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Systematic, molecular level analysis of the Fc receptor ligation on antibody effector functions

Award Number: U01AI148118
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY/ABSTRACT Fc-mediated antibody effector functions, primarily antibody dependent cell phagocytosis (ADCP) and antibody dependent cell cytotoxicity (ADCC), have been established to play a central role on the mechanism of action of therapeutic antibodies including anti-infective antibodies and immune checkpoint inhibitors. Effector functions are triggered by the crosslinking of Fc receptors (FcRs) expressed on cytotoxic leukocyte subsets following binding to target cells opsonized by multiple antibodies. Recent findings have highlighted the key role of myeloid- derived cells, on the clearance of opsonized pathogenic cells by ADCP/ADCC. Myeloid-derived effectors, express multiple FcRs, most relevant being the activating receptors FcRI, FcRIIa and FcRIIIa and the inhibitory FcRIIb. Because multivalent immune complexes (ICs) engage and activate all surface FcRs on myeloid-derived effectors to various degrees (depending on FcR expression, Fc:FcR affinity, immune complex size and antigen density) the magnitude and kinetics of the ADCP and ADCC processes are determined by the integrated outcome of the activation of all surface FcRs to various degrees. The central hypothesis to be tested here is that the quantitative understanding of ADCP and ADCC by myeloid effectors triggered by the ligation of each individual FcR by taking advantage of bulk assays and high phenotypic content single-cell cytotoxicity assays together with phosphoproteomic data to map the specific signaling events on myeloid-derived effector cells, will be essential for providing a sound framework on how to engineer the Fc domain for optimal effector functions. This work will capitalize on our unique set of aglycosylated engineered Fc domains that bind with absolute selectivity and dialed-in affinity to each FcR type. In Specific Aim 1 we will exhaustively and quantitatively map the effector phenotypes (ADCC, ADCP, cytokine release, trogocytosis) performed by human macrophages and monocytes (as well as by neutrophils and by NK cells for thoroughness) triggered by ligation of each FcR as a function of affinity, IC target size and antigen density. In Sp. Aim 2 we will use novel high throughput single cell cytotoxicity assays and on-chip cytometry to determine the precise kinetics of immune synapse formation and cell killing in ADCC (or engulfment for ADCP) as a function of FcR expression levels on individual cells and to interrogate key relevant mechanistic aspects central to these processes. In Sp. Aim 3 we will use phosphoproteomics to: (a) identify and quantitate peptide phosphorylation events triggered by each FcR and (b) detect unique FcR ligation-induced phosphopeptide signatures that correlate with effector functions triggered by that receptor.


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 = $415,059 )
2024	2024	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Allergy and Infectious Diseases Research	000	5	10/27/2023	NON-COMPETING CONTINUATION	$415,059
														Subtotal = $415,059

Issue Date FY: 2023 ( Subtotal = $461,591 )
2023	2023	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Allergy and Infectious Diseases Research	001	4	11/18/2022	NON-COMPETING CONTINUATION	$461,591
2023	2022	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Allergy and Infectious Diseases Research	000	3	11/17/2022	NON-COMPETING CONTINUATION	$0
2023	2021	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Allergy and Infectious Diseases Research	002	2	11/22/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $461,591

Issue Date FY: 2022 ( Subtotal = $461,998 )
2022	2022	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Allergy and Infectious Diseases Research	001	3	3/11/2022	NON-COMPETING CONTINUATION	$0
2022	2022	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Allergy and Infectious Diseases Research	000	3	12/1/2021	NON-COMPETING CONTINUATION	$461,998
														Subtotal = $461,998

Issue Date FY: 2021 ( Subtotal = $462,410 )
2021	2021	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Allergy and Infectious Diseases Research	000	2	11/25/2020	NON-COMPETING CONTINUATION	$462,410
														Subtotal = $462,410

Issue Date FY: 2020 ( Subtotal = $474,247 )
2020	2020	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Allergy and Infectious Diseases Research	000	1	12/19/2019	NEW	$474,247
														Subtotal = $474,247

Grand Total All Awards = $2,275,305

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Systematic, molecular level analysis of the Fc receptor ligation on antibody effector functions

Award Number: U01AI148118

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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