A novel monobody-drug conjugate to treat mutant Ras multiple myeloma

一种治疗突变 Ras 多发性骨髓瘤的新型单体药物偶联物

基本信息

批准号：
10080987
负责人：
DAFNA BAR-SAGI
金额：
$ 39.99万
依托单位：
TEZCAT LABORATORIES LLC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10080987
关键词：
Agreement Antibody-drug conjugates Binding Proteins Biodistribution Biologic Characteristic Biological Biological Assay Biotechnology Bone Tissue Bortezomib Cancer Cell Growth Cell Line Cells Characteristics Clinic Clinical Trials Colorectal Cancer Data Development Dose Drug Compounding Drug Delivery Systems Equus caballus Evaluation Extracellular Fluid Extracellular Protein FDA approved Fibronectins Government Growth Health Hematologic Neoplasms Human In Vitro Incidence Injections Knowledge Laboratories Lead Liquid substance Lytic Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of pancreas Marrow Metabolic Metabolic Clearance Rate Microscopy Modeling Monitor Morbidity - disease rate Multiple Myeloma New York Nutrient Organ Oryctolagus cuniculus Osteogenesis Patients Penetration Permeability Persons Pharmaceutical Preparations Pharmacotherapy Phase Preclinical Testing Process Proteasome Inhibitor Proteins Protocols documentation Research Personnel Resistance Resources Rights SCID Mice Safety Small Business Innovation Research Grant Small Business Technology Transfer Research Solubility Specificity Tail Technology Testing Therapeutic Tissues Toxic effect Toxicology Treatment Efficacy Tumor Burden Universities Validation Veins base cancer cell clinically relevant commercialization cyanine dye 5 cytotoxic cytotoxicity drug candidate efficacy testing expectation experience first-in-human implantation in vivo innovation mortality mouse model mutant nanomolar neoplastic cell novel novel drug class novel therapeutics programs ras Oncogene relapse patients response solute subcutaneous therapeutic development tumor validation studies

项目摘要

Project Summary: Multiple myeloma is an incurable hematologic malignancy with an expected median survival of 7-8 years. The proteasome inhibitors, bortezomib, carfilzomib and the recently approved ixazomib, are a mainstay of current myeloma treatment. Despite an initial response rate approaching 90% to proteasome inhibitor-containing combinations, all patients relapse and eventually become resistant to any treatments. Approximately 50% of these patients harbor mutant NRas or KRas. We have observed that mutant Ras multiple myeloma cells display high levels of macropinocytosis, a nutrient scavenging process that facilitates the bulk engulfment of extracellular fluid and its solutes. Harnessing this metabolic adaptation, we have created macropinocytosis-targeting monobodies that carry an FDA-approved cytotoxic payload (vc- MMAE). In vitro proliferation assays demonstrate that the monobody-drug conjugates show selectivity for macropinocytosis-positive cancer cells, and maintain potency in the low nanomolar range. Monobody-based technologies display fast clearance rates in humans (1-2hr), but maintain beneficial characteristics of biologics such as tumor accumulation through enhanced permeability and retention (EPR) effect. Thus, we hypothesize that our novel macropinocytosis-targeting monobody-drug 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 Ras multiple myeloma. 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 candidate in controlling human cancer cell growth in vitro (Aim 1) and in a clinically-relevant mouse model of multiple myeloma (Aim 2 & 3). TEZCAT Laboratories has entered into an Option Agreement with NYU for exclusive rights to the technology being developed. The commercialization strategy will be based on establishing initial efficacy and nontoxicity of the lead compound in relation to cellular macropinocytosis levels 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：多发性骨髓瘤是一种无法治愈的血液恶性肿瘤，其预期发病率中位生存期为 7-8 年。蛋白酶体抑制剂硼替佐米、卡非佐米以及最近出现的批准的伊沙佐米是当前骨髓瘤治疗的支柱。尽管最初的反应率接近 90% 的患者使用含有蛋白酶体抑制剂的组合，所有患者都会复发最终对任何治疗产生耐药性。大约 50% 的患者患有突变型 NRas 或 KRas。我们观察到突变型 Ras 多发性骨髓瘤细胞表现出高巨胞饮作用的水平，这是一种营养物清除过程，有助于大量吞噬细胞外液及其溶质。利用这种代谢适应，我们创造了携带 FDA 批准的细胞毒性有效负载的巨胞饮靶向单体 (vc- MMAE）。体外增殖测定表明单体-药物缀合物显示对巨胞饮阳性癌细胞具有选择性，并在低纳摩尔浓度下保持效力范围。基于单体的技术在人类中显示出快速的清除率（1-2小时），但仍保持生物制品的有益特性，例如通过增强渗透性实现肿瘤积累和保留（EPR）效应。因此，我们假设我们的新型巨胞饮作用靶向单体药物偶联物将减少传统药物中常见的靶向和脱靶效应抗体-药物偶联物，并填补 Ras 突变患者治疗选择的空白多发性骨髓瘤。我们为 TEZCAT 的研究人员提出第一阶段 STTR 计划实验室和纽约大学朗格健康中心通过具体目标推进这一领先地位评估在体外控制人类癌细胞生长的主要候选药物（目标 1）和在临床相关的多发性骨髓瘤小鼠模型中（目标 2 和 3）。 TEZCAT 实验室有与纽约大学签订了一份期权协议，获得该技术的独家权利发达。商业化战略将基于建立初步功效和第一阶段 STTR 中先导化合物与细胞巨胞饮水平相关的无毒性研究，进一步发展 II 期 SBIR 研究中的 IND 状态，然后是首次用于人体临床试验。因此，我们预计第一阶段 STTR 将为寻求更多数据提供基础第二阶段旨在进行 GMP 协议以及进一步的非 GLP 和 GLP 安全性和毒性研究。