A Novel, Fully Human Anti-fucosyl-GM1 Antibody Demonstrates Potent In Vitro and In Vivo Antitumor Activity in Preclinical Models of Small Cell Lung Cancer.
A Novel, Fully Human Anti-fucosyl-GM1 Antibody Demonstrates Potent In Vitro and In Vivo Antitumor Activity in Preclinical Models of Small Cell Lung Cancer.
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一种新型的，完全人类的抗凝血素-GM1抗体在小细胞肺癌的临床前模型中表现出有效的体外和体内抗肿瘤活性。
DOI：
10.1158/1078-0432.ccr-18-0018
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发表时间：
2018-10-15
期刊：
影响因子：
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通讯作者：
Cardarelli PM
中科院分区：
文献类型：
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作者：
Ponath P;Menezes D;Pan C;Chen B;Oyasu M;Strachan D;LeBlanc H;Sun H;Wang XT;Rangan VS;Deshpande S;Cristea S;Park KS;Sage J;Cardarelli PM
神经节苷脂岩藻糖基-GM 1（FucGM 1）是一种肿瘤相关抗原，在大部分人小细胞肺癌（SCLC）肿瘤中表达，但在大多数正常成人组织中不存在，使其成为免疫肿瘤学中有前途的靶点。本研究旨在评价BMS-986012的临床前疗效，BMS-986012是一种新型非岩藻糖基化全人源IgG 1抗体，可特异性结合FucGM 1。在体外试验中，使用SCLC细胞以及在小鼠异种移植和同系肿瘤模型中，在联合和不联合化疗药物和检查点抑制剂的情况下，评价了BMS-986012的抗肿瘤活性。BMS-986012对FcγRIIIa（CD 16）显示出较高的结合亲和力，导致对FucGM 1表达肿瘤细胞系的抗体依赖性细胞毒性（ADCC）增强。在补体依赖性细胞毒性（CDC）和抗体依赖性细胞吞噬（ADCP）试验中也观察到BMS-986012介导的肿瘤细胞杀伤。在几种小鼠SCLC模型中，BMS-986012表现出功效并且耐受良好。在DMS 79异种移植模型中，使用0.3 mg/kg及更高剂量的BMS-986012实现肿瘤消退;当BMS-986012与标准护理顺铂或依托泊苷组合时，抗肿瘤活性增强。在同系模型中，用BMS-986012或具有小鼠IgG 2a Fc的抗FucGM 1治疗源自SCLC基因工程模型的肿瘤，并评估其反应;当BMS-986012与抗PD-1或抗CD 137抗体联合使用时，治疗反应显着改善。单药BMS-986012显示出稳健的抗肿瘤活性，在相同模型中加入化疗或免疫调节剂进一步抑制SCLC生长。这些临床前数据支持在复发性难治性SCLC患者的I期临床试验中评价BMS-986012。
The ganglioside fucosyl-GM1 (FucGM1) is a tumor-associated antigen expressed in a large percentage of human small cell lung cancer (SCLC) tumors, but absent in most normal adult tissues, making it a promising target in immuno-oncology. This study was undertaken to evaluate the preclinical efficacy of BMS-986012, a novel, nonfuco-sylated, fully human IgG1 antibody that binds specifically to FucGM1. The antitumor activity of BMS-986012 was evaluated in in vitro assays using SCLC cells and in mouse xenograft and syngeneic tumor models, with and without chemotherapeutic agents and checkpoint inhibitors. BMS-986012 showed a high binding affinity for FcγRIIIa (CD16), which resulted in enhanced antibody-dependent cellular cytotoxicity (ADCC) against FucGM1-expressing tumor cell lines. BMS-986012-mediated tumor cell killing was also observed in complement-dependent cytotoxicity (CDC) and antibody-dependent cellular phagocytosis (ADCP) assays. In several mouse SCLC models, BMS-986012 demonstrated efficacy and was well tolerated. In the DMS79 xenograft model, tumor regression was achieved with BMS-986012 doses of 0.3 mg/kg and greater; antitumor activity was enhanced when BMS-986012 was combined with standard-of-care cisplatin or etoposide. In a syngeneic model, tumors derived from a genetically engineered model of SCLC were treated with BMS-986012 or anti-FucGM1 with a mouse IgG2a Fc and their responses evaluated; when BMS-986012 was combined with anti–PD-1 or anti-CD137 antibody, therapeutic responses significantly improved. Single-agent BMS-986012 demonstrated robust antitumor activity, with the addition of chemotherapeutic or immunomodulatory agents further inhibiting SCLC growth in the same models. These preclinical data supported evaluation of BMS-986012 in a phase I clinical trial of patients with relapsed, refractory SCLC.