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Engineering CAR-B cells for an HIV-1 functional cure

Award Number: R01DA056771
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Engineering CAR-B cells for an HIV-1 functional cure - SUMMARY Long-term expression of broadly neutralizing antibodies (bNAbs) has the potential to suppress an established HIV-1 infection. However, current methods for maintaining high bNAb concentrations necessary for this control are inadequate. Passive infusion of bNAbs is prohibitively expensive and requires HIV-1 positive individuals to receive infusions on a weekly or monthly basis. Delivery of bNAbs by gene-therapy vectors almost invariably raises anti-drug antibodies (ADA) against expressed bNAbs, which are immunogenic due to their extensive hypermutation. Most importantly, no single set of antibodies can adequately suppress the range of viruses in the population, in large part because current antibody delivery systems fail to do what an immune system does well: adapt to a diverse and evolving pathogen. Here we describe a series of technical advances that allow us to introduce bNAb heavy- and light-chain genes into their native loci in primary B cells. These technologies enable in vivo improvement of bNAbs through affinity maturation in mice and primates, using the acquired wisdom of the humoral response to rapidly increase antibody potency, breadth, and bioavailability. They also allow us to test the core hypothesis of this proposal that B-cell delivered bNAbs can permanently suppress an established infection in the absence of anti-retroviral therapy (ART). The chief technical advance that enables these studies is the development of an efficient double-editing technique for simultaneously replacing the variable heavy and light chain segments of B cell receptors. This is made possible through use of a newly characterized Cas12a ortholog and a unique homology-directed repair template design capable of efficiently replacing nearly any endogenous BCR variable region. The net consequence is that, unlike related B-cell editing approaches, the full regulatory apparatus of the B cell is left intact, facilitating robust B-cell development and efficient affinity maturation of the B-cell receptor. The project is divided into three aims. Aim 1 will increase the breadth and potency of three well characterized bNAbs through affinity maturation in vivo. Aim 2 will extend CRISPR editing to the Fc domain, introducing a recently described set of mutations into the IgG1 Fc domain that facilitate antibody transfer across the blood- brain barrier. Finally, Aim 3 tests the ability of primary B cells expressing the bNAbs improved in Aim 1 to control a SHIV infection in rhesus macaques. A series of structured treatment interrupts will be performed to drive CAR B proliferation and generate an individualized response to virus that emerges from the reservoir. After these structured interruptions, ART will be permanently withdrawn to determine if CAR B cells alone can control an established infection.


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 = $686,549 )
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Drug Use and Addiction Research Programs	002	4	6/27/2025	NON-COMPETING CONTINUATION	$686,549
2025	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Drug Use and Addiction Research Programs	001	2	1/29/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$435,742
2025	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Drug Use and Addiction Research Programs	000	1	1/29/2025	NEW	-$435,742
														Subtotal = $686,549

Issue Date FY: 2024 ( Subtotal = $651,390 )
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	3	6/13/2024	NON-COMPETING CONTINUATION	$651,390
														Subtotal = $651,390

Issue Date FY: 2023 ( Subtotal = $741,117 )
2023	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Drug Use and Addiction Research Programs	002	2	8/2/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$106,565
2023	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Drug Use and Addiction Research Programs	001	2	7/26/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$634,552
2023	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Drug Use and Addiction Research Programs	000	1	7/26/2023	NEW	$0
														Subtotal = $741,117

Issue Date FY: 2022 ( Subtotal = $695,020 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Drug Use and Addiction Research Programs	000	1	7/29/2022	NEW	$695,020
														Subtotal = $695,020

Grand Total All Awards = $2,774,076

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Engineering CAR-B cells for an HIV-1 functional cure

Award Number: R01DA056771

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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