PHILADELPHIA (August 20, 2019) – The immunostimulatory monoclonal antibody elotuzumab may pack a unique one-two punch to promote cytotoxicity toward multiple myeloma cancer cells, according to new research from Fox Chase Cancer Center.
Elotuzumab given in combination with lenalidomide and dexamethasone is approved for the treatment of patients with relapsed or refractory multiple myeloma. The drug binds signaling lymphocytic activation molecule family member 7 (SLAMF7), a protein that is highly expressed on the surface of myeloma cells.
Prior research showed elotuzumab works through stimulating antibody-dependent cellular cytotoxicity (ADCC) by engaging with the CD16 receptor (FcgRIIIa) on the immune system’s natural killer cells, signaling the cells to attack the cancer cells that have elotuzumab bound to their surface.
However, in addition to being expressed on myeloma cells, SLAMF7 is also expressed on immune cells, most prevalently on natural killer cells, where it acts as a costimulatory receptor.
“In this study, we wanted to see if elotuzumab has a double benefit,” said Kerry S. Campbell, PhD, professor in the Blood Cell Development and Function program at Fox Chase. “First, a benefit by binding to the myeloma target cell and triggering CD16-mediated ADCC, and also by binding to the natural killer cell directly and causing costimulatory signaling that further potentiates the killing of myeloma cells.”
To do that, Campbell and colleagues tested elotuzumab in a cell line of natural killer cells called NK-92 that does not have the CD16 receptor. They found that binding of elotuzumab to SLAMF7 on natural killer cells also induced cytotoxicity independent from CD16-mediated ADCC.
“SLAMF7 is a self-ligand, meaning SLAMF7 on a natural killer cell will bind to SLAMF7 on a myeloma cell, sending a costimulatory signal to the natural killer cell to enhance killing, and elotuzumab enhanced this signal” Campbell said. But if the natural killer cell or the myeloma cell was lacking SLAMF7, this enhanced killing effect was absent.
“The SLAMF7-SLAMF7 effect by elotuzumab also required the intact intracellular domain of SLAMF7 in the natural killer cells, including the signaling sequences in that domain, but did not occur with a truncated SLAMF7,” he added.
Campbell and his team also compared elotuzumab to three other SLAMF7 antibodies and found that only elotuzumab enhanced the SLAMF7-SLAMF7 dependent activation responses.
“This indicated that there is something unique about where elotuzumab binds to the SLAMF7 molecule to potentiate this response,” he said.
The study also showed that elotuzumab’s CD16-independent costimulation was associated with increased NK cell expression of NKG2D, an activating receptor, and ICAM-1 and LFA-1, which are adhesion molecules.
“The upregulated NKG2D was found to play a role in the enhanced killing, and upregulated adhesion molecules presumably also contribute,” Campbell said.
The paper, “Enhanced SLAMF7 Homotypic Interactions by Elotuzumab Improves NK Cell Killing of Multiple Myeloma,” was published in Cancer Immunology Research, a journal of the American Association for Cancer Research.
This work was supported by Bristol Myers Squibb Collaborative Science Center of Excellence grants CA204-013, CA-204-156, and CA204-214, FCCC Bucks County, and Main Line Boards of Associates; National Institutes of Health Training grant T32 CA9035; and National Cancer Institute Comprehensive Cancer Center Support Grant CA06927.