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Molecular mechanisms of adenovirus neutralization

Award Number: R37AI107960
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: 06/01/2014
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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Molecular mechanisms of adenovirus neutralization - ABSTRACT Neutralization by pre-existing neutralizing antibodies (NAbs) is a major barrier for the development of adenovirus- based therapeutics to treat cancer and genetic disorders in affected patient populations world-wide. Immuno- profiling of sera indicates that ~98% of the US population has immunoreactivity to at least one adenovirus (Ad) serotype. When delivering an Ad-based vector intravenously, the vector is exposed to a myriad of host factors in addition to NAbs. These include non-neutralizing antibodies and components of the complement system. We have shown that pre-existing cryptic opsonizing non-neutralizing Abs, CON-Abs, generated by prior natural exposure to Ad, lead to inactivation of Ad vectors by complement. During the previous funding period we engineered a novel vector, AVID-388, that is resistant to inactivation by complement and demonstrates exceptional safety after intravenous injection in mice and non-human primates. However, AVID-388 remains susceptible to neutralization by NAbs. Our recent immunological and structural studies have led to the novel concept that the major Ad capsid protein, hexon, contains a set of localized epitopes, “neutralization hotspots.” We also made a surprising discovery while testing host responses to adenovirus type-5 (Ad5) based vectors in the context of prior immunity from other Ad serotypes, that Ad3-specific CON-Abs reduce Ad5 vector sequestration in the liver 8-fold. Based on these observations, we hypothesize that mutating newly defined “neutralization hotspots” on the Ad5 capsid is a feasible strategy for generating NAb-resistant Ad vectors. We further hypothesize that by leaving non-neutralizing capsid sites intact, reagents based on Ad3-CON-Abs may be developed that, when complexed with NAb-resistant Ad5-based vectors, will reduce liver sequestration. Therefore, in Specific Aim 1 of this project we will assess whether targeted mutation of newly proposed “neutralization hotspots” on the Ad capsid enables vectors to escape pre-existing Ad5-specific neutralizing immunity. To understand the molecular mechanisms underpinning neutralization by NAbs, we will utilize cutting-edge cryo-focused ion beam and cryo-electron tomography methodologies to analyze subcellular structures of virus-infected cells in their native, frozen-hydrated state. In Specific Aim 2 we will analyze the structural basis of NAb escape by adenovirus with “neutralization hotspot” mutations. In Specific Aim 3 we will isolate a panel of Ad3-specific Abs, which minimize liver sequestration of Ad5 vectors, and analyze their epitopes on Ad5 hexon at near-atomic resolution. In Specific Aim 4 we will analyze the safety and efficacy of a newly generated NAb-resistant Ad vector in complex with Ad3-specific Abs for therapeutic gene delivery to human hematopoietic stem cells in vivo. The proposed studies will provide a roadmap for overcoming the challenge of pre-existing NAbs to adenoviral vectors and validate a way to achieve higher gene transduction with lower vector doses. These advances will open the door for safe, effective therapeutic use of adenoviral vectors for treatment of cancer and genetic diseases in all patient populations irrespective of the presence of pre-existing immunity.


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: 2026 ( Subtotal = $806,473 )
2026	2026	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	11	6/3/2026	COMPETING CONTINUATION	$806,473
2026	2026	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	001	11	8/6/2026	COMPETING CONTINUATION	$0
														Subtotal = $806,473

Grand Total All Awards = $806,473

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Molecular mechanisms of adenovirus neutralization

Award Number: R37AI107960

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: 06/01/2014

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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