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Enhanced NK cell-based targeting of HIV reservoirs through engagers and ADCC Engineering

Award Number: R01AI198150
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/21/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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Enhanced NK cell-based targeting of HIV reservoirs through engagers and ADCC Engineering - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $889,101 )
2026	2026	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	1	8/21/2026	NEW	$889,101
														Subtotal = $889,101

Grand Total All Awards = $889,101

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Enhanced NK cell-based targeting of HIV reservoirs through engagers and ADCC Engineering

Award Number: R01AI198150

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/21/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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