title: A phase 1 trial of the anti-inhibitory KIR mAb IPH2101 for AML in complete remission.
abstract: IPH2101 is an anti-killer inhibitory receptor (anti-KIR) mAb that can block KIR-mediated inhibition of natural killer (NK) cells to enhance cytotoxicity against acute myeloid leukemia blasts. We have conducted a phase 1 study of IPH2101 in elderly patients with acute myeloid leukemia in first complete remission. Patients received escalating doses (0.0003-3 mg/kg) of IPH2101 following a 3 + 3 design. Safety, toxicity (primary end points), pharmacokinetics, outcome, and immunologic correlates were evaluated. Twenty-three patients (median age, 71 years), were enrolled. Adverse events were mild and transient, consisting mainly of infusion syndrome and erythema. The maximum tolerated dose was not reached, although full KIR saturation (> 90%) was sustained for more than 2 weeks at 1 and 3 mg/kg. There was a clear correlation between mAb exposure and KIR occupancy. Neither hematologic toxicity nor significant changes in the numbers and distribution of lymphocyte subsets, NK cell receptor expression, or in vitro cytotoxicity were seen. At the highest dose levels (0.3, 1, and 3 mg/kg), transient increases in TNF-α and MIP-1β serum concentrations and NK cell CD69 expression were observed. Overall and relapse-free survival in the present study compared favorably to reports in comparable patient populations. We conclude that IPH2101 administration is safe and can block KIR for prolonged periods of time with limited side effects. Registered with the European Union Drug Regulating Authorities Clinical Trials (EUDRACT) as 2005-005298-31.
authors.affiliation: Institut Paoli-Calmettes, Marseille, France. veyn@ipc.unicancer.fr
authors.forename: Norbert
authors.initials: N
authors.lastname: Vey
authors.forename: Jean-Henri
authors.initials: JH
authors.lastname: Bourhis
authors.forename: Nicolas
authors.initials: N
authors.lastname: Boissel
authors.forename: Dominique
authors.initials: D
authors.lastname: Bordessoule
authors.forename: Thomas
authors.initials: T
authors.lastname: Prebet
authors.forename: Aude
authors.initials: A
authors.lastname: Charbonnier
authors.forename: Anne
authors.initials: A
authors.lastname: Etienne
authors.forename: Pascale
authors.initials: P
authors.lastname: Andre
authors.forename: François
authors.initials: F
authors.lastname: Romagne
authors.forename: Don
authors.initials: D
authors.lastname: Benson
authors.forename: Herve
authors.initials: H
authors.lastname: Dombret
authors.forename: Daniel
authors.initials: D
authors.lastname: Olive
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects / Q000379:methods; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D015470:Leukemia, Myeloid, Acute / Q000276:immunology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D054340:Receptors, KIR / Q000037:antagonists & inhibitors / Q000276:immunology; D012074:Remission Induction; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D054340:Receptors, KIR; C558235:IPH-2101