Elotuzumab is a targeted therapy for multiple myeloma, a cancer of plasma cells in the bone marrow. As a humanized monoclonal antibody sold under the brand name Empliciti, it does not destroy cancerous cells directly. Instead, its role is to harness the body’s immune defenses, guiding them to recognize and eliminate multiple myeloma cells.
Administered intravenously, elotuzumab is used with other medications for patients with relapsed or refractory multiple myeloma. Its development was based on identifying a specific surface protein highly expressed on myeloma cells. This protein provides a distinct target, allowing the drug to direct immune activity precisely where it is needed.
Targeting SLAMF7 on Cancer Cells
The effectiveness of elotuzumab is centered on its ability to bind to a molecule called Signaling Lymphocytic Activation Molecule F7 (SLAMF7). This glycoprotein is found in high abundance on the surface of cancerous plasma cells but is significantly lower on most normal cells. This difference in expression allows the drug to selectively identify and target the cancer.
A key detail for its mechanism is that SLAMF7 is also expressed on the surface of Natural Killer (NK) cells. NK cells are part of the innate immune system responsible for destroying abnormal cells, including cancerous ones. The presence of SLAMF7 on both myeloma and NK cells allows elotuzumab to mediate a direct interaction between them.
Elotuzumab physically connects to SLAMF7 through a specific site on the protein’s IgC2 domain. This binding event is the initial step that triggers the drug’s effects. By latching onto this marker, the antibody sets in motion a coordinated immune response aimed at the cells bearing the SLAMF7 protein.
Dual Mechanism of Immune Activation
Elotuzumab uses a dual-action mechanism to activate the immune system. The first function is a process called Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC). In ADCC, elotuzumab acts as a molecular bridge where one end, the Fab portion, binds to SLAMF7 on a multiple myeloma cell. This action “tags” the cancerous cell for destruction.
Once the myeloma cell is tagged, the other end of the antibody, the Fc region, binds to a CD16 receptor on a Natural Killer (NK) cell. This forms a physical link between the NK cell and the myeloma cell, bringing the immune cell into direct contact with its target. This engagement activates the NK cell, signaling it to release cytotoxic granules containing substances like perforin and granzymes that kill the myeloma cell.
The second part of the mechanism involves the direct activation of NK cells. Elotuzumab also binds to the SLAMF7 protein found on the surface of the NK cells themselves, which acts as an activating signal. This triggers an internal signaling cascade involving an adaptor protein called EAT-2, which is present in NK cells but absent in myeloma cells.
This interaction leads to the phosphorylation of motifs within the SLAMF7 cytoplasmic tail, which recruits EAT-2. This in turn activates other signaling molecules like Phospholipase C gamma (PLCĪ³) and increases intracellular calcium. This cascade enhances the cytotoxic potential of the NK cells, making them more effective at killing myeloma cells, even independent of the ADCC bridge.
Synergy in Combination Treatments
Clinical use has shown that elotuzumab is most effective when administered as part of a combination therapy. It is used with an immunomodulatory agent, such as lenalidomide, and a corticosteroid like dexamethasone. This multi-drug approach creates a synergistic effect, where the combined impact is greater than the sum of their individual effects.
Lenalidomide plays a role in augmenting the activity of the immune cells that elotuzumab recruits. As an immunomodulatory drug, it enhances the function and proliferation of NK cells. This makes the NK cell-mediated killing initiated by elotuzumab more robust and sustained.
Dexamethasone, a corticosteroid, contributes to the regimen with its own direct anti-myeloma effects, helping to reduce the tumor burden. Corticosteroids are also used to manage potential infusion-related reactions or other immune-related side effects from antibody therapies.
The strategy behind this combination is to create an environment that is hostile to cancer cells and supportive of a strong immune response. This integrated approach reflects that a multi-pronged attack is often necessary to effectively manage multiple myeloma.