IND-enabling program for a long-acting anti-methamphetamine monoclonal antibody for treating methamphetamine use disorder

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PROJECT ABSTRACT Nearly 1 million people in the US were diagnosed with a methamphetamine (METH) use disorder (MUD) in 2017. Once established, MUD can last a long time and is very difficult to treat. Yet there are still no FDA-approved medications indicated specifically for MUD. Anti-METH antibodies have been tested preclinically in efficacy models and have shown the ability to reduce METH’s stimulant effects in rodents. In humans, these same antibodies alter METH PK by reducing volume of distribution and likely decreasing distribution to the brain. Current antibodies would be dosed once a month; longer-acting agents would increase compliance due to less frequent dosing. The goal of this application is to identify a follow-on anti-METH monoclonal antibody with an extended half-life and conduct IND-enabling development and toxicology studies so that at the end of the project it is ready for a first-in-human clinical trial. In addition to increased compliance, the benefits of a long-acting antibody for treating MUD may include lower cost of treatment and overall better clinical outcomes. The identified antibody will also be fully humanized, which may lower the risk of antigenicity upon chronic dosing. The project will be accomplished through four Specific Aims. Aim 1 is to select the final lead candidate long- acting antibody. A panel of seven previously humanized METH-binding regions will be produced as Fabs and tested in a METH-stimulated locomotor model in rats. The best will be paired with two IgG constant domains that have selected mutations to extend their half-life. The two IgG will be compared in the same efficacy model, along with in vitro characterization, and the final candidate selected. In Aim 2, a clonal cell line and scalable manufacturing process will be developed for the final candidate IgG. A Master Cell Bank will be generated from the cell line and used for manufacture of clinical batches. A 50L run will produce material for development work and testing, then a 250L batch will be made to provide antibody for toxicology testing in Aim 3. Finally, a 500L GMP batch will be manufactured for first-in-human clinical studies. IND-enabling toxicology studies in rats will be conducted under Aim 3. A single-dose study will test IV doses up to 1.5 g/kg. A multiple-dose study will test doses up to 1 g/kg given every other week for six months. Antibody toxicokinetics and immunogenicity will be determined along with typical toxicology outcomes. Aim 4 consists of the development of the regulatory submissions and other preparations for initial clinical trials. A pre-IND meeting will be held with FDA following the completion of Aim 1, then a clinical protocol will be fully developed based on the discussion. As the program develops, the entire IND including quality, nonclinical, and FDA-specific modules will be written and submitted at the end. The expected outcome of this project is a clinic-ready humanized monoclonal antibody to treat MUD that only has to be dosed once every 2-3 months. Such a candidate would deliver improved patient outcomes with lower treatment burden and higher adherence.