Elotuzumab and daratumumab: emerging new monoclonal antibodies for multiple myeloma

Abstract

Multiple myeloma (MM) has been mostly incurable due to its highly complex and heterogeneous molecular abnormalities and the support from myeloma microenvironment factors. A therapeutic strategy which effectively targets relevant and specific molecule to myeloma cells, and which is potent in overcoming tumor microenvironment-mediated drug resistance needs to be developed. One of the promising fields is the development of immunotherapy using monoclonal antibodies (MoAbs) against myeloma-specific antigens. This review focuses on the basic and clinical aspects of two emerging and promising novel MoAbs for MM, elotuzumab which targets CS1 and daratumumab which targets CD38. Both antigens are relatively specific to myeloma cells and expressed in more than 90% of MM patients, and mediate adhesion of myeloma cells to bone marrow stromal cells. We also discuss the unique characteristics of the two MoAbs by comparing with other MoAbs being developed for MM.

Keywords::

• CD38
• CS1
• daratumumab
• elotuzumab
• monoclonal antibody
• multiple myeloma

Financial & competing interests disclosure

This work was partly supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Taniwaki M and Kuroda J), and the Hoansha Foundation and the Award in Aki's Memory from the International Myeloma Foundation (Kuroda J). The authors were not compensated and retained full editorial control over the content of the paper. 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.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Significant improvements in treatment outcome for multiple myeloma (MM) have been achieved during the past decade by the development of new therapeutic modalities, however, MM remains mostly incurable so far.

• • Two emerging novel monoclonal antibodies (MoAbs) for MM, elotuzumab which targets CS1 and daratumumab which targets CD38, have been developed.

• • Both CS1 and CD38 are expressed on myeloma cells in the majority (>90%) of patients, while their expression levels are strikingly higher in myeloma cells than in other non-myeloma tissues.

• • Elotuzumab exerts its anti-MM effect mainly through antibody-dependent cellular cytotoxicity (ADCC) effect, and both preclinical study and clinical trials showed promising effect of the combination of lenalidomide (LEN) and elotuzumab.

• • Daratumumab exerts its anti-MM effect through complement-dependent cytotoxicity (CDC), ADCC and direct cytotoxic effect, and showed dose-dependent clinical effect for MM as a single agent. This dose-dependent direct anti-MM effect of daratumumab is the first documentation of the use of a single-agent MoAb for MM.

• • Both elotuzumab and daratumumab are also potent in overcoming cell adhesion-mediated drug resistance (CAM-DR) in MM.

• • Future therapeutic strategy for MM will be further progressed with the use of elotuzumab and daratumumab.