Rituximab is a therapeutic antibody designed to target CD20, a protein found on the surface of B cells. This CD20-targeting approach has transformed the treatment of various diseases by selectively removing these cells. Understanding how Rituximab interacts with CD20 provides insight into its effectiveness as a B-cell therapy.
The Role of CD20 on B Cells
B cells, also known as B lymphocytes, are a type of white blood cell that play a significant role in the body’s immune system. They are responsible for humoral immunity, a component of adaptive immunity, primarily by producing antibody molecules. These antibodies bind to foreign substances, called antigens, to neutralize them and help eliminate invading pathogens like viruses and bacteria. B cells also function as antigen-presenting cells, helping to activate other immune cells like T cells.
CD20 is a protein marker found on the surface of B cells, appearing early in their development from pre-B cells through mature and memory B cells. This protein is embedded in the cell membrane. CD20 is involved in regulating calcium conductance across the cell membrane and plays roles in B-cell development, activation, and proliferation.
The presence of CD20 on both healthy and cancerous B cells makes it a valuable therapeutic target. While CD20 is expressed on most B-cell lymphomas and leukemias, it is absent on hematopoietic stem cells and fully differentiated plasma cells, which produce antibodies. This selective expression allows for the targeted removal of B cells while sparing precursors needed for regeneration and some antibody-producing cells, contributing to the specificity of CD20-targeting therapies.
Rituximab’s Targeted Action
Rituximab, a chimeric monoclonal antibody, specifically binds to the CD20 protein on the surface of B cells. Its Fab region recognizes a particular shape on the extracellular loop of the CD20 protein. Once Rituximab attaches to CD20, it initiates immune responses that lead to the elimination of these B cells.
One primary mechanism is Antibody-Dependent Cellular Cytotoxicity (ADCC). After Rituximab binds to CD20, its Fc portion interacts with Fc-gamma receptors (FcγR) on immune effector cells, such as natural killer (NK) cells, macrophages, and neutrophils. This interaction activates the effector cells, prompting them to release cytotoxic molecules like perforin and granzymes. These molecules then induce apoptosis in the targeted B cells.
Another significant mechanism is Complement-Dependent Cytotoxicity (CDC). When Rituximab binds to CD20, it activates the complement system, a part of the immune system that helps clear pathogens. This activation leads to the deposition of complement proteins, such as C1q, on the B-cell surface, forming a membrane attack complex (MAC). The MAC creates pores in the B-cell membrane, causing the cell to lyse and die.
Rituximab can also directly induce apoptosis in some CD20-positive B cells. This direct signaling effect can lead to cell cycle arrest. While ADCC and CDC are major contributors to B-cell depletion, direct induction of apoptosis also plays a role in the overall therapeutic effect of Rituximab.
Diseases Treated by CD20 Targeting
CD20 targeting with Rituximab is used to treat a variety of medical conditions, primarily those involving abnormal or overactive B cells. In non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL), B cells become cancerous and multiply uncontrollably. By depleting these CD20-positive malignant B cells, Rituximab helps to reduce tumor burden and control disease progression.
For autoimmune diseases like rheumatoid arthritis (RA), Rituximab helps by reducing the number of B cells that contribute to autoantibody formation and pathological immune responses. In RA, B cells can produce autoantibodies that attack the body’s own tissues, leading to inflammation and joint damage. Depleting these B cells can reduce disease activity and alleviate symptoms.
Rituximab is also used in certain forms of vasculitis, such as granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). In these conditions, B cells are involved in the production of autoantibodies that attack small blood vessels, causing inflammation and organ damage. B-cell depletion helps to control the autoimmune response and prevent further damage.
Rituximab has also shown efficacy in other autoimmune conditions, including systemic lupus erythematosus (SLE) and IgG4-related disease (IgG4-RD). In SLE, B cells contribute to autoantibody and immune complex formation. For IgG4-RD, B-cell depletion helps manage a fibro-inflammatory disorder.