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: 10225412
• 负责人: Greg Thurber
• 金额: $ 32.62万
• 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/10225412
• 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; 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.

摘要 FDA最近又批准了两种抗体药物结合物(ADC)，这突显了临床上的成功和 这类代理商的增长。然而，尽管获得了这些批准，新的ADC的流失率仍然很高。 在肿瘤学应用中，还没有实体肿瘤的ADC能够复制ADO的成功- 曲妥珠单抗(T-DM1)。已经付出了大量的努力来改进抗体和靶标 选择、结合部位、连接子稳定性和有效负载属性(效价、旁观者效应等)，以及这些 改进将使下一代化合物受益。然而，根本性的问题仍然是如何 设计一种临床有效的药物。具体地说，多种因素之间的相对贡献和相互作用 这些药物的作用机制(受体信号阻断、有效载荷效应和Fc效应功能) 仍然不为人知。长期目标是了解这些复杂药物的基本性质 足够的细节来合理地将抗体、连接物和有效载荷与特定的靶点结合(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。的目标是 这一建议是为了定量地了解直接有效载荷效应在抗原阳性中的相对贡献。 细胞，抗原阴性细胞中的旁观者有效载荷效应，以及Fc效应功能在决定 与抗体药物结合物的疗效。使用近红外荧光成像和流动相结合 细胞计数，每个细胞的完整和降解(触发有效载荷释放)ADC的绝对数 下定决心。通过将这些结果与药效学标记物(例如，烷基化的DNA损伤标记物)配对 药物)，ADC的投放和效果(包括直接和旁观者杀死)可以用单一的 体内细胞分辨率。不同比例的ADC与非结合抗体联合给药将用于 控制组织分布以改变直接致死和间接致死。研究将在两个国家和地区进行 免疫低下和免疫活性(同基因)小鼠模型以确定益处(或 要求)用于激活免疫系统。通过将单细胞测量与黄金标准进行比较 对于临床前疗效(肿瘤生长曲线)，将确定每种机制的相对贡献。 这项工作的结果将使新型ADC的合理设计成为可能，而不是测试无数 通过集中发展a)选择具有更均匀表达和 如果直接靶向占优势，ADC内化，b)最佳的物理化学性质和分布 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 通过联合治疗、FC工程和/或在需要免疫细胞招募的情况下给药方案。一个 大量作为单一疗法失败的单抗正处于休眠状态 制药公司。通过利用有效负载和链接器化学方面的进展以及来自 这一建议，可以迅速加速开发新的临床成功的ADC。