Maximizing Antibody Drug Conjugate Efficacy through Multiple Mechanisms of Action

通过多种作用机制最大化抗体药物偶联物的功效

• 批准号: 10462003
• 负责人: Greg Thurber
• 金额: $ 31.82万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10462003
• 关键词: Alkylating Agents; Antibodies; Antibody-drug conjugates; Antigens; Bystander Effect; Cells; Chemistry; Clinical; Complex; Computer Simulation; DNA Damage; Development; Disease; Dose; Drug Transport; Drug or chemical Tissue Distribution; Engineering; Flow Cytometry; Goals; Gold; Growth; Image Cytometry; Immune; Immune system; Immunocompetent; Immunocompromised Host; Knowledge; Malignant Neoplasms; Measurement; Metabolism; Monoclonal Antibodies; Near-infrared optical imaging; Oncology; Outcome; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Play; Property; Receptor Signaling; Regimen; Research; Resolution; Role; Site; Solid Neoplasm; System; Testing; Trastuzumab; Whole Organism; Work; cancer therapy; clinical efficacy; design; drug action; imaging approach; improved; in vivo; molecular imaging; mouse model; next generation; novel; patient population; pharmacodynamic biomarker; preclinical efficacy; rational design; recruit; small molecule; success; tumor growth

Abstract The recent FDA approval of two more antibody drug conjugates (ADCs) highlights the clinical success and growth in this class of agents. Despite these approvals, however, the attrition rate for new ADCs remains high, and in oncology applications, no ADC for solid tumors has yet been able to repeat the success of ado- trastuzumab emtansine (T-DM1). A substantial effort has been exerted to improve the antibody and target selection, conjugation site, linker stability, and payload properties (potency, bystander effects, etc.), and these improvements will benefit the next generation of compounds. However, fundamental questions remain on how to design a clinically effective agent. Specifically, the relative contribution and interaction between the multiple mechanisms of action of these drugs (receptor signaling blockade, payload efficacy, and Fc effector functions) remains unknown. The long-term goal is to understand the fundamental properties of these complex drugs in sufficient detail to rationally combine the antibody, linker, and payload with a particular target (in a select patient population) for maximum clinical efficacy in both cancer and non-oncologic applications. The goal for this proposal is to quantitatively understand the relative contribution of direct payload effects in antigen positive cells, bystander payload effects in antigen negative cells, and the role of Fc-effector functions in determining efficacy with antibody drug conjugates. Using a combination of near-infrared fluorescence imaging and flow cytometry, the absolute number of intact and degraded (triggering payload release) ADCs per cell can be determined. By pairing these results with pharmacodynamic markers (e.g. DNA damage markers of alkylating agents), the delivery and efficacy of the ADC (both direct and bystander killing) can be quantified with single cell resolution in vivo. Co-administration of varying ratios of ADC with unconjugated antibody will be used to control the tissue distribution to vary direct versus indirect killing. The studies will be conducted in both an immunocompromised and immunocompetent (syngeneic) mouse model to determine the benefit (or requirement) for immune system activation. By comparing the single-cell measurements with the gold standard of preclinical efficacy (tumor growth curves), the relative contribution of each mechanism will be determined. The outcome of the work will enable the rational design of novel ADCs rather than testing the myriad combinations in vivo by focusing development on a) selection of targets with more uniform expression and ADC internalization if direct targeting predominates, b) optimal physicochemical properties and distribution of bystander payloads if bystander effects plays a major role, or c) activation and recruitment of immune cells through co-therapy, Fc engineering, and/or dosing regimens if immune cell recruitment is necessary. A significant number of monoclonal antibodies that failed as monotherapies are sitting dormant within pharmaceutical companies. By leveraging advances in payload and linker chemistry with the knowledge from this proposal, development of new clinically successful ADCs can be rapidly accelerated.

抽象的 FDA 最近批准了另外两种抗体药物偶联物 (ADC)，突显了其临床成功和 此类代理的增长。然而，尽管获得了这些批准，新 ADC 的流失率仍然很高， 在肿瘤学应用中，目前还没有针对实体瘤的 ADC 能够重复 ado- 曲妥珠单抗 emtansine (T-DM1)。我们付出了巨大的努力来改进抗体和靶标 选择、缀合位点、接头稳定性和有效负载特性（效力、旁观者效应等），以及这些 改进将有利于下一代化合物。然而，基本问题仍然是如何 设计临床有效的药物。具体来说，多重因素之间的相对贡献和相互作用 这些药物的作用机制（受体信号传导阻断、有效负载功效和 Fc 效应器功能） 仍然未知。长期目标是了解这些复杂药物的基本特性 足够的细节来合理地将抗体、接头和有效负载与特定靶标（在选择的 患者群体）以在癌症和非肿瘤应用中获得最大的临床疗效。目标为 该提案旨在定量了解抗原阳性中直接有效负载效应的相对贡献 细胞、抗原阴性细胞中的旁观者有效负载效应以及 Fc 效应器功能在确定中的作用 抗体药物缀合物的功效。结合使用近红外荧光成像和流动 通过细胞计数，每个细胞的完整和降解（触发有效负载释放）ADC 的绝对数量可以是 决定。通过将这些结果与药效标记物（例如烷基化的 DNA 损伤标记物）配对 剂），ADC 的传递和功效（直接杀伤和旁观者杀伤）可以用单个 体内细胞分辨率。不同比例的 ADC 与未缀合抗体的共同施用将用于 控制组织分布以改变直接杀伤和间接杀伤。这些研究将在两个国家和地区进行 免疫功能低下和免疫功能正常（同基因）小鼠模型以确定益处（或 要求）以激活免疫系统。通过将单细胞测量结果与金标准进行比较 根据临床前疗效（肿瘤生长曲线），将确定每种机制的相对贡献。 这项工作的成果将使新型 ADC 的合理设计成为可能，而不是测试无数的 ADC 体内组合，重点开发a）具有更均匀表达的靶标的选择和 如果直接靶向占主导地位，则 ADC 内化，b) 最佳理化特性和分布 旁观者有效载荷（如果旁观者效应起主要作用），或 c) 免疫细胞的激活和招募 如果需要免疫细胞募集，可以通过联合治疗、Fc 工程和/或剂量方案。一个 大量因单一疗法失败的单克隆抗体处于休眠状态 制药公司。通过利用有效负载和连接化学方面的进步以及来自 根据这一提议，可以迅速加速新的临床成功的 ADC 的开发。