JOC-x: Chemotherapy conjugates that open tumor tight junctions to treat cancer

项目总结 肿瘤耐药的一个核心机制是维持 恶性细胞阻止分子穿透肿瘤微环境。我们有 生成的连接开放蛋白(JO)是一种与桥粒芯糖蛋白2(DSG2)结合的小蛋白，a 在许多癌症中过度表达的连接蛋白。静脉注射JO增加 肿瘤的渗透性和多种癌症治疗方法的疗效。我们的研究表明， 当药物与JO联合使用时，化疗有效剂量可以减少。乔 在肿瘤组织中的积聚是正常组织的100倍，使其成为靶点 肿瘤的机制。我们还发布了JO的申请尚未关联 在hDSG2转基因小鼠中的毒性以及联合应用JO和化疗 在非人类灵长类动物中被很好地耐受。 在第一阶段，我们能够证明：(1)我们可以制造JOC-x结合物来治疗一些癌症 治疗和成像应用；以及(2)JOC-x结构在肿瘤中保持其活性 模特们。我们现在有动力在阶段1中生成的有前景的数据的基础上进行构建并采取行动 这些结合物用于临床试验：(1)为cGMP顺应性生产准备JOC-x 通过工艺开发、规模调整和编写生产批次记录；(2)生产JOC-x 与不同的功能相结合，以展示平台的实用性和灵活性；以及 在动物模型中测试这些JOC-x结合物 在这里提出的研究的结论中，我们将产生一种可结合的肿瘤 可以在多个实施例中使用的结开放候选。每一种产品 可以成为独立的治疗方法，并向临床试验发展。

PROJECT SUMMARY A central mechanism of tumor drug resistance is the maintenance of tight junctions between malignant cells preventing penetration of molecules into the tumor microenvironment. We have generated junction openers (“JO”) that are small proteins that bind to desmoglein 2 (DSG2), a junction protein that is overexpressed in many cancers. Intravenous injection of JO increases tumor penetration and efficacy of many types of cancer therapy. Our studies have shown that the effective doses of chemotherapy can be reduced when the drugs are combined with JO. JO accumulates in tumor tissue as much as 100-fold above normal tissues making it a targeting mechanism to tumors. We have also published that application of JO has not been associated with toxicities in hDSG2 transgenic mice and that the co-administration of JO and chemotherapy was well tolerated in non-human primates. In phase 1 we were able to show that: (1) we can make JOC-x conjugates for a number of cancer treatment and imaging applications; and (2) that the JOC-x constructs retain their activity in tumor models. We now are motivated to build on the promising data generated in phase 1 and move these conjugates towards clinical testing by: (1) Preparing JOC-x for cGMP compliant production by process development, scaling, and writing manufacturing batch records; (2) Producing JOC-x conjugates with distinct functionalities to demonstrate utility and flexibility of the platform; and (3) Testing these JOC-x conjugates in animal models At the conclusion of the research proposed here we will have produced a conjugatable tumor tight junction opening candidate that can be used in a number of embodiments. Each of the products could become stand-alone therapeutics and be developed towards clinical testing.