NIH grant: Enhanced NK cell-based targeting of HIV reservoirs through engagers and ADCC Engineering (1R01AI198150-01)

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NIH grant 1R01AI198150-01: Enhanced NK cell-based targeting of HIV reservoirs through engagers and ADCC Engineering
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Luis J Montaner. Award: $889101.
Start: 2026-08-21T00:00:00.
Summary
Actively replicating HIV infected cells are the source of progeny virions and the basis of persistent reservoirs.
We will develop and test innovative strategies to eliminate actively replicating cells by enhancing NK-mediated
Antibody Dependent Cellular Cytotoxicity (ADCC) responses against HIV. Recent evidence showing the ability
of Broadly Neutralizing antibodies (BNAbs) to control viremia highlights the potential to complement the ADCC
response with exogenous BNAbs able to target diverse HIV isolates. Bi-specific antibodies also enhance HIV-1
specific ADCC by high affinity bridging between effector NK cells (through CD16 targeting) and HIV infected cells
(through envelope targeting). Tri-specific NK cell engager molecules (TriKEs) offer even more advantages for
mediating ADCC against HIV-1 infected cells via the addition of an IL-15 cytokine moiety that stimulates NK cell
activity while strengthening target cell engagement. Here, we will increase the half-life and anti-viral efficacy of
HIV-specific TriKEs via Poly Antigen Cytokine Complex (PACC) enhancement and/or by directly loading similar
IgGFc Killer Engagers ex vivo onto CD64 gene-modified NK cells that sustain Fc binding for days and are not
subject to ADAM17-mediated negative regulation like CD16. Taken together, we hypothesize that CD4/HSA
TriKE-PACC-IL-15 with an Fc component loaded onto CD64 expressing NK cells administered during
early ART will be superior to soluble TriKEs in targeting HIV infected cells, reducing persistent HIV levels
and viral rebound upon ART interruption in humanized mice. Two specific aims will test this hypothesis:
Aim 1: Generation of CD4 Ecto-Domain 1 (CD4ECD1) TriKE and CD4/HSA TriKE/PACC for half-life and anti-
viral efficacy assessment in the IL-15 transgenic NSG humanized mouse model of HIV. Two versions of
an HIV-specific CD4 Ecto-Domain 1 (CD4ECD1) targeting TriKE with IL-15 cytokine moiety as well as a single
domain antibody (sdAb/VHH) against CD16 will be created with and without a PACC complex containing the IL-
15 receptor alpha chain and human serum albumin (HSA) to enhance NK cell signaling and increase the
molecule half-life, respectively. Activity will be tested in vitro and in vivo in an ART-suppressed HIV-infected IL-
15 transgenic NSG humanized mouse model.
Aim 2: Demonstrate durable retention and anti-viral efficacy of a IgGFc Killer Engagers pre-loaded ex
vivo onto CD64 expressing NK cells in vitro and in vivo. NK cells will be genetically modified using mRNA
LNPs to express the high-affinity Fc receptor CD64 and then pre-loaded ex vivo with “IgGFc Killer Engagers”
containing a HIV-specific CD4ECD1 domain along with IL-15 and an Fc component. Activity tested as in Aim 1.
The culmination of both aims will allow us to compare and identify the best strategy between the CD4 TriKE,
CD4/HSA TriKE-PACC, or CD64 NK preloaded with IgGFc Killer Engagers for anti-viral potency on HIV reservoir
dynamics in the humanized mice. The best strategy identified will facilitate prioritizing a comprehensive single
NK cell therapy strategy to advance into human Phase I studies.

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