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

一种治疗突变型 KRas 胰腺癌的新型单体药物缀合物。

基本信息

批准号：
10666997
负责人：
DAFNA BAR-SAGI
金额：
$ 21万
依托单位：
TEZCAT LABORATORIES LLC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10666997
关键词：
Administrative Supplement Antibody-drug conjugates Attention Biological Assay Biological Products Biotechnology Cancer Control Characteristics Clinical Trials Data Development Event FDA approved Growth Health Immunotherapy In Vitro Laboratories Lead Malignant Neoplasms Malignant neoplasm of pancreas Metabolic New York Patients Pharmaceutical Preparations Phase Process Proteins Protocols documentation Research Personnel Safety Small Business Innovation Research Grant Small Business Technology Transfer Research Specificity Testing Therapeutic Toxic effect Universities austin base cancer cell cellular targeting clinically relevant commercialization cytotoxic drug candidate first-in-human in vivo innovation mouse model mutant nanomolar neoplastic cell novel pancreatic cancer cells pancreatic cancer model programs systemic toxicity tumor

项目摘要

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.

项目摘要：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，可治疗大多数疾病顽固性癌症，例如 KRas 突变型胰腺癌。作为定位的替代方案突变 KRas 本身，人们对针对因 KRas 突变而导致的细胞事件给予了很多关注。突变型 KRas。新的努力正在进行中，以利用以前未被识别的漏洞。我们观察到突变型 KRas 胰腺癌细胞表现出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带有 FDA 批准的细胞毒性有效负载的缀合物。体外和体内试验表明蛋白质-药物缀合物对突变 KRas 癌细胞表现出选择性，并维持低纳摩尔范围内的效力。蛋白质-药物缀合物表现出相对快速的全身性清除但保持生物制剂的有益特性，例如降低全身性毒性和肿瘤积累。因此，我们假设我们的新型缀合物将减少传统抗体药物偶联物经常出现的靶向和脱靶效应，填补了空白 KRas 突变型胰腺癌患者的治疗选择。我们提出了一个针对 TEZCAT 实验室和纽约大学研究人员的第一阶段 STTR 计划 Langone Health 将通过评估领导者能力的具体目标来推进这一领导者的发展控制胰腺癌小鼠模型中癌症生长的候选药物。我们进一步建议使用行政补充来 1）测试我们针对其他专有蛋白质的领先地位 - 利用相同作用机制的药物缀合物，以及 2) 测试我们的领先组合在临床上最相关的胰腺癌小鼠模型中进行免疫治疗。这商业化战略将基于确定先导药物的初步功效和无毒性第一阶段 STTR 研究中与突变 KRas 状态相关的化合物，进一步开发进入 II 期 SBIR 研究的 IND 状态，然后进行首次人体临床试验。因此，我们期望第一阶段 STTR 和行政补充文件为追求第二阶段的附加数据旨在 GMP 协议以及进一步的非 GLP 和 GLP 安全性和毒性研究。