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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：
10164739
负责人：
Joseph P Balthasar
金额：
$ 36.27万
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/10164739
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 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.

尽管在癌症治疗方面取得了进展，但对许多患者来说，治疗方法还不够，而且这种治疗方法也不太有效