A novel monobody-drug conjugate to treat mutant KRas pancreatic cancer.

项目摘要：TEZCAT实验室有限责任公司是一家位于奥斯汀的早期生物技术公司 公司开发具有独特作用机制的新型生物制剂，以治疗大多数 顽固性癌症，如突变的KRAS胰腺癌。作为目标的替代方案 突变的KRAS本身，人们已经非常关注靶向细胞事件，这些事件是由 突变的KRAS。目前正在进行新的努力，以利用以前未被识别的漏洞。我们 已经观察到突变的KRAS胰腺癌细胞显示出高水平的蛋白质 拾荒过程。利用这种新陈代谢适应，我们创造了蛋白质药物 携带FDA批准的细胞毒性有效载荷的结合物。体外和体内测试表明 蛋白质-药物结合物对突变的KRAS癌细胞显示出选择性，并保持 在低纳摩尔范围内的效力。蛋白质-药物结合物表现出较快的系统性 清除，但保持生物制剂的有益特性，如降低系统性 毒性和肿瘤堆积。因此，我们假设我们的新型共轭化合物将减少 靶上和靶外效应通常见于传统的抗体-药物结合物，填补了一个空白 突变的KRAS胰腺癌患者的治疗方案。我们已经提出了一个 为TEZCAT实验室和纽约大学的研究人员提供的第一阶段STTR计划 朗格内健康公司通过评估领导能力的具体目标来推进这一领导 在胰腺癌小鼠模型中控制肿瘤生长的候选药物。我们进一步 建议使用行政副刊1)测试我们相对于其他专利蛋白质的领先地位- 使用相同作用机制的药物结合物，以及2)组合测试我们的领先优势 在临床上最相关的胰腺癌小鼠模型中进行免疫治疗。这个 商业化战略将建立在确定铅的初步疗效和无毒基础上 与突变KRAS状态有关的化合物在第一阶段STTR研究中的进一步发展 在第二阶段SBIR研究中走向IND状态，然后是第一次人体临床试验。因此，我们 预计第一阶段STR和行政补编将为以下工作提供基础 第二阶段的其他数据针对GMP协议和其他非GLP和GLP安全和 毒性研究。

Project Summary: TEZCAT Laboratories LLC is an early-stage, Austin-based biotechnology company developing novel biologics with a unique mechanism of action to treat the most recalcitrant cancers, such as mutant KRas pancreatic cancer. As an alternative to targeting mutant KRas itself, much attention has been paid to targeting cellular events that are a result of mutant KRas. New efforts are underway to exploit previously unrecognized vulnerabilities. We have observed that mutant KRas pancreatic cancer cells display high levels of a protein scavenging process. Harnessing this metabolic adaptation, we have created protein-drug conjugates that carry an FDA-approved cytotoxic payload. In vitro and in vivo assays demonstrate that the protein-drug conjugates show selectivity for mutant KRas cancer cells and maintain potency in the low nanomolar range. The protein-drug conjugates display relatively fast systemic clearance but maintain beneficial characteristics of biologics such as decreased systemic toxicities and tumor accumulation. Thus, we hypothesize that our novel conjugates will reduce on-target and off-target effects often seen with traditional antibody-drug conjugates and fill a void of therapeutic options for patients with mutant KRas pancreatic cancer. We have proposed a Phase I STTR program for investigators at TEZCAT Laboratories and New York University Langone Health to advance this lead through Specific Aims that evaluate the ability of the lead drug candidate to control cancer growth in mouse models of pancreatic cancer. We further propose to use an Administrative Supplement to 1) test our lead against other proprietary protein- drug conjugates that utilize the same mechanism of action, and 2) test our lead in combination with immunotherapy in the most clinically-relevant mouse model of pancreatic cancer. The commercialization strategy will be based on establishing initial efficacy and nontoxicity of the lead compound in relation to mutant KRas status in Phase I STTR studies, further development towards IND status in Phase II SBIR studies, and then first-in-human clinical trials. Thus, we expect Phase I STTR and the Administrative Supplement to provide the basis for pursuit of additional data in Phase II aimed at GMP protocols and further non-GLP and GLP safety and toxicity studies.