PPHM and Tarvacin discussion

[Preciouslife1]

Data on Peregrine's VTA coaguligand and VEA anti-cancer development programs.

Researchers working with Peregrine presented data on progress in the company's VTA coaguligand development program, its VEA program and its initiatives to develop second-generation anti-PS monoclonal antibodies.
* Peregrine's VTA coaguligands program has developed fusion proteins that combine a vascular targeting antibody with modified tissue factor, a protein that can induce blocking and destruction of targeted blood vessels. Since Peregrine's VTAs specifically target tumor blood vessels, the fusion proteins are intended to affect only the established blood vessels that are essential for the survival and growth of tumors. Researchers reported on their progress in successfully developing and testing a series of VTA coaguligands that currently are in further testing in animal cancer models. * Peregrine researchers gave an oral presentation on novel methods the company is employing in its drug discovery efforts for its VEA program. VEAs are a new class of therapeutics comprised of tumor-specific antibodies fused to vasoactive compounds such as interleukin-2. They are designed to increase the uptake of cancer therapeutics at the tumor site, thereby increasing anti-tumor efficacy without having to increase the dose and risk greater toxicity. The novel R&D methods described by Peregrine scientists enabled the company to identify potential VEA clinical candidates for further evaluation in animal cancer models. * Peregrine researchers also reported on their successful efforts to develop second-generation fully humanized anti-PS antibodies for possible use in a variety of Peregrine development programs. Data assessing the fully human version of the antibody indicated that it was eq.uivalent to the current chimeric version. Fully humanized antibodies may have advantages in some applications and also provide Peregrine with greater flexibility in designing and differentiating new drug candidates.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 programs for HCV infection and a range of solid cancers in the U.S. and India 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.

Contacts: GendeLLindheim BioCom Partners Investors Media info@peregrineinc.com Barbara Lindheim (800) 987-8256 (212) 918-4650SOURCE Peregrine Pharmaceuticals, Inc.
Investors, +1-800-987-8256, info@peregrineinc.com, or Media, Barbara Lindheim,+1-212-918-4650, both of GendeLLindheim BioCom Partners, for PeregrinePharmaceuticals, Inc.

[Preciouslife1]

Posted by: Preciouslife1
In reply to: None
Date:4/21/2007 8:51:20 AM
Post #of 45526

AACR Meeting Roundup.
BIOWORLD Today - Apr. 21, 2007

As the American Association for Cancer Research meeting in Los Angeles wrapped up Wednesday, Peregrine Pharmaceuticals Inc. was among a number of firms presenting promising preclinical and early clinical data.

Tustin, Calif.-based Peregrine reported that a preclinical study of 2aG4, described as a mouse eq.uivalent to its anti-phosphatidylserine antibody bavituximab, demonstrated vaccine-like activity in a brain cancer model and suggested a potential for inducing a curative response. Researchers presenting the data demonstrated that the improvement in survival for 2aG4-treated animals likely was attributable to the antibody's ability to help the treated animals mount an effective immune response against an aggressive cancer type.

Rats in the study were injected with irradiated glioma cells along with 2aG4. Among those that were pretreated with the 2aG4-treated irradiated cells, 57 percent achieved long-term survival vs. zero percent of animals receiving no prior treatment. However, a group receiving irradiated control antibodies, without the anti-PS activity of 2aG4, only achieved a 16 percent long-term survival rate. In calculating long-term survival, researchers determined that those animals receiving the 2aG4 regimen had more than 99.99 percent of the glioma cells destroyed by their immune systems, indicating that the 2aG4 vaccine-like regimen resulted in a strong immune response not seen in controls.
Based on those data, Peregrine said it intends to continue evaluating bavituximab as a vaccine-like regimen for potential application against a variety of cancers.

Bavituximab is a targeted monoclonal antibody that binds to phospholipids called phosphatidylserine, which becomes exposed on the outside of cells that line the blood vessels of tumors. Once bound to the blood vessel, the antibody is designed to alert the body's immune system to attack the tumor's blood supply, resulting in cell death. The compound is in a Phase Ib trial in combination with docetaxel and other chemotherapy agents in patients with advanced solid cancers, including prostate, breast and lung cancers. Based on interim data, more than half the patients to complete treatment to date demonstrated stable disease or an objective response.

In separate news, Peregrine reported preclinical data showing that fusion proteins combining the cytokines alpha interferon and interleukin 2 with 2aG4 demonstrated anticancer activity in models of B-cell lymphoma and melanoma. In those studies, the antibody-cytokine fusion proteins generated an antitumor response without any observable toxicity.

Immunocytokine fusion proteins incorporating antibodies that target the blood vessels of tumors are being developed under the company's Vascular Targeting Agent technology platform.
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[Preciouslife1]

Phosphatidylserine on HIV Envelope Is a Cofactor for Infection of Monocytic Cells



Abstract

HIV-1 is an enveloped retrovirus that acquires its outer membrane as the virion exits the cell. Because of the association of apoptosis with the progression of AIDS, HIV-1-infected T cells or macrophages might be expected to express elevated levels of surface phosphatidylserine (PS), a hallmark of programmed cell death. Virions produced by these cells would also be predicted to have PS on the surface of their envelopes. In this study, data are presented that support this hypothesis and suggest that PS is required for macrophage infection. The PS-specific protein annexin V was used to enrich for virus particles and to inhibit HIV-1 replication in primary macrophages, but not T cells. HIV-1 replication was also significantly inhibited with vesicles consisting of PS, but not phosphatidylcholine. PS is specifically required for HIV-1 infection because viruses pseudotyped with vesicular stomatitis virus G and amphotropic murine leukemia virus envelopes were not inhibited by PS vesicles or annexin V. These data indicate that PS is an important cofactor for HIV-1 infection of macrophages.




