to several weeks in some subjects. Serum cytokine analyses are ongoing.
Conclusions: Single IV doses of bavituximab up to 6 mg/kg were safe and well tolerated. It has a predictable pharmacokinetic profile. The transient reductions in serum viral load were consistent with the proposed mechanism of immune stimulation. Unlike conventional therapy, bavituximab is a unique therapeutic that targets viruses and virally infected cells by channeling host’s defense against them. Since it does not target viral proteins, bavituximab is unlikely to elicit traditional viral resistance.

[Preciouslife1]

PR 10-24-06: Enrollment Complete in Bavi/REPEAT 1B Trial

”Peregrine Completes Patient Enrollment in Phase Ib Bavituximab Hepatitis C Trial - Enrollment in Repeat Dose Study Completed Ahead of Schedule”

TUSTIN, CA, Oct. 24 2006: Peregrine Pharmaceuticals, Inc. (Nasdaq: PPHM), a biopharmaceutical company developing targeted therapeutics for the treatment of cancer and hepatitis C virus (HCV) infection, today reported that patient enrollment has been completed for the company's Phase Ib repeat dose, dose escalation study of bavituximab in patients with chronic HCV infection. The primary objective of the study is to determine the safety, distribution and pharmacokinetic properties of bavituximab as a multiple dose monotherapy in HCV patients. Changes in viral load, measured as serum HCV RNA levels, are also being monitored.

"Completing patient enrollment in this study ahead of schedule is a positive development for Peregrine and for the momentum of the bavituximab HCV program," said Steven W. King, president and CEO of Peregrine. "We believe that bavituximab has the potential to be a significant new therapy for HCV patients, and achieving this milestone will allow us to continue advancing bavituximab through clinical development. We are already actively designing the next bavituximab HCV clinical studies, and the data we obtain from this repeat dose trial should be extremely valuable in helping us to optimize those plans."

24 patients (4 cohorts of 6 patients each) were enrolled in the study with each cohort scheduled to receive 4 doses of bavituximab over a 14-day period. Subjects received bavituximab at escalating dose levels of 0.3, 1, 3 or 6 milligram per kilogram (mg/kg) of body weight. Patients in all cohorts are being followed for 12 weeks. Final data from the trial will be available when patients complete the 12 week follow-up and data analyses are complete. Initial data from the trial is expected to be available during the first quarter of 2007.

Previously Peregrine reported preliminary results from a Phase la single dose, dose escalation study of bavituximab in patients who had failed other HCV regimens, which showed that the drug was well tolerated and demonstrated encouraging signs of anti-viral activity. Final results from the Phase I single dose study will be presented at the American Association for the Study of Liver Diseases (AASLD) meeting in Boston on October 30, 2006.

About Bavituximab:
Bavituximab is the first agent in a new class of anti-phosphotidylserine (PS) immunotherapeutics that targets and binds to cellular components that are normally not present on the outside of cells, but which become exposed on certain virally infected cells and on the surface of enveloped viruses. Bavituximab is a monoclonal antibody that helps stimulate the body's immune defenses to destroy both the virus particles and the infected cells. Similar to their proposed anti-viral mechanism, anti-PS agents also bind to phospholipids exposed on tumor blood vessels in all solid cancers tested to date. Bavituximab is in Phase I clinical trials for the treatment of solid tumor cancers in the U.S. and a combination trial with chemotherapy in cancer patients in India will soon be underway.


About Peregrine:
Peregrine Pharmaceuticals, Inc. is a biopharmaceutical company with a portfolio of innovative product candidates in clinical trials for the treatment of cancer and hepatitis C virus (HCV) infection. The company is pursuing 5 separate clinical trials in cancer and HCV infection with its lead product candidates bavituximab and Cotara(R) in the U.S. and India. Peregrine also has in-house manufacturing capabilities through its wholly owned subsidiary Avid Bioservices, Inc. (http://www.avidbio.com), which provides development and bio-manufacturing services for both Peregrine and outside customers. Additional information about Peregrine can be found at http://www.peregrineinc.com.