[Developing anti-CD20 molecules and B cell depletion in multiple sclerosis]

The efficacy of anti-CD20 therapies in multiple sclerosis (MS) has been recognized since 2008. Since then, three anti-CD20 monoclonal antibodies - ocrelizumab, ofatumumab, and ublituximab - have been developed and approved for MS treatment, whereas rituximab, the first monoclonal antibody shown to be effective, remains an off-label therapy in this indication. Anti-CD20 antibodies deplete B cells primarily through two mechanisms: complement-dependent cytotoxicity (CDC) and natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC). The relative contribution of these mechanisms differs among individual antiCD20 antibodies. NK cell-mediated ADCC is modulated by the glycosylation state of the antibody Fc region as well as by genetic polymorphisms in FcγRIIIa, the Fc receptor on NK cells responsible for Fc binding. Fc engineering can enhance ADCC and partially overcome the functional consequences of FcγRIIIa polymorphisms. This article reviews the structure and mechanisms of action of immunoglobulins and anti-CD20 antibodies; outlines the development of antibody humanization and Fc engineering to enhance efficacy and tolerability; presents clinical data from ublituximab treatment; and discusses additional strategies for achieving effective B-cell depletion.