The objective of this Phase II SBIR project is to build on the success of a Phase 1 SBIR FLAIR grant to produce and characterize a chimeric form of antibody against human CD137 that is suitable for human clinical testing. CD137 (also called 4-1BB) is a membrane glycoprotein that is inducibly expressed on human leukocytes. Stimulation of CD137 by its natural ligand or by agonistic antibodies potentiates an antitumor response that causes regression of established mouse tumors in various models. Anti-CD137 offers great promise as a potential therapeutic agent against certain solid tumors. In Phase I, we generated transgenic goats expressing anti-human CD137 at commercially feasible levels and provided preliminary evidence of bioactivity in a human tumor xenograft model in SCID mice. This antibody is a chimeric protein that contains: 1) the antigen binding regions from a well-characterized agonistic mouse anti-human CD137 mAb (Clone GW); and 2) human CH and CL sequences that are designed to minimize reactions against murine proteins in therapeutic regimens that require repeated administrations. The next steps in the clinical translation of anti-CD137 for human cancer therapy are to: 1) qualify the transgenic goats as founder animals; 2) optimize and scale up a commercially feasible process to purify chimeric anti-human CD137 from goat milk; 3) biochemically characterize the purified anti-human CD137; and 4) test the efficacy of purified anti-human CD137 against human tumors in mice. The long-term goal of this research program is to produce a novel anti-cancer drug, chimeric anti-human CD137 monoclonal antibody, in the milk of transgenic goats and to test purified preparations in appropriate experimental models in preparation for future clinical trials in melanoma cancer patients. Successful completion of this project will lead to final preclinical safety analysis and then to human clinical trials to test the efficacy of anti-human CD137 against solid tumors. ? ? ?
| Lin, Wei; Voskens, Caroline J; Zhang, Xiaoyu et al. (2008) Fc-dependent expression of CD137 on human NK cells: insights into ""agonistic"" effects of anti-CD137 monoclonal antibodies. Blood 112:699-707 |
