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12-2011: Thorpe Article on FH-Bavi/Optical-Imaging in Translational Oncology…

12-2011: ”Near-infrared Optical Imaging of Exposed Phosphatidylserine in a Mouse Glioma Model”
Dawen Zhao *, Jason H. Stafford †, Heling Zhou *, Philip E. Thorpe †
*Dept. of Radiology, UTSW-MC/Dallas
†Dept. of Pharmacology, UTSW-MC/Dallas
Translational Oncology, Dec.2011, pgs.355-64. Epub 12-1-2011
http://www.ncbi.nlm.nih.gov/pubmed/22191000
http://www.translationaloncology.org
FULL 10-pg. Article: http://www.transonc.com/pdf/manuscript/v04i06/neo11178.pdf
ABSTRACT
Phosphatidylserine (PS) is normally intracellular but becomes exposed on the luminal surface of vascular endothelial cells in tumors. It also becomes exposed on tumors cells responding to therapy. In the present study, we optically imaged exposed PS in vivo using PGN635 [Note: PGN635 = Fully-Human BAVI=AT004=1N11], a novel monoclonal antibody that binds PS. The F(ab')(2) fragment of PGN635 was labeled with the near-infrared (NIR) dye, IRDye800CW. In vivo dynamic NIR imaging was performed after injection of 800CW-PGN635 into mice bearing radiation-treated or untreated U87 glioma xenografts growing subcutaneously or orthotopically. NIR optical imaging revealed a clear tumor contrast in nonirradiated subcutaneous U87 gliomas after injection of 800CW-PGN635. The tumor contrast was visible as early as 4 hours later and was maximal 24 hours later (tumor-to-normal tissue ratio [TNR] = 2.8 ± 0.7). Irradiation enhanced the tumor contrast at 24 hours (TNR = 4.0 ± 0.3). Similar results were observed for orthotopic gliomas. Localization of 800CW-PGN635 to tumors was antigen specific because 800CW-Aurexis, a control probe of irrelevant specificity, did not localize to the tumors, and preadministration of unlabeled PGN635 blocked the uptake of 800CW-PGN635. Fluorescence microscopy confirmed that 800CW-PGN635 was binding to PS-positive vascular endothelial cells in nonirradiated gliomas. Irradiation of the gliomas increased PS exposure on both tumor vascular endothelial cells and tumor cells and gave rise to an increase in tumor contrast with 800CW-PGN635 that was predictive of the reduction in tumor growth. 800CW-PGN635 may be a useful new imaging probe for detection of exposed PS in tumors responding to therapy.
DISCUSSION: “…In summary, we have combined NIR optical imaging with PGN635, a novel monoclonal antibody that binds to PS, to monitor in vivo dynamics of exposed PS on mouse gliomas. We show that irradiation increases the PS signal, predictive of the response to therapy. The high tumor specificity of PGN635 in the present study underscores the prospects of using PGN635 and related antibodies to treat cancer in humans.”
ACKNOWLEDGMENTS: The authors thank Peregrine Pharmaceuticals, Inc. for the provision of PGN635 antibody. The authors also thank Kwang Song, Timothy Solberg, Debabrata Saha, and Abhijit Bugde for technical support and Ralph Mason for collegial support.

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12-12-11 Qtly. Conf. Call (King/Shan/Lytle) Transcript http://tinyurl.com/75rfwrv
Steve King (Q&A): “I think we want to advance both of those programs [BaviAV/nonHCV & Imaging). As you mentioned, we still have a very active program in Infectious Diseases. Of course, we’re looking for the Phase II data from the HCV trial, but also looking at still the applications of the technology platform. That approach, as we think about it today as a kind of a monoclonal antibody unconjugated approach but also as a delivery platform in which we could expand into antibody drug conjugates utilizing the PS-targeting platform. Imaging, I think, is something we're all pretty excited about. I mean, I think that's something that we want to see in the clinic. It is something that we would like to look out from a number of different standpoints. Of course, there's just further validating the technology platform through imaging and showing the specificity of the target itself. There's the potential for companion diagnostic-type applications and those are types of things we could look at potentially in ISTs as a go forward. And then there's just imaging and in our ability to show the effectiveness of therapy. And that was something that you saw at the AACR last year, we continue to expand on that at some recent conferences. So yes, that's one we want to see in the clinic moving forward. As always, we have to monitor our internal resources with our ability to continue to push forward those programs. So you may see some of them move forward in our hands, some in partner's hands as resources are permitting. . . Yes, you'll definitely some more data coming through the Imaging program. Again, very active. We're looking to publish data in peer-reviewed journals, as well as, of course, at some of the upcoming conferences. So, you will hear more about the Imaging program in 2012 even than you did in 2011 when we really pretty much first started talking about it from a more concerted-effort standpoint.”

