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Engineering potent antibodies against human cytomegalovirus

Award Number: R21AI181328
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: 03/01/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Engineering potent antibodies against human cytomegalovirus - SUMMARY Human cytomegalovirus (CMV) is an enveloped, double-stranded DNA beta-herpes virus that has co-evolved with humans for ~200 million years. Over 90% of octagenarians are seropositive for CMV antigens, often with no knowledge that they harbor the virus. While its prevalence goes relatively unnoticed by the general public, CMV is the primary infectious cause of congenital birth defects and causes significant morbidity and mortality in immunocompromised individuals. Despite considerable effort, the many therapeutic antibodies and vaccines evaluated in clinical trials have not progressed, while commonly used antivirals have significant toxicities and induce resistance. The largest vaccine trial to date observed ~50% efficacy, which correlated with non- neutralizing antibody responses, suggesting key roles for antibody-dependent effector functions in protection. A challenge in developing CMV antibody therapeutics and vaccines is the arsenal of immune evasion strategies deployed by this virus. Antibody MSL109 failed phase II trials apparently due to an escape mechanism that resulted in new viral particles being coated with MSL109. The mechanism appeared to involve viral proteins that bind human IgG Fc domains (viral Fcg receptors or vFcgRs) and impeded antibody effector functions by blocking interactions with host Fcg receptors on immune cells. We hypothesize that blocking antibody capture by viral Fcg receptors will enhance protection by anti-CMV antibodies. We will evaluate this hypothesis using two complementary aims with translational relevance. Aim 1 will engineer the human IgG1 antibody Fc to identify variants that resist vFcgR capture and could be incorporated into future anti-CMV therapeutics, while Aim 2 will evaluate the ability of antibodies whose Fab domains bind the vFcgRs to block Fc capture and thereby enhance antibody protection. The antibodies produced in this project will be rigorously characterized in vitro for antigen and host Fc receptor affinities, the ability to mediate antibody-dependent cellular cytotoxicity and prevent viral spread using CMV-infected cells in vitro since there is no simple animal model of CMV disease. The long-term goal of this research is to support development of potent antibody therapeutics and vaccines that prevent cytomegalovirus disease in high-risk populations, including newborns and organ transplant recipients. The specific objective of this proposal is to determine the impact of antibody Fc capture on anti- CMV antibody activities and the potential for strategies blocking these interactions to eliminate CMV-infected cells and prevent viral spread. The expected outcomes include (i) engineered human IgG1 Fc variants that resist capture by the two best characterized vFcgRs and (ii) determining the increased protection that can be gained by blocking Fc capture. This project will provide insights into a key CMV immune evasion strategy and the contributions of Fc-dependent functions to CMV protection with relevance for future CMV therapeutics.


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 = $0 )
2026	2025	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Allergy and Infectious Diseases Research	000	2	11/14/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $219,127 )
2025	2025	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Allergy and Infectious Diseases Research	000	2	1/16/2025	NON-COMPETING CONTINUATION	$219,127
														Subtotal = $219,127

Issue Date FY: 2024 ( Subtotal = $186,279 )
2024	2024	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Allergy and Infectious Diseases Research	000	1	2/29/2024	NEW	$167,651
2024	2024	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Allergy and Infectious Diseases Research	001	1	9/11/2024	NEW	$18,628
														Subtotal = $186,279

Grand Total All Awards = $405,406

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Engineering potent antibodies against human cytomegalovirus

Award Number: R21AI181328

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: 03/01/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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