64IN - New Antibodies in the Post-Rituximab-Era: Another Breakthrough?

Abstract

ABSTRACT Monoclonal antibodies (mAb) are one of the successes of modern cancer medicine, with rituximab the first to enter widespread clinical application following the demonstration of significant activity as a single agent, and superior results when combined with chemotherapy for a variety of CD20+ lymphoma types. In parallel to extensive clinical studies, we continue to uncover novel aspects of biology of the lymphoid cell surface. The molecules to which mAb have been targeted were identified several decades ago and few new ones have emerged recently, but there is now increasing interest in effector mechanisms, selective delivery of radionuclides or toxins, and bispecific molecules to target T- or NK- cells. Once thought of as a comparatively inert component of the cell membrane, CD20 is in fact a dynamic molecule. It can undergo rapid redistribution, and different mAb cause different effects: those like Rituximab (“type I”) elicit redistribution into lipid-rich rafts, mediate complement fixation and antibody-directed cell-mediated cytotoxicity (ADCC). In contrast, those like the first anti-B-cell mAb characterised, B1 (“type II”) do not cause redistribution into rafts but mediate homotypic cell adhesion and programmed cell death. These differences have important therapeutic results, and we have found that in lymphomas expressing the CD32 antigen (Fcgamma-R2b), type ImAb mediate rapid internalization of CD20 with lysosomal consumption, while type II do not. This has potential consequences for the therapeutic effect, as does the avidity with which mAb with different sugar groups bind to various Fc receptors. As well as radioconjugates, we are also returning to previously discarded approaches such as immunotxins, which have benefitted from advances in linker chemistry to improve their therapeutic ratio. Problems of toxin liberation and systemic toxicity have been largely overcome, and a new generation of conjugates is finding application in lymphoma therapy. Finally, the capacity to generate bispecific constructs that allow targeting of T-cells to the malignant cell surface holds the promise of harnessing cellular as well as humoral immunity. The initial promise of antibody therapy for lymphoma is already being fulfilled, and the next generation of compounds holds exciting challenges and great potential. Disclosure P. Johnson: Advisory Boards for Pfizer, Millenium Takeda, Roche, Boehringer Ingelheim. Research funding from Janssen-Cilag.