Research and Development Department, Keymed Biosciences (Chengdu) Limited, Chengdu, China.
Department of Ecology and Evolutionary Biology, Tulane University, New Orleans, MS, United States.
Front Immunol. 2024 May 3;15:1410457. doi: 10.3389/fimmu.2024.1410457. eCollection 2024.
CM313 is currently under clinical investigation for treatments of multiple myeloma, systemic lupus erythematosus, and immune thrombocytopenia. We aimed to report the preclinical profile of the novel therapeutic anti-CD38 monoclonal antibody (mAb) CM313, with an emphasis on the difference with other CD38-targeting mAb.
The binding of CM313 to CD38 recombinant protein across species was assessed using ELISA. The binding of CM313 to CD38-positive (CD38) cells was detected using flow cytometry assays. CM313-induced complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and apoptosis on different CD38 cells were assessed by LDH release assays or flow cytometry assays. The effect of CM313 on CD38 enzymatic activity was measured using fluorescence spectroscopy. CM313 immunotoxicity in human blood was assessed using flow cytometry assays, ELISA, and LDH release assays. Anti-tumor activity of CM313 was assessed in multiple mouse xenograft models. Safety profile of CM313 were evaluated in cynomolgus monkeys and human CD38 transgenic (B-hCD38) mice.
There exist unique sequences at complementarity-determining regions (CDR) of CM313, which facilitates its affinity to CD38 is consistently higher across a spectrum of CD38 cell lines than daratumumab. In vitro studies showed that CM313 induces comparable killing activity than daratumumab, including ADCC, CDC, ADCP, apoptosis induced by Fc-mediated cross-linking, and effectively inhibited the enzymatic activity of CD38. However, CM313 showed more potent CDC than isatuximab. , CM313 dose-dependently inhibited xenograft tumor growth, both as a monotherapy and in combination with dexamethasone or lenalidomide. Furthermore, CM313 was well tolerated with no drug-related clinical signs or off-target risks, as evidenced by 4-week repeat-dose toxicology studies in cynomolgus monkeys and B-hCD38 mice, with the later study showing no observed adverse effect level (NOAEL) of 300mg/kg once weekly.
CM313 is a novel investigational humanized mAb with a distinct CDR sequence, showing comparable killing effects with daratumumab and stronger CDC activity than isatuximab, which supports its clinical development.
CM313 目前正在进行多发性骨髓瘤、系统性红斑狼疮和免疫性血小板减少症的临床试验。我们旨在报告新型治疗性抗 CD38 单克隆抗体 (mAb) CM313 的临床前特征，重点介绍与其他 CD38 靶向 mAb 的区别。
使用 ELISA 评估 CM313 与跨物种 CD38 重组蛋白的结合。使用流式细胞术检测 CM313 与 CD38 阳性 (CD38+) 细胞的结合。通过 LDH 释放测定或流式细胞术检测 CM313 在不同 CD38 细胞上诱导的补体依赖性细胞毒性 (CDC)、抗体依赖性细胞毒性 (ADCC)、抗体依赖性细胞吞噬作用 (ADCP) 和细胞凋亡。使用荧光光谱法测量 CM313 对 CD38 酶活性的影响。使用流式细胞术、ELISA 和 LDH 释放测定评估 CM313 在人血中的免疫毒性。使用多种小鼠异种移植模型评估 CM313 的抗肿瘤活性。在食蟹猴和人 CD38 转基因 (B-hCD38) 小鼠中评估 CM313 的安全性概况。
CM313 的互补决定区 (CDR) 存在独特序列，这有助于其对 CD38 的亲和力在一系列 CD38 细胞系中始终高于达妥木单抗。体外研究表明，CM313 诱导的杀伤活性与达妥木单抗相当，包括 ADCC、CDC、ADCP、Fc 介导交联诱导的细胞凋亡，并且有效抑制 CD38 的酶活性。然而，CM313 比依鲁替尼显示出更强的 CDC。CM313 剂量依赖性地抑制异种移植肿瘤生长，无论是作为单一疗法还是与地塞米松或来那度胺联合使用。此外，在食蟹猴和 B-hCD38 小鼠的 4 周重复剂量毒性研究中，CM313 耐受性良好，没有与药物相关的临床体征或脱靶风险，后者研究显示每周一次 300mg/kg 的无观察不良效应水平 (NOAEL)。
CM313 是一种新型的研究性人源化 mAb，具有独特的 CDR 序列，与达妥木单抗具有相当的杀伤效果，与依鲁替尼相比具有更强的 CDC 活性，这支持其临床开发。
