Development of Claudin MAbs for Treating Solid Tumors

摘要 在美国，实体瘤每年导致580，000人死亡，而对于许多晚期肿瘤， 阶段性实体瘤缺乏。仅卵巢癌每年就导致14，000人死亡，许多患者没有 对目前可用的治疗方法作出反应。紧密连接蛋白Claudin 6（CLDN6）是一种经过验证的 许多实体瘤类型的治疗靶点，包括卵巢、子宫内膜、睾丸、胃和胰腺 癌CLDN6在癌细胞上差异表达，在正常健康组织中几乎不表达。 尽管是一个有吸引力的靶标，但由于CLDN6的免疫缺陷，靶向CLDN6的治疗性MAb难以发现。 绝对需要高特异性。总共有26个人CLDN家族成员，并且大多数广泛分布于 表达和高度保守，使得靶向CLDN时的药物特异性至关重要， 特别具有挑战性。CLDN6的胞外区与广泛表达的CLDN9非常相似（3 氨基酸不同）。由其他人发现的少数CLDN6 MAb已经证明与CLDN6的显著结合。 其他CLDN家族成员和大多数现在已经停止发展。在这里，我们将开发一个CLDN6 用于实体瘤的治疗剂。

ABSTRACT Solid tumors lead to 580,000 deaths annually in the US, and safe and effective therapeutics for many late- stage solid tumors are lacking. Ovarian cancer alone kills 14,000 people each year, and many patients do not respond to currently available treatments. The tight junction protein Claudin 6 (CLDN6) is a validated therapeutic target for many solid tumor types, including ovarian, endometrial, testicular, gastric, and pancreatic cancer. CLDN6 is differentially expressed on cancer cells with almost no expression in normal, healthy tissue. Despite being an attractive target, therapeutic MAbs targeting CLDN6 are difficult to discover due to an absolute need for high specificity. There are 26 human CLDN family members in total and most are broadly expressed and highly conserved, making drug specificity when targeting the CLDNs critically important but especially challenging. The extracellular region of CLDN6 closely resemble the widely expressed CLDN9 (3 amino acids different). The few CLDN6 MAbs discovered by others have demonstrated significant binding to other CLDN family members and most have now been halted in development. Here, we will develop a CLDN6 therapeutic for solid tumors.