Replies to post #297558 on Avid Bioservices Inc (CDMO)

[hutschi]

http://journals.sagepub.com/doi/pdf/10.1177/1536012117708722

[hutschi]

Amyn Habib, M.D.

http://profiles.utsouthwestern.edu/profile/61448/amyn-habib.html

[hutschi]

The whole BAVITUXIMAB-part:


Phosphatidylserine-Targeting Antibody and Its Mode of Action

Phosphatidylserine-targeting antibodies have been developed by the Thorpe laboratory, including murine antibodies 2aG4 and 3G4 and a chimeric monoclonal antibody bavituximab.10,20-23 The antibodies recognize PS complexed with the PS-binding protein, ß2-glycoprotein 1 (ß2GP1).24 The ß2GP1 is a 50-kDa glycoprotein that binds weakly to anionic phospholipids under physiological conditions. With the PS antibodies, the binding of ß2GP1 to exposed PS is enhanced to form a stable multivalent complex of antibody ß2GP1-PS.25 Since there are abundant ß2GP1 in blood, it is unnecessary for in vivo study to have exogenous ß2GP1. The PS antibodies are observed to localize to PS-positive blood vessels in multiple tumor models after systemic infusion. Further studies have shown that the PS-bound antibodies induce monocytes to bind to the tumor vasculature and destroy it by antibody-dependent cellular cytotoxicity, leading to tumor growth inhibition.21,22 Antitumor effects of these antibodies are enhanced by chemotherapy,22 radiation,18,21 and small molecule tyrosine kinase inhibitor,19 all of which increase the levels of exposed PS in the tumors and thus amplify the target for attack by the antibodies. More recent studies have suggested that exposed PS suppresses host immunity against tumor cells and PS-targeting antibodies enhance antitumor effect with immune checkpoint cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or Programmed cell death protein 1 (PD-1) blockade by inducing more CD8+ T cells and fewer immune suppressive myeloid-derived suppressor cells and M2 macrophages.26-29 Bavituximab, the chimeric monoclonal PS-targeting antibody (blood half-life ~30 hours), is in advanced clinical trials in patients with lung and breast cancer.30,31 More recently, a new, fully human PS-targeting antibody, PGN635, is similar in affinity to bavituximab (Kd ˜10-10 M).32-34 In vitro binding assay has demonstrated its high specificity for the cell-exposing PS. The PS antibodies have a more restricted specificity for PS than does annexin V, known as a PS-binding ligand. Annexin V also recognizes Phosphatidylethanolamine (PE) in addition to PS and other anionic phospholipids.9,25 Moreover, annexin V has a blood half-life of 3 to 7 minutes, which may limit its use for clinical imaging and measuring peak probe uptake responses to therapy.34 We have exploited F(ab')2 fragment PGN635 (blood half-life ~16 hours) for development of PS-targeted imaging probes and nanoplatforms, which will be described in details in the following sections.



Phosphatidylserine-Targeted Molecular Cancer Imaging



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In vivo molecular imaging enables visualization of cellular and molecular events in living organisms.35,36 Unlike the invasive pathohistological examination, molecular imaging provides a noninvasive means to assess sensitivity and specificity of disease biomarkers. Various imaging modalities have been applied for evaluation of PS as a cancer biomarker.


Near-Infrared Optical Imaging

Optical imaging is increasingly being used in preclinical cancer research.37,38 It is being used in particular to study cancer-specific markers, drug pharmacokinetics, and to monitor drug effects in small animals.39-41 The attraction of the technique is that it is inexpensive, simple to conduct, and gives real-time results. In the clinic, optical imaging by visualizing fluorescently labeled tumor cells has recently emerged as an attractive approach to facilitate intraoperative identification of tumor margins or sentinel lymph node metastases.42,43 We have thus previously labeled the F(ab')2 fragment of PGN635 with a near-infrared (NIR) dye, IRDye 800CW to image U87 glioma xenografts in a mouse model.32 Near-infrared optical imaging revealed a clear tumor contrast as early as 4 hours post (intravenous) IV injection of PGN-800CW, which became maximal 24 hours later. Pretreatment of gliomas with a single dose of 6 Gy irradiation to induce increased PS exposure resulted in significantly enhanced tumor contrast. Localization of PGN-800CW to tumors was antigen specific, since an 800CW-labeled control probe of irrelevant specificity did not localize to the tumors. Similarly, Gong et al observed significantly higher uptake of PGN-800CW in docetaxel-treated than nontreated PC3 prostate tumors.34 Compared to the visible fluorophores, NIR fluorescence penetrates more deeply into tissues, as evidenced in the above study of imaging orthotopic glioma in mice.32 Clinical applications of optical imaging are currently limited to the detection of tumor margins or deposits during surgery, to the detection of superficial tumors, and to the detection of deep-seated tumors by endoscopy.


