# Project 2: Limiting anti-drug antibodies

> **NIH NIH U19** · SCRIPPS FLORIDA · 2021 · $1,122,917

## Abstract

PROJECT SUMMARY (Project 2 – Limiting anti-drug antibodies against AAV-delivered bNAbs)
Given the remarkable collection of human monoclonal antibodies with potent neutralizing activity against a
broad range of HIV-1 isolates (bNAbs), it has become possible to envision long-term delivery of a
combination of such antibodies as a means for achieving stringent, long-term virological control in the
absence of continuing antiviral drug therapy. In preliminary data and recently published paper in
Immunity, we shown that sustained AAV-mediated expression of two bNAbs, 10-1074 and 3BNC117,
introduced 86 weeks after an untreated SHIV-AD8 infection resulted in robust long-term suppression of
viral replication for over three years. This monkey has been referred to as “the Miami monkey”. We also
nonetheless show that consistent delivery of bNAbs using AAV has been severely hampered by anti-drug
antibody (ADA) responses to the bNAb in the majority of macaques. Although the broad antibody-like
immunoadhesin eCD4-Ig is less immunogenic, it also raises ADA that could potentially limit its efficacy or
its safety in humans. This project is therefore committed to finding approaches that can effectively and
practically suppress ADA responses to an antibody, using the immunogenic bNAb 3BCN117 as our
primary test case. In this project we will evaluate three approaches for doing so: (1) elimination of CpG
motifs in the transgene, (2) oral tolerization, and (3) tolerization with a bispecific antibody that coordinates
bNAb binding to erythrocytes. In addition, we will assist in evaluating the ADA responses from different
capsids and promoters (Project 1), and those from an AAV transgene whose expression has been
delayed by four months (Project 4). We will then use the best combination of these approaches and AAV-
expressed bNAbs to establish and characterize functional cures in ART-treated and untreated rhesus
macaques. This project will therefore address a central challenge to the use AAV-expressed bNAbs for
HIV-1 prophylaxis and therapy.

## Key facts

- **NIH application ID:** 10145592
- **Project number:** 5U19AI149646-02
- **Recipient organization:** SCRIPPS FLORIDA
- **Principal Investigator:** Ronald C Desrosiers
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,122,917
- **Award type:** 5
- **Project period:** 2020-04-15 → 2022-04-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10145592

## Citation

> US National Institutes of Health, RePORTER application 10145592, Project 2: Limiting anti-drug antibodies (5U19AI149646-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10145592. Licensed CC0.

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