A phase 1 trial of the anti-KIR antibody IPH2101 in patients with relapsed/refractory multiple myeloma
A phase 1 trial of the anti-KIR antibody IPH2101 in patients with relapsed/refractory multiple myeloma
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DOI：
10.1182/blood-2012-06-438028
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发表时间：
2012-11-22
期刊：
影响因子：
20.3
通讯作者：
Farag, Sherif S.
中科院分区：
文献类型：
--
作者：
Benson, Don M., Jr.;Hofmeister, Craig C.;Farag, Sherif S.
自然杀伤（NK）细胞引起针对多发性骨髓瘤（MM）的细胞毒性;然而，MM细胞表达HLA I类分子作为NK细胞抑制性杀伤免疫球蛋白样受体（KIR）的配体，作为免疫逃避的一种手段。KIR-配体错配可能改善MM异基因移植的结局。根据这一概念外推，我们在复发/难治性MM患者中进行了IPH 2101（一种抗KIR抗体）的1期试验。IPH 2101在7个剂量递增队列（0.0003-3 mg/kg）中每28天静脉内给药一次，最多4个周期。完成了药代动力学、药效学和相关免疫学研究。共入组32例患者。在整个给药周期内实现了完全KIR 2D占用的生物学终点，没有剂量限制性毒性或最大耐受剂量。观察到1例严重不良事件。药代动力学和药效学结果接近临床前预测，IPH 2101增强了离体患者来源的NK细胞对MM的细胞毒性。未观察到自身免疫的证据。这些发现表明，IPH 2101在达到完全抑制KIR饱和的剂量下是安全和可耐受的，并且这种方法保证了在MM中的进一步开发。该试验在www.clinicaltrials.gov上注册为#NCT00552396。（血。2012;120（22）：4324-4333）
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. (Blood. 2012;120(22):4324-4333)