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.

项目摘要：Tezcat Laboratories LLC是一个早期的，位于奥斯汀的生物技术公司开发新颖的生物制剂，具有独特的行动机制来治疗最多顽固的癌症，例如突变的KRAS胰腺癌。作为定位的替代方案突变的Kras本身，已经非常关注针对蜂窝事件的结果突变克拉斯。正在进行新的努力，以利用先前未知的漏洞。我们已经观察到突变的KRAS胰腺癌细胞显示高水平的蛋白清除过程。利用这种代谢适应，我们创建了蛋白质 - 药物结合携带FDA批准的细胞毒性有效载荷的结合物。体外和体内测定证明蛋白质 - 药物缀合物显示出突变的KRAS癌细胞的选择性，并维持低纳摩尔范围内的效力。蛋白质 - 药物缀合物显示出相对快速的全身性清除但保持生物制剂的有益特征，例如系统性降低毒性和肿瘤积累。因此，我们假设我们的新型偶联将减少靶向和脱靶效果经常与传统的抗体 - 药物缀合物见面并填充无效突变KRAS胰腺癌患者的治疗选择。我们提出了第一阶段 Tezcat Laboratories和New York University Langone的调查人员的STTR计划健康通过特定目标来促进这一领先在胰腺癌的临床小鼠模型中控制人类癌细胞的生长。 Tezcat Laboratories正在与NYU合作，以促进许可基础知识分子涵盖正在开发的技术的物业。商业化策略将基于建立铅化合物与突变体KRAS相关的初始功效和无毒性 I期STTR研究中的状态，进一步发展II II期SBIR研究中的IND状态，然后是人类的第一个临床试验。因此，我们期望I阶段ISTTR为针对GMP方案以及进一步的非GLP和GLP安全的II阶段中的其他数据和毒性研究。