达拉图穆马
多发性骨髓瘤
医学
抗体
癌症研究
抗体依赖性细胞介导的细胞毒性
浆细胞白血病
体内
骨髓
免疫学
硼替佐米
内科学
单克隆抗体
生物
生物技术
作者
Kristine A. Frerichs,Marloes E.C. Broekmans,Jhon A. Marin Soto,Berris van Kessel,Martijn W. Heymans,Lisa C. Holthof,Christie P.M. Verkleij,Rengasamy Boominathan,Bhavesh Vaidya,Jocelyn Sendecki,Amy Axel,François Gaudet,Kodandaram Pillarisetti,Sonja Zweegman,Homer Adams,Tuna Mutis,Niels W.C.J. van de Donk
标识
DOI:10.1158/1078-0432.ccr-19-2299
摘要
Abstract Purpose: Multiple myeloma (MM) patients with disease refractory to all available drugs have a poor outcome, indicating the need for new agents with novel mechanisms of action. Experimental Design: We evaluated the anti-MM activity of the fully human BCMA×CD3 bispecific antibody JNJ-7957 in cell lines and bone marrow (BM) samples. The impact of several tumor- and host-related factors on sensitivity to JNJ-7957 therapy was also evaluated. Results: We show that JNJ-7957 has potent activity against 4 MM cell lines, against tumor cells in 48 of 49 BM samples obtained from MM patients, and in 5 of 6 BM samples obtained from primary plasma cell leukemia patients. JNJ-7957 activity was significantly enhanced in patients with prior daratumumab treatment, which was partially due to enhanced killing capacity of daratumumab-exposed effector cells. BCMA expression did not affect activity of JNJ-7957. High T-cell frequencies and high effector:target ratios were associated with improved JNJ-7957–mediated lysis of MM cells. The PD-1/PD-L1 axis had a modest negative impact on JNJ-7957 activity against tumor cells from daratumumab-naïve MM patients. Soluble BCMA impaired the ability of JNJ-7957 to kill MM cells, although higher concentrations were able to overcome this negative effect. Conclusions: JNJ-7957 effectively kills MM cells ex vivo, including those from heavily pretreated MM patients, whereby several components of the immunosuppressive BM microenvironment had only modest effects on its killing capacity. Our findings support the ongoing trial with JNJ-7957 as single agent and provide the preclinical rationale for evaluating JNJ-7957 in combination with daratumumab in MM.
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