Bispecific and Multivalent Antibodies - New Swords to Combat Hematological Malignancies

With about 40 approved monoclonal antibodies these biologicals are of high significance especially for cancer treatment. Nevertheless, since anti-tumor responses to antibody therapies are often limited and a lot of patients finally relapse, much effort is spent to increase the therapeutic efficacy, e.g., by optimizing the Fc-part of antibodies, thereby developing second generation antibodies. Albeit, monoclonal antibodies, even second generation formats are limited inasmuch as immune effector cells could only be unspecifically redirected via Fc-receptor binding and even more important, T cells as the most potent immune effector cells cannot be addressed at all. Thus, the idea arose to create antibodies with two different specificities. This enables specifically redirecting selected immune effector cells to target cells like tumor cells. A lot of different bispecific and multispecific antibody formats and platforms were designed to circumvent these constraints, like diabodies, single chain diabodies, chemically crosslinked F(ab)s fragments, tandem single chain Fv fragments, bispecific T cell engagers (BiTEs), triplebodies or knob in a hole as well as the dock and lock platforms. Despite major efforts in producing and testing new bsAb formats, the first approved bispecific antibody was the quadroma produced trifunctional antibody catumaxomab (anti-EpCAM x anti-CD3), demonstrating the eminent therapeutic potency of this full length antibody format. The recent approval of the anti-CD3 x anti-CD19 BiTE blinatumomab by the FDA furthermore emphasized the eminent role of bispecific antibodies. In this chapter an overview of the current development of bi- and multispecific antibodies for treatment of B-cell malignancies will be presented.

Keywords: Bispecific antibodies, B cell malignancies, antibody formats, cancer therapy, T-cell binding.