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The immune regulation of macrophage antibody dependent cellular phagocytosis

Award Number: U01AI148153
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/10/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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The immune regulation of macrophage antibody dependent cellular phagocytosis - Project Summary The killing of target cells by therapeutic antibodies is expanding the effective treatment options for a wide range of autoimmune diseases and cancers. Mounting evidence from mouse models, humanized mouse systems and the analysis of human tissues, indicates that macrophages are principal effectors of therapeutic antibodies, mediating the destruction of infected, malignant and immunologically aberrant cells. Fcγ receptors (FcR) on the surface of macrophages bind target-cell associated monoclonal IgG class antibodies (mAbs) to initiate antibody-dependent cellular phagocytosis (ADCP) and killing of the target cell. Patient responses to mAb therapies can vary from complete remission to minimal therapeutic effect. One poorly explored possibility is that the variability of the ADCP response is its dependence on macrophage polarization under the influence of immune modulation. Specifically, immunosuppressive environments alter macrophage polarization leading to ineffective ADCP. Conversely, stimulators of interferon genes agonists (STINGa), acting through type 1 interferons (IFN-1) can dramatically potentiate ADCP and overcome immunosuppression. Our overarching goal is to elucidate the mechanistic pathways by which macrophage activation controls FcR function and ADCP using a systems biology approach across in vivo transcriptomics and whole genome CRISPR screens. Identified gene-function relationships for ADCP will be validated in a novel vivo model and translated to human macrophages and therapeutic antibodies. We hypothesize that ADCP is regulated across major axes of macrophage polarization (M0, M1(IFNγ/LPS), M(IFN-1/STING), M2(IL4/13) and M(S)) by gene-expression changes of yet undefined genes that modulate the A:I ratios of FcRs, their signaling machinery and innate cellular recognition receptors. Our proposal has two innovative aims that will vastly expand understanding of the regulation FcR-dependent ADCP. In Aim 1, we will elucidate the macrophage genes contributing to differential FcR function and ADCP across M1, M(IFN-1/STING), M2 and M(S). This aim takes advantage of a new CRISPR-based whole genome screening strategy to identify genes that promote and inhibit ADCP in primary derived macrophages. Aim 2 will delineate macrophage gene regulation supporting FcR function and ADCP in vivo. Here we will translate findings from patient data and the CRISPR screen from Aim 1 to define regulators of ADCP in vivo. Both aims will focus on clinically relevant anti-B cell (Rituximab) and anti-T cell (CAMPATH) antibodies, and will generate findings that extend our understanding of Fc-dependent killing mechanism of ADCP.


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: 2024 ( Subtotal = $372,801 )
2024	2024	SOUTH DAKOTA STATE UNIVERSITY	940 ADMINISTRATION LN	BROOKINGS	SD	57007	BROOKINGS	USA	Allergy and Infectious Diseases Research	000	5	4/25/2024	NON-COMPETING CONTINUATION	$372,801
														Subtotal = $372,801

Issue Date FY: 2023 ( Subtotal = $373,365 )
2023	2023	SOUTH DAKOTA STATE UNIVERSITY	2201 ADMINISTRATION LANE	BROOKINGS	SD	57007	BROOKINGS	USA	Allergy and Infectious Diseases Research	000	4	4/13/2023	NON-COMPETING CONTINUATION	$373,365
														Subtotal = $373,365

Issue Date FY: 2022 ( Subtotal = $373,915 )
2022	2022	SOUTH DAKOTA STATE UNIVERSITY	2201 ADMINISTRATION LANE	BROOKINGS	SD	57007	BROOKINGS	USA	Allergy and Infectious Diseases Research	000	3	4/26/2022	NON-COMPETING CONTINUATION	$373,915
														Subtotal = $373,915

Issue Date FY: 2021 ( Subtotal = $370,159 )
2021	2021	SOUTH DAKOTA STATE UNIVERSITY	2201 ADMINISTRATION LANE	BROOKINGS	SD	57007	BROOKINGS	USA	Allergy and Infectious Diseases Research	000	2	4/23/2021	NON-COMPETING CONTINUATION	$370,159
														Subtotal = $370,159

Issue Date FY: 2020 ( Subtotal = $384,728 )
2020	2020	SOUTH DAKOTA STATE UNIVERSITY	2201 ADMINISTRATION LANE	BROOKINGS	SD	57007	BROOKINGS	USA	Allergy and Infectious Diseases Research	000	1	7/9/2020	NEW	$384,728
														Subtotal = $384,728

Grand Total All Awards = $1,874,968

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The immune regulation of macrophage antibody dependent cellular phagocytosis

Award Number: U01AI148153

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 07/10/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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