Evolution of anti-CD20 monoclonal antibody therapeutics in oncology

Abstract

Approval of an anti-CD20 chimeric monoclonal antibody, rituximab, has revolutionized cancer treatment and also validated CD20 targeting for providing benefit and improvement of overall response rate in B cell malignancies. Although many patients have benefited from the treatment of rituximab, there are still significant numbers of patients who are refractory or develop resistance to the treatment. Here we discuss pre-clinically well-defined potential mechanisms of action for rituximab and review the ways next generation anti-CD20 monoclonal antibodies can potentially exploit them to further enhance the treatment of B cell malignancies. Although the relative importance of each of these mechanism remains to be established in the clinic, well-designed clinical trials will help to define the efficacy and understanding of which effector activity of modified next generation anti-CD20 mAb will be important in the treatment of B-cell malignancies.

Figure 1

Mechanism of action of rituximab. rituximab can induce cell death via several mechanisms. Antigen-antibody (Ag-Ab) complexes formation and Fc-Fc gamma receptor (FcγR) complexes binding to CD20 can induce programmed cell death (PCD) by triggering the intrinsic pathway of apoptotic caspase activation via the Bcl-2 family proteins (Signal A) and mitochondrial outer membrane permeabilisation (MOMP) (Signal B). in antibody-dependent cell-mediated-cytotoxicity (ADCC), Rituximab recruits effector cells by binding to their Fcγ receptors and this triggers effector cells to release of pre-forming proteins and proteases thus resulting in target cell death. In antibody-dependent cellular-phagocytosis (ADCP) Rituximab recruits monocytes/macrophages by binding to their Fcγ receptors and this results in engulfment of antibody coated tumor cells. In complement-mediated cytotoxicity (CDC), rituximab activates complement cascade and generates membrane attack complexes and as a result induce cell death. MOR, mechanisms of resistance; sCD20, soluble CD20; Cir, complement inhibitory receptors.