The Mechanism of Action of the Anti-CD38 Monoclonal Antibody Isatuximab in Multiple Myeloma

Abstract

Purpose: Knowledge about the mechanism of action (MoA) of monoclonal antibodies (mAbs) is required to understand which multiple myeloma (MM) patients benefit the most from a given mAb, alone or in combination therapy. While there is considerable research about daratumumab, knowledge about other anti-CD38 mAbs remains scarce. Experimental Design: We performed a comprehensive analysis about the MoA of isatuximab. Results: Isatuximab induces internalization of CD38 but not significant release from MM cell' surface. Additionally, we uncovered an association between levels of CD38 expression and different MoA: i) isatuximab was able to induce direct apoptosis on MM cells with very high CD38 but not on MM cells with CD38 levels closer to those in MM patients; ii) isatuximab sensitized CD38^hi MM cells to bortezomib plus dexamethasone in the presence of stroma; iii) antibody-dependent cellular cytotoxicity (ADCC) was triggered by CD38^lo and CD38^hi tumor PCs; iv) antibody-dependent cellular phagocytosis (ADCP) was triggered only by CD38^hi MM cells, whereas; v) complement-dependent cytotoxicity could be triggered in less than half of the patient samples (those with elevated levels of CD38). Furthermore, we showed that isatuximab depletes CD38^hi B-lymphocyte precursors and NK-lymphocytes ex vivo, the latter through activation followed by exhaustion and eventually phagocytosis. Conclusions: This study provides a framework to understand response determinants in patients treated with isatuximab based on the number of MoA triggered by CD38 levels of expression, and for the design of effective combinations aimed at capitalizing disrupted tumor-stroma-cell protection, augmenting NK-lymphocyte mediated ADCC, or facilitating ADCP in CD38^lo MM patients.