Introduction

Human immunodeficiency virus is an enveloped retrovirus whose entry into permissive target cells is dependent on receptor-mediated fusion between viral and target cell membranes. Binding and fusion are mediated by viral envelope proteins gp120, which interacts with host CD4 and chemokine receptors, and gp41, which contains an N-terminal fusion peptide. Recent attention has focused on interactions between gp120 and chemokine receptors, especially CXCR4 and CCR5, providing insight into factors that influence tropism of HIV-1, the progression of AIDS, and potential novel treatment strategies (1). Although CD4, chemokines, and their receptors are clearly important in the establishment of HIV infection, there is increasing evidence that additional surface molecules act as cofactors for binding and entry. Reports of primary HIV isolates that infect cell lines lacking CD4 and chemokine receptors suggest that there are uncharacterized accessory molecules that participate in infection (2, 3, 4, 5). In addition, HIV envelope, which is acquired as the virus particle exits the cell, includes proteins and lipids that are selectively obtained from the host membrane. The inclusion of host-derived proteins such as ICAM-1 and MHC-II molecules has been demonstrated to enhance infection possibly by binding counterreceptors on target cells and stabilizing virus-cell interactions (6, 7, 8, 9, 10).

Although much attention has focused on how specific proteins mediate virus-cell fusion, relatively little is known about the role lipids have in this process. The presence of different lipids in either target cell or virus membranes can dramatically influence infection. For example, glycosphingolipids in target cell membranes have been shown to increase HIV infection (3, 11, 12, 13). Furthermore, the viral envelope, despite being acquired from host cells, has a lipid composition that differs from the host plasma membrane with elevated levels of sphingolipids, cholesterol, and a subset of phospholipid species (14).

One enriched membrane phospholipid in the HIV envelope is phosphatidylserine (PS)6 (14). PS is normally sequestered to the inner leaflet of the plasma membrane bilayer. However, during the course of apoptosis, the mechanism that normally maintains PS in the inner leaflet is down-regulated (15), allowing the appearance of PS on the cell surface. PS exposure is a hallmark of apoptosis and a recognition signal for phagocytic cells that clear dying cells (16, 17). Several macrophage receptors have been implicated in recognizing PS on apoptotic cells, including various scavenger receptors, CD36, CD14, and PS receptor (PSR) (16). Thus, PS has a demonstrated ability to mediate cell-cell interactions and to function as a ligand, making its appearance in the viral membrane highly suspect as a factor in virus-target cell fusion.

Because the primary targets of HIV infection are CD4+ T cells and macrophages, the virus envelope will acquire specific properties of these cellular plasma membranes. Following HIV-1 infection, T cells are highly susceptible to programmed cell death, and peak levels of T cell apoptosis correlate with high levels of virus replication (18). Furthermore, mature macrophages constitutively express PS in the outer leaflet of their plasma membranes (19), although their precursors, monocytes, do not (20). Therefore, HIV-infected T cells and macrophages would be expected to have elevated levels of surface PS, and HIV-1 particles produced by these cells would have PS incorporated into the outer leaflet of their envelopes. We directly tested this hypothesis and demonstrated that PS is present on the surface of the HIV-1 envelope. More importantly, our results suggest that this phospholipid is a cofactor for macrophage infection.



The Journal of Immunology

Melissa K. Callahan2,3,*, Paul M. Popernack2,{dagger}, Shigeki Tsutsui4,{ddagger}, Linh Truong{ddagger}, Robert A. Schlegel*,§ and Andrew J. Henderson5,*,{dagger},{ddagger}


End of Part #1....posted by jazzbeerman on IHUB.com

[Preciouslife1]

Discussion

The interaction between HIV-1 and its target cells is complex and not explained entirely by the presence or absence of CD4 and chemokine receptors such as CXCR4 and CCR5 (2, 31). Several molecules, including ICAM-1, LFA-1, MHCII, CD28, glycosaminoglycans, and glycosphingolipids, on the surface of the cell and virus have been shown to participate in HIV-1 infection, possibly by stabilizing virus-cell interactions or promoting postbinding events (3, 4, 5, 6, 8, 9, 11, 12, 13, 32). Furthermore, HIV-1 infection independent of CD4 and chemokine receptors has been described, suggesting that novel receptors may be expressed on different cell types (2).

Little attention has been devoted to the lipid composition of the HIV-1 envelope or the potential importance that lipids have in the infection process. Anionic phospholipids, including PS, have been implicated as receptors and cofactors for several viruses, including VSV, rhabdoviruses, hepatitis B, influenza viruses, hemorrhagic septicemia, Sendai virus, rubella virus, and Sindbus virus (33, 34, 35, 36, 37, 38, 39, 40). Characterization of lipid composition of HIV-1 envelope shows that many lipids, including glycosphingolipids, cholesterol, and PS, are found in the membrane at a higher frequency than what is represented in the host membrane, suggesting a selective incorporation of these lipids (14). It has been demonstrated that glycosphingolipids on the surface of the cell enhance HIV-1 infection. Furthermore, HIV-1 envelope requires cholesterol for membrane organization and function (41, 42, 43). Using model liposomes, HIV-1 fusion has been shown to be dependent on lipid composition, and cardiolipin vesicles inhibit infection (44, 45). Our results would add PS to this short list of critical lipids that influence HIV-1 infection.

We demonstrate that PS is in the outer leaflet of the HIV-1 membrane, and if this lipid is blocked by annexin V or competed for by excess PS, infection of monocytic cells is significantly inhibited. Because HIV-1 acquires its envelope from the host cell, the observation that PS is in the outer leaflet of the virus membrane is consistent with studies that show a positive correlation between HIV-1 replication and apoptosis (18). Annexin V is most likely inhibiting infection by blocking PS on the envelope, rather than the target cells, because cells do not positively stain with annexin V before infection. That the effect is restricted to monocytic cells and does not extend to T cells implicates a PSR(s) on macrophages. Macrophages express an array of receptors that recognize PS, including members of the scavenger receptor family, {beta} integrins, PSR, and CD14 (reviewed in Refs. 16 , 46 , and 47), although whether any of these receptors participate in HIV-1 infection has not been investigated. Preliminary studies suggest a limited role for CD14 in HIV-1 infection of macrophages because Abs that block CD14 did not adversely affect virus entry (data not shown).

