Novel Approaches to Improve Myeloma Cell Killing by Monoclonal Antibodies

Abstract

The monoclonal antibodies (mAbs) have significantly changed the treatment of multiple myeloma (MM) patients. However, despite their introduction, MM remains an incurable disease. The mAbs currently used for MM treatment were developed with different mechanisms of action able to target antigens, such as cluster of differentiation 38 (CD38) and SLAM family member 7 (SLAMF7) expressed by both, MM cells and the immune microenvironment cells. In this review, we focused on the mechanisms of action of the main mAbs approved for the therapy of MM, and on the possible novel approaches to improve MM cell killing by mAbs. Actually, the combination of anti-CD38 or anti-SLAMF7 mAbs with the immunomodulatory drugs significantly improved the clinical effect in MM patients. On the other hand, pre-clinical evidence indicates that different approaches may increase the efficacy of mAbs. The use of trans-retinoic acid, the cyclophosphamide or the combination of anti-CD47 and anti-CD137 mAbs have given the rationale to design these types of combinations therapies in MM patients in the future. In conclusion, a better understanding of the mechanism of action of the mAbs will allow us to develop novel therapeutic approaches to improve their response rate and to overcome their resistance in MM patients.

The gene regulatory network controlling plasma cell function

“…While there are currently effective therapies to specifically deplete the B cell population, such as the anti‐CD20 monoclonal antibody Rituximab, these therapies are unable to target the ASC compartment as the expression of CD20 and many other B cell surface markers are downregulated during the terminal differentiation process 113 . The development of monoclonal antibodies targeting MM surface proteins CD38 (Daratumumab and Isatuximab) and Slamf7 (Elotuzumab) have improved the treatment of MM as they induce the killing of tumor cells through ADCC 114,115 . CD38 and Slamf7 are also expressed on non‐malignant ASCs and could potentially be used to target these populations in antibody‐driven autoimmune conditions.…”

“…CD38 and Slamf7 are also expressed on non‐malignant ASCs and could potentially be used to target these populations in antibody‐driven autoimmune conditions. However, CD38 and Slamf7 expression is also not ASC restricted as CD38 is expressed on red blood cells, T regulatory cells and myeloid derived suppressor cells, while Slamf7 is expressed on the surface of natural killer cells, DCs and CD8 + T cells 114,115 . Multiple therapies targeting BCMA (encoded by TNFRSF17 ), which is more selectively expressed on the surface of ASCs, are currently in clinical trials, and if approved these therapies may allow for the specific targeting of myeloma cells and the plasma cell population 116 .…”

CK1α/RUNX2 Axis in the Bone Marrow Microenvironment: A Novel Therapeutic Target in Multiple Myeloma

“…The use of immunoconjugated drugs targeting the B-Cell Maturation Antigen (BCMA) is currently being investigated in clinical trials with refractory/relapsed MM patients [ 67 ]. Recently, the monoclonal antibody anti-BCMA conjugated with the MonoMethyl Auristatin F, GSK2857916 (Belantamab Mafodotin) [ 68 ], has shown promise when tested in different studies, either as a single agent or in combination with other drugs, in the therapy of heavily pre-treated MM patients [ 69 , 70 ].…”

Treatment horizon in multiple myeloma

“…The four main mechanisms of action for mAbs are ADCC, antibodydependent cellular phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), and direct cell kill. 72 To be considered for therapeutic use, the surface molecules must have a high level of expression in MM cells and a low level of expression in normal cells. 89 Isatuximab is an IgG-k chimeric mAb that binds to a specific CD38 epitope.…”