High-throughput Development of Fc-independent Biepitopic Antibodies that Activate T cell Receptors

Abstract

Antibodies that activate immunomodulatory receptors (e.g., the CD137 T cell receptor) to regulate the immune system are a promising class of emerging therapeutics against cancer. However, most “agonist” antibodies have poor therapeutic efficacy due to their reliance on external factors such as Fcγ receptors to mediate sufficient activity. The development of “biepitopic” antibodies targeting two different areas on the same receptor represents a novel approach towards mediating robust activity, but there is a lack of high-throughput methodology to generate such antibodies. In my capstone project, I intend to utilize a unique methodology for discovering novel epitopes against the CD137 receptor and designing tetravalent antibodies with improved agonist activity. Towards this goal, I will screen antibody libraries to discover variants with unique epitopes compared to the clinical antibody utomilumab. Next, I will generate tetravalent biepitopic or monoeptiopic antibodies by pairing the discovered clones with utomilumab. Finally, I will evaluate the biological activity and characteristics of the antibody constructs using primary T cell assays and binding experiments. My specific contributions to the project are screening antibody libraries for specific clones, developing the gene sequences that encode for the antibody constructs, and characterizing the biological activity of the antibodies.