Shedding Light on Elotuzumab’s Mechanism of Action in Treating Myeloma
Posted: Wednesday, December 18, 2019
Kerry S. Campbell, PhD, of Fox Chase Cancer Center, Philadelphia, and colleagues suggest that the monoclonal antibody elotuzumab may promote the activity of natural killer cells in multiple myeloma cells in both a CD16-dependent and -independent manner via the promotion of SLAMF7-SLAMF7 interactions. Elotuzumab targets SLAMF7, which is found on natural killer cells and expressed often on multiple myeloma cells.
“Our data further elucidate the mechanism of action of elotuzumab beyond the previously established mechanism of antibody-dependent cellular cytotoxicity (ADCC). Furthermore, these findings are specific to elotuzumab compared to other SLAMF7 antibodies tested, demonstrating the unique mechanistic attributed of [natural killer] co-activation and ADCC dually mediated by elotuzumab,” stated the authors in Cancer Immunology Research.
NK-92 cell lines were first generated in two types: those expressing high-affinity CD16 and those expressing low-affinity CD16. CD16 polymorphism effects were pronounced in natural killer cells that expressed high-affinity CD16, as low concentrations of elotuzumab promoted stronger natural killer cell–mediated ADCC of SLAMF7-positive multiple myeloma cells. Furthermore, cell-line manipulations supported the need for SLAMF7 expression on natural killer cells and the bivalent structure of elotuzumab to enhance natural killer–mediated killing of tumor cells, an observation seen even in CD16-lacking NK-92 cells.
An Fc-mutant form of elotuzumab was generated, lacking the CD16-binding properties. This mutant type also promoted killing of multiple myeloma target cells by natural killer cells from five of seven healthy donors, especially when the natural killer cells were cultured with interleukin-2. According to the study authors, “this finding is of significant interest,” because elotuzumab appears to be ineffective as a single agent in patients with multiple myeloma, but it is “highly effective when co-administered with lenalidomide and dexamethasone.”
Disclosure: For full disclosures of the study authors, visit cancerimmunolres.aacrjournals.org.