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最近获得了另外两种抗体药物缀合物（ADC）的批准，重点介绍了临床成功和 这类代理商的增长。尽管有这些批准，但是新ADC的流失率仍然很高， 在肿瘤学应用中，尚无实体瘤的ADC能够重复ADO的成功 曲妥珠单抗Emtansine（T-DM1）。已经付出了巨大的努力来改善抗体和靶标 选择，连接站点，接头稳定性和有效载荷属性（效力，旁观者效果等），这些 改进将使下一代化合物受益。但是，基本问题仍然是关于如何 设计临床有效的代理。具体而言，多个多元之间的相对贡献和相互作用 这些药物的作用机制（受体信号阻塞，有效载荷功效和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 足够的详细信息可以合理地将抗体，连接器和有效载荷与特定目标相结合（在选择中 患者人群）在癌症和非肿瘤学应用中最大程度地临床疗效。目标 该建议是定量了解抗原阳性中直接有效载荷效应的相对贡献 细胞，旁观者有效载荷在抗原负细胞中的影响以及FC效应功能在确定的作用 抗体药物缀合物的功效。结合近红外荧光成像和流动 细胞仪，完整和退化的绝对数量（触发有效载荷释放）每个单元格可以是 决定。通过将这些结果与药效学标记配对（例如烷基化的DNA损伤标记 代理），可以用单个量化ADC的传递和功效（直接杀害和旁观者杀人） 体内细胞分辨率。 ADC与未结合抗体的不同比率的共同给药将用于 将组织分布控制为直接与间接杀戮的变化。研究将在两个 免疫功能低下和免疫能力（合成）小鼠模型以确定益处（或 要求）免疫系统激活。通过将单细胞测量与黄金标准进行比较 临床前功效（肿瘤生长曲线），将确定每种机制的相对贡献。 作品的结果将使新颖ADC的合理设计成为现实，而不是测试众多 通过将开发集中在a）选择具有更均匀表达和更均匀的靶标和的情况下组合体内组合 ADC内部化如果直接靶向为主导，则b）最佳物理化学特性和分布的分布 旁观者有效载荷如果旁观者效应起主要作用，或C）激活和募集免疫细胞 如果需要免疫细胞募集，则通过共治疗，FC工程和/或给药方案。一个 由于单疗法失败的大量单克隆抗体处于休眠状态 制药公司。通过利用有效载荷和连接器化学的进步， 该建议，可以迅速加速新的临床成功ADC的发展。