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First-In-Human Study of a Humanized Anti-Cocaine Monoclonal Antibody

人源化抗可卡因单克隆抗体的首次人体研究

基本信息

批准号：
9750966
负责人：
ANDREW B NORMAN
金额：
$ 477.07万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9750966
关键词：
Address Affinity Age Animals Antibodies Behavior Binding Biological Assay Blood Circulation Blood Volume Blood specimen Brain Cell Line Cells Chemistry Clinical Clinical Trials Cocaine Cocaine Abuse Cocaine Users Conjugated Carrier Cyclic GMP Development Disease Dose Double-Blind Method Drug Kinetics Engineering Enzyme-Linked Immunosorbent Assay Evaluation Female Formulation Funding Future Goals Half-Life Haptens Health Hour Human Human Volunteers IgG1 Immunotherapy In Vitro Industrialization Industry Collaboration Infusion procedures Inpatients Intravenous infusion procedures Investigational Drugs Investigational New Drug Application Laboratories Light Measurement Measures Modeling Molecular Monitor Monoclonal Antibodies Mus National Institute of Drug Abuse Nursing Staff Outcome Outpatients Patients Peripheral Pharmacists Pharmacological Treatment Pharmacology and Toxicology Pharmacotherapy Phase Phase I Clinical Trials Physicians Preparation Probability Production Protocols documentation Public Health Rattus Recombinants Recording of previous events Records Recovery Relapse Reporting Research Running Safety Sampling Schedule Section 8 Self Administration Series Serum Specificity Structure Technology Testing Therapeutic Time Toxic effect Toxicology Translational Research United States National Institutes of Health Vaccines Venipunctures cGMP production cell bank clinical development clinical efficacy cocaine use cohort commercialization cross reactivity design efficacy trial first-in-human healthy volunteer human study human subject human tissue humanized monoclonal antibodies in vivo male meetings multidisciplinary pre-clinical pre-clinical research preclinical development prevent response scale up vaccine trial

项目摘要

PROJECT SUMMARY/ABSTRACT Our multidisciplinary translational research team has generated and developed a humanized monoclonal antibody (mAb) with a high affinity (Kd = 4 nM) for cocaine and specificity over cocaine's inactive metabolites. This unique new molecular entity (preclinical designation, h2E2) consists of a human gamma 1 (1) heavy chain and a human/mouse chimeric lamda () light chain and has approximately 95% sequence identity with a fully human IgG1. This anti-cocaine mAb has met or exceeded all the necessary pre-clinical development milestones as a therapeutic to treat cocaine use disorders. Anti-cocaine mAbs bind and sequester cocaine in the peripheral circulation and we have shown that h2E2 dramatically lowers brain cocaine concentrations in mice and in rats. Furthermore, h2E2 antagonizes the effect of cocaine in a rat model of relapse. These studies predict efficacy in human cocaine abusers. Our industry collaborator, Catalent Inc., has established a GLP Master Cell Bank (MCB) with a selected cell line that serves as the platform for the GMP manufacture of industrial quantities of purified recombinant h2E2. The recombinant h2E2 from this MCB shows no cross- reactivity in vitro with an extensive panel of human tissues, and no indications of toxicity at high doses in animal toxicology studies. These IND-enabling GLP studies predict that h2E2 will be safe for use in humans. In coordination with NIDA we have scheduled a pre-IND meeting with the FDA for early September of 2018 in preparation for the filing of an IND and then proceeding to first-in-human clinical trials to establish safety. The pharmacokinetics of h2E2 in humans will also be established and the development of any anti-h2E2 antibodies will be monitored. The successful completion of these Specific Aims will permit and inform the design of future clinical trials to assess the safety of h2E2 in the presence of cocaine and the safety of h2E2 after repeated administrations. The clinical development would then proceed to Phase II clinical efficacy trials. Given its mostly human structure, h2E2 should be safe for repeated treatments in patients and its anticipated slow clearance in humans should confer long-term efficacy. Positive outcomes of these clinical development milestones will add value to the product and facilitate commercialization.

项目总结/文摘