title: 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.
authors.affiliation: University of Arkansas for Medical Sciences, Myeloma Institute for Research and Therapy, Little Rock AR 72205, USA. vanrheefrits@uams.edu
authors.forename: Frits
authors.initials: F
authors.lastname: van Rhee
authors.forename: Susann M
authors.initials: SM
authors.lastname: Szmania
authors.forename: Myles
authors.initials: M
authors.lastname: Dillon
authors.forename: Anne M
authors.initials: AM
authors.lastname: van Abbema
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Mary K
authors.initials: MK
authors.lastname: Stone
authors.forename: Tarun K
authors.initials: TK
authors.lastname: Garg
authors.forename: JuMei
authors.initials: J
authors.lastname: Shi
authors.forename: Amberly M
authors.initials: AM
authors.lastname: Moreno-Bost
authors.forename: Rui
authors.initials: R
authors.lastname: Yun
authors.forename: Balaji
authors.initials: B
authors.lastname: Balasa
authors.forename: Bishwa
authors.initials: B
authors.lastname: Ganguly
authors.forename: Debra
authors.initials: D
authors.lastname: Chao
authors.forename: Audie G
authors.initials: AG
authors.lastname: Rice
authors.forename: Fenghuang
authors.initials: F
authors.lastname: Zhan
authors.forename: John D
authors.initials: JD
authors.lastname: Shaughnessy
authors.forename: Bart
authors.initials: B
authors.lastname: Barlogie
authors.forename: Shmuel
authors.initials: S
authors.lastname: Yaccoby
authors.forename: Daniel E H
authors.initials: DE
authors.lastname: Afar
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D016022:Case-Control Studies; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D011719:Pyrazines / Q000627:therapeutic use*; D014183:Transplantation, Heterologous
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001897:Boronic Acids; D008562:Membrane Glycoproteins; D011719:Pyrazines; C546027:elotuzumab; D000069286:Bortezomib