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Ultralong CDR3 antibodies targeting exhausted T cells

Award Number: R21AI144828
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: 02/11/2020
PERIOD OF PERFORMANCE END DATE: 01/31/2023

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Ultralong CDR3 antibodies targeting exhausted T cells - Abstract T cell exhaustion prevents effective immune responses against many tumors and chronic infectious diseases. Several antibody drugs termed “checkpoint inhibitors” target receptors (e.g. PD-1, PD-L1, CTLA4) on exhausted T cells and can reverse their phenotype, leading to re-activation and the ability to function as killer cells. While molecules such as PD-1, PD-L1, LAG-3, Tim-3, TIGIT and ICOS have been described as markers of exhausted T cells, the cell surface phenotype is insufficiently defined; thus, more markers and possible drug targets may exist on the surface of exhausted T cells. Cluster of Differentiation (or “CD”) molecules were traditionally defined based on the reactivity of monoclonal antibodies to the cell surface of leukocytes. These antibodies were identified by immunizing rodents with preparations of white blood cells. It has recently become clear that the antibody repertoires of different species are dramatically different with regards to their structural diversity. Cows, in particular, have heavy chain complementarity determining regions (CDR H3s) of up to 70 amino acids in length comprised of novel -ribbon “stalk” and disulfide bonded “knob” mini domain structures. This contrasts with rodents, where antibodies for most CD molecules were discovered, whose antibodies have flat binding surfaces comprised of very short (10 amino acids) CDR H3 loops. Cow antibodies have the ability to bind epitopes that are relatively refractory to other species’ repertoires, and provide a novel opportunity to further define the exhausted T cell surface. To this end, we will immunize cattle with exhausted T cells and identify unique antibody:antigen pairs and demonstrate functional activity of the antibodies by in vitro and in vivo reversal of the exhausted T cell phenotype. Antibodies from this research could serve as experimental therapeutics for cancer or chronic infection, diagnostics, or important research tools to further define exhausted T cell subsets and differentiation pathways.


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 = -$1,392 )
2024	2021	APPLIED BIOMEDICAL SCIENCE INSTITUTE	11011 VIA FRONTERA	SAN DIEGO	CA	92127	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	2	3/9/2024	NON-COMPETING CONTINUATION	-$1,392
														Subtotal = -$1,392

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	APPLIED BIOMEDICAL SCIENCE INSTITUTE	11011 VIA FRONTERA	SAN DIEGO	CA	92127	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	2	8/15/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $234,525 )
2021	2021	APPLIED BIOMEDICAL SCIENCE INSTITUTE	10929 TECHNOLOGY PL	SAN DIEGO	CA	92127	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	2	1/25/2021	NON-COMPETING CONTINUATION	$234,525
														Subtotal = $234,525

Issue Date FY: 2020 ( Subtotal = $303,450 )
2020	2020	APPLIED BIOMEDICAL SCIENCE INSTITUTE	10929 TECHNOLOGY PL	SAN DIEGO	CA	92127	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	1	9/16/2020	NEW	$0
2020	2020	APPLIED BIOMEDICAL SCIENCE INSTITUTE	10929 TECHNOLOGY PL	SAN DIEGO	CA	92127	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	1	2/11/2020	NEW	$303,450
														Subtotal = $303,450

Grand Total All Awards = $536,583

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Ultralong CDR3 antibodies targeting exhausted T cells

Award Number: R21AI144828

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: 02/11/2020

PERIOD OF PERFORMANCE END DATE: 01/31/2023

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