Thursday, January 1, 2026 1/1/2026

Structure, Function and Mechanistic Analysis of LAG3

Award Number: R01AI144422
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: 01/08/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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Structure, Function and Mechanistic Analysis of LAG3 - PROJECT SUMMARY LAG3 (CD233) is an inhibitory receptor that plays a critical role in controlling T cell tolerance, preventing autoimmunity and limiting immune-mediated tissue damage. It is highly upregulated on exhausted T cells in tumors and in chronic viral infections, limiting the development of sterilizing immunity. Consequently, LAG3 is now a major immunotherapeutic target for the treatment of cancer and other diseases. In early 2022, the FDA approved a combinatorial treatment with anti-PD1 and anti-LAG3 for treatment of metastatic melanoma. Despite extensive analysis of LAG3 for over 33 years and with more than 20 LAG3 targeting therapeutic antagonists in the clinic, there is still a considerable number of critical, unanswered questions regarding how LAG3 works and thus whether we have, and how we might develop, not only more optimal LAG3-targeting therapeutic antagonists but also therapeutic agonists to treat autoimmune and inflammatory diseases. Therefore, our goal for this proposal is to gain critical insight into the requirements for optimal LAG3 function enabling us to design more efficacious immunotherapeutic strategies that block or enhance LAG3 function. AIM 1: Determine the impact of EP-mediated LAG3 signaling and its importance relative to other motifs. We will address 2 questions: (A) What is the importance of the LAG3 EP motif in vivo relative to other motifs? (B) What is the relative importance, hierarchy and functional impact of all LAG3 motifs? AIM 2: Define LAG3-TCR/CD3 association and its functional relevance compared to MHCII and FGL1. We will address the structural basis for the biological function of LAG3 by asking 4 questions: (A) Which regions/residues mediate LAG3 interaction with TCR/CD3 and are they distinct from those that mediate MHCII or FGL1 interaction? (B) What is the relative importance of LAG3 association with TCR/CD3 versus MHCII and FGL1 in mediating its function? (C) Do current clinical antibodies disrupt LAG3 association with TCR/CD3 and/or FGL1 relative to MHCII? (D) Can we enhance LAG3 function? AIM 3: Define the functional impact of LAG3 dimerization. We will address 3 questions: (A) What are the functional consequences of monomeric versus dimeric LAG3? (B) Does the proportion LAG3 dimer on the cell surface change depending upon activation status? (C) Can LAG3 dimerization be modulated by anti-LAG3 mAbs? Given our extensive analysis of LAG3 function for ~25 years, the unique tools we have in hand, and our strong and technically diverse collaborative team, we are ideally positioned to conduct this research. Successful completion of this project will significantly enhance our understanding of LAG3 function and mechanism of action, providing key insight to generate enhanced LAG3 therapeutics that can improve treatment for multiple diseases.


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 = $768,273 )
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	8	12/29/2025	NON-COMPETING CONTINUATION	$768,273
														Subtotal = $768,273

Issue Date FY: 2025 ( Subtotal = $745,225 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	7	1/7/2025	NON-COMPETING CONTINUATION	$745,225
2025	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	002	6	1/21/2025	COMPETING CONTINUATION	$76,802
2025	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	001	5	1/21/2025	NON-COMPETING CONTINUATION	-$76,802
														Subtotal = $745,225

Issue Date FY: 2024 ( Subtotal = $783,023 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	002	6	9/4/2024	COMPETING CONTINUATION	$74,777
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	001	6	2/21/2024	COMPETING CONTINUATION	$708,246
2024	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	5	2/20/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $783,023

Issue Date FY: 2023 ( Subtotal = $711,977 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	5	12/22/2022	NON-COMPETING CONTINUATION	$711,977
														Subtotal = $711,977

Issue Date FY: 2022 ( Subtotal = $711,977 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	4	12/17/2021	NON-COMPETING CONTINUATION	$711,977
														Subtotal = $711,977

Issue Date FY: 2021 ( Subtotal = $711,977 )
2021	2021	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	3	12/10/2020	NON-COMPETING CONTINUATION	$711,977
														Subtotal = $711,977

Issue Date FY: 2020 ( Subtotal = $711,977 )
2020	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	2	12/31/2019	NON-COMPETING CONTINUATION	$711,977
														Subtotal = $711,977

Issue Date FY: 2019 ( Subtotal = $726,102 )
2019	2019	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	1	1/8/2019	NEW	$726,102
														Subtotal = $726,102

Grand Total All Awards = $5,870,531

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Structure, Function and Mechanistic Analysis of LAG3

Award Number: R01AI144422

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: 01/08/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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