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)

• 批准号: 8145646
• 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
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8145646
• 关键词: Affinity; Antibodies; Binding; Blood Circulation; Brain; Cell Line; Clinical; Cocaine; Cocaine Abuse; Data; Development; Goals; Human; Immunoglobulin Constant Region; Immunotherapy; Industry Collaborators; Lead; Light; Mammalian Cell; Modeling; Molecular; Monoclonal Antibodies; Mus; Patients; Peripheral; Production; Proteins; Rattus; Relapse; Research Project Grants; Safety; Site-Directed Mutagenesis; Specificity; Staging; Structure; Toxicology; Translational Research; Variant; Work; commercialization; cost effectiveness; disorder later incidence prevention; in vivo; meetings; multidisciplinary; novel; pre-clinical; protein expression

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 applicati

描述（由申请人提供）：该多学科转化研究项目产生了一种主要为人的序列单克隆抗体（mAb），对可卡因具有高亲和力（Kd = 4 nM），对可卡因的非活性代谢物具有特异性。这种独特的新分子实体（临床前名称，2E2，人类γ 1（？1)重链和小鼠λ（？）轻链）处于临床前开发的高级阶段，用于 预防寻求治疗的可卡因滥用者复发。2E2的开发已经达到了几个关键的安全性和有效性里程碑。这种mAb的主要人类结构对于患者的重复治疗应该是安全的，并且应该具有长期疗效。抗可卡因单克隆抗体结合并隔离外周循环中的可卡因，我们已经证明2E2显著降低小鼠脑中的可卡因浓度。此外，2E2降低了可卡因在复发大鼠模型中的作用。我们的行业合作伙伴Vybion Inc.已经重新设计了一个新版本的我们的单克隆抗体与人类kappa（？）轻链恒定区 替换小鼠恒定区。重组的mAb蛋白（h2E2）已被瞬时表达，h2E2保留了与2E2相同的可卡因亲和力和特异性。这是一个概念验证的里程碑，h2E2代表了我们商业化的新领导候选人。将继续致力于开发能够高水平生产h2E2的稳定转染的哺乳动物细胞系，这是其临床开发所需的。h2E2一级结构的靶向修饰旨在提高蛋白质表达水平和稳定性，从而提高生产的成本效益。拟议研究的总体目标是为h2E2的高表达变体提供全面的结构和功效数据，然后生产足够量的纯化h2E2，以支持IND申请所需的体内毒理学研究。