Figure 3: Mechanisms of Action of Anti-CD20 Antibodies. Anti-CD20 antibodies bind to the CD20 molecule on the surface of the malignant B cell in non-Hodgkin's lymphoma (NHL), leading to cell death. Three mechanisms of action of anti-CD20 antibodies have been proposed. In complement-dependent cytotoxicity, the first component of complement (C1) binds to the Fc portion of the anit-CD20 molecule, resulting in the activation of the complement cascade and cell lysis through the formation of membrane attack complexes (MAC). In antibody-dependent cell-mediated cytotoxicity (ADCC), effector cells, such as natural killer cells or macrophages, bind to the Fc portion of the anti-CD20 molecule through Fcγ receptors; the effector cells then release effector molecules such as perforin, which causes cell lysis. In direct cytotoxicity, the anti-CD20 antibody induces internal signaling within the tumor cell, causing antiproliferative effects or cell death, which may involve apoptosis or other cell-death pathways. In the top inset, anti-CD20 antibodies bind to an extracellular portion of the CD20 molecule. Most anti-CD20 antibodies, including rituximab, tositumomab, and obinutuzumab, bind to the larger of the two extracellular loops within the CD20 molecule; this loop includes the alanine-N-proline (ANP) residues at positions 170 to 172. Ofatumumab binds to two sites on the CD20 molecule: the smaller extracellular loop and positions 159 to 166 on the larger loop. This unique binding pattern of ofatumumab, which results in increased proximity of the antibody to the cell membrane, may account for the greater potency of the drug in inducing complement-mediated lysis. In the lower inset, the structure of chimeric and human antibodies is shown. (http://mulicia.pixnet.net/blog/post/29459210-%5Bnejm%5Danti-cd20-antibody-therapy-for-b-cell-lymphomas)
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