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

描述(申请人提供)：这个多学科的翻译研究项目已经产生了一种主要是人类序列的单抗(MAb)，对可卡因的非活性代谢产物具有高亲和力(Kd=4 NM)和特异性。这种独特的新分子实体(临床前命名为2E2，人γ1(？1)重链和小鼠Lamda(？)Light Chain)处于临床前开发的高级阶段，可用于 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。这种单抗的主要人体结构应该是安全的，可以在患者身上重复治疗，并应该具有长期疗效。抗可卡因单抗与可卡因结合并在外周循环中隔离可卡因，我们已经证明2e2显著降低了小鼠大脑中的可卡因浓度。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.已经重新设计了我们的mAb的一个新版本，它带有人类kappa(？)轻链恒定区 替换鼠标常量区域。重组mAb蛋白(H2E2)已瞬时表达，并保持了与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，而h2E2是我们新的商业化候选产品。将继续努力开发一种稳定转基因的哺乳动物细胞系，能够高水平地生产h2E2，这将是其临床开发所需的。对h2E2‘S一级结构的靶向修饰旨在提高蛋白表达水平和稳定性，从而提高生产的成本效益。拟议研究的总体目标是为高表达的h2E2变体提供全面的结构和疗效数据，然后生产足够数量的纯化h2E2，以支持IND应用所需的体内毒理学研究

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