Tuesday, May 13, 2025 5/13/2025

Targeted depletion of programmed death-1 positive cells, a method that not only stops autoimmune attack but also preserves adaptive immunity

Award Number: R01AI139535
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Targeted depletion of programmed death-1 positive cells, a method that not only stops autoimmune attack but also preserves adaptive immunity - Project Summary Autoimmune diseases (ADs) affect 50 million Americans and 12.5% of people worldwide, and for the vast majority of AD patients, there is no cure or effective prevention methods. The root cause of ADs is immune attack on self-tissues by auto-reactive effector lymphocytes and antibodies secreted by the lymphocytes. Therefore, lymphocyte suppression has been utilized as a strategy to ameliorate ADs. This strategy has yielded drugs that slow the progression of some ADs but do not prevent or cure ADs. Further, these drugs cause long-term immune deficiency and render AD patients susceptible to lethal opportunistic infections. One core reason for these deficiencies is the failure of current lymphocyte suppression drugs to focus on autoreactive effector cells. The drugs suppress and deplete native lymphocytes that do not contribute to ADs, which cause unnecessary and broad immune deficiency. Meanwhile, the current drugs fail to suppress all autoreactive effector lymphocytes: only B effector cells or only T effector cells are suppressed. To address this issue, we propose a novel lymphocyte suppression approach that encompasses all autoreactive effector cells but not naive cells. The approach utilizes the programmed death-1 receptor (PD-1) as a biomarker to identify, target and eliminate autoreactive effector cells. PD-1 is expressed on both B and T effector lymphocytes. Thus, it is possible to target all autoreactive effector lymphocytes using the PD-1 marker. More importantly, PD-1-positive (PD-1+) cells have been found to infiltrated inflamed tissues in ADs, and the infiltration is intensified while the ADs progress. An enhancement of the activity and amplification of PD-1+ cells by blocking PD-1 on these cells induced and aggravated ADs in animals and humans. On the contrary, our preliminary data showed that depletion of PD-1+ cells is very promising to treat autoimmune type-1 diabetes and chronic experimental autoimmune encephalomyelitis (EAE). On the hand, naive lymphocytes do not express PD-1, so depletion of PD-1+ cells will keep them intact. Taken together, we hypothesize that targeted depletion of PD-1-positive cells not only ameliorates in ADs but also preserves healthy immunity. To test this hypothesis, we generated an elegant protein molecule for in vivo PD-1+ cell depletion, aPD-1-ABD-PE. aPD-1-ABD-PE was designed to have three functional elements, an anti-PD-1 antibody (aPD-1) to target PD-1+ cells, an albumin-binding domain (ABD) to increase plasma presence of aPD-1-ABD-PE, and a Pseudomonas exotoxin (PE) to kill the cells that aPD-1-ABD-PE enters. aPD-1-ABD-PE has selective toxicity to PD-1+ cells. In this project, we will test the hypothesis through three specific aims: Aim 1: Characterize and prepare aPD-1-ABD-PE as a tool for targeted PD-1+ cell depletion; Aim 2: Establish that PD-1+ cell depletion ameliorates T1D, EAE, and SLE, three representative ADs; Aim 3: Establish that long-term PD-1+ cell depletion does not cause long-term immune deficiency. This project responds directly to the prominent need to improve the treatment for ADs, a priority area of study of the National Institute of Allergy and Infectious 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: 2025 ( Subtotal = $0 )
2025	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Allergy and Infectious Diseases Research	000	5	2/12/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $912,099 )
2024	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Allergy and Infectious Diseases Research	001	5	5/20/2024	NON-COMPETING CONTINUATION	$91,209
2024	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Allergy and Infectious Diseases Research	000	5	12/26/2023	NON-COMPETING CONTINUATION	$820,890
														Subtotal = $912,099

Issue Date FY: 2023 ( Subtotal = $150,861 )
2023	2023	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Allergy and Infectious Diseases Research	000	4	2/6/2023	NON-COMPETING CONTINUATION	$150,861
														Subtotal = $150,861

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Allergy and Infectious Diseases Research	000	3	12/20/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $531,480 )
2021	2021	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Allergy and Infectious Diseases Research	000	3	12/23/2020	NON-COMPETING CONTINUATION	$531,480
														Subtotal = $531,480

Issue Date FY: 2020 ( Subtotal = $543,680 )
2020	2020	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Allergy and Infectious Diseases Research	000	2	12/21/2019	NON-COMPETING CONTINUATION	$543,680
														Subtotal = $543,680

Issue Date FY: 2019 ( Subtotal = $556,805 )
2019	2019	UNIVERSITY OF UTAH, THE	201 S PRESIDENT CIRCLE RM 408	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Allergy and Infectious Diseases Research	000	1	1/24/2019	NEW	$556,805
														Subtotal = $556,805

Grand Total All Awards = $2,694,925

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Targeted depletion of programmed death-1 positive cells, a method that not only stops autoimmune attack but also preserves adaptive immunity

Award Number: R01AI139535

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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