The results presented in this study suggest that recognition of PS by macrophage receptors is not required for virus binding. However, by engaging specific receptors on macrophages, PS could stabilize virus-cell interaction and contribute to more efficient fusion. It is also possible that viral-associated PS engaging a specific receptor or complex of receptors initiates signaling cascades that activate host cell processes, such as cytoskeletal rearrangements, necessary for virus entry. This would be consistent with a recent model proposed for phagocytosis of apoptotic cells, which suggests that upon engagement with PS, the PSR transduces signals required for activating the phagocytosis machinery (46, 48, 49).

PS, by virtue of its physical properties, may contribute to a more fusion-competent virion. PS in the outer leaflet of membranes has been implicated in mediating cell fusion, exocytosis, and signal transduction (50, 51, 52). Studies with erythrocytes have shown that fatty acyl side chains of PS are less saturated than the side chains of other phospholipids, and that loss of membrane asymmetry increases membrane fluidity and surface hydrophobicity (50). Therefore, by altering membrane structure and organization, PS in the outer bilayer of the HIV-1 envelope may enhance virus fusion and entry.

The above models assume that PS is acting by influencing virus entry; however, annexin V or PS vesicles do not dramatically influence HIV-1 attachment to target cells, suggesting that it is unlikely that PSRs are serving as major coreceptors for HIV-1. It has been suggested that at least one PSR on macrophages is not responsible for binding, but rather for signal transduction (48). Furthermore, engulfment of apoptotic cells, which requires external PS, alters cytokine expression and macrophage function (51, 52, 53, 54). Therefore, it is possible that recognition of virus-associated PS by macrophages could directly affect reverse transcription and/or proviral transcription or indirectly influence HIV-1 replication by altering the cytokine microenvironment. Although we have not seen any effects on HIV-1 transcription in infected monocytes/macrophages treated with annexin V or PS vesicles, we cannot rule out that PS recognized in the context of a virus particle or apoptotic cell alters HIV-1 expression (54, 55). Current studies are focusing on mechanisms by which PS influences HIV-1 replication and at what stages in the viral life cycle this lipid is acting.

In summary, our data demonstrate that PS in the outer leaflet of the HIV-1 virion is critical for HIV-1 fusion and entry into macrophages. In addition to identifying a lipid cofactor that influences HIV-1 infection and novel targets for blocking HIV-1 entry, these studies suggest that general properties of virus membranes impact infection, tropism, and the course of AIDS.

[Preciouslife1]

PPHM and Affitech news out on Business Wire...

Positive results using Affitech-identified human antibody that blocks VEGF binding to VEGF receptor 2 in Preclinical cancer model reported by Peregrine...

Oslo, Norway, April 23, 2007 Affitech AS, the human antibody therapeutics company announced today that Peregrine Pharmaceuticals, Inc. reported positive in vivo test results of R3, a fully human monoclonal antibody developed by Affitech, in a pancreatic cancer model at the recently concluded Centennial Annual Meeting of the American Association for Cancer Research (AACR). R3 has been designed by the two companies for selective blocking of VEGF (vascular endothelial growth factor) binding to VEGF receptor 2, as opposed to other anti-angiogenic agents which block activity of both VEGF receptors.

The R3 antibody, which was generated by Affitech's phagemid antibody library screening method, when tested by Peregrine on a pancreatic cancer model, showed significant reduction of the growth, vascularization and macrophage infiltration of pancreatic tumors in mice. This is the first antibody from Affitech's library that has been tested in a preclinical development model. Peregrine announced that the positive results of R3 antibody support the Company's intent to progress its anti-VEGF program towards clinical trials.

"We are delighted with this in vivo result", commented Martin Welschof, Ph.D., Chief Executive Officer of Affitech. "Affitech and Peregrine have several collaborative antibody projects. The quality of the antibody and excellent collaborative research by the scientists of our two organizations are contributing to advancing Peregrine's anti-VEGF portfolio. This success also has important implications for accelerating our own human therapeutic antibody program"

Note to editors:

Affitech AS is a privately held human therapeutic antibody discovery and development company with headquarters and R&D facilities in Oslo, Norway and its US subsidiary in the San Francisco Bay Area. The Company's current disease focus is oncology and it utilizes two discrete but unique approaches for the discovery of fully human antibodies - (i) Molecule Based Antibody Discovery, and (ii) Cell Based Antibody Discovery. Molecule Based Antibody Discovery involves proprietary PhagemidScreeN and AffiScreenN™ technologies and uses validated targets for discovery purpose. Cell Based Antibody Discovery is based on CBAS™ technology, which is a "reverse-screening" approach for discovering antibodies and their cognate targets utilizing disease-specific cells. Several of the Company's proprietary product candidates currently in development were generated by CBAS™. Affitech also sells its proprietary Protein L product line for the purification of antibody and antibody fragments. Affitech offers collaborators a flexible business model and very competitive price structure with low royalty stacking.

