A Human Antibody as an Immunotherapy for Cocaine Abuse

描述（由申请方提供）：尽管了解可卡因滥用的药理学基础，但尚未开发出有效的药物治疗，这表明药物治疗可能不切实际。另一种方法是开发一种直接靶向可卡因的免疫疗法。为此，主要是人的单克隆抗体（mAb）与高亲和力（Kd = 4 nM）的可卡因和可卡因的非活性代谢物的选择性已被生成和测序。这种被指定为2 E2的主要候选新分子实体（NME）被设计为对患者进行重复治疗是安全的，并且应该为寻求治疗的可卡因滥用者预防复发提供长期疗效。2 E2处于临床前开发的后期阶段，已达到或超过安全性和有效性的关键里程碑标准。在广泛的人体组织中未发现交叉反应性，这是临床使用安全性的一个有希望的指标。在小鼠中，mAb不穿过血脑屏障，并在外周隔离可卡因，从而减少可卡因进入大脑。这降低了可卡因的所有中枢作用。因此，在复发的大鼠模型中，mAb拮抗可卡因诱导的自我给药的恢复。这些效果是有效性的积极指标，并提供了概念验证。临床前开发的下一阶段是完成动物体内毒理学测试。然而，当前杂交瘤在细胞培养中的低效生产是该产品开发中的限速步骤。因此，该II期竞争性更新申请的目的是使用标准技术，通过将编码mAb两条链的基因与高效启动子一起转染到中国卵巢癌（CHO）细胞中，从而生成高效可规模化生产平台。将选择在无血清培养基中产生至少0.25 gm/L 2 E2的单个细胞系。CHO衍生的2 E2必须保持其对可卡因的高亲和力和特异性及其在动物模型中的功效。CHO细胞衍生的2 E2的功效将通过长消除半衰期、防止可卡因分布至脑的效力和拮抗可卡因诱导的自我施用恢复的能力来定义。将最大限度地提高2 E2的CHO细胞产量，并优化符合药品生产质量管理规范（GMP）标准的纯化方案。实现这些目标将加速该领先候选NME进入临床试验，并将其成本降低约100倍，使其具有商业可行性。10.可卡因滥用、成瘾和依赖是对我国公共健康的一个主要威胁。然而，尽管数十年来针对可卡因在大脑中作用部位的药物疗法进行了研究，但这些潜在的可卡因滥用治疗方法都没有成功。另一种方法是使用单克隆抗可卡因抗体，直接靶向可卡因本身并阻止其快速进入大脑。该申请详细描述了将推进独特的主要是人序列的抗可卡因单克隆抗体用于预防可卡因滥用复发的临床试验的研究。

DESCRIPTION (provided by applicant): Despite an understanding of the pharmacological basis of cocaine abuse no effective pharmacotherapy has been developed, suggesting that pharmacotherapy may be impractical. An alternative approach is to develop an immunotherapy that directly targets cocaine. To this end, a predominantly human monoclonal antibody (mAb) with a high affinity (Kd = 4 nM) for cocaine and selectivity over cocaine's inactive metabolites has been generated and sequenced. This lead candidate New Molecular Entity (NME), designated 2E2, is designed to be safe for repeated treatments in patients and should confer long-term efficacy for the prevention of relapse in treatment-seeking cocaine abusers. 2E2 is at an advanced stage of pre-clinical development and has met or exceeded key milestone criteria for safety and efficacy. No cross-reactivity was found with an extensive panel of human tissues, a promising indicator of safety in clinical use. In mice the mAb does not cross the blood- brain barrier and sequesters cocaine in the periphery, thereby decreasing the entry of cocaine into the brain. This reduces all of the central effects of cocaine. Consequently, in a rat model of relapse the mAb antagonizes the cocaine-induced reinstatement of self-administration. These effects are positive indicators of efficacy and provide proof-of-concept. The next stage of pre-clinical development is to complete in vivo toxicology testing in animals. However, the inefficient production in cell culture by the current hybridoma is the rate-limiting step in the development of this product. Therefore, the aim of this Phase II Competing Renewal application is to use standard technology to generate a high efficiency scaleable production platform by transfecting the genes coding for both chains of the mAb with high efficiency promoters into Chinese Hamster Ovary (CHO) cells. A single cell line will be selected that produces, in serum free media, at least 0.25 gm/L of 2E2. The CHO- derived 2E2 must retain its high affinity and specificity for cocaine and its efficacy in animal models. The efficacy of the CHO cell-derived 2E2 will be defined by a long elimination half-life, the potency to prevent cocaine distribution to the brain and the ability to antagonize cocaine-induced reinstatement of self- administration. CHO cell production of 2E2 will be maximized and purification protocols compatible with Good Manufacturing Practices (GMP) standards will be optimized. Accomplishing these goals will accelerate this lead candidate NME towards clinical trials and will reduce its cost approximately 100-fold, making it commercially viable. /Relevance Cocaine abuse, addiction and dependence represent a major threat to our national public health. However, despite decades of research into pharmacotherapies that target the sites of cocaine's action in the brain, none of these potential treatments for cocaine abuse have been successful. An alternative approach is to use a monoclonal anti-cocaine antibody that directly targets cocaine itself and prevents its rapid entry into the brain. This application details studies that will advance a unique predominantly human sequence anti- cocaine monoclonal antibody towards clinical trials for the prevention of relapse in cocaine abuse.