Preclinical Characterization of a Novel Monoclonal Antibody NEO-201 for the Treatment of Human Carcinomas.
Preclinical Characterization of a Novel Monoclonal Antibody NEO-201 for the Treatment of Human Carcinomas.
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DOI：
10.3389/fimmu.2017.01899
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发表时间：
2017
影响因子：
7.3
通讯作者：
Arlen PM
中科院分区：
文献类型：
--
作者：
Fantini M;David JM;Saric O;Dubeykovskiy A;Cui Y;Mavroukakis SA;Bristol A;Annunziata CM;Tsang KY;Arlen PM
NEO-201是一种新型人源化IgG1单克隆抗体，该抗体是从混合异体结肠肿瘤组织提取物中提取的肿瘤相关抗原的免疫原性制备中获得的。研究发现，它对多种培养的人类癌细胞系都有反应，对许多不同类型的肿瘤组织，包括结肠癌、胰腺癌、胃癌、肺癌和乳腺癌，都有很高的反应。NEO-201也表现出肿瘤特异性，因为大多数正常组织不被该抗体识别。功能分析显示，NEO-201能够介导针对肿瘤细胞的抗体依赖性细胞毒性（ADCC）和补体依赖性细胞毒性（CDC）。此外，单独使用NEO-201或与作为ADCC效应细胞源的人外周血单个核细胞联合使用NEO-201治疗，人胰腺异种移植物肿瘤在体内的生长明显减弱。人类肿瘤移植小鼠体内生物分布研究表明，NEO-201优先在肿瘤中积累，而不是在器官组织中积累。最后，在非人类灵长类动物中进行的单剂量毒性研究证明了NEO-201的安全性和耐受性，因为观察到的唯一相关副作用是循环中性粒细胞的短暂减少。这些发现表明NEO-201值得作为一种新的诊断和治疗药物进行临床试验，用于治疗多种癌症。
NEO-201 is a novel humanized IgG1 monoclonal antibody that was derived from an immunogenic preparation of tumor-associated antigens from pooled allogeneic colon tumor tissue extracts. It was found to react against a variety of cultured human carcinoma cell lines and was highly reactive against the majority of tumor tissues from many different carcinomas, including colon, pancreatic, stomach, lung, and breast cancers. NEO-201 also exhibited tumor specificity, as the majority of normal tissues were not recognized by this antibody. Functional assays revealed that treatment with NEO-201 is capable of mediating both antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) against tumor cells. Furthermore, the growth of human pancreatic xenograft tumors in vivo was largely attenuated by treatment with NEO-201 both alone and in combination with human peripheral blood mononuclear cells as an effector cell source for ADCC. In vivo biodistribution studies in human tumor xenograft-bearing mice revealed that NEO-201 preferentially accumulates in the tumor but not organ tissue. Finally, a single-dose toxicity study in non-human primates demonstrated safety and tolerability of NEO-201, as a transient decrease in circulating neutrophils was the only related adverse effect observed. These findings indicate that NEO-201 warrants clinical testing as both a novel diagnostic and therapeutic agent for the treatment of a broad variety of carcinomas.