*****The Company has concluded deals with commercial organizations such as Peregrine, XOMA, NatImmune, Viventia, Dyax, Micromet, Pharmexa and others. Further information at www. affitech. com*****

[Preciouslife1]

Posted by: cjgaddy
In reply to: NoneDate:5/17/2007 7:23:05 AM
Post #of 13865
PPHM’s Dr. Parseghian presents VEA’s today

May17 2007: “Cambridge Healthtech Institute's 2nd Annual PEGS (Protein Engineering Summit): Recombinant Antibodies – From Concept to Clinic”, Boston
http://www.pegsummit.com/07-RAB2.asp

5-17-07 CASE STUDIES - 9:00am
“Engineering Vasopermeability or Vascular Leakage into an Immunotherapeutic”
Missag Parseghian, Ph.D., Director, R&D, Peregrine Pharmaceuticals
Vascular Leak Syndrome (VLS) is the major dose-limiting toxicity which has prevented the utilization of interleukins and immunotoxins as useful cancer therapeutics. While many promising drug development programs at major pharmaceutical firms have been halted because of this, at Peregrine Pharmaceuticals, we have turned the issue on its head and are investigating a new class of drugs as potential cancer therapeutics that would promote increased vasopermeation or VLS selectively at the tumor site. Vasopermeation Enhancement Agents (VEAs) are designed to increase the uptake of cancer therapeutics at the tumor site, resulting in greater efficacy of existing therapies. Engineering such a novel therapeutic has required 1) a systematic structural study of antibody-interleukin fusion molecules in order to find the most optimally expressed construct; and 2) a novel screening method utilizing the chorioallantoic membrane (CAM) of a chick embryo to evaluate the potency of these VEA candidates.

Note: PEREGRINE’S curr. webpage on VEA’s: http://www.peregrineinc.com/***********************************.php?mi=NTg
More on Dr. Parseghian’s 5-17-07 VEA talk: http://tinyurl.com/35p4vc

Biochem Cell Biol. 2006 Aug ;84:589-604 16936831
http://lib.bioinfo.pl/auid:7361835
“Beyond the Walls of the Nucleus: The Role of Histones in Cellular Signaling and Innate Immunity”
Missag Parseghian, Keith Luhrs - Peregrine Pharmaceuticals, Inc, R&D, Tustin, CA
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=169368 31&...
ABSTRACT: “…More provocatively, immunologists are becoming convinced that they can also be found in the lumen of several tissues, acting as antimicrobial agents—critical components of an ancient innate immune system. Perhaps nowhere is this observation as dramatic as in the ability of neutrophils to entrap bacterial pathogens by casting out "nets" of DNA and histones that not only act as a physical barrier, but also display bactericidal activity. As our views regarding the role of histones inside and outside the cell evolve, some have begun to develop therapies that either utilize or target histones in the fight against cancer, microbial infection, and autoimmune disease. It is our goal here to begin the process of merging the dichotomous lives of histones both within and without the nuclear membrane.”
Peregrine’s DR. KEITH LUHRS – works with Parseghian on TNT/VEA/NHS76.
“The Evolution of Histone Antibodies into Cancer Therapeutics Part III: Establishing Histone Antibodiesas a Carrier Platform for Therapeutics and Diagnostics”
Dr. Keith Luhrs. Peregrine Pharmaceuticals
Biochem. Cell Biology, - Vol. 84, Aug. 2006
“…We have further investigated the specificity of a fully human anti-H1 antibody, NHS76… We have now begun to exploit this characteristic by using these antibodies as the chief delivery platform of effector molecules into the core of a solid tumor.”

[Preciouslife1]

Peregrine Pharmaceuticals to Initiate New Bavituximab HCV Clinical Trial in Patients Co-Infected With HIV

09:30 a.m. 05/17/2007 Provided by-
Trial to Evaluate Potential of Bavituximab in Important HCV Population Representing Up to 30% of All U.S. HIV Patients -TUSTIN, Calif., May 17, 2007 /PRNewswire-FirstCall via COMTEX/ -- Peregrine Pharmaceuticals, Inc. (PPHM), a clinical stage biopharmaceutical company developing targeted antibodies for the treatment of cancer and hepatitis C virus (HCV) infection, today announced it has filed a new clinical trial protocol with the FDA to study bavituximab in patients co-infected with HCV and the human immunodeficiency virus (HIV). The multi-center trial will initially be conducted at Saint Michael's Medical Center in Newark, NJ under the direction of Dr. Stephen Smith, director of the Peter Ho Memorial Clinic, the largest HIV/AIDS treatment facility in the state."Chronic co-infection with the hepatitis C virus affects a significant proportion of our HIV patients, yet current HCV therapies are often ineffective or poorly tolerated," said Dr. Smith. "These patients are particularly vulnerable since co-infection is associated with more aggressive progression of HCV-associated liver disease. We look forward to the opportunity to study bavituximab in co-infected patients so we can begin to assess whether its distinctive immunotherapeutic mechanism might be of value in treating this underserved population."The new study is an open-label, dose escalation study designed to assess the safety and pharmacokinetics of bavituximab in approximately 24 patients chronically infected with HCV and HIV. Patient cohorts will receive ascending dose levels of bavituximab weekly for up to 8 weeks. HCV and HIV viral titers and other biomarkers will be tracked, although they are not formal study endpoints."We believe that bavituximab's unique targeting mechanism has the potential to act on both HCV and HIV virus infections," said Steven W. King, president and CEO of Peregrine. "Greater understanding of bavituximab's activity in the HCV/HIV co-infection setting should help guide our future development efforts, potentially allowing us to treat an HCV patient population typically excluded from clinical studies. We are especially pleased to be pursuing this clinical trial in collaboration with Dr. Smith, a leader in researching infectious diseases and in providing high quality care to people with HIV."In the United States alone, an estimated 300,000 individuals are co-infected with HIV and HCV, representing up to 30% of all HIV-infected patients. Co-infected patients have been shown to have a lower response to interferon/ribavirin HCV regimens and the adverse effects of these regimens can be especially problematic for some HIV patients.Bavituximab is a monoclonal antibody 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, including both HCV and HIV. Bavituximab helps stimulate the body's immune defenses to destroy both the virus particles and the infected cells. Since bavituximab's PS target comes from the host and not the virus, bavituximab is expected to be less susceptible to the development of anti-viral resistance than many other therapies. Bavituximab has successfully completed Phase la and lb clinical trials as monotherapy in patients with chronic HCV infection, which showed that the drug is well tolerated and demonstrated encouraging signs of anti-viral activity.

