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Bispecific and Trispecific Anti-Env Antibodies for Eliminating HIV Reservoir Cells

Award Number: R01AI129802
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: 07/10/2017
PERIOD OF PERFORMANCE END DATE: 06/30/2023

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Bispecific and Trispecific Anti-Env Antibodies for Eliminating HIV Reservoir Cells - PROJECT SUMMARY/ABSTRACT Antibodies constitute a powerful weapon to fight viral infections. They could neutralize the infectivity of virus particles as well as mediate killing of productively infected cells via mechanisms such as antibody-dependent cell-mediated cytotoxicity (ADCC). In the past five years, our group has utilized the advances made in the antibody engineering field, as well as the growing lists of broadly neutralization antibodies (bNAbs) identified by other investigators, to construct new bispecific antibodies that have exquisite antiviral breadth and potency for the purpose of HIV-1 prevention. Now, with this proposal, we wish to expand our antibody engineering effort to generate a collection of bispecific and trispecific antibodies that are optimized for killing of Env-expressing cells, and for important properties such as pharmacokinetics. Instead of screening for virus-neutralization activity as we have previously done, we will now engineer and screen a library of Env-targeting multi-specific antibodies for cell-binding and cell-killing activities in vitro. The best performing antibody constructs will then be evaluated systematically in vivo in a humanized mouse model for the effect on their cell-killing capacity, their ability to restrict or eliminate latent reservoir cells after activation, and their ability to prevent or limit the establishment of the HIV-1 latent reservoir. Along with our knowledge of HIV-1 bNAbs and antibody engineering, our deep understanding of viral dynamics and our prior experience studying the HIV-1 latent reservoir will be brought to bear on the design, conduct, and interpretation of experiments to evaluate and quantify the antiviral effects of our top antibody constructs in humanized mice. Our group has successfully engineered two bispecific antibodies with exquisite HIV-1-neutralizing activity, and we have since extended our know-how in antibody engineering to the construction of bispecific or trispecific antibodies that target Env for the purpose of facilitating the elimination of infected cells. In the end, we hope to offer to the field one or two multi-specific antibodies that could be applied toward the elimination of latent reservoir cells as one critical component of a multi-pronged approach to HIV-1 eradication.


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 = $0 )
2024	2021	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Allergy and Infectious Diseases Research	000	6	3/25/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $713,872 )
2021	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Allergy and Infectious Diseases Research	000	6	6/23/2021	NON-COMPETING CONTINUATION	$713,872
														Subtotal = $713,872

Issue Date FY: 2020 ( Subtotal = $634,203 )
2020	2020	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Allergy and Infectious Diseases Research	003	5	7/27/2020	NON-COMPETING CONTINUATION	$715,773
2020	2019	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Allergy and Infectious Diseases Research	001	4	1/17/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$368,083
2020	2019	AARON DIAMOND AIDS RESEARCH CENTER FOR THE CITY OF NEW YORK, INC., THE	455 FIRST AVE 7TH FL	NEW YORK	NY	10016	NEW YORK	USA	Allergy and Infectious Diseases Research	002	3	5/12/2020	NON-COMPETING CONTINUATION	$0
2020	2019	AARON DIAMOND AIDS RESEARCH CENTER FOR THE CITY OF NEW YORK, INC., THE	455 FIRST AVE 7TH FL	NEW YORK	NY	10016	NEW YORK	USA	Allergy and Infectious Diseases Research	000	3	1/17/2020	NON-COMPETING CONTINUATION	-$449,653
														Subtotal = $634,203

Issue Date FY: 2019 ( Subtotal = $893,315 )
2019	2019	AARON DIAMOND AIDS RESEARCH CENTER FOR THE CITY OF NEW YORK, INC., THE	455 FIRST AVE 7TH FL	NEW YORK	NY	10016	NEW YORK	USA	Allergy and Infectious Diseases Research	000	3	7/2/2019	NON-COMPETING CONTINUATION	$893,315
														Subtotal = $893,315

Issue Date FY: 2018 ( Subtotal = $910,463 )
2018	2018	AARON DIAMOND AIDS RESEARCH CENTER FOR THE CITY OF NEW YORK, INC., THE	455 FIRST AVE 7TH FL	NEW YORK	NY	10016	NEW YORK	USA	Allergy and Infectious Diseases Research	000	2	6/29/2018	NON-COMPETING CONTINUATION	$910,463
														Subtotal = $910,463

Issue Date FY: 2017 ( Subtotal = $930,446 )
2017	2017	AARON DIAMOND AIDS RESEARCH CENTER FOR THE CITY OF NEW YORK, INC., THE	455 FIRST AVE 7TH FL	NEW YORK	NY	10016	NEW YORK	USA	Allergy and Infectious Diseases Research	001	1	7/6/2017	NEW	-$13,838
2017	2017	AARON DIAMOND AIDS RESEARCH CENTER FOR THE CITY OF NEW YORK, INC., THE	455 FIRST AVE 7TH FL	NEW YORK	NY	10016	NEW YORK	USA	Allergy and Infectious Diseases Research	000	1	7/5/2017	NEW	$944,284
														Subtotal = $930,446

Grand Total All Awards = $4,082,299

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Bispecific and Trispecific Anti-Env Antibodies for Eliminating HIV Reservoir Cells

Award Number: R01AI129802

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: 07/10/2017

PERIOD OF PERFORMANCE END DATE: 06/30/2023

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