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Monoclonal Antibody Targeting Sialyl-di-Lewisa - Containing Internalizing and non-Internalizing Glycoproteins with Cancer Immunotherapy Development Potential
Molecular Cancer Therapeutics ( IF 5.7 ) Pub Date : 2019-12-23 , DOI: 10.1158/1535-7163.mct-19-0221
Silvana T Tivadar 1 , Richard S McIntosh 1 , Jia Xin Chua 2 , Robert Moss 1 , Tina Parsons 2 , Abed M Zaitoun 3 , Srinivasan Madhusudan 1 , Lindy G Durrant 1, 2 , Mireille Vankemmelbeke 2
Affiliation  

Tumor glycans constitute attractive targets for therapeutic antibodies. The sialylated glycocalyx plays a prominent role in cancer progression and immune evasion. Here, we describe the characterization of the mAb, FG129, which targets tumor-associated sialylated glycan, and demonstrate its potential for multimodal cancer therapy. FG129, obtained through BALB/c mouse immunizations with liposomes containing membrane glycan extracts from the colorectal cancer cell line LS180, is an mIgG1κ that targets sialyl-di-Lewisa–containing glycoproteins. FG129, as well as its chimeric human IgG1 variant, CH129, binds with nanomolar functional affinity to a range of colorectal, pancreatic, and gastric cancer cell lines. FG129 targets 74% (135/182) of pancreatic, 50% (46/92) of gastric, 36% (100/281) of colorectal, 27% (89/327) of ovarian, and 21% (42/201) of non–small cell lung cancers, by IHC. In our pancreatic cancer cohort, high FG129 glyco-epitope expression was significantly associated with poor prognosis (P = 0.004). Crucially, the glyco-epitope displays limited normal tissue distribution, with FG129 binding weakly to a small percentage of cells within gallbladder, ileum, liver, esophagus, pancreas, and thyroid tissues. Owing to glyco-epitope internalization, we validated payload delivery by CH129 through monomethyl auristatin E (MMAE) or maytansinoid (DM1 and DM4) conjugation. All three CH129 drug conjugates killed high-binding colorectal and pancreatic cancer cell lines with (sub)nanomolar potency, coinciding with significant in vivo xenograft tumor control by CH129-vcMMAE. CH129, with its restricted normal tissue distribution, avid tumor binding, and efficient payload delivery, is a promising candidate for the treatment of sialyl-di-Lewisa–expressing solid tumors, as an antibody–drug conjugate or as an alternative cancer immunotherapy modality.

中文翻译:

靶向唾液酸二刘易斯的单克隆抗体 - 含有内化和非内化糖蛋白,具有癌症免疫治疗发展潜力

肿瘤聚糖构成治疗性抗体的有吸引力的靶标。唾液酸化的糖萼在癌症进展和免疫逃避中起着重要作用。在这里,我们描述了靶向肿瘤相关唾液酸化聚糖的 mAb FG129 的表征,并展示了其在多模式癌症治疗中的潜力。FG129 通过使用含有来自结肠直肠癌细胞系 LS180 的膜聚糖提取物的脂质体对 BALB/c 小鼠进行免疫接种获得,它是一种 mIgG1κ,靶向含有唾液酸二刘易萨的糖蛋白。FG129 及其嵌合人 IgG1 变体 CH129 以纳摩尔的功能亲和力与一系列结肠直肠癌细胞系、胰腺癌细胞系和胃癌细胞系结合。FG129 靶向 74% (135/182) 的胰腺、50% (46/92) 的胃、36% (100/281) 的结直肠、27% (89/327) 的卵巢、和 21% (42/201) 的非小细胞肺癌,通过 IHC。在我们的胰腺癌队列中,高 FG129 糖表位表达与不良预后显着相关(P = 0.004)。至关重要的是,糖表位显示出有限的正常组织分布,FG129 与胆囊、回肠、肝脏、食道、胰腺和甲状腺组织内的一小部分细胞微弱结合。由于糖表位内化,我们验证了 CH129 通过单甲基 auristatin E (MMAE) 或美登木素 (DM1 和 DM4) 偶联来传递有效载荷。所有三种 CH129 药物偶联物均以(亚)纳摩尔效力杀死高结合性结肠直肠和胰腺癌细胞系,这与 CH129-vcMMAE 对体内异种移植肿瘤的显着控制一致。CH129,由于其正常组织分布受限,与肿瘤结合强烈,
更新日期:2019-12-23
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