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.

Public Health Relevance

This Integrated Preclinical/Clinical Program for HIV Topical Microbicides will develop a combination monoclonal antibody product for use as a vaginal microbicide to protect against sexually transmitted infections, including HIV/AIDS and HSV/gential herpes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
3U19AI096398-03S1
Application #
8803840
Study Section
Special Emphasis Panel (ZAI1-ESB-A (M2))
Program Officer
Turpin, Jim A
Project Start
2011-08-01
Project End
2016-07-31
Budget Start
2014-03-07
Budget End
2014-08-31
Support Year
3
Fiscal Year
2014
Total Cost
$27,182
Indirect Cost
Name
Boston University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
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Anderson, Deborah J; Politch, Joseph A; Zeitlin, Larry et al. (2017) Systemic and topical use of monoclonal antibodies to prevent the sexual transmission of HIV. AIDS 31:1505-1517
Zhao, Chunxia; Gunawardana, Manjula; Villinger, Francois et al. (2017) Pharmacokinetics and Preliminary Safety of Pod-Intravaginal Rings Delivering the Monoclonal Antibody VRC01-N for HIV Prophylaxis in a Macaque Model. Antimicrob Agents Chemother 61:
Daggett Jr, Gregory J; Zhao, Chunxia; Connor-Stroud, Fawn et al. (2017) Comparison of the vaginal environment in rhesus and cynomolgus macaques pre- and post-lactobacillus colonization. J Med Primatol 46:232-238
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Wessler, Timothy; Chen, Alex; McKinley, Scott A et al. (2016) Using Computational Modeling To Optimize the Design of Antibodies That Trap Viruses in Mucus. ACS Infect Dis 2:82-92
Nunn, Kenetta L; Wang, Ying-Ying; Harit, Dimple et al. (2015) Enhanced Trapping of HIV-1 by Human Cervicovaginal Mucus Is Associated with Lactobacillus crispatus-Dominant Microbiota. MBio 6:e01084-15
Chen, Alex; McKinley, Scott A; Shi, Feng et al. (2015) Modeling of Virion Collisions in Cervicovaginal Mucus Reveals Limits on Agglutination as the Protective Mechanism of Secretory Immunoglobulin A. PLoS One 10:e0131351
Anderson, Deborah J; Politch, Joseph A (2015) Role of Seminal Plasma in Human Female Reproductive Failure: Immunomodulation, Inflammation, and Infections. Adv Exp Med Biol 868:159-69
Ayehunie, Seyoum; Islam, Ayesha; Cannon, Chris et al. (2015) Characterization of a Hormone-Responsive Organotypic Human Vaginal Tissue Model: Morphologic and Immunologic Effects. Reprod Sci 22:980-90

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