Development of bispecific antibodies with optimized T cell costimulatory activity

Abstract

Dissertation ist gesperrt bis 19. Oktober 2022 !

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.