A Human Antibody as an Immunotherapy for Cocaine Abuse

描述（由申请人提供）：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方法，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针对可卡因的免疫疗法。为此，一种对可卡因具有高亲和力（Kd = 4 nM）且对可卡因无活性代谢物具有选择性的主要人源单克隆抗体（mAb）被生成并测序。新分子实体（New Molecular Entity， NME），命名为2E2，可安全用于患者的重复治疗，并具有预防寻求治疗的可卡因滥用者复发的长期疗效。2E2处于临床前开发的后期阶段，已经达到或超过了安全性和有效性的关键里程碑标准。在广泛的人体组织中没有发现交叉反应性，这是临床使用安全性的一个有希望的指标。在小鼠中，单抗不能穿过血脑屏障，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主要影响。因此，在大鼠复发模型中，单克隆抗体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，并提供了概念证明。临床前开发的下一阶段是完成动物体内毒理学试验。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，本II期竞争更新申请的目的是利用标准技术，通过将具有高效启动子的单抗两条链的编码基因转染到中国仓鼠卵巢（CHO）细胞中，产生一个高效可扩展的生产平台。选择在无血清培养基中产生至少0.25 gm/L 2E2的单株细胞系。CHO衍生的2E2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有效性。CHO细胞衍生的2E2的功效将由其较长的消除半衰期、阻止可卡因向大脑分布的效力以及对抗可卡因诱导的自我给药恢复的能力来确定。将最大限度地提高2E2的CHO细胞产量，并优化符合良好生产规范（GMP）标准的纯化方案。实现这些目标将加速这一主要候选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。可卡因滥用、成瘾和依赖是对我国公共卫生的重大威胁。然而，尽管针对大脑中可卡因作用部位的药物疗法进行了数十年的研究，但这些潜在的治疗可卡因滥用的方法都没有成功。另一种方法是使用单克隆抗可卡因抗体，该抗体直接针对可卡因本身并阻止其快速进入大脑。本应用程序详细研究将推进一种独特的主要人类序列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。

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.