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Catch and Release Immunotoxins: CAR-Bombs for Cancer

捕获并释放免疫毒素：治疗癌症的 CAR 炸弹

基本信息

批准号：
10062878
负责人：
Joseph P Balthasar
金额：
$ 36.42万
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：
2016
资助国家：
美国
起止时间：
2016-12-07 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10062878
关键词：
Affinity American Cancer Society Antibodies Binding Biological Carcinoembryonic Antigen Cell surface Cells Cessation of life Colorectal Cancer Cytoplasm Data Diagnosis Dissociation Dose Drug Kinetics Endosomes Evaluation Exhibits GALA Health Human Immunotoxins In Vitro Incidence Individual Investigation Kinetics Liposomes Malignant Neoplasms Membrane Modeling Monoclonal Antibodies Mus Operative Surgical Procedures Pattern Peptides Physiological Plasma Population Proteins Radiation Ribosomes Safety Small Interfering RNA Sum System Testing Toxic effect Toxin Toxin Conjugates Tumor Suppression United States Work analog anti-cancer antibody conjugate antigen binding base cancer cell cancer therapy cancer type cellular targeting chemotherapy cytotoxicity human model improved in vivo macromolecule membrane model mouse model neoplastic cell novel pharmacokinetic model receptor binding receptor mediated endocytosis targeted delivery tumor tumor growth tumor xenograft uptake virtual virtual delivery

项目摘要

Abstract The American Cancer Society estimates that in 2016 there will be 1.7 million new cancer cases diagnosed and 600,000 cancer deaths in the United States. Although advances have been made in the treatment of cancer with surgery, radiation, chemotherapy, and with biologics, there is a critical need to develop novel treatment approaches with promise for improved selectivity, potency, and efficacy. This project introduces a new and previously untested platform strategy to enhance the efficiency of delivery of macromolecules to the cytoplasm of targeted cells. The central component of the strategy is the use of “catch-and-release” monoclonal antibodies (CAR), with pH-dependent receptor binding. The CAR antibodies are conjugated to highly potent macromolecular toxins (CAR-toxin) and to endosome escape peptides (CAR-EEP). Combined administration of CAR-toxin and CAR-EEP conjugates allows efficient, targeted delivery and release of the toxin in the cytoplasm, enabling highly selective and potent anti-cancer efficacy. To pursue this project, we have developed a novel catch-and-release anti-carcinoembryonic antigen (CEA) antibody (10H6), with high affinity CEA binding at physiological pH, and with dramatically reduced binding at acidic pH. Preliminary data have been generated to assess the binding, cytotoxicity, and pharmacokinetics of 10H6, which in sum, strongly support the feasibility of the work. An interdisciplinary team has been assembled to evaluate this approach, with three experimental aims that will: (1) examine and optimize the utility of catch and release conjugates for cytoplasmic delivery of macromolecules to cancer cells in vitro, (2) test hypotheses regarding the tumor selectivity of in vivo disposition of the antibody conjugates, and (3) evaluate the safety and efficacy of the catch-and-release mAb conjugates in the treatment of mice bearing human xenograft tumors. The project, if successful, will establish a new targeting concept, with potential utility in enhancing the efficiency of cytoplasmic delivery of virtually any macromolecule to any type of cancer.

摘要美国癌症协会估计，2016年将有170万新的癌症病例被诊断出来，美国有60万人死于癌症。虽然癌症治疗已经取得了进展通过手术、放疗、化疗和生物制剂，迫切需要开发新的治疗方法这些方法有望提高选择性、效力和功效。该项目引入了一个新的，以前未经测试的平台策略，以提高大分子向细胞质的递送效率的靶细胞。该策略的核心组成部分是使用“捕获和释放”单克隆抗体。抗体（CAR），具有pH依赖性受体结合。CAR抗体缀合至高效的大分子毒素（CAR-毒素）和内体逃逸肽（CAR-EEP）。组合施用 CAR-毒素和CAR-EEP缀合物的结合允许毒素在细胞中的有效、靶向递送和释放。细胞质，从而实现高度选择性和有效的抗癌功效。为了完成这个项目，我们开发了一种新型的捕获-释放型抗癌胚抗原（CEA）抗体（10 H6），具有高亲和力， CEA在生理pH值下结合，在酸性pH值下结合显着降低。初步数据显示，已生成用于评估10 H6的结合、细胞毒性和药代动力学，总而言之，支持工作的可行性。已经组建了一个跨学科小组来评估这一方法，具有三个实验目的，将：（1）检查和优化捕获和释放缀合物的效用，体外大分子向癌细胞的细胞质递送，（2）检验关于肿瘤的假设抗体缀合物的体内处置的选择性，和（3）评价抗体缀合物的安全性和功效。捕获和释放mAb缀合物在治疗携带人异种移植肿瘤的小鼠中的应用。如果项目成功，将建立一个新的目标定位概念，在提高效率的潜在效用，细胞质递送几乎任何大分子到任何类型的癌症。