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.
