A CD37 antibody is a specialized form of targeted immunotherapy for cancer treatment. It harnesses the immune system by deploying antibodies designed to recognize specific markers on cancer cells. By precisely targeting these markers, CD37 antibodies aim to selectively eliminate malignant cells while minimizing harm to healthy tissues. This approach is being explored in various cancer research and clinical settings, particularly for certain blood cancers.
Understanding the CD37 Protein Target
The CD37 protein is a member of the tetraspanin superfamily of cell surface proteins. It is prominently expressed on mature B-lymphocytes, a type of white blood cell. While also present on normal B cells, CD37 is found in high quantities on malignant B cells in certain blood cancers, such as non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL).
The presence of CD37 on cancerous B cells, coupled with its limited expression on early progenitor cells or terminally differentiated plasma cells, makes it an attractive target for therapeutic intervention. This differential expression allows for a more focused attack on cancer cells. Targeting this protein offers a pathway to disrupt the survival and proliferation of these malignant cells.
How CD37 Antibodies Work
CD37 antibodies are engineered as monoclonal antibodies that specifically bind to the CD37 protein on cancer cells. Once bound, these antibodies can trigger several mechanisms to induce cancer cell death. One way is by directly signaling the cancer cell to undergo apoptosis, a process of programmed cell death.
Another mechanism is Antibody-Dependent Cellular Cytotoxicity (ADCC). The CD37 antibody acts as a flag, marking the cancer cell for destruction. The Fc region of the antibody binds to specific receptors on immune effector cells, such as natural killer (NK) cells, activating them to release cytotoxic substances like perforin and granzymes that destroy the flagged cancer cell.
CD37 antibodies can also function as Antibody-Drug Conjugates (ADCs) to deliver a toxic payload directly to the cancer cell. A chemotherapy drug is chemically linked to the antibody. When the ADC binds to CD37 on the cancer cell, the entire complex is internalized, releasing the toxic drug inside the cell. Naratuximab emtansine (IMGN529) exemplifies this, delivering the cytotoxic agent DM1 directly to CD37-expressing cells.
Therapeutic Applications in Cancer Treatment
CD37 antibodies are being explored for their therapeutic potential in various B-cell malignancies. They are primarily investigated for treating chronic lymphocytic leukemia (CLL) and B-cell non-Hodgkin lymphomas (B-NHL), including diffuse large B-cell lymphoma (DLBCL).
Several investigational CD37 antibody drugs are in clinical development. Otlertuzumab (TRU-016) is a humanized anti-CD37 monoclonal antibody that has shown antitumor activity in preclinical models and underwent phase 1 studies for CLL. Another example is naratuximab emtansine (IMGN529), an Antibody-Drug Conjugate (ADC) that links an anti-CD37 antibody to the cytotoxic drug DM1.
Naratuximab emtansine has demonstrated promising activity in preclinical and early clinical trials for NHL, including DLBCL. In a phase II trial for relapsed or refractory DLBCL patients, treatment with naratuximab emtansine in combination with rituximab resulted in an objective response rate of 44.7%, with approximately one-third of patients achieving complete responses.
Associated Side Effects and Safety
Clinical studies of CD37 antibodies have identified a range of potential side effects. Common reactions include infusion-related responses, which can occur during or shortly after administration. Patients may also experience fatigue.
Effects on blood counts are observed, with potential reductions in certain blood cell types. These can include neutropenia, a decrease in neutrophils, which are a type of white blood cell that helps fight infection, and thrombocytopenia, a reduction in platelet count, which affects blood clotting. These hematologic changes are closely monitored during treatment.
The specific side effect profile can vary depending on the type of CD37 antibody used. For instance, Antibody-Drug Conjugates (ADCs) carry an additional toxic payload, which can contribute to a different set of adverse effects compared to “naked” antibodies. Naratuximab emtansine, an ADC, for example, has shown mainly hematologic adverse events in clinical trials.