PROJECT SUMMARY/ABSTRACT Our multidisciplinary translational research team has generated and developed a humanized monoclonal antibody (mAb) with a high affinity (Kd = 4 nM) for cocaine and specificity over cocaine's inactive metabolites. This unique new molecular entity (preclinical designation, h2E2) consists of a human gamma 1 (1) heavy chain and a human/mouse chimeric lamda () light chain and has approximately 95% sequence identity with a fully human IgG1. This anti-cocaine mAb has met or exceeded all the necessary pre-clinical development milestones as a therapeutic to treat cocaine use disorders. Anti-cocaine mAbs bind and sequester cocaine in the peripheral circulation and we have shown that h2E2 dramatically lowers brain cocaine concentrations in mice and in rats. Furthermore, h2E2 antagonizes the effect of cocaine in a rat model of relapse. These studies predict efficacy in human cocaine abusers. Our industry collaborator, Catalent Inc., has established a GLP Master Cell Bank (MCB) with a selected cell line that serves as the platform for the GMP manufacture of industrial quantities of purified recombinant h2E2. The recombinant h2E2 from this MCB shows no cross- reactivity in vitro with an extensive panel of human tissues, and no indications of toxicity at high doses in animal toxicology studies. These IND-enabling GLP studies predict that h2E2 will be safe for use in humans. In coordination with NIDA we have scheduled a pre-IND meeting with the FDA for early September of 2018 in preparation for the filing of an IND and then proceeding to first-in-human clinical trials to establish safety. The pharmacokinetics of h2E2 in humans will also be established and the development of any anti-h2E2 antibodies will be monitored. The successful completion of these Specific Aims will permit and inform the design of future clinical trials to assess the safety of h2E2 in the presence of cocaine and the safety of h2E2 after repeated administrations. The clinical development would then proceed to Phase II clinical efficacy trials. Given its mostly human structure, h2E2 should be safe for repeated treatments in patients and its anticipated slow clearance in humans should confer long-term efficacy. Positive outcomes of these clinical development milestones will add value to the product and facilitate commercialization.

We have generated and developed a unique humanized anti-cocaine monoclonal antibody, h2E2, and have met all of the IND-enabling pre-clinical milestones that predict its safety and efficacy in the treatment of cocaine use disorders. The overall goal of these proposed first-in-human studies is to demonstrate safety of recombinant h2E2, manufactured from a Master Cell Bank, in healthy human volunteers and to measure its pharmacokinetics in humans. The successful completion of these goals will advance the clinical development of this unique pharmacotherapeutic agent and an effective pharmacotherapy for cocaine abuse would have a major impact on this devastating public health problem.