Enhanced NK cell-based targeting of HIV reservoirs through engagers and ADCC Engineering
NIAID - National Institute of Allergy and Infectious Diseases
About This Grant
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.
Grant Summary
Enhanced NK cell-based targeting of HIV reservoirs through engagers and ADCC Engineering is a NIAID - National Institute of Allergy and Infectious Diseases grant providing up to $889K for university, nonprofit, healthcare org. Applications are due 2031-07-31 (open). Check eligibility and apply with FindGrants.
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How to Apply
Up to $889K
2031-07-31
- 1Confirm your organization is eligible for Enhanced NK cell-based targeting of HIV reservoirs through engagers and ADCC Engineering from NIAID - National Institute of Allergy and Infectious Diseases, checking organization type, location, and any population or project requirements.
- 2Gather the required documents and information, including your organization details, project plan, and budget figures.
- 3Draft your application narrative and budget addressing the funder's priorities and review criteria. FindGrants can draft each section for you to review and edit.
- 4Review every section against the requirements checklist, then export a submission-ready application pack and submit it to NIAID - National Institute of Allergy and Infectious Diseases before the deadline.
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Enhanced NK cell-based targeting of HIV reservoirs through engagers and ADCC Engineering: Frequently Asked Questions
Who is eligible for the Enhanced NK cell-based targeting of HIV reservoirs through engagers and ADCC Engineering?
Enhanced NK cell-based targeting of HIV reservoirs through engagers and ADCC Engineering is offered by NIAID - National Institute of Allergy and Infectious Diseases and is generally open to university, nonprofit, healthcare org. It is open to organizations nationwide unless the funder specifies otherwise. Review the specific eligibility terms before applying, since funders set their own requirements around organization type, location, and the population or project being served.
How much funding does the Enhanced NK cell-based targeting of HIV reservoirs through engagers and ADCC Engineering provide?
Enhanced NK cell-based targeting of HIV reservoirs through engagers and ADCC Engineering provides up to $889K per award from NIAID - National Institute of Allergy and Infectious Diseases. Actual award sizes depend on the scope of your project, available program funds, and the number of applicants, so build a budget that reflects realistic, allowable costs rather than the maximum figure.
When is the Enhanced NK cell-based targeting of HIV reservoirs through engagers and ADCC Engineering deadline?
Applications for Enhanced NK cell-based targeting of HIV reservoirs through engagers and ADCC Engineering are due 2031-07-31 (open). Because deadlines can change, verify the date with the funder, NIAID - National Institute of Allergy and Infectious Diseases, and give yourself enough time to prepare a complete, competitive application before the close date.
How do you apply for the Enhanced NK cell-based targeting of HIV reservoirs through engagers and ADCC Engineering?
To apply for Enhanced NK cell-based targeting of HIV reservoirs through engagers and ADCC Engineering, confirm your eligibility, gather the required documents, and prepare a narrative and budget that address the funder's priorities. FindGrants guides you step by step and can draft each section, then exports a submission-ready application pack for this grant from NIAID - National Institute of Allergy and Infectious Diseases.