About Peregrine PharmaceuticalsPeregrine 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 programs in cancer and HCV infection in the U.S. and India 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]

Enhancing the immunogenicity of glioma cells with anti-phosphatidylserine antibody.


Jin He, Troy A. Luster, Philip E. Thorpe. UT Southwestern Medical Ctr., Dallas, TX

Malignant gliomas grow aggressively and infiltrate surrounding normal brain. None of the traditional therapies prevents the lethal growth of infiltrating tumor cells. In a previous study, we showed that phosphatidylserine (PS) becomes exposed on the surface of tumor vascular endothelium and F98 glioblastoma cells after exposure to irradiation. Rats having orthotopic glioblastomas were treated with single fractionated radiation combined with 2aG4, a mouse monoclonal antibody against PS. The treatment resulted in a marked prolongation of survival time and some tumor cures (15%). Surviving animals were immune to intracerebral challenge with live, untreated F98 cells. These findings suggested that PS on tumor cells might be suppressing host immune response to the tumor cells and that blocking PS with 2aG4 restored immunogenicity. In the present study, we explored the possibility of enhancing the immunogenicity of irradiated F98 cells by treating them with 2aG4 in vitro. Fisher/344 rats received biweekly s.c. injection of 107 irradiated F98 cells premixed with 2aG4, control antibody C44, or PBS for three weeks. One week after the last injection, rats were challenged with intracerebral injection of 105 F98 cells. A 57% long-term survival rate was observed in the 2aG4 group, versus a 16% and 0% for rats immunized in the control antibody group and PBS group, respectively. The superior survival in the 2aG4 group was statistically significant (P < 0.01). 2aG4-coated F98 cells were efficiently phagocytosed by DCs through FcgR on DCs. Co-culture of tumor-loaded DCs and T-cells demonstrated that antibody-coated F98 glioma cells are able to elicit specific T-cell responses, as judged by enhanced production of tumor-reactive IFN-g producing T cells and increased cytotoxicity of T cells on F98 tumors. These data suggest that anti-PS antibody treatment of tumor cells can enhance cross-presentation of tumor antigens and the generation of glioma-specific T cells by dendritic cells. Anti-PS antibody treatment might be combined with radiosurgery in clinical settings to treat brain tumor patients.
This work was conducted with the support of a grant from the Gillson Longenbaugh Foundation and a sponsored research agreement with Peregrine Pharmaceuticals Inc.
Posted by jazzbeerman on the IHUB.com board.


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[Preciouslife1]

PPHM Peregrine Pharmaceuticals Reports Positive Top-Line Results in Bavituximab Combination Therapy Trial in Advanced Cancer Patients

Last update: 5/31/2007 9:30:00 AM-
50% of All Evaluable Patients Receiving Combination of Bavituximab Plus Chemotherapy Achieved Objective Tumor Response or Stable Disease - - 75% of Patients Receiving Combination of Bavituximab Plus Gemcitabine Achieved Objective Tumor Response or Stable Disease - - 50% of Patients Receiving Combination of Bavituximab Plus Carboplatin/Paclitaxel Achieved Objective Tumor Response - -

Trial Results Support Advancing to Exploratory Phase II Efficacy Studies Currently Planned for Later This Year -
TUSTIN, Calif., May 31, 2007 /PRNewswire-FirstCall via COMTEX/ -- Peregrine Pharmaceuticals, Inc. (PPHM), a clinical stage biopharmaceutical company developing monoclonal antibodies for the treatment of cancer and hepatitis C virus (HCV) infection, today reported positive top-line results of its Phase lb open label trial of bavituximab in combination with chemotherapy. This trial was designed to assess the safety and tolerability of bavituximab in combination with common chemotherapy agents in advanced cancer patients with me.tastatic disease who had failed prior therapy. Patients in the trial were also assessed for tumor response. In the trial, the safety profile of bavituximab in combination with chemotherapy appeared similar to that seen in advanced cancer patients undergoing chemotherapy alone. The combination of bavituximab and chemotherapy showed positive signs of clinical activity, achieving objective tumor response or stable disease in 50% of the patients who were evaluable for tumor response. Patients receiving bavituximab in combination with gemcitabine demonstrated an even greater response, with 75% achieving an objective tumor response or stable disease, while 50% of patients receiving bavituximab with carboplatin/paclitaxel demonstrated an objective tumor response. Data from this study are being further analyzed to support the initiation of Phase II cancer trials later this year. "We are encouraged to see objective responses in these patients with refractory advanced solid cancers after only a limited exposure to a regimen of bavituximab plus chemotherapy," said Joseph Shan, executive director of clinical and regulatory affairs at Peregrine. "We look forward to conducting the next set of clinical studies to further explore the potential of bavituximab as a novel cancer treatment." The Phase Ib open label trial at clinical sites in India was designed to test the safety and tolerability of up to eight weekly doses of bavituximab given in combination with standard chemotherapy regimens including docetaxel, gemcitabine and carboplatin/paclitaxel. Study endpoints included safety, tolerability and pharmacokinetics. Although efficacy assessments were not formal endpoints of the study, patients were evaluated for tumor response according to Response Evaluation Criteria in Solid Tumors (RECIST) parameters, receiving CT or MRI scans prior to therapy and at the end of the combination treatment course. Tumor types in the trial included cancers of the breast, lung and ovary, among others. "We are very encouraged by these results which indicated that the combination of bavituximab plus chemotherapy appeared to have a safety profile consistent with chemotherapy alone, while demonstrating the ability to shrink tumors or achieve stable disease in half of these very ill patients with advanced cancer," said Steven W. King, president and CEO of Peregrine. "The safety results and signs of anti-tumor activity seen in this combination therapy trial fully support moving bavituximab into exploratory efficacy trials slated for later this year," Patients were categorized as having "stable disease" if they had less than a 20% increase in the size of the tumor up to a 30% reduction in tumor size, "partial response" was defined as greater than a 30% reduction in tumor size and "complete response" was defined as disappearance of all lesions. Patients were categorized as having "progressive disease" if they had greater than a 20% increase in tumor size or the presence of new lesions. Patients with objective tumor responses (partial and/or complete responses) were eligible to continue with chemotherapy and bavituximab on a compassionate use basis. The trial was conducted according to International Conference on Harmonization (ICH) and Good Clinical Practices (GCP) guidelines. Bavituximab is a monoclonal antibody that targets and binds to a phospholipid called phosphatidylserine, which is located on the inside of normal cells but which becomes exposed on the outside of the cells that line the blood vessels of tumors, creating a specific target for anti-cancer treatments. Bavituximab is currently in clinical trials in the U.S. for the treatment of solid tumors and as a treatment for chronic hepatitis C infection in patients co-infected with HIV. Clinical data to date has shown that bavituximab is generally safe and well tolerated, and extensive preclinical data demonstrate good anti-tumor activity in a variety of tumor types, especially when bavituximab is administered in combination with chemotherapy or radiation. Peregrine intends to present more complete data from this trial at an appropriate scientific meeting later this year. 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 five separate clinical trials in cancer and HCV infection in the U.S. and India with its lead product candidates bavituximab and Cotara(R). Peregrine also has in-house manufacturing capabilities through its wholly owned subsidiary Avid Bioservices, Inc. (), which provides development and bio-manufacturing services for both Peregrine and outside customers. info@peregrineinc.com, orMedia, Barbara Lindheim of Peregrine Pharmaceuticals, Inc.,
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[Preciouslife1]

