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Development of Claudin MAbs for Treating Solid Tumors

用于治疗实体瘤的 Claudin MAb 的开发

基本信息

批准号：
10631161
负责人：
JOSEPH Benjamin RUCKER
金额：
$ 70.93万
依托单位：
INTEGRAL MOLECULAR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10631161
关键词：
Abbreviations Address Adverse effects Affinity American Amino Acids Antibodies Binding Biological Assay Biopsy Biosensor CD3 Antigens CD34 gene Cancer cell line Cell model Cessation of life Clinic Clinical Data Development Drug Kinetics Endometrial Carcinoma Engineering Exhibits Failure Family member Funding Future Human In Vitro Integral Membrane Protein Isoelectric Point Lead Malignant neoplasm of lung Malignant neoplasm of ovary Malignant neoplasm of pancreas Malignant neoplasm of testis Mass Spectrum Analysis Mediating Membrane Membrane Proteins Modeling Monoclonal Antibodies Mus Patients Peripheral Blood Mononuclear Cell Persons Pharmaceutical Preparations Proteins Proteome Public Health Risk Risk Assessment Safety Small Business Innovation Research Grant Solid Neoplasm Specificity T cell infiltration T-Cell Activation T-Cell Proliferation T-Lymphocyte Temperature Testing Therapeutic Therapeutic Monoclonal Antibodies Tight Junctions Time Tissues Toxic effect Tumor Volume Viscosity Work Xenograft Model Xenograft procedure biopharmaceutical industry cancer cell cancer type candidate selection cell killing claudin 6 clinical development clinical efficacy cytokine cytokine release syndrome differential expression effective therapy efficacy testing experimental study extracellular human disease humanized mouse in vivo light scattering malignant stomach neoplasm manufacture melting neoplastic cell ovarian neoplasm overexpression pre-clinical stem cells therapeutic target therapeutically effective timeline tumor

项目摘要

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.

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。