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

JOC-x：打开肿瘤紧密连接以治疗癌症的化疗结合物

• 批准号: 10020907
• 负责人: DARRICK Albert CARTER
• 金额: $ 55.66万
• 依托单位: PAI LIFE SCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-20 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020907
• 关键词: Agonist; Animal Model; Back; Binding; Binding Proteins; Biological; Cancer Model; Carcinoma; Chromatography; Clinical; Coupled; Cyclic GMP; Cysteine; Data; Development; Dose; Doxorubicin Hydrochloride Liposome; Drug resistance; Ensure; Epithelial; Epithelium; Fermentation; Human; Image; Immune Targeting; Immunocompetent; Immunotherapy; Intravenous; Maintenance; Malignant Neoplasms; Malignant neoplasm of ovary; Methodology; Modeling; Monoclonal Antibodies; Mus; Normal tissue morphology; Oncolytic viruses; Particle Size; Patients; Penetration; Pharmaceutical Preparations; Phase; Poly I-C; Polymers; Process; Production; Proteins; Publishing; Recombinant Proteins; Records; Reproducibility; Research; Seeds; Serine; Signal Pathway; Site; Sterically Stabilized Liposome; T cell therapy; TLR3 gene; Testing; Therapeutic; Therapeutic Effect; Tight Junctions; Toxic effect; Transgenic Mice; Treatment Efficacy; Tumor Tissue; Work; Writing; Xenograft Model; Xenograft procedure; cancer cell; cancer imaging; cancer therapy; cancer type; chemotherapy; desmoglein 2; epithelial to mesenchymal transition; flexibility; global health; in vivo; in vivo evaluation; intravenous injection; lipid nanoparticle; nonhuman primate; overexpression; phase 1 study; prevent; research clinical testing; scale up; tumor; tumor microenvironment

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.

项目摘要 肿瘤耐药性的中心机制是维持细胞间的紧密连接， 恶性细胞阻止分子渗透到肿瘤微环境中。我们有 产生的连接开放器（“JO”）是结合桥粒芯糖蛋白2（DSG 2）的小蛋白， 在许多癌症中过度表达的连接蛋白。静脉注射JO增加 肿瘤渗透和许多类型的癌症治疗的功效。我们的研究表明， 当药物与JO组合时，可以减少化疗的有效剂量。JO 在肿瘤组织中的积累是正常组织的100倍， 肿瘤的机制我们亦曾公布，联合办事处的申请并没有与 在hDSG 2转基因小鼠中具有毒性，并且联合施用JO和化疗 在非人类灵长类动物中耐受性良好。 在第一阶段，我们能够证明：（1）我们可以为许多癌症制备JOC-x缀合物， 治疗和成像应用;和（2）JOC-x构建体在肿瘤中保持其活性 模型我们现在有动力在第1阶段产生的有希望的数据的基础上继续前进， 通过以下步骤将这些偶联物用于临床测试：（1）制备用于符合cGMP的生产的JOC-x 通过工艺开发、规模化和编写生产批记录;（2）生产JOC-x 具有不同功能的缀合物，以证明平台的实用性和灵活性;和（3） 在动物模型中测试这些JOC-x缀合物 在这里提出的研究的结论，我们将产生一个可接合的肿瘤紧 结开口候选物，其可用于多个实施例中。每个产品 可以成为独立的治疗方法，并向临床试验发展。