Development of bispecific antibodies with optimized T cell costimulatory activity

Abstract

In recent years, the clinical application of therapeutic antibodies has already significantly improved the therapy and prognosis of various malignant diseases. Notably, immunomodulating antibodies demonstrated the possibility to selectively modify the T cell-response and thus represent an attractive therapeutic strategy. However, in many cases, the therapeutic success of monospecific antibodies is limited or comes with severe systematic side-effects in patients. In comparison, the use of bispecific antibodies demonstrated several advantages by enabling the recruitment and activation of effector cells such as T cells, specifically at the tumor side. This thesis presents the in-vitro generation, characterization, and optimization of novel immunomodulating bispecific antibodies for target cell-restricted modulation of T cell activation. The bispecific antibodies were subjected to an extensive characterization process aiming at the identification of the optimal antibody format and clone. Finally, secondary work focused on a successful humanization by CDR grafting to decrease the risk of immunogenicity. Taken together, certain immunomodulating antibodies described in this work demonstrated a beneficial effect on activated T cells only in a target cell-restricted manner and demonstrate the potential of a novel promising therapeutic candidate for selective cancer treatment.