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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：
10323748
负责人：
DAFNA BAR-SAGI
金额：
$ 39.87万
依托单位：
TEZCAT LABORATORIES LLC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10323748
关键词：
Address Antibody-drug conjugates Apoptosis Attention Biologic Characteristic Biological Biological Assay Biotechnology Blood Vessels Cancer Cell Growth Cancer cell line Cell Line Characteristics Clinic Clinical Trials Data Dendritic Cells Development Disease Dose Drug Delivery Systems Endothelium Equus caballus Evaluation Event Extracellular Protein FDA approved Fibronectins Future Government Health Human In Vitro Incidence Intellectual Property KPC model Knowledge Laboratories Lead Lesion Licensing Liposomes Liquid substance Lung Malignant Neoplasms Malignant neoplasm of pancreas Maximum Tolerated Dose Metabolic Metastatic Neoplasm to the Liver Morbidity - disease rate Nature Neoplasm Metastasis New York Normal Cell Oncogenes Paclitaxel Pancreatic Ductal Adenocarcinoma Patients Penetration Persons Pharmaceutical Preparations Phase Preclinical Testing Process Proteins Protocols documentation Renal function Research Personnel Resources Safety Serum Small Business Innovation Research Grant Small Business Technology Transfer Research Solubility Specificity Technology Therapeutic Tissues Toxic effect Universities Xenograft procedure austin base cancer cell cancer type cellular targeting clinically relevant commercialization companion diagnostics cytotoxic drug candidate efficacy study expectation experience first-in-human improved in vivo in vivo Model innovation irinotecan liver function macrophage mortality mouse model mutant nanomolar nanoparticle neoplastic cell neutrophil novel novel therapeutics pancreatic cancer cells pancreatic cancer model pancreatic ductal adenocarcinoma model premalignant programs standard of care synthetic protein systemic toxicity therapeutic development therapeutically effective tumor tumor progression validation studies

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 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.

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。新的努力正在进行中，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。体外和体内试验表明蛋白质-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。