The B-lymphocyte antigen CD20 is a membrane protein predominantly expressed on the surface of B cells at various stages of development and differentiation. CD20 is encoded by the gene MS4A1 and plays a critical role in B cell activation, proliferation and survival, making it an attractive target for therapeutic intervention in B cell malignancies and autoimmune diseases. The discovery of CD20 as a drug target has led to the development of several monoclonal antibodies and related therapeutic proteins that have significantly impacted the treatment landscape for diseases such as non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL) and autoimmune diseases such as rheumatoid arthritis (RA).
NCBI Gene ID: 931
UniProtKB ID: P11836
CD20 is a 33-37 kDa non-glycosylated phosphoprotein that forms a tetraspan structure in the B cell membrane. It is expressed on pre-B cells, immature B cells, and mature B cells, but is lost upon terminal differentiation into plasma cells. The exact function of CD20 remains unclear, but it is thought to be involved in calcium ion influx, which is essential for B cell activation and proliferation. Its constant expression on B cells throughout their development makes CD20 an ideal target for therapeutic antibodies.
The expression of CD20 is tightly regulated at multiple levels:
While the exact role of CD20 is not completely understood, several functional aspects have been proposed:
Anti-CD20 monoclonal antibodies exert their therapeutic effects through several mechanisms:
| Therapy Strategy | Mechanism | Outcome | Example |
|---|---|---|---|
| Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) | The Fc (fragment crystallizable) region of the anti-CD20 antibody binds to Fcγ receptors (FcγR) expressed on immune effector cells, such as natural killer (NK) cells, macrophages, and neutrophils. This binding triggers the activation of these effector cells, leading to the release of cytotoxic granules (e.g., perforin and granzymes) or the production of reactive oxygen species, which induce apoptosis in the target CD20-positive B cells. | The targeted B cells are lysed, reducing the population of pathogenic or malignant B cells. | Rituximab, a widely used anti-CD20 antibody, is known to mediate ADCC effectively. |
| Complement-Mediated Cytotoxicity (CDC) | When the anti-CD20 antibody binds to the CD20 antigen on the surface of B cells, it initiates the classical complement pathway. This involves the binding of the C1q complex to the Fc region of the antibody, leading to a cascade of complement activation. The final step in this cascade is the formation of the membrane attack complex (MAC), which creates pores in the cell membrane, causing osmotic imbalance and cell lysis. | Direct destruction of CD20-positive B cells through complement-mediated lysis. | Ofatumumab is an anti-CD20 antibody with enhanced CDC activity compared to earlier-generation antibodies. |
| Direct Effects on B-Cell Signaling | Some anti-CD20 antibodies can directly interfere with intracellular signaling pathways that are critical for B cell survival and proliferation. For example, binding to CD20 can disrupt the activation of downstream signaling molecules such as Src family kinases, leading to apoptosis or cell cycle arrest. | Inhibition of B-cell survival and proliferation, independent of immune effector mechanisms. | Obinutuzumab, a type II anti-CD20 antibody, is known to induce direct cell death in addition to other mechanisms. |
| Antibody-Dependent Phagocytosis (ADP) | The Fc region of the anti-CD20 antibody can also bind to Fcγ receptors on phagocytic cells such as macrophages and dendritic cells. This interaction facilitates the engulfment and internalization of antibody-bound B cells into phagocytes, where they are degraded by lysosomal enzymes. | Clearance of CD20-positive B cells through phagocytosis. | Obinutuzumab has been shown to have enhanced ADP activity compared to rituximab. |
Figure 1. Summary of the
known mechanisms of action of anti-CD20 monoclonal antibodies and an overview of potential factors affecting resistance to anti-CD20 therapy in malignant B
cells. Anti-CD20 monoclonal antibodies act through several mechanisms, including complement-dependent cytotoxicity (CDC), complement-dependent cellular
cytotoxicity (CDCC), antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular cytotoxicity (ADCC), and induction of direct apoptosis.
(Pavlasova and Mraz, 2020)
While CD20-targeted therapies are highly effective, they can have side effects, including:
In summary, CD20-targeted therapies have transformed the treatment of B-cell related cancers and autoimmune diseases. Creative BioMart offers high quality, high performance therapeutic proteins targeting CD20. Please contact us for any questions or inquiries.
References
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