# Bispecific-Antibody-Drug Conjugates for Selective Targeting and Activation of the HIV Latent Reservoir

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $496,151

## Abstract

PROJECT SUMMARY/ABSTRACT
Latent HIV reservoirs, primarily comprised of HIV-infected and long-lived subpopulations of CD4+ resting
memory T cells are established during the earliest stage of infection. While currently available antiretroviral
therapies (ART) can reduce the level of HIV in blood to an undetectable level, they cannot eliminate the latent
reservoir, thereby imposing a major obstacle to curing the infection. A number of latency reversal agents
(LRAs) has shown activity in vitro, but all have little or no impact on the latent reservoir in clinical trials to date.
Because increasing the doses of LRAs is prohibitive in their current forms due to the potential for increased
systemic toxicity, alternative strategies for the specific targeting and activation of the latent HIV reservoir are
needed. We therefore propose to harness the exquisite specificity of monoclonal antibodies (mAbs) and to
further increase their specificity through the construction of bispecific antibodies for targeting the HIV latent
reservoir. We will engineer a panel of bispecific antibodies capable of targeting the narrow subsets of CD4+
resting memory T cells that have been characterized as the likely HIV reservoir cells in blood and tissues. We
will then conjugate a panel of LRAs to each of the promising bispecific antibodies to deliver such agents
preferentially to the latently infected cells. To evaluate the activity of all of our engineered bispecific antibodies
and antibody-drug conjugates (ADCs), we will take an iterative approach to assess binding affinity and avidity,
selectivity of LRA delivery, and HIV activation from the latent reservoir in vitro or ex vivo. The ADCs with the
most promising in vitro or ex vivo properties will be further evaluated for their impact on the latent reservoir in
vivo using a humanized mouse model of HIV infection and treatment. The underlying hypothesis of the
proposed studies is that the use of bispecific antibodies to concentrate LRAs in cell populations harboring
latent HIV, while minimizing the exposure to cells that are virus free, could markedly increase the therapeutic
index of LRAs by several orders of magnitude. We believe that our proposal offers a promising and novel
strategy for highly specific and potent activation of HIV reservoir cells, and it is our belief that one or several of
our engineered antibody drug conjugates could become a key component in a multi-pronged approach to
eliminating the latent reservoir and curing HIV-1 infection.

## Key facts

- **NIH application ID:** 10222490
- **Project number:** 5R01AI134328-06
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** DAVID D HO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $496,151
- **Award type:** 5
- **Project period:** 2017-07-25 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10222490

## Citation

> US National Institutes of Health, RePORTER application 10222490, Bispecific-Antibody-Drug Conjugates for Selective Targeting and Activation of the HIV Latent Reservoir (5R01AI134328-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10222490. Licensed CC0.

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