Ovarian cancer continues to represent an unmet clinical need, as two-thirds of diagnosed patients eventually die of the disease and new therapeutics have made little impact over the past decade. In this proposal, we will utilize a novel panel of anti-MUC16 antibodies and our extensive knowledge of how Fc?-receptor (Fc?R) pathways contribute to the anti-tumor activities of therapeutic antibodies to perform a preclinical study for the optimization of anti-MUC16 antibodies for the treatment of ovarian cancer. MUC16 is an attractive target for antibody-based immune therapies for ovarian cancer because of its tissue-specific overexpression in most of the ovarian cancers. We have obtained a novel panel of monoclonal Abs (mAbs) against the extracellular portion of MUC16, and will characterize the in vivo mechanisms by which these mAbs mediate anti-tumor activities in novel syngeneic and spontaneous tumor models that express human MUC16.
In Aim 1, we will determine the specific Fc?R interactions required by anti-MUC16 antibodies for their optimal in vivo anti-tumor activities by using Fc mutants and strains specifically lacking Fc?Rs. We will exploit these results and utilize our unique strain of Fc?R- humanized mice as a preclinical platform to develop humanized Fc-engineered anti-human MUC16 antibodies optimized for augmented in vivo anti-tumor activity.
In Aim 2, we will exploit our recent finding that passive administration of cytotoxic anti-tumor antibodies stimulates and anti-tumor cellular immune reponses to determine whether combining anti-MUC16 mAb with immunomodulatory antibodies that also stimulate cellular anti-tumor immune responses synergistically enhances anti-tumor immunity. For these studies, we will focus on agonistic anti-CD40 and antagonist anti-CTLA-4 antibodies that have been Fc engineered for optimal engagement of the appropriate Fc?R pathways that mediate their effects in vivo. By testing humanized anti- MUC16 antibodies in a preclinical in vivo models expressing the human Fc?R pathways and human MUC16 as a target, the proposed research is highly translatable to human patients, and if successful, may lead to the development of specific clinical candidate antibodies for trials.
The proposed research aims to develop new antibody-based therapeutic candidates for the treatment of ovarian cancer. Anti-MUC16 antibodies will be engineered to optimally interact with the effector systems that mediate their anti-tumor activities, and will be tested in combination with other anti-tumor antibody therapeutics for synergistically augmented anti- tumor activities.
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