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。我们建议第一阶段 TEZCAT实验室和纽约大学Langone研究人员的STTR计划 卫生部通过评估以下领域的主要候选药物的具体目标来推进这一领先地位： 在胰腺癌的临床相关小鼠模型中控制人癌细胞生长。 TEZCAT实验室正在与纽约大学合作， 包括正在开发的技术。商业化战略将基于 确定先导化合物对突变型KRas的初始有效性和无毒性 I期STTR研究的状态，II期SBIR研究中IND状态的进一步发展， 然后进行首次人体临床试验。因此，我们预计第一阶段STTR将为 在II期研究中寻求旨在GMP方案和进一步的非GLP和GLP安全性的额外数据 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 propose 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 lead drug candidates in controlling human cancer cell growth in a clinically-relevant mouse model of pancreatic cancer. TEZCAT Laboratories is working with NYU to facilitate licensing the underlying intellectual property covering the technology being developed. 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 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.