A Human Antibody as an Immunotherapy for Cocaine Abuse

描述(申请人提供)：尽管了解了可卡因滥用的药理学基础，但尚未开发出有效的药物疗法，这表明药物疗法可能不切实际。另一种方法是开发一种直接针对可卡因的免疫疗法。为此，已经产生了一种对可卡因具有高亲和力(Kd=4 NM)并对可卡因的非活性代谢物具有选择性的以人为主的单抗(MAb)并进行了测序。这种被命名为2E2的领先候选新分子实体(NME)被设计为对患者的重复治疗是安全的，并应对寻求治疗的可卡因滥用者提供防止复发的长期疗效。2E2处于临床前开发的高级阶段，已经达到或超过了安全性和有效性的关键里程碑标准。没有发现与广泛的人体组织的交叉反应，这是临床使用安全性的一个有前景的指标。在小鼠中，mAb不会越过血脑屏障，将可卡因隔离在外周，从而减少可卡因进入大脑。这就减少了可卡因的所有中枢效应。因此，在复发的大鼠模型中，mAb拮抗可卡因诱导的自我给药恢复。这些效果是疗效的积极指标，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，目前杂交瘤在细胞培养中的低效生产是该产品开发的限速步骤。因此，这一二期竞争性更新应用的目的是利用标准技术，通过高效启动子将mAb两链编码基因导入中国仓鼠卵巢(CHO)细胞，从而产生一个高效可扩展的生产平台。将选择一株在无血清培养中产生至少0.25gm/L 2e2的细胞系。CHO来源的2E2必须保持其对可卡因的高亲和力和特异性，以及它在动物模型中的疗效。CHO细胞衍生的2E2的疗效将由较长的消除半衰期、防止可卡因分布到大脑的效力以及对抗可卡因诱导的自我给药恢复的能力来定义。将最大限度地提高2e2的CHO电池产量，并优化符合良好制造规范(GMP)标准的净化方案。实现这些目标将加速这一领先候选NME进入临床试验，并将其成本降低约100倍，使其在商业上可行。可卡因滥用、上瘾和依赖是对我国公共健康的重大威胁。然而，尽管几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，但这些针对可卡因滥用的潜在治疗方法都没有成功。另一种方法是使用抗可卡因的单抗，该抗体直接针对可卡因本身，防止其快速进入大脑。这项申请详细说明了将一种独特的、主要是人类序列的抗可卡因单抗推向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.