Preclinical and clinical evaluation of elotuzumab, a SLAMF7-targeted humanized monoclonal antibody in development for multiple myeloma

Abstract

Although multiple myeloma has historically been treated with chemotherapy, prolonged survival has only been possible since the introduction of thalidomide, lenalidomide and bortezomib. However, multiple myeloma remains largely incurable, and new treatments are needed to improve long-term outcome. Elotuzumab is a humanized IgG1 monoclonal antibody that targets Signaling Lymphocyte Activation Molecule Family member 7 (SLAMF7) to activate NK cells, enabling selective killing of myeloma cells with minimal effects on normal tissue. The combination of elotuzumab with antimyeloma therapies that stimulate host immunity may be an attractive treatment option for patients with newly diagnosed or relapsed/refractory multiple myeloma. Here, we review the role of SLAMF7 in the pathogenesis of multiple myeloma and the preclinical and clinical development of elotuzumab.

Keywords:

• antibody-dependent cell cytotoxicity
• clinical trials
• drug evaluation
• elotuzumab
• multiple myeloma
• preclinical

Financial & competing interests disclosure

A Palumbo has received honoraria from Amgen, Array Biopharma, Bristol-Myers Squibb, Genmab A/S, Celgene, Millennium, Onyx, Sanofi and Janssen. He has also served as a consultant to Amgen, Bristol-Myers Squibb, Genmab A/S, Celgene, Janssen, Millennium and Onyx. P Sonneveld is on the advisory board of Celgene, Janssen, Amgen, Takeda, Karyopharm and Novartis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. The authors wish to acknowledge Matthew Brierley, PhD of StemScientific, funded by Bristol-Myers Squibb, for providing writing and editorial support. The authors take full responsibility for the content of this publication and confirm that it reflects their viewpoint and medical expertise. Neither Bristol-Myers Squibb nor StemScientific influenced the content of the manuscript, nor did the authors receive financial compensation for authoring the manuscript.

Key issues

• With an estimated incidence rate of 8 per 100,000 people, multiple myeloma (MM) is the second most common hematological cancer after lymphoma.

• Although historically treated with chemotherapy, the recent approvals of thalidomide, lenalidomide and bortezomib have prolonged survival of patients with MM; nevertheless, fewer than 50% of patients survive for 5 years after diagnosis.

• Therefore, new treatments are urgently required to improve the long-term outlook of such patients, particularly those with relapsed MM.

• Elotuzumab is a humanized IgG1 monoclonal antibody that binds to Signaling Lymphocyte Activation Molecule Family member 7 (SLAMF7), a glycoprotein expressed by myeloma and NK cells.

• The binding of elotuzumab to SLAMF7 activates NK cells, but not myeloma cells. Elotuzumab bound to myeloma cells via SLAMF7 further activates NK cells via a CD16-mediated pathway, enabling selective killing of myeloma cells with minimal effects on normal tissue.

• Due to its distinct mechanism of action, elotuzumab is likely to act synergistically with treatment modalities that stimulate host antimyeloma immunity; thus, the combination of elotuzumab with antimyeloma therapies that stimulate host immunity is an attractive treatment option, especially early in the course of the disease before disease-related immune dysfunction and multiple courses of treatment negatively impact immune function.

• Indeed, the combination of elotuzumab with bortezomib or lenalidomide plus low-dose dexamethasone has shown promising activity in two Phase I clinical trials in patients with relapsed or refractory MM; Phase III combination trials in patients with newly diagnosed or relapsed/refractory MM are ongoing.

• The results of these trials may support the use of elotuzumab-based treatment regimens in MM.

Notes