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B-cell-specific transduction for anti-HIV antibody and B-cell receptor expression

Award Number: R01AI145044
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: 02/15/2019
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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B-cell-specific transduction for anti-HIV antibody and B-cell receptor expression - PROJECT SUMMARY Neutralizing antibodies against HIV-1 are very potent in suppressing HIV-1 replication. However, the serum concentrations of the antibodies must be kept at therapeutic levels for long periods of time to eliminate HIV-1-infected cells, because persistently infected cells reside in the deep tissue. Therefore, multiple administrations of the antibodies are required, which could be expensive and labor-intensive. Gene therapy vectors can be used to produce therapeutic antibodies. However, transgene expression by any gene therapy vectors, including lentiviral vectors, can induce immune reactions against the transgenes, thereby decreasing the therapeutic effects of transgene products and eliminating the transduced cells. Therefore, it is important to express transgenes in the cell types that can develop tolerance to transgene products. B-cells physiologically express wide varieties of valuable antibody regions generated by recombination and mutations in genes. B-cells are known to induce tolerance to the valuable regions. This ability of B-cells was previously used to induce tolerance to self-antigens for therapy of autoimmune diseases and coagulation factor IX for treatment of hemophilia. Therefore, transduction of B-cells is likely to generate long-term anti-HIV-1 antibodies without inducing immune reactions to the antibodies. We have developed lentiviral vectors that can specifically transduce desired target cell types after systemic administration. The vector can selectively transduces splenic B-cells without conjugation of any B-cell-targeting ligand. By exploiting this B-cell-specific transduction by our lentiviral vectors, we will attempt to express anti-HIV-1 proteins specifically in B-cells to develop tolerance to the transgene products. We will further increase specificity of transgene expression with our targeting vector by combining it with transcriptional B-cell targeting by a B-cell-specific promoter. Using this highly B-cell-specific transgene expression system, we will express eCD4-Ig, a highly potent anti-HIV-1 reagent consisting of IgG and soluble CD4, in immunocompetent mice. We will investigate whether eCD4-Ig expression, specifically in B-cells, can induce long-term expression of eCD4-Ig by inducing developing tolerance. We will next express both secretory and membrane-anchored forms of eCD4-Ig in B-cells to generate an anti-HIV-1 B-cell receptor (BCR) on B-cells. We will investigate whether anti-HIV-1 BCR elicits signals upon binding to the HIV-1 envelope protein, inducing differentiation and growth of the transduced cells. The growth of transduced B-cells will increase the serum concentrations of eCD4-Ig. Differentiation of transduced cells to memory B-cells and plasma cells will extend the period of eCD4-Ig expression by prolonging the life span of transduced B-cells. We will then evaluate the therapeutic effects of B-cell-specific expression of eCD4-Ig in HIV-1 infection of humanized BLT mice. These experiments are designed to develop a novel gene therapeutic antibody that can be applied not only to therapy of HIV-1 infection, but also other types of 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	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	5	6/2/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $390,000 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	5	1/13/2023	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2022 ( Subtotal = $390,000 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	4	1/12/2022	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2021 ( Subtotal = $390,000 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	3	1/12/2021	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2020 ( Subtotal = $390,000 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	2	1/14/2020	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2019 ( Subtotal = $390,000 )
2019	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	1	2/15/2019	NEW	$390,000
														Subtotal = $390,000

Grand Total All Awards = $1,950,000

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B-cell-specific transduction for anti-HIV antibody and B-cell receptor expression

Award Number: R01AI145044

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: 02/15/2019

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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