Peregrine Pharmaceuticals Enters Into Development Collaboration with Dios Therapeutics
Thursday May 31, 3:54 pm ET
-Terms of the Agreement Provide for Peregrine to Receive Development Fees and Potential Royalties That Could Exceed $50 Million.

TUSTIN, Calif., May 31 /PRNewswire-FirstCall/ -- Peregrine Pharmaceuticals, Inc. (Nasdaq: PPHM - News), a clinical stage biopharmaceutical company developing monoclonal antibodies for the treatment of cancer and hepatitis C virus (HCV) infection, announced today that it has entered into a development collaboration with Dios Therapeutics, Inc., an emerging biotechnology company founded in 2006. Under the terms of the agreement, Peregrine will provide process development and manufacturing services and know-how to support early clinical development for Dios' proprietary humanized monoclonal antibody for the treatment of thyroid associated ophthalmopathy (TAO) using existing development and manufacturing capacity once Dios provides Peregrine with its lead humanized antibody product candidate. In exchange for these development efforts, Peregrine has the option to convert its development fees into either cash or equity in Dios at a preferential conversion rate after Phase I trials. Peregrine also could receive a royalty on net product sales or Dios has the option to buy out the royalty obligation for a one-time fee which could total up to $50 million dollars. The buy-out option is exercisable anytime for a period up to two years after first commercial sale. Under the terms of the agreement, Dios is responsible for all third party expenses related to manufacturing process development as well as all pre-clinical and clinical trial costs.


"Even with increased demand for our manufacturing services from outside clients, we continue to seek attractive opportunities such as this to create value out of our existing manufacturing expertise and capacity," stated David King, Peregrine's vice president of business development. "We are particularly pleased to enter into this collaboration with Dios for this exciting first-in-class technology that has already shown promising signs of activity."

"We are delighted to enter into this strategic relationship with Peregrine because of its proven capabilities and track record in cGMP manufacturing of monoclonal antibodies and product development," said Dr. Glenn Albrecht, Dios' president and chief executive officer. "We believe this collaboration creates substantial opportunities and upside potential for both companies and is a sign of the potential value of our company and our novel therapeutic."

About Dios Therapeutics

Dios Therapeutics, Inc. is an emerging biotechnology company focused on developing non-immunosuppressing therapeutics for the treatment of multiple autoimmune indications including Graves disease, Hashimoto disease and rheumatoid arthritis. The Company was founded in 2006 with the aim of commercializing potentially path breaking discoveries from the University of California, Los Angeles. Dios will use these novel molecular insights to develop better autoimmune disease therapeutics without the generalized immune suppression associated with current therapies. The Company is initially focusing on developing therapeutics to treat thyroid associated ophthalmopathy (TAO), a severe form of Graves disease that can lead to vision loss.

[Preciouslife1]

Melina Soares, Sameer Syed, Gustavo Barbero and Philip E Thorpe Pharmacology, University of Texas Southwestern Medical Center, 2201 Inwood Road, NC7.304, MC 9041, Dallas, TX, 75390

J. Immunol., Apr 2007; 178: 47.21.

Abstract

The anionic phospholipid phosphatidylserine (PS) is found exclusively in the inner leaflet of the plasma membrane of resting mammalian cells. We hypothesized that certain events that occur during virus replication (eg cell activation or membrane rearrangement) would trigger the exposure of anionic phospholipids on the outer surface of virus- infected cells and subsequently on the enveloped viruses that bud out of these virus- infected cells. We further hypothesized that these exposed anionic phospholipids would serve as targets for anti-viral therapy. We demonstrate here that anionic phospholipids become exposed on the enveloped Pichinde Virus (a model virus for Lassa Fever virus, a potential bioterrorism agent) and on Pichinde virus-infected cells. To detect anionic phospholipids, we used a chimeric monoclonal antibody, bavituximab, that binds anionic phospholipids in a B2-glycoprotein I dependent manner. We show that bavituximab treatment is able to cure overt disease in guinea pigs lethally infected with Pichinde virus. Bavituximab treatment reduced the amounts of virus in multiple tissues and caused direct clearance of virus from the blood. Direct clearance of free virus and antibody-dependent cellular cytotoxicity of virus-infected cells appear to be the major mechanisms that contribute to the anti-viral effect of bavituximab. Bavituximab-treated survivors were immune to reinfection. Furthermore, the murine version of bavituximab, 3G4, shows therapeutic efficacy in a lethal murine model for human cytomegalovirus. Our study demonstrates the promise of anionic phospholipids as targets for new broad-spectrum anti-viral drugs.

