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A Human Antibody as an Immunotherapy for Cocaine Abuse (DP1)

人类抗体作为可卡因滥用的免疫疗法 (DP1)

基本信息

批准号：
8705483
负责人：
ANDREW B NORMAN
金额：
$ 76.15万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8705483
关键词：
Affinity Amino Acid Sequence Amino Acids Antibodies Archives Basic Science Behavior Binding Blood Circulation Blood Volume Brain Cell Line Cells Chinese Hamster Ovary Cell Clinical Cocaine Cocaine Abuse Complementary DNA Data Development Development Plans Disease Engineering Goals Growth Human Hybridomas IgG1 Immunoglobulin Constant Region Immunotherapeutic agent Immunotherapy In Vitro Industry Collaborators Interdisciplinary Study Investigational New Drug Application Lead Length Light Mammalian Cell Modeling Molecular Monoclonal Antibodies Mus Patients Peptide Sequence Determination Peripheral Pharmaceutical Preparations Production Proteins Protocols documentation Public Health Rattus Relapse Reporting Research Project Grants Roche brand of rituximab Safety Selection Criteria Self Administration Serum-Free Culture Media Site-Directed Mutagenesis Societies Specificity Staging Structure System Testing Therapeutic Equivalency Thermodynamics TimeLine Toxic effect Toxicology Transfection Translating Translational Research Universities Variant Work addiction base commercialization cost effective cost effectiveness cross reactivity design disorder later incidence prevention effective therapy expression vector human tissue humanized monoclonal antibodies immunogenicity improved in vivo meetings monoclonal antibody production multidisciplinary novel pre-clinical prevent product development protein expression success thermostability

项目摘要

DESCRIPTION (provided by applicant): This multidisciplinary translational research project has generated a predominantly human sequence monoclonal antibody (mAb) with high affinity (Kd = 4 nM) for cocaine and specificity over cocaine's inactive metabolites. This unique new molecular entity (preclinical designation, 2E2, a human gamma 1 (?1) heavy chain and mouse lamda (?) light chain) is at an advanced stage of preclinical development for use in the prevention of relapse in treatment-seeking cocaine abusers. The development of 2E2 has met several key safety and efficacy milestones. The mostly human structure of this mAb should be safe for repeated treatments in patients and should confer long-term efficacy. Anti-cocaine mAbs bind to and sequester cocaine in the peripheral circulation and we have shown that 2E2 dramatically lowers brain cocaine concentrations in mice. Furthermore, 2E2 decreases the effect of cocaine in a rat model of relapse. Our industry collaborator, Vybion Inc., has reengineered a novel version of our mAb with a human kappa (?) light chain constant region replacing the mouse constant region. The reengineered mAb protein (h2E2) has been transiently expressed and h2E2 retains the identical affinity and specificity for cocaine as 2E2. This represents a proof-of-concept milestone and h2E2 represents our new lead candidate for commercialization. Work will be continued towards the development of a stably transfected mammalian cell line capable of the high level production of h2E2, which will be required for its clinical development. Targeted modifications of h2E2's primary structure aim to increase protein expression levels and stability, thereby enhancing the cost-effectiveness of production. The overall goal of the proposed studies is to provide the comprehensive structural and efficacy data for the highly expressed variant of h2E2 and then produce sufficient quantities of purified h2E2 to support the in vivo toxicology studies that are required for an IND application to the FDA.

描述（由申请人提供）：这个多学科的转化研究项目产生了一种主要是人序列的单克隆抗体（mAb），对可卡因具有高亲和力（Kd = 4 nM），对可卡因的无活性代谢物具有特异性。这种独特的新分子实体(临床前命名，2E2，一种人类γ - 1 (？1)重链和小鼠lamda（?）轻链（?）正处于临床前开发的后期阶段