Rituximab is a chimeric anti CD 20 monoclonal , remarkably effective in non-Hodgkin lymphomas, and also addresses rheumatoid arthritis (where lymphocytes play a key role). Its Fc fragment ("cristallisable fragment"), borne by the hinge, CH2 and CH3 heavy chain constant domains , has 2 roles :
- activating the C1q protein (member of the protein enzymatic pathway called Complement), which then activates C1r, which produces C1esterase. This esterase activates C2 and C4, hence a cascade of activations (chemokines, anaphylatoxins) which lead to polymerization of the C9 fraction of Complement into a tubular structure that drills a hole in the lymphocyte's membrane;
- activating the Fc gamma receptor of Immunologically competent cells, which then secrete cytokines that attack the target cell, and which can phagocytize it : ADCC (antibody dependent cytotoxicity)
Ofatumumab is a fully human anti CD 20 (BLA filed Jan 30 2009). It binds to the small loop epitope of the CD20 Ag.. It powerfully induces complement activation, shown by "streamer" formation (structures protruding from cell surface).
3rd generation anti CD 20s are humanized and have a glycoengineered Fc fragment with enhanced binding to Fc gamma receptors, which increases ADCC. Modifications in the variable regions can enhance caspase independent apoptosis (see AACR 2007 # 4186, on GA101)
TRU-015 small molecular immunopharmaceutical with only anti CD 20 F(ab) and Fc, in clinical trials.
