CS1-Directed Monoclonal Antibody Therapy for Multiple Myeloma

Therapeutic monoclonal antibodies (mAbs) have revolutionized treatment options for many cancers. However, the extension of effective mAb-mediated therapy for multiple myeloma (MM) has been limited thus far by lack of an optimal target. Results of experimental agents targeting a number of potential candidate molecules expressed on the surface of MM tumor cells have been reported (including CD20, CD40, CD56, CD74, CD138, CD200, epidermal growth factor receptor, and beta-2 microglobulin), as have those of mAbs targeting other proteins involved in the MM immunologic microenvironment (interleukin-6, vascular endothelial growth factor, and killer immunoglobulin-like inhibitory receptors). Despite these efforts, the benefit of mAb-based therapy directed at these targets in MM remains incompletely articulated. The most promising target for mAb-mediated MM therapy to date seems to be CS1 (also referred to as CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24), a human membrane glycoprotein and member of the immunoglobulin superfamily. CS1 cell surface expression seems nearly ubiquitous in both primary MM tumor cells as well as virtually all MM cell lines. Soluble CS1 is also detectable in serum of patients with MM and correlates with both disease stage and need for therapy. Furthermore, CS1 is expressed in some leukocyte subsets (eg, natural killer [NK] cells and some T-cell subsets) but not in the majority of healthy tissues or other forms of malignancy. Relatively little is known regarding the function of CS1 in MM cells. The CS1 gene resides on the long arm of chromosome 1 (1q23.11q24.1), and gains of chromosome 1q are frequent alterations in MM tumor cells; thus CS1 overexpression may contribute to the pathobiology of the disease. CS1 has been shown to colocalize with CD138 in uropod membranes on the surface of polarized MM cells, which may promote cell-cell adhesion. Moreover, a direct role for CS1 in MM cell adhesion to, and interaction with, bone marrow stromal cells (BMSCs) has been conclusively demonstrated. This is important for MM pathobiology, because the protective effect of BMSCs comprises a substantial component of therapeutic resistance in this tumor type. Much of what is known about human CS1 signaling, however, is derived from studies in other lymphocyte subsets. In NK cells, for example, CS1 is a self ligand that promotes activation through selective expression of the adaptor protein EAT-2. In fact, CS1 may serve an inhibitory role in T cells that lack EAT-2. CS1 ligation independent of Fc R ligation in NK cells results in signal transduction events that activate several pathways including phosphatidylinositol 3-kinase, mitogen-activated protein kinase, and phospholipase C gamma. Whether EAT-2 is expressed in MM cells remains unknown; similarly, the signal transduction events consequent to CS1 ligation in MM cells are a matter of ongoing investigation. Elotuzumab (formerly HuLuc63), a humanized immunoglobulin G1 anti-CS1 mAb, has been shown to impair MM cell adhesion and exert direct (albeit modest) effects on primary MM cell survival in vitro, either alone or in the presence of BMSCs. Its principal mechanism of action, however, is thought to be antibody-dependent cellular cytotoxicity (ADCC). Here, ADCC is mediated by NK cells through interaction of their Fc RIIIa receptor with the Fc binding region of the therapeutic antibody. Preliminary data suggest that elotuzumab may also directly activate NK cells through direct CS1 ligation. Interestingly, elotuzumab-associated NK-cell cytotoxicity via ADCC is directed specifically against CS1-bearing MM tumor cells and not fraternal CS1-bearing NK cells, as demonstrated in both in vitro and correlative studies performed during clinical investigation. Figure 1 summarizes the known functions of CS1 in MM and apparent