肿瘤细胞治疗研究
英文原题：SAR442085, a novel anti-CD38 antibody with enhanced antitumor activity against multiple myeloma.
抗CD38单克隆抗体（mAbs）是多发性骨髓瘤（MM）治疗的一项突破，但部分患者对该疗法无应答或迅速进展，凸显了对新方法的需求。
抗CD38单克隆抗体（mAbs）代表了多发性骨髓瘤（MM）治疗的突破，然而部分患者对该疗法无应答或迅速进展，凸显了对新方法的需求。在本研究中，我们比较了SAR442085——一种对活化型Fc受体（Fc R）具有增强亲和力的下一代抗CD38 mAb——与第一代抗CD38 mAb daratumumab和isatuximab的临床前疗效。在表面等离子体共振和细胞结合实验中，我们发现SAR442085对Fc RIIa（CD32a）和Fc RIIIa（CD16a）的结合亲和力高于daratumumab和isatuximab。SAR442085还对一组表达不同CD38受体密度的MM细胞（包括MM患者原代浆细胞）表现出更好的体外抗体依赖性细胞毒性（ADCC）。使用携带低亲和力和高亲和力Fc RIIIa（CD16a）-158F/V变体的NK-92细胞，证实了SAR442085增强的ADCC。使用MM患者原代骨髓细胞，我们证实SAR442085与Fc RIIIa结合的能力增强，导致对原代浆细胞的自然杀伤（NK）细胞活化和脱颗粒高于现有的Fc野生型抗CD38 mAbs。最后，使用在其人类调控元件控制下表达人类Fc受体的人FcgR转基因小鼠，我们证明SAR442085对过表达人类CD38的EL4胸腺瘤或VK*MYC骨髓瘤细胞具有更高的NK细胞依赖性体内抗肿瘤疗效和更好的生存期，优于daratumumab和isatuximab。这些结果突出了SAR442085的临床前疗效，并支持目前对该下一代抗CD38抗体在复发/难治性MM患者中进行的I期临床开发评估。
Anti-CD38 monoclonal antibodies (mAbs) represent a breakthrough in the treatment of multiple myeloma (MM), yet some patients fail to respond or progress quickly with this therapy, highlighting the need for novel approaches. In this study we compared the preclinical efficacy of SAR442085, a next-generation anti-CD38 mAb with enhanced affinity for activating Fc receptors (Fc R), with first-generation anti-CD38 mAb daratumumab and isatuximab. In surface plasmon resonance and cellular binding assays, we found that SAR442085 had higher binding affinity than daratumumab and isatuximab for Fc RIIa (CD32a) and Fc RIIIa (CD16a). SAR442085 also exhibited better in vitro antibody-dependent cellular cytotoxicity (ADCC) against a panel of MM cells expressing variable CD38 receptor densities including MM patients' primary plasma cells. The enhanced ADCC of SAR442085 was confirmed using NK-92 cells bearing low and high affinity Fc RIIIa (CD16a)-158F/V variants. Using MM patients' primary bone marrow cells, we confirmed that SAR442085 had an increased ability to engage Fc RIIIa, resulting in higher natural killer (NK) cell activation and degranulation against primary plasma cells than preexisting Fc wild-type anti-CD38 mAbs. Finally, using huFcgR transgenic mice that express human Fc receptors under the control of their human regulatory elements, we demonstrated that SAR442085 had higher NK cell-dependent in vivo antitumor efficacy and better survival than daratumumab and isatuximab against EL4 thymoma or VK*MYC myeloma cells overexpressing human CD38. These results highlight the preclinical efficacy of SAR442085 and support the current evaluation of this next-generation anti-CD38 antibody in phase I clinical development in patients with relapsed/refractory MM.
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