权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Enhancement of ADC selectivity by inverse targeting: Mechanistic studies and optimization

通过反向靶向增强 ADC 选择性：机理研究和优化

基本信息

批准号：
10415220
负责人：
Joseph P Balthasar
金额：
$ 35.6万
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：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10415220
关键词：
Address Affinity Antibodies Antibody-drug conjugates Antineoplastic Agents Binding Blood Circulation Bystander Effect Camptothecin Cancer Patient Catabolism Cell Culture Techniques Cell membrane Cells Cessation of life Charge Clinical Trials Conjugating Agent Development Diffuse Diffusion Dose Drug Kinetics Engineering Enhancers Evaluation Extracellular Fluid Failure Filtration Gemtuzumab Ozogamicin Hydrolysis Immunocompetent Immunoglobulin Fragments Immunoglobulin G In Vitro Kidney Kinetics Lead Left Malignant Neoplasms Membrane Proteins Metabolic Clearance Rate Modality Molecular Monoclonal Antibodies Morbidity - disease rate Pathway interactions Patients Pharmacodynamics Population Refractory Regimen Resistance Safety Series Site Structure Testing Therapeutic Tissues Toxic effect Toxicokinetics Toxin Translations Trastuzumab Tumor Antigens United States Work anti-cancer base cancer cell cancer therapy clinical application clinical investigation cytotoxicity design efficacy evaluation experimental study extracellular improved in vivo evaluation malignant breast neoplasm mathematical model mortality mouse model nanobodies novel pharmacokinetics and pharmacodynamics premature prevent pyrrolobenzodiazepine receptor mediated endocytosis research clinical testing targeted delivery targeted treatment tumor tumor eradication tumor specificity uptake

项目摘要

Cancer is a major cause of morbidity and mortality in the US, with 1.8 million cases and 600 thousand cancer deaths projected for 2020. Substantial progress in cancer treatment has been made in the past two decades, largely through the development of highly targeted therapies, including development of antibody-drug conjugates (ADCs). ADCs employ monoclonal antibodies with specificity for tumor-associated antigens to increase the efficiency and selectivity of the delivery of anti-cancer toxins (i.e., payloads) to cancer cells. Although this approach has proven to be successful, with 9 anti-cancer ADCs approved for use in the US (brentuximab vedotin, trastuzumab emtansine, gemtuzumab ozogamicin, inotuzumab ozogamicin, polatuzumab vedotin, enfortumab vedotin, belantamab mafodotin, trastuzumab deruxtecan, and sacituzumab govitecan), ADC therapies are often associated with substantial off-target toxicity, narrow therapeutic windows, and high failure rates in clinical testing. This project introduces a new pharmacokinetic strategy to increase the tumor-selectivity of antibody- directed delivery of anti-cancer drugs. In our approach, payload-binding antibody fragments, termed payload- binding selectivity enhancers (PBSE), are co-administered with ADCs to decrease the exposure of healthy tissues to payload agents, thereby reducing the development of off-target toxicity, increasing the tolerable dose of ADCs, and increasing ADC efficacy. The strategy is based on the recognition that off-site ADC toxicity is primarily attributed to the released (“free”) payload molecule, and also on the hypothesis that PBSE may be employed to prevent cellular entry of free payload molecules in non-targeted cells (by preventing diffusion across plasma membranes) without altering entry of ADCs into targeted cells (which proceeds via receptor mediated endocytosis). Work in this project will focus on the development and evaluation of a novel series of PBSE that have been shown to decrease the cytotoxicity of free SN38 and Dxd. These agents are camptothecin derivatives that are employed as payloads for sacituzumab govitecan and trastuzumab deruxtecan, two recently approved ADC molecules that have shown some efficacy, but substantial toxicity, in clinical investigations. Mechanistic studies proposed in Aim #1 and Aim #2 examine relationships between PBSE molecular attributes (e.g., affinity, molecular modality [i.e., IgG, Fab, scFv, sdAb], selectivity for unconjugated payload, molecular charge, etc.) and PBSE utility in enhancing the pharmacokinetic and pharmacodynamic selectivity of ADC therapy. These findings will be integrated through the use of mechanistic mathematical modeling to assist in the selection of an optimal agent and dosing regimen for evaluation of efficacy and toxicity in Aim #3. The novel agents developed in this work may be suitable for immediate translation toward optimization of sacituzumab govitecan and trastuzumab deruxtecan therapy of refractory and resistant breast cancer.

癌症是美国发病率和死亡率的主要原因，有180万病例和60万癌症患者