Positron Emission Tomography and Single-Photon Emission Computed Tomography Imaging

Both positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are nuclear medicine imaging techniques involving introduction of radioactive tracers into patients and detection of gamma rays emitted directly or indirectly from the tracer. Because of the superb sensitivity and clinical applicability of PET and SPECT imaging, development of radiotracers for cancer imaging has attracted intense interest. Technetium-99m (99mTc, t1/2 ˜6 hours) has been used to label annexin V for SPECT in humans and has shown prognostic value for various cancers.44,45 However, to best match the biological half-life of PS-targeting antibody (bavituximab, ~30 hours), those radioisotopes with longer half-life of radioactive decay are preferable. Jennewein et al selected arsenic radioisotope,74As (ß+, t1/2 = 17.8 days) in their study to radiolabel bavituximab for PET imaging of prostate tumors in rats .46 N-succinimidyl S-acetylthioacetate-modified bavituximab was used to react with 74As (Arsenic triiodide [AsI3]) to achieve stable conjugates. The PET imaging data showed that the prostate tumor-to-liver ratio was 22 for bavituximab compared with 1.5 for an isotype-matched control antibody at 72 hours postinjection. To obtain shorter blood residence times than those required for 74As-bavituximab imaging, Stafford and colleagues chose to use the F(ab')2 fragment of PGN635 (blood half-life ˜16 hours) conjugated with iodine-124, 124I (t1/2 = 4.2 days).33 Forty-eight hours after injection, PET imaging detected 124I-PGN635 F(ab')2 uptake in the PC3 prostate tumors in mice that was significantly higher than that of the 124I-labeled F(ab')2 of a control antibody. An SPECT imaging radioisotope, indium-111 (111In, t1/2 = 2.8 days), was also used to radiolabel the full-length bavituximab in a study of non–small cell lung cancer (NSCLC) xenografts.47 Similar to the PET findings, the SPECT imaging detected a peak uptake (tumor to muscle ratio = 5.2) by the NSCLC tumors at 72 hours post IV injection of 111In-DOTA-bavituximab.


http://journals.sagepub.com/doi/full/10.1177/1536012117708722

[jakedogman1]

good find... yes... the IP needs some heavy duty funding to get it in high gear... i agree the end game is near...

[hutschi]

Acknowledgements

The author would like to pay tribute to the late Dr Philip Thorpe for his pioneered research on phosphatidylserine and development of a series of PS-targeting antibodies. The authors thank Peregrine Pharmaceuticals Inc, Tustin, California, for the provision of PGN635 antibody.


Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: GBM research has been supported in part by NIH R01 CA194578 (DZ), Wells Fargo Scholar Program (DZ), and the Wake Forest Baptist Comprehensive Cancer Center’s NCI Cancer Center (grant P30CA012197), as well as a grant from the Department of Veteran’s Affairs I01BX002559 (AH).

[biopharm]

Hutschi so you think this Stafford knows John Stafford ...?

"PET imaging data showed that the prostate tumor-to-liver ratio was 22 for bavituximab compared with 1.5 for an isotype-matched control antibody at 72 hours postinjection. To obtain shorter blood residence times than those required for 74As-bavituximab imaging, Stafford and colleagues chose to use the F(ab')2 fragment of PGN635 (blood half-life ˜16 hours) conjugated with iodine-124, 124I (t1/2 = 4.2 days).33 Forty-eight hours after injection, PET imaging detected 124I-PGN635 F(ab')2 uptake in the PC3 prostate tumors in mice that was significantly higher than that of the 124I-labeled F(ab')2 of a control antibody..."

Hold those PPHM shares