Combinatorial efficacy of anti-CS1 monoclonal antibody elotuzumab (HuLuc63) and bortezomib against multiple myeloma

Abstract

Monoclonal antibody (mAb) therapy for multiple myeloma, a malignancy of plasma cells, has not been clinically efficacious in part due to a lack of appropriate targets. We recently reported that the cell surface glycoprotein CS1 (CD2 subset 1, CRACC, SLAMF7, CD319) was highly and universally expressed on myeloma cells while having restricted expression in normal tissues. Elotuzumab (formerly known as HuLuc63), a humanized mAb targeting CS1, is currently in a phase I clinical trial in relapsed/refractory myeloma. In this report we investigated whether the activity of elotuzumab could be enhanced by bortezomib, a reversible proteasome inhibitor with significant activity in myeloma. We first showed that elotuzumab could induce patient-derived myeloma cell killing within the bone marrow microenvironment using a SCID-hu mouse model. We next showed that CS1 gene and cell surface protein expression persisted on myeloma patient-derived plasma cells collected after bortezomib administration. In vitro bortezomib pretreatment of myeloma targets significantly enhanced elotuzumab-mediated antibody-dependent cell-mediated cytotoxicity, both for OPM2 myeloma cells using natural killer or peripheral blood mononuclear cells from healthy donors and for primary myeloma cells using autologous natural killer effector cells. In an OPM2 myeloma xenograft model, elotuzumab in combination with bortezomib exhibited significantly enhanced in vivo antitumor activity. These findings provide the rationale for a clinical trial combining elotuzumab and bortezomib, which will test the hypothesis that combining both drugs would result in enhanced immune lysis of myeloma by elotuzumab and direct targeting of myeloma by bortezomib. [Mol Cancer Ther 2009;8(9):2616-24]

A phase 2 safety study of accelerated elotuzumab infusion, over less than 1 h, in combination with lenalidomide and dexamethasone, in patients with multiple myeloma

“…The median number of study treatment cycles was 6 (range [1][2][3][4][5][6][7][8][9][10][11][12][13] and 49 patients (70%) received 90% of the relative intended dose of elotuzumab. Of the 1,113 elotuzumab infusions given, 87% (968) were given at the maximum 5 mL/min rate; of the remaining 13% (145), 144…”

“…Combined treatments (usually three agents; triplets) have been notably effective in improving patient outcomes. 6,7 Unfortunately, long-term prognosis remains poor despite recent advances, with relapse and subsequent development of refractory disease being almost inevitable. 8,9 Additionally, treatment with intravenous agents can involve frequent and/or time-consuming *Affiliation at the time of the study.…”

“…15 Furthermore, elotuzumab in combination with lenalidomide (an IMiD) and bortezomib (a PI) enhanced ADCC in vitro, potentially mediated through enhancement of natural killer cell activity. 6,[15][16][17] On November 30, 2015, the US Food and Drug Administration approved the three-drug combination of elotuzumab plus lenalidomide and dexamethasone for use in patients with MM who had received 1-3 prior therapies, based on the positive results of the ELOQUENT-2 study (NCT01239797). 4,18 Approval by the European Medicines Agency followed in May 2016 for adult patients with MM who had received one or more therapies.…”

Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM

“…7,8 Elotuzumab showed enhanced activity when combined with bortezomib in a preclinical myeloma model. 9 In a phase 1 doseescalation safety study, IV elotuzumab plus Bd (EBd) was well tolerated in patients with RRMM, with an overall response rate (ORR) of 48% and median time to progression of 9.5 months, which suggests improved activity compared with bortezomib alone. 10 We therefore hypothesized that the addition of elotuzumab to Bd would increase progression-free survival (PFS) relative to Bd alone in patients with RRMM.…”

PD-1 blockade enhances elotuzumab efficacy in mouse tumor models

“…16,17 The efficacy of elotuzumab in these models was NK cell-dependent and was enhanced by coadministration of bortezomib, lenalidomide, or mAbs that additionally stimulated NK cell activity. 16,17,[23][24][25] Furthermore, elotuzumab promotes cytotoxicity against myeloma cells through direct engagement of SLAMF7 on NK cells. 26 SLAMF7 is a self-ligand that stimulates NK cell activation in the presence of the adaptor protein EWS-Fl1-activated transcript-2 [27][28][29] ; however, elotuzumab does not activate, inhibit, or directly induce apoptosis of myeloma cells.…”