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ON THE SHELF 6





AACR 2007 (Apr14-18) – 10 PPHM-related Posters

“More than 17,000 scientists from all over the world will gather under the AACR’s banner in what has become the field’s most important intl. annual cancer research meeting.”
http://www.aacr.org/home/scientists/meetings--workshops/annual-meeting-2007/program-in-progress.aspx - click “ONLINE PROCEEDINGS”

1. #3273 (Apr16) ‘Vascular Targeting Antibody Improves Chemotherapy of Prostate Cancer’
Yi Yin, Xianming Huang, Jin He, Troy A. Luster, Philip E. Thorpe - UTSW-MC/Dallas
”Treatment with the combination [2aG4+Docetaxel] reduced the growth of small LNCaP & PC3 tumors by 80-82% and of well-established LNCaP & PC3 tumors by 92-94%. The antitumor effect of the combination treatment was significantly superior to that of the individual treatments (P < 0.01). The combination therapy was no more toxic to the mice than was docetaxel alone as judged by physical signs and body weight changes… The present results provide the foundation for using bavituximab plus docetaxel to treat prostate cancer patients.”
FULL ABSTRACT: http://www.investorshub.com/boards/read_msg.asp?message_id=17860805

2. #4089 (Apr17) ‘Fusion Proteins Composed of Mouse Igg2a Fc and Mouse Beta-2-Glycoprotein 1 Bind to Endothelial Cells with Exposed Phosphatidylserine’ [‘BETABODIES’]
Troy A. Luster, Philip E. Thorpe - UTSW-MC/Dallas
”Recently we determined that 3G4 recognizes PS through the formation of a complex with plasma protein beta-2-glycoprotein 1 (B2GP1)… 3G4 enhances the avidity of B2GP1 for membrane surfaces with exposed PS through the formation of multivalent 3G4/B2GP1/PS complexes. This increased avidity of B2GP1 for PS is likely responsible for targeting of 3G4 to tumor EC with exposed PS… We report here the construction of recombinant fusion proteins composed of mouse IgG2a Fc and mouse b2GP1… These Fc-B2GP1 compounds [‘BETABODIES’] have potential as tumor therapeutic or imaging agents.”
FULL ABSTRACT: http://www.investorshub.com/boards/read_msg.asp?message_id=17860821

3. #4091 (Apr17) ‘Enhancing the Immunogenicity of Glioma Cells with Anti-Phosphatidylserine Antibody’
Jin He, Troy A. Luster, Philip E. Thorpe - UTSW-MC/Dallas
”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… Anti-PS antibody treatment might be combined with radiosurgery in clinical settings to treat brain tumor patients.”
FULL ABSTRACT: http://www.investorshub.com/boards/read_msg.asp?message_id=17860816

4. #3539 (Apr17) ‘Inhibition of Tumor Growth by Targeting Cytokines to the Inside-Out Phosphatidylserine (PS) on Tumor Vascular Endothelium with 2ag4’
Xianming Huang, Dan Ye, Philip Thorpe - UTSW-MC/Dallas
”In this study, immunocytokines between 2aG4, a tumor vascular targeting antibody specific to PS on tumor vascular endothelium, and murine type I interferons or interleukin 2 were developed. The resulting fusion proteins demonstrated both antigen binding and cytokine activities in vitro. The fusion protein was capable of targeting tumor blood vessels and displayed potent anticancer effects in various murine tumor models in vivo without causing any observable toxicity. Especially, the combination of 2aG4-IL-2 with 2aG4-IFNa was significantly better than either single agent alone… These studies demonstrate that 2aG4 immunocytokines could have great potential for targeted immunotherapy of solid tumors.”
FULL ABSTRACT: http://www.investorshub.com/boards/read_msg.asp?message_id=17860809

5. #2128 (Apr16) ‘Blockade of Tumor-Derived VEGF Activation Of VEGF Receptor 2 Reduces Macrophage Infiltration into Tumors and Decreases Metastasis in a Pre-Clinical Orthotopic Model of Pancreatic Cancer’ [HUMAN 2C3]
Juliet G. Carbon, Shane E. Holloway, Andrew F. Miller, Anita Kavlie, Kyle Schlunegger, Jason B. Fleming, Rolf A. Brekken. UTSW-MC/Dallas, Affitech AS, Oslo, Norway, Peregrine Pharm., UT-MDA/Houston
”VEGF binds and activates VEGF receptors 1 and 2 (VEGFR1 & VEGFR2), which are expressed on endothelial and other cell types. Most of the current anti-angiogenic strategies in clinical trials against pancreatic cancer block the activity of both receptors. We have developed 2C3, a mouse monoclonal (mAb) that selectively inhibits VEGF from binding and activating VEGFR2 but not VEGFR1… To bring 2C3 to the clinic, we have developed fully human IgG constructs (Hu2C3) with the same specificity as 2C3. We have found that Hu2C3 reduces the growth, vascularization, and macrophage infiltration of subcutaneous A673 tumors xeongrafts in mice… We have demonstrated that VEGF-VEGFR2 binding is critical for VEGF-induced infiltration of host macrophages into tumors, and selective blockade of this interaction is an attractive therapeutic strategy against pancreatic cancer.”
FULL ABSTRACT: http://www.investorshub.com/boards/read_msg.asp?message_id=17860841

