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

项目概述：多发性骨髓瘤是一种无法治愈的血液恶性肿瘤， 中位生存期7-8年。蛋白酶体抑制剂，硼替佐米，卡非佐米和最近的 批准的ixazomib是目前骨髓瘤治疗的支柱。尽管最初的回复率 接近90%的患者接受含蛋白酶体转运蛋白的组合治疗后，所有患者均复发， 最终会对任何治疗产生抗药性。大约50%的患者 突变的NRas或KRas。我们已经观察到突变型Ras多发性骨髓瘤细胞显示出高表达， 水平的巨胞饮作用，一种营养清除过程，促进大量吞噬 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载荷（vc-1）的靶向巨胞饮的单体。 MMAE）。体外增殖测定表明，单抗体-药物缀合物显示出 对巨胞饮阳性癌细胞的选择性，并在低纳摩尔浓度下保持效力 范围基于单抗体的技术在人体中显示出快速的清除率（1- 2小时），但维持 生物制剂的有益特性，例如通过增强的渗透性的肿瘤积聚 和保留（EPR）效应。因此，我们假设我们的新型巨胞饮靶向 单抗体-药物缀合物将减少传统药物缀合物中常见的靶向和脱靶效应。 抗体-药物缀合物，并填补了突变Ras患者的治疗选择的空白 多发性骨髓瘤我们为TEZCAT的研究人员提出了第一阶段STTR计划 实验室和纽约大学Langone Health通过Specific Aims推进这一领先地位 该研究评估了体外控制人类癌细胞生长的主要候选药物（目标1）， 在多发性骨髓瘤的临床相关小鼠模型中（目的2和3）。TEZCAT实验室拥有 与纽约大学签订了一项选择权协议，以获得该技术的独家权利， 开发商业化策略将基于建立初始疗效， I期STTR中先导化合物与细胞巨胞饮水平相关的无毒性 研究，在II期SBIR研究中进一步发展为IND状态，然后首次用于人体 临床试验因此，我们希望第一阶段STTR为追求更多的数据提供基础， II期旨在GMP方案和进一步的非GLP和GLP安全性和毒性研究。

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.