■CM313目前正在临床研究多发性骨髓瘤的治疗方法,系统性红斑狼疮,和免疫性血小板减少症。我们旨在报告新型治疗性抗CD38单克隆抗体(mAb)CM313的临床前概况,重点是与其他CD38靶向mAb的差异。
使用ELISA评估CM313与CD38重组蛋白跨物种的结合。使用流式细胞术测定法检测CM313与CD38阳性(CD38+)细胞的结合。CM313诱导的补体依赖性细胞毒性(CDC),抗体依赖性细胞毒性(ADCC),通过LDH释放试验或流式细胞术试验评估不同CD38+细胞的抗体依赖性细胞吞噬作用(ADCP)和凋亡.使用荧光光谱法测量CM313对CD38酶活性的影响。CM313在人血液中的免疫毒性使用流式细胞术测定来评估,ELISA,和LDH释放测定。在多个小鼠异种移植模型中评估CM313的抗肿瘤活性。在食蟹猴和人CD38转基因(B-hCD38)小鼠中评价CM313的安全性特征。
在CM313的互补决定区(CDR)处存在独特的序列,其促进其对CD38的亲和力在CD38+细胞系的谱中始终高于达雷木单抗。体外研究表明,CM313诱导的杀伤活性与达拉图单抗相当,包括ADCC,CDC,ADCP,Fc介导的交联诱导的细胞凋亡,并有效抑制CD38的酶活性。然而,CM313显示比伊沙妥昔单抗更有效的CDC。在体内,CM313剂量依赖性地抑制异种移植肿瘤生长,既可以作为单一疗法,也可以与地塞米松或来那度胺联合使用。此外,CM313耐受性良好,没有药物相关的临床症状或脱靶风险,在食蟹猴和B-hCD38小鼠中进行的4周重复剂量毒理学研究证明了这一点,与后来的研究显示没有观察到的不良作用水平(NOAEL)300mg/kg每周一次。
■CM313是一种具有独特CDR序列的新型研究人源化mAb,达雷妥单抗显示出可比的杀伤作用和比伊沙妥昔单抗更强的CDC活性,支持其临床开发。
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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. In vivo, 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.
UNASSIGNED: 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.