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Engineering mono-fucosylated IgGs to fine-tune antibody-mediated effector functions

Award Number: R21AI175869
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: 02/03/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Engineering mono-fucosylated IgGs to fine-tune antibody-mediated effector functions - Monoclonal IgG antibodies (mAbs) constitute a critically important class of drugs for the treatment of a wide range of diseases. Their abilities to recruit and stimulate immune system cells, which is required for their clinical effectiveness, especially in the immunotherapeutic treatment of cancer, are harbored in their Fc domains. For clinically relevant IgG antibodies, Fc domains engage Fc γ receptors (FcγRs) and complement C1q in order to induce antibody-mediated effector functions that direct the killing of cells in vivo. Methods to engineer IgG Fc domains to manipulate their in vivo killing capacities lag substantially behind those for customizing their antigen- binding Fab domains due to the presence of a conserved N-linked glycan in the Fc domain at residue Asn297 that is overwhelmingly the most important molecular determinant of FcγR and C1q binding. The next generation of immunotherapeutic mAbs depends on our ability to efficiently and rationally modify the chemical structure of this Asn297-linked glycan. The most important molecular feature of this glycan is a fucose sugar unit connected through an α-1,6 linkage to the Asn-proximal N-acetylglucosamine (GlcNac) saccharide. The absence of this core fucose moiety imparts Fc domains with increased binding affinity to FcγR3A, an activating FcγR, resulting in substantially increased antibody-mediated in vivo cellular killing. Naturally produced antibodies, though, are fucosylated and, thus, numerous methods have been developed to create antibodies without fucosylation, resulting in three afucosylated IgG1 antibodies that have recently been approved by the FDA. Antibodies with a fucose on the Asn297-linked glycan on one Fc chain but not on the other – mono-fucosylated antibodies – present a third fucosylation state that could provide fine-tuning of antibody-mediated effector functions, thereby expanding the ability to balance efficacy and toxicity for the treatment of a wide range of diseases. However, mono-fucosylated antibodies do not exist in nature and have never been produced or engineered. Here we propose methods to create mono-fucosylated IgG antibodies for the first time and to assess the biological consequences of antibody mono-fucosylation. We hypothesize that mono-fucosylated IgG antibodies will exhibit biophysical and functional properties distinct from those of fully afucosylated and di-fucosylated IgG antibodies, which can be leveraged to develop a new class of immunotherapeutic monoclonal antibodies that will induce levels of antibody-mediated effector functions optimal for certain clinical indications. This work is significant because it develops and explores an entirely new class of engineered antibodies that could become important for the immunotherapeutic treatment of cancer. The proposed studies are innovative in that they will investigate an entirely novel concept – mono-fucosylated antibodies – with the potential to manipulate antibody-mediated effector functions in ways that have never been explored before. The research plan will be accomplished by leveraging our expertise in IgG-specific glycan remodeling, molecular biophysics and structural biology.


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: 2025 ( Subtotal = -$1,847 )
2025	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	2	5/5/2025	NON-COMPETING CONTINUATION	-$1,847
														Subtotal = -$1,847

Issue Date FY: 2024 ( Subtotal = $234,750 )
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	2	1/8/2024	NON-COMPETING CONTINUATION	$211,275
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	001	2	5/22/2024	NON-COMPETING CONTINUATION	$23,475
														Subtotal = $234,750

Issue Date FY: 2023 ( Subtotal = $195,625 )
2023	2023	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	001	1	7/24/2023	NEW	$0
2023	2023	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	1	2/3/2023	NEW	$195,625
														Subtotal = $195,625

Grand Total All Awards = $428,528

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Engineering mono-fucosylated IgGs to fine-tune antibody-mediated effector functions

Award Number: R21AI175869

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: 02/03/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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