6. #4095 (Apr17) ‘Selective Targeting Of Cellular Immune Responses by Chimeric and Humanized Monoclonal Antibodies To Phosphatidylserine Exposed in Tumor Vasculature’
Monica Friedrich, Amy Brideau-Andersen, Bruce Freimark, Connie Chang - Peregrine Pharm.
”In this study, we evaluate the ability of the chimeric and humanized antibodies to exert anti-tumor effects through various mechanisms, including ADCC, on cellular targets expressing PS… These data demonstrate that humanized 3G4 has comparable target recognition and effector function to bavituximab and, therefore, could be used to treat human cancer patients.”
FULL ABSTRACT: http://www.investorshub.com/boards/read_msg.asp?message_id=17860825

7. #4190 (Apr17) ‘Vasopermeation Enhancement Agents [VEAs]: A Case Study In Screening For The Most Potent Variant In A New Class Of Compounds By Using A Novel Avian Embryonic System’ (Minisymposium)
Kelly A. Felton, John D. Lewis, Andries Zijlstra, Jennifer Chase, Keith A. Luhrs, Aparna I. Roy, Debra A. Harris, Christian Frosch, Steven W. King, Missag H. Parseghian - Peregrine Pharm., London Regional Cancer Program, London, ON, Canada, Vanderbilt Univ., Nashville, TN, Innovascreen, Halifax, NS, Canada, Biobroker, Hamburg, Germany
”Vasopermeation Enhancement Agents (VEAs) are a new class of biologics that are designed to increase the uptake of cancer therapeutics at the tumor site, resulting in a greater efficacy of the compounds, without increasing dosages given to the patient… The lead vasoactive compound under investigation is Interleukin-2 (IL-2) or fragments of that protein… Sensitive quantitative measurements obtained in our novel in vivo assay have allowed us to determine the efficacy of these 11 vasoactive compounds, and this has allowed us to choose the most promising candidates for further pre-clinical studies in mice and monkeys. We believe this is the 1st report of an avian embryonic system being utilized for the commercial evaluation of clinical drug candidates prior to more costly investigations in traditional animal models.”
FULL ABSTRACT: http://www.investorshub.com/boards/read_msg.asp?message_id=17860854

8. #4092 (Apr17) ‘Targeting Truncated Tissue Factor with Tumor Vasculature Specific Monoclonal Antibodies: Developing Coaguligands as Cancer Therapeutics’ [tTF+VTAmabs]
Richard H. Archer, Mary Wakabayashi, Roy Sevilla, Scott Summers, Steven King, Ronald T. Aimes - Peregrine Pharm.
”We have been developing a series of agents that specifically target the established vasculature of solid tumors. Coaguligands, one class of these VTAs, target a truncated form of the procoagulant tissue factor to tumor blood vessels. Truncated tissue factor (tTF) has very weak ability to induce blood coagulation by itself, but becomes a powerful thrombogen for tumor blood vessels when targeted by monoclonal antibodies to tumor vasculature. The coaguligand specifically induces coagulation of tumor vasculature, leading to tumor infarction. We have developed 3 coaguligands (PGN-502, PGN-503, and PGN-504) that link truncated tissue factor to vascular targeting mabs.”
FULL ABSTRACT: http://www.investorshub.com/boards/read_msg.asp?message_id=17860847

***THESE 2 SEEMINGLY INVOLVE DR. MICHAEL ROSENBLUM’S (MDA/TARGA) WORK WITH PPHM’S VTA FUSION TOXIN VEGF121/rGel (sublic. by SUPG from PPHM in 2001)…
…Status a/o 11-2006: "Targa plans to begin mfg. this compound before the end of 2006 in prep. for Ph.1 trials at M.D.Anderson”
…see http://tinyurl.com/ylevod & http://www.targatherapeutics.com/vegfshortsummary.html

9. #4093 (Apr17) ‘The Vascular Ablative Agent VEGF121/rGel Targets Osteoblast Proliferation and Inhibits Prostate Cancer-Induced Bone Formation’ - Khalid A. Mohamedali, Zhi Gang Li, Sehoon Kim, Nora Navone, Michael G. Rosenblum. UT MDA Cancer Center, Houston.
”Our results suggest that VEGF121/rGel may have a therapeutic effect against prostate cancer-mediated osteoblastic lesions in bone.”

