title: A phase 1 trial of the anti-KIR antibody IPH2101 in patients with relapsed/refractory multiple myeloma.
abstract: Natural killer (NK) cells elicit cytotoxicity against multiple myeloma (MM); however, MM cells express HLA class I molecules as ligands to NK cell inhibitory killer immunoglobulin-like receptors (KIRs) as a means of immunoevasion. KIR-ligand mismatch may improve outcomes in allogeneic transplantation for MM. Extrapolating on this concept, we conducted a phase 1 trial of IPH2101, an anti-KIR antibody, in patients with relapsed/refractory MM. IPH2101 was administered intravenously every 28 days in 7 dose-escalated cohorts (0.0003-3 mg/kg) for up to 4 cycles. Pharmacokinetic, pharmacodynamic, and correlative immunologic studies were completed. A total of 32 patients were enrolled. The biologic endpoint of full KIR2D occupancy across the dosing cycle was achieved without dose-limiting toxicity or maximally tolerated dose. One severe adverse event was noted. Pharmacokinetic and pharmacodynamic findings approximated preclinical predictions, and IPH2101 enhanced ex vivo patient-derived NK cell cytotoxicity against MM. No objective responses were seen. No evidence of autoimmunity was observed. These findings suggest that IPH2101 is safe and tolerable at doses that achieve full inhibitory KIR saturation, and this approach warrants further development in MM. This trial was registered at www.clinicaltrials.gov as #NCT00552396.
authors.affiliation: Division of Hematology, The Ohio State University, Columbus, OH 43210-1240, USA. don.benson@osumc.edu
authors.forename: Don M
authors.initials: DM
authors.lastname: Benson
authors.forename: Craig C
authors.initials: CC
authors.lastname: Hofmeister
authors.forename: Swaminathan
authors.initials: S
authors.lastname: Padmanabhan
authors.forename: Attaya
authors.initials: A
authors.lastname: Suvannasankha
authors.forename: Sundar
authors.initials: S
authors.lastname: Jagannath
authors.forename: Rafat
authors.initials: R
authors.lastname: Abonour
authors.forename: Courtney
authors.initials: C
authors.lastname: Bakan
authors.forename: Pascale
authors.initials: P
authors.lastname: Andre
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Efebera
authors.forename: Jérôme
authors.initials: J
authors.lastname: Tiollier
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.forename: Sherif S
authors.initials: SS
authors.lastname: Farag
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000276:immunology; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000276:immunology / Q000628:therapy*; D054340:Receptors, KIR / Q000037:antagonists & inhibitors / Q000276:immunology; D012008:Recurrence
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D054340:Receptors, KIR; C558235:IPH-2101