The objective of this proposal is to establish the feasibility of producing anti-human CD137 antibody, an immune modulator that may be effective against solid tumors, in the milk of transgenic animals. CD137 (also called 4-1BB) is a membrane glycoprotein that can be induced in several types of lymphoid cells. An agonistic monoclonal antibody (mAb) against murine CD137 shrank mouse tumors in vivo and prevented their recurrence, suggesting that anti-CD137 may be effective against human tumors. The next technical hurdle to clinical translation is to develop a genetically engineered form of the anti-human CD137 that is suitable for clinical use, and to demonstrate that it is effective against human tumors in an appropriate mouse model. Genetic engineering can produce a chimeric anti-CD137 containing mostly human sequences, which should reduce the risk that patients will mount an immune response against the therapeutic antibody. GTC-Bio has developed a safe and cost-effective production source of mAbs, antibody fragments and modified immunoglobulin products by expressing recombinant proteins in the milk of transgenic dairy animals. We now propose to establish proof of principle for commercially production of chimeric anti-human CD137 by: 1) producing and characterizing transgenic mice expressing chimeric anti-human CD137 in their milk; and 2) demonstrating that this protein is bioactive in human tumor xenograft models in immuno-deficient mice. If this work is successful, it will lead to a Phase II proposal to produce chimeric anti-human CD137 in transgenic goats and to test purified preparations in preclinical studies and in clinical trials with ovarian cancer patients.
