Pharmacokinetic strategies to increase monoclonal antibody uptake, distribution, and efficacy for treatment of solid tumors

增加单克隆抗体摄取、分布和治疗实体瘤疗效的药代动力学策略

基本信息

批准号：
10623152
负责人：
Joseph P Balthasar
金额：
$ 35.59万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10623152
关键词：
Affinity Antibodies Antibody Affinity Antibody Therapy Antibody-drug conjugates Antigens Binding Binding Sites Biological Blood Vessels Breast Bypass Cancer Patient Carcinoembryonic Antigen Catabolism Cell Surface Receptors Cessation of life Cetuximab Characteristics Chimeric Proteins Clostridium Collagen Colorectal Cancer Data Development Dissociation Drug Kinetics ERBB2 gene Endosomes Enzymes Evaluation Exocytosis Extracellular Fluid Extracellular Matrix Extravasation Gemtuzumab Ozogamicin Health Hematologic Neoplasms Human Immunoglobulin Fragments Immunoglobulin Idiotypes In Vitro Incidence Injections Intercellular Fluid Investigation Lung Lymphangiogenesis Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Mediating Modeling Monoclonal Antibodies Oncology Patients Pharmaceutical Preparations Prevalence Prostate Safety Site Solid Neoplasm Syndrome Testing Translations Trastuzumab Treatment Efficacy Tumor Antibodies Tumor Antigens United States Vascularization Work antagonist anti-cancer cancer diagnosis cancer therapy cell growth chemotherapy collagenase design human cancer mouse model human model improved in silico in vivo inhibiting antibody malignant breast neoplasm malignant stomach neoplasm mathematical model models and simulation mouse model nanobodies neonatal Fc receptor novel novel strategies pressure prevent receptor mediated endocytosis research clinical testing rituximab side effect targeted cancer therapy targeted delivery treatment optimization tumor uptake

项目摘要

Although advances have been made in the treatment of cancer, therapy is inadequate for many patients, and it is projected that there will be over 607,000 cancer deaths in the US in 2019. Many of these deaths will result from cancers that develop as solid tumors, which are particularly difficult to treat with chemotherapy or with biological drugs. Sub-optimal efficacy of anti-cancer monoclonal antibodies (mAb) and antibody-drug conjugates (ADC) has been explained, in part, by poor uptake and distribution of these agents within solid tumors. Pathophysiologic characteristics of solid tumors include their chaotic cellular growth, dense extracellular matrices, poor and disorganized vascularization, decreased lymphangiogenesis, and high interstitial fluid pressure. These characteristics limit the convective and diffusive transport of mAb and ADC within tumors, leading to poor and heterogeneous intra-tumoral distribution. This proposal tests three new platform strategies designed to improve the selectivity and efficacy of anti-cancer monoclonal antibody-based therapy by enhancing the distribution of mAb and ADCs within solid tumors. Aim #1 introduces a novel strategy for overcoming the “binding-site barrier” within tumors through transient inhibition of antibody binding to antigen, as achieved co- administration of anti-idiotypic agents that allow short-term and reversible antagonism of mAb binding. Aim #2 will investigate the use of antibodies with pH-dependent, “catch-and-release” binding to bypass the catabolic sink associated with receptor-mediated endocytosis of anti-cancer mAb. In Aim #3, targeted delivery of matrix- modulating enzymes will be employed to achieve selective depletion of collagen in tumors, and to enable improved intra-tumoral distribution of mAb and ADC. Each aim is strongly supported by mechanistic mathematical modeling and by preliminary data demonstrating utility and feasibility. Pharmacokinetics, efficacy, and safety of optimized anti-HER2 mAb and ADC therapy will be assessed using mouse models of HER2- positive human cancer. The novel agents developed in this work may be suitable for immediate translation toward optimization of trastuzumab and ado-trastuzumab emtansine treatment of HER2-positive breast and gastric cancer patients. Additionally, the approaches introduced in this proposal may be extended for use in optimizing therapy with all mAb and ADC applied to the treatment of solid tumors, potentially providing benefit to hundreds of thousands of patients.

尽管在癌症治疗方面已经取得了进步，但对于许多患者而言，治疗不足，并且预计2019年美国将有超过607,000例癌症死亡。这些死亡将导致许多死亡从形成实体瘤的癌症中，这些癌症特别难以治疗化学疗法或与生物药物。抗癌单克隆抗体（MAB）和抗体 - 药物结合物的次优效率（ADC）部分通过在实体瘤中的摄取和分布不足来解释。实体瘤的病理生理特征包括它们混乱的细胞生长，细胞外密集基质，较差和混乱的血管形成，淋巴管生成降低和高间隙液压力。这些特征限制了mAb和ADC在肿瘤中的对流和扩散运输，导致肿瘤内分布差和异质。该建议测试三种新的平台策略旨在提高抗癌单克隆抗体治疗的选择性和效率 MAB和ADC在实体瘤中的分布。 AIM＃1引入了一种克服的新策略肿瘤中的“结合位点屏障”通过瞬时抑制与抗原的抗体结合，如达到的抗原给予抗IDIOTYPIC剂，允许短期和可逆的mAb结合拮抗作用。目标＃2 将调查使用具有pH依赖性的“捕获和释放”结合到绕过分解代谢的抗体的使用与受体介导的抗癌单胞胞菌的内吞作用相关的水槽。在AIM＃3中，针对矩阵的有针对性传递将采用调节酶来实现肿瘤中胶原蛋白的选择性部署，并启用 MAB和ADC的肿瘤内分布改善。每个目标都得到机械的强烈支持数学建模和通过初步数据证明了实用性和可行性。药代动力学，效率，以及优化的抗HER2 MAB和ADC治疗的安全性将使用HER2-的小鼠模型进行评估阳性人类癌。这项工作中开发的新型代理可能适合立即翻译成曲妥珠单抗和Ado-trastuzumab Emtansine的优化对HER2阳性乳房和胃的治疗癌症患者。此外，本提案中介绍的方法可以扩展用于优化所有MAB和ADC的治疗都适用于实体瘤的治疗，有可能为数百种提供益处成千上万的患者。