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：
10397091
负责人：
Joseph P Balthasar
金额：
$ 35.54万
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/10397091
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 Convection Data Development Diffuse Dissociation Drug Kinetics ERBB2 gene Endosomes Enzymes Evaluation Exocytosis Extracellular Fluid Extracellular Matrix Extravasation Gemtuzumab Ozogamicin Health Hematologic Neoplasms Human Immunoglobulin Fragments 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 Physiological Prevalence Prostate Safety Site Solid Neoplasm Syndrome Testing Therapeutic Monoclonal Antibodies 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 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.

尽管癌症治疗已取得进展，但对于许多患者来说治疗还不够，而且预计 2019 年美国将有超过 607,000 人因癌症死亡。其中许多死亡将因来自发展为实体瘤的癌症，这些肿瘤特别难以用化疗或其他方法治疗抗癌单克隆抗体（mAb）和抗体药物偶联物的次优药物。 (ADC) 的部分原因是实体瘤内这些药物的摄取和分布不良。实体瘤的病理生理学特征包括其细胞生长混乱、细胞外致密基质、血管化不良和紊乱、淋巴管生成减少、间质液含量高这些特性限制了 mAb 和 ADC 在肿瘤内的对流和扩散运输，该提案测试了三种新的平台策略。旨在通过增强抗癌单克隆抗体疗法的选择性和功效目标#1 引入了一种克服实体瘤中 mAb 和 ADC 的新策略。通过瞬时抑制抗体与抗原的结合，在肿瘤内形成“结合位点屏障”，施用抗独特型药物，可短期且可逆地拮抗 mAb 结合。将研究使用具有 pH 依赖性、“捕获并释放”结合的抗体来绕过分解代谢与受体介导的抗癌单克隆抗体内吞作用相关的水槽在目标#3中，基质-的靶向递送。将采用调节酶来实现肿瘤中胶原蛋白的选择性消耗，并使得改善 mAb 和 ADC 的肿瘤内分布每个目标都得到机制的有力支持。数学模型和初步数据证明药代动力学、功效、优化的抗 HER2 mAb 和 ADC 疗法的安全性将使用 HER2-小鼠模型进行评估这项工作中开发的新型药物可能适合立即转化为人类癌症。曲妥珠单抗和 ado-曲妥珠单抗 emtansine 治疗 HER2 阳性乳腺和胃病的优化此外，该提案中引入的方法可以扩展用于优化。将所有 mAb 和 ADC 应用于实体瘤治疗，可能为数百人带来益处数以千计的患者。