MECHANISM OF ACTION OF ELOTUZUMAB
The mechanisms of action of elotuzumab include 1) enhancing natural killer (NK) cells’ cytotoxicity through the Fab portion of elotuzumab binding to signaling lymphocytic activation molecule F7 (SLAMF7) receptor on NK cells; 2) elotuzumab binds to SLAMF7 receptor on MM cells and CD16 receptor on NK cells that activate NK cells to kill MM cells by mediating ADCC and 3) elotuzumab inhibits MM cells to interact with bone marrow stromal cells (BMSCs) (Figure 1). Blockade of the CD16 (Fc receptor) on NK cells or depletion of NK cells from peripheral blood mononuclear cells (PBMCs) significantly inhibits elotuzumab-mediated ADCC activity. There is no effect on elotuzumab-mediated ADCC by depleting T cells, B cells or monocytes from PBMCs, suggesting ADCC induction by elotuzumab is dependent on NK cells.16
In coculture experiments, elotuzumab treatment or reducing the expression of SLAMF7 interfered with MM cell adhesion to BMSCs, suggesting elotuzumab may reverse cell adhesion-mediated drug resistance associated with conventional therapies.17–19
PRECLINICAL EXPERIENCES WITH ELOTUZUMAB
HuLuc63, later named elotuzumab, is a humanized anticell surface 1 (CS1) mAb, which recognizes the extracellular domain of CS1 (also known as SLAMF7). HuLuc63 significantly abrogated the growth of the human myeloma cell line OPM2 using a murine xenograft model by ADCC induction. The antitumor activity is related to the presence of functional NK cells.16
CS1 belongs to the SLAM family and was found to be highly expressed in malignant and normal plasma cells. CS1 is also expressed on the CS of NK cells, NK-like T cells, CD8-positive T cells, mature dendritic cells and activated B cells but was not found on other normal tissues.16,20,21 Expression of CS1 is frequent in MM cell lines (mRNA 45 of 45; protein 14 of 15 are expressed). CS1 was detected in the majority of MM specimens (98 of 101), but not in healthy donors and is one of the critical regulators of immune response contributing to survival regulation in MM. Due to restricted expression of SLAMF7; elotuzumab demonstrates minimal adverse effects (AEs) on normal tissue, suggesting a high therapeutic index in MM.21
Lenalidomide (Celgene Corporation; Summit, NJ, USA) is a highly effective IMiD approved for MM patients.22–24 Evidence has shown that antitumor activity of lenalidomide is through multiple mechanisms including enhancement of T-cell and NK-cell activations, repression of angiogenesis, altering cytokine production and direct inhibition of tumor cell growth.25–27
Lymphocyte function-associated antigen 1, also known as LFA-1 (CD11a/CD18) is an adhesion molecule. LFA-1 is a requirement for the adhesion of NK cells to target cells through binding to intercellular adhesion molecule (ICAM-1). The interaction of LFA-1 and ICAM-1 is associated with multidrug resistance induction in vitro. Using anti-CD18 mAb to interrupt LFA-1/ICAM-1 interaction decreased elotuzumab activity as a single agent or in combination with lenalidomide-using both cell MM cell death and NK activity as endpoint measurements.28,29 Together, these data suggest that elotuzumab-induced cell death and NK activity is partially dependent on LFA-1 function on NK cells.
The combination of elotuzumab with lenalidomide enhanced antiproliferative effect more than elotuzumab or lenalidomide monotherapy using either in vitro or in vivo models of MM.30 This enhanced anti-myeloma activity correlated with NK activation, increased cytokine secretion and LFA-1/ICAM-1 interaction.31,32
Bortezomib (Takeda Pharmaceutical Company, Osaka, Japan) is the first PI approved for MM patients.31 Evidence indicated that bortezomib sensitized myeloma cell lines and primary myeloma cells to elotuzumab-mediated ADCC. Moreover, the combination of elotuzumab and bortezomib significantly increased anti-myeloma activity compared with single agent in the OPM2 MM xenograft model.33
In addition to direct effects on the myeloma cell, bortezomib was shown to downregulate major histocompatibility complex class I expression on the MM cell lines and patient MM cells leading to enhanced sensitivity of MM cells to NK cell-mediated lysis.32 The increase in NK-mediated lysis may contribute to the favorable anti-myeloma response when elotuzumab is combined with bortezomib. CS1 (SLAMF7) RNA and protein expressions of patients with MM (n=103) resulted in no significant change on the CS after bortezomib administration, compared with the untreated group indicating that changes in CS expression of CS1 do not correlate with increased activity of the combination treatment regimen.
Taken together, the preclinical data suggest that elotuzumab is an attractive agent to combine with conventional therapies such as lenalidomide and bortezomib.
CLINICAL EXPERIENCES WITH ELOTUZUMAB
The first-in-human study of elotuzumab was designed as a monotherapy to evaluate the safety, tolerability and pharmacokinetic and pharmacodynamic properties of elotuzumab in patients with RRMM. Thirty-five patients were enrolled and received escalating doses of elotuzumab from 0.5 to 20 mg/kg by intravenous (IV) infusion on an every 14 days scheme. According to European Group for Bone and Marrow Transplantation myeloma response criteria, 26.5% (n=9) patients had stable disease, also the best-observed response. However, no objective responses were observed in this trial. Collectively the preclinical and early clinical data suggested that elotuzumab alone, albeit safe, was not sufficient to produce tumor response in RRMM but maybe a candidate for combination strategy.34
Preclinical studies demonstrated that elotuzumab in combination with other agents, including lenalidomide and bortezomib showed increased antitumor activity compared to single agent treatment.21,33 To evaluate the maximum tolerated dose (MTD), efficacy, safety of elotuzumab in combination with lenalidomide and dexamethasone. A Phase I study of elotuzumab at a dose of 5, 10 and 20 mg/kg with lenalidomide and low-dose dexamethasone in patients with RRMM yielded an overall response rates (ORRs) of 82% (23 of 28); the median time to progression (TTP) had not been reached after a median of 16.4 months of follow-up in the 20 mg/kg cohort.35 Another Phase I/II, multicenter, open-label multiple-dose, dose escalation study investigated MTD safety and efficacy of elotuzumab in combination with bortezomib in patients with RRMM (ClinicalTrials.gov Identifier: NCT00726869). Twenty-eight patients with a median of two prior therapies were enrolled and received escalating doses of elotuzumab from 2.5 to 20 mg/kg IV and bortezomib (1.3 mg/m2 IV). The ORR was 48% (n=13) and 63% (n=17) of patients achieved a minor response or better. The median TTP was 9.46 months. Two of three (66.7%) patients who were bortezomib-refractory previously showed objective response with the addition of elotuzumab. Seventy percent (7 of 10) of patients with high-risk cytogenetics showed an objective response. MTD was not observed at the maximum planned dose of 20 mg/kg of elotuzumab.36