Project 5: Pre-Clinical Evaluation of mAb Microbicide Products in Nonhuman Primates

In the absence of an efficient vaccine, prevention of HIV transmission remains the primary and economically feasible infection prevention method available to date. Unfortunately, condoms have remained the single most effective method available to date, and such prevention method is not necessarily available or acceptable ini certain communities. Thus the rationale for well tolerated and efficacious microbicides are a given as highlighted in this proposal. Unfortunately, previous clinical trials with promising microbicide formulations have not only failed to protect from transmission but in certain cases have even had the opposite effect by facilitating viral passage through the mucosa. These findings dictate the need for thorough pre-clinical safety and efficacy testing using an animal model representative of man. This project aims to use the nonhuman primate model to fulfill these pre-requisites before moving to the clinical arena.

The project will therefore utilize a total of 55 cycling female cynomolgus macaques to evaluate the biodistribution,  pharmacokinetics and potential localized and systemic toxicity of HEC gel versus vaginal rings or mucoadhesive films formulated to release monoclonal antibodies capable of neutralizing a wide variety of HIV isolates and HSV-2gD into the vaginal environment. An initial dose finding study will be performed to identify protective doses for each HIV mAb agains multiple low dose esposures to a clade B SHIV. This data will be used to formulate a combined mAb dose to deliver via films or intravaginal rings as compared to gel. After completion of pharmacokinetics and pharmacodynamic studies, this combination delivered via stable mucoadhesive films  will be tested for protective efficacy against repeated low dose SHIV challenges. Finally, in Specific Aim 4, we will compare delivery of the mAbs via IVR to films for protective efficacy against multiple vaginal exposures to either a clade B or C SHIV with a final high dose challenge as a final test of protection. Outcome of these preclinical studies will provide invaluable data for the validation and optimization of subsequent phase I and II human clinical trials.

Specific Aims:

Specific Aim 1: What are the minimal effective doses of recombinant broadly HIV neutralizing 4E10 and VRC01 monoclonal antibodies needed to prevent vaginal transmission of a CCR5 tropic SHIV infection in macaque monkeys using repeated low dose challenges?

Specific Aim 2: Can the combination of two HIV (4E10 and VRC01) and one HSV neutralizing mAbs delivered via mucoadhesive films or intravaginal ring deliver and distribute monoclonal antibodies in the mucosal environment with residence time and levels similar to HEC gel formulation? How much mAb delivered via either method will be needed to prevent infection? What is the potential acute and chronic toxicity of mAb delivered to the vagina via gel, film or ring? How deep will 4E10 mAbs penetrate vaginal epithelium to block HIV from docking to resident target cells?

Specific Aim 3: Does repeated daily dosing of map66 provide superior protection from infection compared to single pre-challenge dosing using multiple low dose and a final high dose vaginal challenge with a pathogenic infectious CCR5 tropic SHIV?

Specific Aim 4: How do monoclonal antibodies delivered from a vaginal ring compare to daily mapp66 administration intravaginally in providing protection from infection following multiple low doses and a final high dose vaginal challenge with a pathogenic infectious CCR5 tropic SHIV?

Data from these experiments in the nonhuman primate model will guide decisions concerning the critical parameters of product format, dose and dosing regimen that will be invaluable for the optimization of this mAb-based microbicide product in advance of clinical safety and efficacy studies.