An anti-CD37 antibody is a specialized type of biological drug designed to target the CD37 protein found on the surface of certain cells. These antibodies function as a form of targeted therapy. By specifically binding to CD37, they aim to interfere with the function or survival of the cells expressing this protein. This approach represents a precise way to deliver therapeutic effects, distinguishing them from traditional, less specific treatments.
The CD37 Target
CD37 is a protein involved in various cellular processes, including cell signaling, adhesion, and membrane organization. It is predominantly expressed on the surface of B-lymphocytes, a type of white blood cell involved in the immune system. It is also found, though at lower levels, on other immune cells like T cells, macrophages, monocytes, granulocytes, and dendritic cells.
The precise normal function of CD37 is still under investigation, but it plays a role in regulating B-cell function, survival, and proliferation. This protein can act as an adapter, facilitating interactions between other proteins on the cell surface.
CD37 is an attractive target for therapeutic intervention because of its high expression on malignant B-cells in various lymphomas and leukemias, compared to its more restricted expression on healthy tissues. For instance, CD37 is highly expressed in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). This differential expression allows anti-CD37 antibodies to selectively target and affect cancer cells while minimizing harm to healthy cells.
How Anti-CD37 Antibodies Work
Anti-CD37 antibodies exert their therapeutic effects through several mechanisms to eliminate target cells. One direct approach is the induction of apoptosis, or programmed cell death, in the target cells. This occurs when the antibody binding to CD37 triggers the cell’s self-destruction.
Another mechanism is Antibody-Dependent Cellular Cytotoxicity (ADCC). In ADCC, the anti-CD37 antibody binds to the cancer cell. Natural Killer (NK) cells, which are a type of immune effector cell, recognize the antibody-coated cancer cell through their Fc receptors. Upon recognition, NK cells release cytotoxic mediators like perforin and granzymes, which induce apoptosis in the targeted cancer cell.
Complement-Dependent Cytotoxicity (CDC) is also a mechanism by which these antibodies can act. When the antibody binds to the CD37 protein on the cancer cell surface, it can activate the complement system. This activation leads to a cascade of events that result in the formation of a membrane attack complex, which punctures the cancer cell membrane, causing it to lyse or burst.
Beyond direct killing and immune recruitment, anti-CD37 antibodies can also work by modulating cell signaling pathways within the cancer cell. By binding to CD37, the antibody can interfere with the cancer cell’s survival pathways. This interference can shift the cellular balance towards pathways that inhibit growth or encourage cell death.
Therapeutic Applications
Anti-CD37 antibodies are used in the treatment of B-cell malignancies, including non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). The rationale for their use in these specific diseases stems from the high expression of CD37 on malignant B-cells, making it a suitable target for selective therapy.
In conditions like CLL, anti-CD37 antibodies have shown promising outcomes. These therapies are often considered as targeted treatments, especially when other conventional treatments have not been effective or in combination with existing agents like rituximab or chemotherapy. The aim is to enhance treatment efficacy and potentially reduce toxicity by specifically targeting cancer cells. Clinical trials have explored these agents as monotherapy and in combination with standard chemotherapeutics, showing promising results.
Types of Anti-CD37 Antibodies
Naked antibodies are standard monoclonal antibodies that function through direct cell killing and immune effector mechanisms like ADCC and CDC. These antibodies bind to CD37 on the cell surface and initiate the body’s own immune responses to eliminate the targeted cells.
Antibody-drug conjugates (ADCs) link the antibody to a potent chemotherapy drug. Once the anti-CD37 antibody binds to the CD37-expressing cell, the entire ADC is internalized into the cell. Inside the cell, the chemotherapy drug is released, delivering a concentrated dose of the drug directly to the cancer cell while minimizing systemic exposure and potential side effects on healthy tissues. For example, IMGN529 is an anti-CD37 ADC linked to the maytansinoid DM1 payload, which inhibits cell division by affecting microtubules.
Radioimmunoconjugates are anti-CD37 antibodies linked to a radioactive isotope. This design allows the antibody to deliver localized radiation directly to CD37-expressing cancer cells. The radiation then damages the cancer cells, leading to their destruction. An example is Betalutin, which consists of the CD37-targeting antibody tetulomab conjugated to the beta-emitting Lutetium-177 radionuclide. This approach aims to provide a “cross-fire” effect, where radiation can reach nearby tumor cells even if they have lower antigen expression or are less accessible to the antibody itself.