Monoclonal Antibody-based Multipurpose Microbicides

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DESCRIPTION (provided by applicant): This Integrated Preclinical/Clinical Program for HIV Topical Microbicides (IPCP-HTM) brings together a network of investigators to perform multidisciplinary preclinical and exploratory clinical studies with the goal of advancing a safe, novel multi-antibody topical microbicide, mapp66. Mapp66 contains a combination of three monoclonal antibodies (Mabs), produced by genetic engineering in Nicotiana benthamiana (N), that are designed to block distinct mechanisms of HIV sexual transmission: 1) neutralization of free HIV virions (4E10 and VRCOl Mab-N); and 2) prevention of herpes simplex virus (HSV) infection, a sexually transmitted pathogen that enhances HIV infection (HSV8 Mab-N). The Mab-Ns will be formulated into a biodegradable film and controlled release vaginal rings, and will be tested in vitro and in vivo for pharmacokinetics/dynamics, toxicity and anti-microbial (HIV, HSV) efficacy. Six interrelated scientific projects and an Administrative Core are proposed. Project 1 (Dr. Whaley, PI) is the critical path project that will produce cGMP Mab-Ns for the basic and preclinical studies, conduct quantitative Mab-N antibody tests to support studies performed by all projects, and submit an IND for mapp66. Project 2 (Dr. Anderson, PI) will investigate the efficacy of individual Mab-Ns and mapp66 formulations in vitro and ex vivo in cervicovaginal HIV and HSV infection assays. Project 3 (Dr. Lai, PI) will study Mab-N interactions with genital mucins, and will conduct efficacy trials with mapp66 Mabs in the murine HSV infection model. Project 4 (Drs. Moench and Smith) will produce devices (Duet, vaginal rings) with sustained Mab delivery to enhance the efficacy of this approach. Project 5 (Dr. Villinger, PI) will conduct nonhuman primate pharmacokinetic/dynamic, toxicity and SHIV-challenge studies with mapp66-gel, film and vaginal rings. Project 6 (Dr. Mayer, PI) consists of a Phase la clinical trial to assess the phamacodynamics/kinetics and safetyof mapp66-film used with and without a cervical barrier (Duet device) in women. An Administrative Core (Dr. Anderson) and executive and external advisory committees will provide scientific and administrative leadership and support in coordinating the multiple investigators and sites that make up this IPCP-HTM program.