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

• 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
• 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

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性恶性肿瘤 中位生存期7 - 8年。蛋白酶体抑制剂，硼替佐米，carfilzomib和最近 经批准的ixazomib是当前骨髓瘤治疗的中流。尽管有初始答复率 接近90％的蛋白酶体抑制剂组合，所有患者复发和 最终会抵抗任何治疗。这些患者中约有50％ 突变的nras或kras。我们已经观察到突变的RAS多发性骨髓瘤细胞显示高 大型细胞增多症的水平，这是一种营养清除过程，促进了批量吞噬 细胞外流体及其溶质。利用这种代谢适应，我们创造了 含有FDA批准的细胞毒性有效载荷的大型细胞增生靶向单体形成（VC- MMAE）。体外增殖测定表明，单体毒物结合物显示 大胞症阳性癌细胞的选择性，并保持低纳莫尔的效力 范围。基于单体的技术显示人类（1-2HR）的快速清除率，但保持 生物制剂的有益特征，例如通过增强的渗透性积累 和保留（EPR）效应。因此，我们假设我们的新型大型细胞增多症靶向 单手毒物偶联物将减少靶向和脱离目标的效果 抗体 - 药物结合物，并为突变RAS患者填充治疗选择 多发性骨髓瘤。我们为Tezcat的调查人员提出了I阶段ISTTR计划 实验室和纽约大学Langone Health通过特定目标推进这一领先 在控制人类癌细胞生长的体外（AIM 1）和 在多发性骨髓瘤的临床上与临床相关的小鼠模型中（AIM 2和3）。 Tezcat实验室拥有 与NYU签订了期权协议，以获得该技术的专有权 发达。商业化策略将基于建立初始功效和 铅化合物在I期STTR中与细胞大型细胞增生水平相关的无毒性 研究，进一步发展II阶段SBIR研究，然后是人类的第一阶段 临床试验。因此，我们希望I阶段ISTTR为追求其他数据提供基础 II期针对GMP方案以及进一步的非GLP和GLP安全性和毒性研究。