Optimizing antibody-based therapy through a system platform of pharmacokinetics-pharmacodynamics-immunodynamics

通过药代动力学-药效学-免疫动力学系统平台优化抗体治疗

• 批准号: 9321035
• 负责人: Yanguang Cao
• 金额: $ 37.3万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9321035
• 关键词: Antibodies; Antibody Therapy; Antigens; Autoimmune Diseases; Binding; Blood; Cells; Disease; Dose; Drug Kinetics; Engineering; Environment; Event; Exposure to; FDA approved; Face; Immune system; Infiltration; Intercellular Fluid; Label; Lymphocyte; MS4A1 gene; Malignant Neoplasms; Methods; Monitor; Patients; Pharmacodynamics; Physiology; Property; Resistance; Series; Site; Solid Neoplasm; Support System; System; Therapeutic; Therapeutic antibodies; Time; Tissues; base; complement system; drug sensitivity; exhaust; immunological status; improved; in vivo; migration; molecular imaging; novel; radiological imaging; response; success; tumor; tumor microenvironment

PROJECT SUMMARY/ ABSTRACT Therapeutic antibodies have achieved great success in a variety of diseases such as autoimmune disorders and cancers; however, their therapeutic potential has not been fully realized yet. Many FDA-approved antibodies now face high therapeutic hurdles, such as inadequate efficacy in monotherapy and high rates of resistance. Some hurdles can be overcome by engineering new antibody entities with either improved target selectivity or functionality. Many others remain unresolved, as they are not just about the antibody itself, rather essentially as a result of antibody discordant interactions with the host system. For instance, CD20-targeted antibodies often confront resistance that is due to overwhelming antibody exposure to the immune system leading to exhausted effector function and then loss of drug sensitivity. To resolve those issues, we plan to develop a system platform that collectively consolidates the fundamental properties of the antibody and the host system, and integrate their spatial/temporal coordination. If it is established, this platform will alleviate or even sidestep these therapeutic hurdles and facilitate efforts to optimize the current antibody-based therapies. We will develop this system platform on multiple scales from cells to the whole body, by collectively evaluating all steps of antibody actions from dosing to final responses. Specifically, we will collaborate with experts in the fields of radiology and molecular imaging to develop novel labeling approaches to track antibody entities at multiple levels (i.e., blood, tissue, interstitial fluid, and cell) and assess antibody system persistence and distribution to the site(s)-of-action (pharmacokinetics) (Project 1). We will apply a series of combined experimental and computational approaches to assess the temporal and spatial antibody- antigen interactions in vivo, and the subsequent cellular and subcellular events (Project 2). Advanced cell- labeling methods will be applied to monitor lymphocyte migration, infiltration, functional orientation, and dynamics of effector function (e.g., FcγR) and the complement system (e.g., C3 and C4) in the tumor microenvironment. Patient-derived blood and solid tumors will be used to prepare lymphocytes, on which dynamics of effector function will be assessed. This will better mimic the tumor environment and increase our ability to predict patient responses. Antibody therapy will be further tailored to coordinate the status of immune system and the dynamics of effector function for maximal effect (Project 3). All these quantitative studies will support this system platform to facilitate the proper selection of an antibody, determine the precise dose and dosing interval to attain the desired target exposure and target engagement. The time course of target binding will coordinate physiology and dynamics of the immune system to achieve optimal treatment.

项目摘要/摘要 治疗性抗体在自身免疫性疾病等多种疾病中取得了巨大的成功。 和癌症；然而，它们的治疗潜力尚未完全实现。许多是FDA批准的 抗体现在面临着很高的治疗障碍，例如单一疗法的疗效不足和高发病率 抵抗。一些障碍可以通过设计新的抗体实体来克服，无论是哪一种改进的目标 选择性或功能性。许多其他的问题仍然没有解决，因为它们不仅仅是关于抗体本身，而是 基本上是由于抗体与宿主系统的不协调相互作用的结果。例如，CD20-靶向 抗体经常会遇到由于免疫系统接触到大量抗体而产生的抗药性。 导致效应器功能衰竭，进而丧失药物敏感性。为了解决这些问题，我们计划 开发一个系统平台，共同巩固抗体的基本属性 和宿主系统，并整合它们的空间/时间协调。如果它建立了，这个平台 将缓解甚至绕过这些治疗障碍，并促进优化当前 基于抗体的疗法。我们将在从单元到整体的多个尺度上开发这个系统平台 通过集体评估抗体作用的所有步骤，从剂量到最终反应。具体来说，我们将 与放射学和分子成像领域的专家合作，开发新的标记方法 在多个层次(即血液、组织、间质液体和细胞)跟踪抗体实体并评估抗体 系统持久性和现场分布(S)作用(药代动力学)(项目1)。我们将应用一个 一系列结合实验和计算的方法来评估时间和空间抗体- 体内的抗原相互作用，以及随后的细胞和亚细胞事件(项目2)。高级细胞- 将应用标记方法来监测淋巴细胞的迁移、渗透、功能定位和 肿瘤中效应器功能(如Fc、γ、R)和补体系统(如C3、C4)的动态变化 微环境。患者的血液和实体肿瘤将被用于制备淋巴细胞，在其上 将评估效应器功能的动力学。这将更好地模拟肿瘤环境，并增加我们的 预测病人反应的能力。抗体治疗将进一步调整以协调免疫状态 系统和效应器功能的动力学以达到最大效果(项目3)。所有这些定量研究 将此系统作为支撑平台，便于正确选择抗体，准确确定 剂量和剂量间隔，以达到所需的靶标曝光和靶标接合。时间进程 靶标结合将协调免疫系统的生理和动力学，以达到最佳 治疗。