IMAGING APPLICATIONS Of PS-TARGETING MABS:
12-2011: Thorpe Article on FH-Bavi/Optical-Imaging in Translational Oncology http://tinyurl.com/7vcnbz2
11-14-11: Dr. Bruce Freimark presents PS IMAGING poster at AACR-NCI-EORTC Conf./SanFran http://tinyurl.com/89hpydn
9-12-11: Drs. Thorpe & Freimark present PS IMAGING posters at World Imaging Congress/S.Diego http://tinyurl.com/3uv5rgr
9-9-11: PS IMAGING potential discussed in Qtly. Conf. Call: http://tinyurl.com/3q7hzjh
4-2011/Neoplasia: Dr. Thorpe 9-pg. article on Exposed-PE/Imaging http://tinyurl.com/5uoy6fh
…Dr. Thorpe: "PE also has potential as a marker for Imaging human malignancies."
4-6-11/AACR'11: Tumor Imaging Applications of PS-Targeting Antibodies http://tinyurl.com/68p9zs4
…Steve King: "Molecular imaging is a growing field and represents an entirely new development opportunity for our first-in-class PS-targeting antibody platform… our antibodies labeled with imaging tracers hold potential for illustrating exposed PS in a clinical oncology setting, imaging PS as a companion diagnostic with bavituximab therapy, as well as ultimately assessing patient response to a range of cancer therapies."
3-14-11: Dr. Thorpe discusses PS IMAGING in Conf. Call: http://tinyurl.com/4p4hqr5
…Dr. Thorpe: "The quality of the images is quite extraordinary. The antibody homes to tumor blood vessels beautifully in all tumors that we've seen with really very, very little of a staining seen in other tissues, and that's just what you'd like to see in a diagnostic - we are looking at that very seriously. And also, that binding is correlated to response, both with radiotherapy & chemotherapy. So again, we have the possibility of making a diagnostic that would be predictive of response. We are evaluating that possibility at this time... Duramycin binds PE; binding PE expands our coverage of our broad aminophospholipid-targeting platform, so it really dovetails very beautifully with the existing antibody portfolios. It's expanding our desire to explore different phospholipids as potential targets for therapy & diagnosis… PE is phosphatidylethanolamine and it is the brother of PS. So where PE goes, so does PS and vice versa. So the 2 lipids co-segregate normally on the inside surface of the plasma membrane, but in activated cells or apoptotic cells or stress cells, both lipids flip, and both are potential targets for therapeutics or diagnostics… Duramycin is a little peptide, that's a small molecule and has quite different qualities from an antibody in terms of penetrants. So we're intrigued to see how it plays out, too."
6-24-09 U.S. Patent #7,550,141 granted: Anti-PS for Tumor Imaging: http://tinyurl.com/ln9ub8
3-3-08: Thorpe/Mason C.C.R. (AACR) article on Arsenic-labeled Bavi for Imaging Tumors: http://tinyurl.com/32jbfl
…3-5-08 Chemistry World followup article on CCR Bavi+Arsenic/IMAGING: http://tinyurl.com/4m4lbse
2006/SMI: Thorpe/Mason, "Optical Imaging of Exposed PS in Tumors" http://tinyurl.com/42nh7d9
…"We believe optical imaging with Bavituximab holds great promise for assessing PS expression, and therapeutic activity in vivo and optimizing treatment protocols."