Avid Bioservices Inc (CDMO)

[entdoc]

AMAZING!#4632 Phosphatidylserine-targeting ‘betabodies’ for the treatment of cancer Xianming Huang1, Dan Ye1, Troy Luster2, Philip E. Thorpe1. 1UT Southwestern Medical Ctr., Dallas, TX; 2Human Genome Sciences, Rockville, MD
Bavituximab is a chimeric monoclonal antibody that is being combined with chemotherapy to treat patients with lung or pancreatic cancer in randomized Phase II clinical trials. Bavituximab targets the immunosuppressive lipid, phosphatidylserine (PS), which becomes exposed on the outer membrane surface of tumor blood vessels and tumor cells in tumors responding to therapy. The antibody acts by destroying tumor vasculature and by reactivating tumor immunity. Here, we generated new PS-targeting therapeutics by fusing domains of the PS-binding plasma protein, mouse ß2-glycoprotein I (ß2GP1), to the Fc region of mouse IgG2a. Such ‘betabodies’ potentially have advantages over bavituximab. They bind directly to PS, whereas bavituximab requires a cofactor protein (ß2GP1) for binding; they can be made fully human; they are smaller in size (100KDa versus 250KDa for the bavituximab: ß2GP1 complexes); and they have slower blood clearance rates. Many different constructions of betabodies were tested, each having different orientations, domains, and glycosylation patterns. Constructs were identified that bound strongly to PS-expressing cells and plates, localized to tumor vascular endothelium in vivo, and had ß-phase blood half-lives of approximately seven days after intravenous injection into mice as compared with two days for a murine version of bavituximab. Betabodies could potentially be the next generation of PS-targeting cancer therapeutics.