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

项目概述：TEZCAT Laboratories LLC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 胰腺癌，如突变型KRas胰腺癌。作为瞄准目标的替代方法， 突变KRas本身，已经将很多注意力放在靶向细胞事件上， 突变型KRas。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KRas胰腺癌细胞显示高水平的蛋白质 清除过程利用这种代谢适应，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缀合物。体外和体内试验证明， 蛋白质-药物缀合物显示出对突变KRas癌细胞的选择性， 在低纳摩尔范围内的效力。蛋白质-药物缀合物显示相对快速的系统性 清除，但保持生物制剂的有益特性，如降低全身 毒性和肿瘤蓄积。因此，我们假设我们的新型缀合物将减少 靶向和脱靶效应通常见于传统的抗体-药物偶联物， 突变型KRas胰腺癌患者的治疗选择。我们提出了一种 TEZCAT实验室和纽约大学研究人员的第一阶段STTR计划 Langone Health将通过评估潜在客户能力的特定目标来推进该潜在客户 在胰腺癌小鼠模型中控制癌症生长的候选药物。我们进一步 建议使用行政补充1）测试我们的铅对其他专有蛋白质- 利用相同作用机制的药物缀合物，和2）测试我们的组合中的领先者 在临床上最相关的胰腺癌小鼠模型中进行免疫治疗。的 商业化策略将基于确立铅的初始有效性和无毒性 I期STTR研究中与突变型KRas状态相关的化合物，进一步开发 在II期SBIR研究中获得IND地位，然后进行首次人体临床试验。因此我们 预计第一阶段STTR和行政补充文件将为实现以下目标提供基础： II期研究中旨在GMP方案和进一步非GLP和GLP安全性的其他数据， 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.