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.

Figures

Figure 1

Serial NK cell assessments in patients on study over time. (A) Normalized % IPH2101(+) NK cells (compared with predose) over time in cycle 1. This did not appear to change over time or be influenced by baseline peripheral NK cell count. (B) Representative finding of NK cell and T cell % KIR occupancy from a patient on cohort 4 (0.075 mg/kg). In most patients, the number of T cells recognized by IPH2101 was too low for evaluation; however, in n = 9 evaluable patients, % KIR occupancy between NK and T cells appeared closely correlated as shown. Peripheral absolute (C) and percent (D) NK cell counts over time (normalized to NK cell count obtained just before first administration of IPH2101). Neither absolute nor percent NK cell count appeared to change significantly from baseline over the duration of IPH2101 therapy. (Note patient n per time points shown varies as not all patients received all 4 cycles of planned therapy.)

Figure 2

IPH2101 pharmacokinetics over time. Pharmacokinetic data are shown as IPH2101 concentration (ng/mL) over time for all treated subjects by dose cohorts in cycle 1 (A) and across all cycles (B). A clear relationship between dose and concentration over time was observed.

Figure 3

IPH2101 pharmacodynamics over time. Pharmacodynamic data are shown as KIR occupancy (%) over time for all treated subjects by dose cohorts in cycle 1 (A) and across all cycles (B). Full KIR2D occupancy was defined as > 90%, and the cut-off value was defined as 30%. A clear relationship between dose and KIR occupancy over time was observed.

Figure 4

Evidence of NK cell activation by IPH2101. (A) Left panel: Increased expression of CD69 24 hours after first administration of IPH2101 compared with baseline (P = .016) for all patients. Center and right panels: Increased expression of CD69 (P = .0009) and CD25 (P = .026) in patients (n = 11) receiving IPH2101 doses > 0.075 mg/kg, suggesting a dose-response effect regarding NK-cell activation (as this was not observed in patients who received < 0.075 mg/kg). (B) IPH2101 binding appears to correlate with NK-cell activation. Data shown are from n = 8 evaluable subjects on the 3 mg/kg extension cohort where the percentage of IPH2101(+) NK cells appears to correlate with NK cell expression of CD107a (P = .000000093), CD25 (P = .00000000012), and CD69 (P = .01).

Figure 5

Evidence of NK cell cytotoxicity by IPH2101. (A) In n = 6 of 8 subjects evaluated, IPH2101 appeared to increase NK cell cytotoxicity against MM. Shown are ex vivo NK cell cytotoxicity results measuring NK cell production of GrB by ELISPOT in coculture with RPMI 8226 MM cell line targets. The light gray condition shows GrB production against MM cell line targets before first dose of IPH2101. The black bar represents GrB production 24 hours after first dose of IPH2101. As a control for the possibility of spontaneous activation; and dark gray bar, effector cell GrB production after IPH2101 dosing in the absence of targets. All pair-wise comparisons between predose and postdose and effectors alone versus postdose are statistically significant: *P < .05. (B) NK cell cytotoxicity for n = 5 patients who received repeated doses of IPH2101 on the extension cohort. *GrB production significantly greater than baseline.