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[Preciouslife1]

Peregrine Pharmaceuticals Initiates Patient Enrollment In New Cotara(R) Brain Cancer Trial


- Access to Large Population of Glioblastoma Patients in India Expected to Support Rapid Enrollment in Phase II Safety and Efficacy Study of Promising Investigational Brain Cancer Therapy -

- Results from This Study are Expected to Help Advance Cotara Toward Phase III Product Registration Trials -

TUSTIN, Calif., June 25 /PRNewswire-FirstCall/ -- Peregrine Pharmaceuticals, Inc. (Nasdaq: PPHM), a clinical stage biopharmaceutical company developing targeted monoclonal antibodies for the treatment of cancer and hepatitis C virus infection, today announced initiation of a new clinical trial designed to evaluate the safety and efficacy of its tumor necrosis therapy (TNT) agent Cotara(R) in patients with glioblastoma multiforme (GBM), a deadly form of brain cancer. In pilot studies Cotara has shown encouraging results, demonstrating a 58% increase in the expected median survival time in a group of 28 patients suffering from recurrent late stage glioblastoma multiforme. This was considered a promising development in this serious and deadly disease, which kills half of its victims within 14 months of diagnosis. Peregrine believes that combined positive data from this new study in India and ongoing U.S. glioblastoma trials would provide a foundation for advancing Cotara into Phase III trials.
"Cotara has demonstrated promising increases in survival in previous clinical studies of late stage glioblastoma patients, and we are optimistic that the very large population of glioblastoma patients served by our Indian study centers will facilitate timely enrollment in this important new trial," said Steven W. King, president and CEO of Peregrine. "We anticipate that positive data from this study, together with dosimetry and dosing data being collected in ongoing U.S. Cotara trials, will help us determine the optimal design of Phase III product registration trials."
This multi-center open label Phase II safety and efficacy study is designed to enroll up to 40 glioblastoma patients who have experienced a first relapse. The study's primary objective is to confirm the maximum tolerated dose of Cotara in patients with GBM at first relapse. Secondary objectives include estimates of overall patient survival, progression free survival and the proportion of patients alive at six months. Patients in the trial are receiving a single infusion of Cotara by convection-enhanced delivery (CED), an NIH-developed technique that delivers the agent to the tumor with great precision, achieving up to a 10,000-fold greater concentration in local therapy exposure than conventional intravenous drug administration, while minimizing unwanted exposure to healthy tissue. This delivery method is expected to further enhance the tumor-killing efficacy of Cotara.
Mr. King continued, "We are launching this Cotara clinical program in India to take advantage of the large population of GBM patients served by our study centers and the high level of experience with CED delivery of the participating neurosurgeons, as well as the fact that the contract research organization overseeing the trial is highly experienced in conducting similar glioblastoma trials with many of the investigators involved with our study."
The new Cotara study is being conducted according to internationally accepted ICH GCP guidelines.
About Cotara(R)
Cotara is an experimental new treatment for brain cancer that links a radioactive substance designed for medical uses -- a radioactive isotope -- to a targeted monoclonal antibody. This monoclonal antibody is designed to bind to a type of DNA that is exposed only on dead and dying cells. Solid tumors, including brain tumors, have a significant number of dead and dying cells at their center, and Cotara's targeting mechanism enables it to home in on these dying tumor cells, delivering its radioactive "payload" directly to the center of the tumor mass. Cotara thus destroys the tumor "from the inside out," with minimal radiation exposure to healthy tissue. Cotara is delivered through a special method called convection-enhanced delivery (CED), which directs Cotara to the tumor by using a catheter to bypass the blood brain barrier and target the specific tumor site in the brain.
In pilot studies, 28 late stage glioblastoma patients achieved a median survival of 36 weeks, a 58% increase over the median survival time of 24 weeks for patients treated with standard of care therapy. Of this group, 25% of patients survived for more than a year post treatment and 10% of patients survived for more than three years. Patients receiving the dose being used in the current Cotara studies experienced even better increases in median survival.
In addition to the trial now underway in India, Cotara is currently in a dosimetry and dose confirmation trial in glioblastoma patients at a number of leading U.S. academic brain cancer centers. Cotara has been granted orphan drug status and fast track designation for the treatment of glioblastoma multiforme and anaplastic astrocytoma by the U.S. Food and Drug Administration.
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 programs in cancer and HCV infection in the U.S. and India 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]

Posted by: Preciouslife1
In reply to: NoneDate:6/26/2007 9:13:43 AM
Post #of 48977
Medical University of South Carolina Initiates New Trial of Cotara(R) in Brain Cancer Patients
Tuesday June 26
http://biz.yahoo.com/prnews/070626/latu042.html?.v=101
Veteran Cotara Researcher Dr. Sunil Patel Opens New U.S. Clinical Trial Site

TUSTIN, Calif., June 26, 2007 /PRNewswire-FirstCall via COMTEX News Network/
Peregrine Pharmaceuticals, Inc. (Nasdaq: PPHM), a clinical stage biopharmaceutical company developing targeted antibodies for the treatment of cancer and hepatitis C virus infection, today announced that the Medical University of South Carolina (MUSC) is now enrolling patients in a dose confirmation and dosimetry trial of its tumor necrosis therapy (TNT) Cotara(R) in patients with glioblastoma multiforme (GBM), a deadly form of brain cancer. Cotara is also being studied at other clinical sites in the U.S. and in a multicenter Phase II trial in India.