10. #5481 (Apr18) ‘Multi-Modality Molecular Imaging of Glioblastoma Growth Inhibition Using the Vascular-Targeting Fusion Toxin VEGF121/rGel’ - Andrew R. Hsu, Weibo Cai, Anand Veeravagu, Kai Chen, Khalid A. Mohamedali, Hannes Vogel, Lewis C. Hou, Victor C.K. Tse, Michael G. Rosenblum, Xiaoyuan Chen. Stanford Univ. School of Medicine, Stanford, CA, UT MDA Cancer Ctr., Houston.
”The results of this study clearly suggest that future clinical multi-modality imaging and therapy using VEGF121/rGel…”

THIS ONE BY DR. ALAN EPSTEIN – UNCERTAIN IF THIS WORK IS RELATED TO PPHM:
#2743 (Apr16) ‘Immune Signatures Reveal Tumor Escape Targets In Mice And Man’ - Rebecca E. Sadun, Suzanne M. Sachsman, William Z. Morris, Xiaoying Chen, Alan L. Epstein - Keck-USC School of Medicine
”groups of tumor-bearing mice were treated with an immunotherapy regimen, LEC/chTNT-3 + PC61, known to produce significant tumor regression in a tumor model-dependent fashion.”

***INTERESTING UNIV-IOWA AACR 2007 POSTER ON THE ROLE OF PS IN THE TUMOR ENVIRONMENT:
#213 (Apr15) ‘Neuroblastoma Express Phosphatidlyserine: Mechanism for Immune Evasion’
Kara Doffek, Xiaocia Yan, Sonia L. Sugg, Bryon Johnson, Joel Shilyansky. Medical College of Wisconsin, Milwaukee, WI, Univ. of Iowa
ABSTRACT:
Introduction: We examined the effect of phosphatidylserine (PS) on tumor immunity. PS is a membrane phospholipid that is restricted to the inner surface of plasma membrane in living cells, but flips to the cell surface during apoptosis. PS may be also expressed on the surface of live tumor cells. PS was reported to promote tolerance, possibly by inhibiting antigen presentation and inflammation. The effect of tumor PS on the immune response against neuroblastoma (NB), a childhood malignancy, was examined in a murine model.
Methods: PS on NB cell surface was determined using Annexin-V (AnV) binding and flow cytometry. To block PS in vivo, NB cells were engineered to secrete AnV protein covalently fused to FLAG, which specifically binds and blocks PS. Western blot was used to determine AnV expression. A/J mice were injected with 104 NB cells subcutaneously and tumor growth was determined.
Results: NB cells were transfected with pre-pro-trypsin AnV-FLAG construct. Western blot analysis was used to quantify AnV production in supernatants and identify NB clones that secreted AnV (AnV-NB). Clones that proliferated in vitro at the same rate as wild type (wt) NB cells were selected. Supernatants from AnV-NB cells blocked PS on the surface of wt NB cells preventing staining with FITC-conjugated recombinant AnV. The findings suggest that secreted AnV blocked PS. The wt and AnV-NB cells were then injected subcutaneously into A/J mice. Tumor homogenates showed continuous AnV expression in vivo. In immunocompetent mice, wt tumors grew faster than AnV-NB cells. In mice depleted of T cells with anti-Thy1.2, no difference in growth rate between wt and AnV-NB tumors was noted. Mice were then immunized two times, 7 days apart, with AnV-NB or control cells. 7 days later mice were injected subcutaneously with 105 wt NB cells. Immunization with An-NB, but not control cells, protected mice from wt NB challenge.
Conclusions: The study demonstrated that mouse NB cells express PS on the cell surface. Blocking PS in vivo by engineering NB cells to secrete AnV slowed tumor growth in immunocompetent but not T cell depleted mice. Importantly, immunization with AnV-NB cells was protective. The findings suggest that PS inhibited anti-tumor T cell immunity in mice. The mechanism of PS action may be indirect inhibition of anti-tumor CTL responses, or activation of regulatory T cells. The studies support the hypothesis that PS expression is a potential mechanism for tumor immune evasion.