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Exploiting the Hydrophobic Glycosyl Pocket of IgG1 for Imaging and Drug Delivery Applications

Award Number: R01GM140026
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Exploiting the Hydrophobic Glycosyl Pocket of IgG1 for Imaging and Drug Delivery Applications - Project Summary: Due to the rapidly growing importance of antibody-mediated drug delivery, there is a critical need for simple and efficient site-specific conjugation techniques that do not require extensive antibody engineering efforts. Moreover, there is significant need to identify sites of conjugation that are protected from plasma enzymes and are useful for the attachment of hydrophobic payloads. The goal of this proposal is to optimize conjugation technology at the conserved Q295 residue in order to meet these challenges. In contrast to most sites of conjugation, the Q295 site is contained within a large hydrophobic cavity that is sterically shielded from plasma and is particularly amenable to the conjugation of large nonpolar payloads. Remarkably, the properties of this hydrophobic pocket are largely unexplored to-date and our preliminary research shows that there are significant untapped opportunities for exploiting the unique features of this site. The goal of this project is to demonstrate the broad utility of this site-specific conjugation technology through the preparation and evaluation of antibody conjugates for oncology, immunology, and imaging applications. We will accomplish this goal through the achievement of three aims. Aim#1 focuses on developing a thorough molecular understanding of the local environment around the Q295 residue and optimizing linkers that can place the payload within the associated hydrophobic pocket. The goal of this aim is to thoroughly understand the chemical properties of the hydrophobic pocket that surrounds the Q295 moiety. Aim#2 focuses on demonstrating the therapeutic utility of this technology through the preparation of ADCs that deliver a wide range of payloads – particularly focusing on payloads that have exhibited difficulties when attached through traditional (“stochastic”) conjugation approaches. Four particular payloads were selected: MMAE (due to its clinical relevance and known linker stability issues), Tubulysin (due to interest in payloads with low PGP efflux and also a labile ester functionality that has caused problems with traditional approaches), Thailanstatin A (due to its unique mechanism of action and to the labile functional groups in its structure), and Brequinar (due to its potency as an immunosuppressive agent and its very high hydrophobicity that has so-far prevented ADC delivery). The resulting B-cell targeting ADCs will be thoroughly evaluated for their pharmacokinetic profile and efficacy in a B-cell xenograft model. Aim#3 focuses on using the Q295 site for the development of Raman imaging probes that can be used for generating live-cell time lapse images. Importantly, there have been no reported attempts to use Raman imaging to study ADC trafficking. Traditional ADC conjugation methods cannot be employed for the attachment of the Raman tags due to their very high hydrophobicity. Successful achievement of these aims will provide the drug-delivery community with a valuable new tool for site-specific conjugation of problematic payloads and will establish new imaging techniques for the study of ADC trafficking and catabolism.


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 = $308,528 )
2024	2024	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Biomedical Research and Research Training	000	4	5/20/2024	NON-COMPETING CONTINUATION	$308,528
														Subtotal = $308,528

Issue Date FY: 2023 ( Subtotal = $308,528 )
2023	2023	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Biomedical Research and Research Training	000	3	5/16/2023	NON-COMPETING CONTINUATION	$308,528
														Subtotal = $308,528

Issue Date FY: 2022 ( Subtotal = $378,638 )
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Biomedical Research and Research Training	001	2	7/28/2022	SUPPLEMENT FOR EXPANSION	$70,110
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Biomedical Research and Research Training	000	2	5/25/2022	NON-COMPETING CONTINUATION	$308,528
														Subtotal = $378,638

Issue Date FY: 2021 ( Subtotal = $308,528 )
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Biomedical Research and Research Training	000	1	7/28/2021	NEW	$308,528
														Subtotal = $308,528

Grand Total All Awards = $1,304,222

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Exploiting the Hydrophobic Glycosyl Pocket of IgG1 for Imaging and Drug Delivery Applications

Award Number: R01GM140026

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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