Rituximab and Anti-CD20 Therapy: Mechanism, Uses, and Resistance

Rituximab, a chimeric anti-CD20 monoclonal antibody, revolutionized the treatment of B cell malignancies and autoimmune diseases when it was first approved in 1997. Today, anti-CD20 therapy remains the cornerstone of B cell lymphoma treatment and has spawned a family of next-generation anti-CD20 antibodies with improved properties.

CD20: The Target

CD20 is a tetraspanning membrane protein expressed on the surface of B cells from the pre-B cell stage through mature B cells and into plasmablasts, but is lost on fully differentiated plasma cells. It is not expressed on hematopoietic stem cells or pro-B cells, which means anti-CD20 therapy eliminates mature B cells but allows reconstitution from CD20-negative progenitors.

CD20's biological function remains somewhat unclear—it appears to function as a calcium channel and may regulate B cell activation. Importantly, CD20 does not shed from the cell surface and does not internalize upon antibody binding, making it an ideal antibody target.

Mechanisms of Action

Anti-CD20 antibodies eliminate B cells through multiple mechanisms: complement-dependent cytotoxicity (CDC), where antibody bound to CD20 activates the complement cascade leading to membrane attack complex formation and cell lysis; antibody-dependent cellular cytotoxicity (ADCC), where NK cells and macrophages recognize the Fc portion of bound antibody and kill the target cell; direct signaling, which can induce apoptosis in some B cell subsets; and phagocytosis by macrophages recognizing opsonized cells.

Clinical Applications

Anti-CD20 therapy has transformed numerous conditions: in B cell lymphomas (DLBCL, follicular lymphoma, mantle cell lymphoma, CLL/SLL) it is combined with chemotherapy; in autoimmune diseases (rheumatoid arthritis, granulomatosis with polyangiitis) it depletes autoreactive B cells; in multiple sclerosis it depletes B cells that contribute to neuroinflammation; in neuromyelitis optica spectrum disorder (NMOSD) it reduces relapse rates; and in pemphigus vulgaris it depletes autoantibody-producing B cells.

Resistance Mechanisms

Despite widespread success, anti-CD20 therapy resistance occurs through several mechanisms: CD20 downregulation or loss; mutations preventing CDC or ADCC; complement consumption or escape; and enhanced intracellular survival pathways. Next-generation anti-CD20 antibodies like obinutuzumab have been engineered with enhanced ADCC activity and reduced CDC dependence to overcome some resistance mechanisms.

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