MUSC trial lead Dr. Sunil Patel conducted earlier studies of Cotara in GBM patients that showed promising signs of anti-tumor activity, including one patient who is still alive six years post-treatment, when most patients with recurrent GBM live only about a year.

"Based on the positive results we saw in prior clinical studies of Cotara in patients with recurrent brain cancer, I am pleased to be leading this new study," said Sunil Patel, M.D., clinical chairman of the MUSC Department of Neurosciences. "Glioblastoma remains a deadly disease with few good treatment options, and I look forward to assessing Cotara's clinical potential using convection-enhanced delivery, which may further improve the life extending potential seen in earlier Cotara trials."

This open label study is enrolling glioblastoma patients who have recurrent disease. Patients will receive Cotara by convection-enhanced delivery (CED), an NIH-developed technique that delivers the agent to the tumor with great precision. The study's main objectives are to confirm the maximum tolerated dose; to determine radiation dosimetry; and to assess overall patient survival, progression free survival and the proportion of patients alive at six months following Cotara administration.

"Our efforts to accelerate these critical Cotara studies in the U.S. and India are now bearing fruit, with enrollment underway in the 40-patient phase II study in India and the U.S. dose confirmation and dosimetry trial proceeding well," said Steven W. King, president and CEO of Peregrine. "We believe these efforts will be significantly strengthened by the addition of the new trial at MUSC led by Cotara expert Dr. Patel. Cotara potentially could provide an important new option for the treatment of this deadly disease that lacks effective therapies. We look forward to working with all of our investigators to generate clinical data this year that should be critical for confirming the potential of Cotara for the treatment of brain cancer."

Peregrine is working directly with several of its New Approaches to Brain Tumor Therapy (NABTT) clinical sites in the U.S. and with additional centers such as MUSC to ensure the timely completion of the U.S. dose confirmation and dosimetry trial. The design of this new Cotara study is a modified version of the protocol developed for the NABTT program.

About Cotara(R)

Cotara is an experimental new treatment for brain cancer that links a radioactive substance designed for medical uses -- a radioactive isotope -- to a targeted monoclonal antibody. This monoclonal antibody is designed to bind to a type of DNA that is exposed only on dead and dying cells. Solid tumors, including brain tumors, have a significant number of dead and dying cells at their center, and Cotara's targeting mechanism enables it to hone in on these dying tumor cells, delivering its radioactive "payload" directly to the center of the tumor mass. Cotara thus destroys the tumor "from the inside out," with minimal radiation exposure to healthy tissue.

Cotara is delivered through a special method called convection-enhanced delivery (CED), which directs Cotara to the tumor by using a catheter to bypass the blood brain barrier and target the specific tumor site in the brain. This type of delivery has been shown to achieve up to a 10,000-fold greater concentration in local therapy exposure than conventional intravenous drug administration, while minimizing unwanted exposure to healthy tissue.

In previous clinical studies Cotara has demonstrated encouraging results in patients with advanced brain cancer. One study demonstrated a 58% increase in median survival time in a group of patients suffering from late stage glioblastoma multiforme who were treated with Cotara. This was considered a promising development in this serious and deadly disease. In addition to the trial now underway in India, Cotara is currently in a dosimetry and dose confirmation trial in glioblastoma patients at a number of leading U.S. academic brain cancer centers. Cotara has been granted orphan drug status and fast track designation for the treatment of glioblastoma multiforme and anaplastic astrocytoma by the U.S. Food and Drug Administration.

About MUSC

Founded in 1824 in Charleston, The Medical University of South Carolina is the oldest medical school in the south. Today, MUSC continues the tradition of excellence in education, research, and patient care. MUSC is home to over 3,000 students and residents, as well as nearly 10,000 employees, including 1,300 faculty members. MUSC operates a 600 bed medical center, which includes a nationally recognized Children's Hospital and a leading Institute of Psychiatry. http://www.musc.edu
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[Preciouslife1]

Peregrine Pharmaceuticals to Announce Fourth Quarter and Full Year FY 2007 Financial Results
Tuesday July 3, 1:02 pm ET

TUSTIN, Calif., July 3 /PRNewswire-FirstCall/ -- Peregrine Pharmaceuticals, Inc. (Nasdaq: PPHM - News), a clinical stage biopharmaceutical company developing monoclonal antibodies for the treatment of cancer and hepatitis C virus (HCV) infection, today announced that it will release its fourth quarter and full year FY 2007 financial results on July 11, 2007 at 7:00 a.m. EDT, and will host a conference call and webcast to discuss the results at 11:00 a.m. EDT on the same day.
ADVERTISEMENT

Participating members of Peregrine senior management will include president and chief executive officer Steven W. King and chief financial officer Paul Lytle. Management will discuss financial results for the fourth quarter and fiscal year ended April 30 2007, review recent events and provide an update on clinical programs. A question-and-answer session will follow management's discussion. All interested parties are encouraged to listen to the live conference call or the live or archived webcast.

The conference call and webcast will begin at 11:00 a.m. EDT/8:00 a.m. PDT.

To listen to a live broadcast of the call over the Internet or to review the archived call, please visit: http://www.peregrineinc.com. The webcast will be archived on Peregrine's website for 30 days.

To listen to the call via telephone, please call the following number approximately 10 minutes prior to the scheduled time of the conference call: 1-800-860-2442. A telephonic replay of the conference call will be available through July 18, 2007 by calling (877) 344-7529, passcode 382933#.
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[Preciouslife1]

Peregrine Pharmaceuticals to present at this October BioInvestor Forum: Thanx to the Thing on IHUB for the link..


http://investorforum.bio.org/opencms/bif/2007/program/presenters.jsp