Development of Claudin MAbs for Treating Solid Tumors

摘要 在美国，实体肿瘤每年导致58万人死亡，对许多晚期患者来说，安全有效的治疗方法- 缺乏分期的实体瘤。仅卵巢癌每年就导致1.4万人死亡，而许多患者并不是这样 对目前可用的治疗方法做出反应。紧密连接蛋白Claudin 6(CLDN6)是一种有效的 多种实体肿瘤的治疗靶点，包括卵巢、子宫内膜、睾丸、胃和胰腺 癌症。CLDN6在癌细胞上差异表达，而在正常健康组织中几乎不表达。 尽管是一个有吸引力的靶点，但针对CLDN6的治疗性单抗很难发现，因为 绝对需要高度的特异性。总共有26个人类CLDN家族成员，其中大多数是广泛的 表达并高度保守，使得靶向CLDN时的药物特异性至关重要，但 尤其具有挑战性。CLDN6的胞外区与广泛表达的CLDN9(3 氨基酸不同)。其他人发现的为数不多的CLDN6单抗已证明与 CLDN家族的其他成员和大多数人现在已经停止了开发。在这里，我们将开发一款CLDN6 治疗实体肿瘤。

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.