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Engineering monoclonal antibodies against Staphylococcus aureus

Award Number: R01AI148543
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: 12/13/2019
PERIOD OF PERFORMANCE END DATE: 01/31/2030

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Engineering monoclonal antibodies against Staphylococcus aureus - ABSTRACT Staphylococcus aureus infection is a frequent cause of sepsis in humans, a disease associated with high mortality and without specific intervention. The development of immune therapeutics, vaccines and monoclonal antibodies against S. aureus, has been a major goal since the discovery of this pathogen. These approaches have focused on antigen selection, targeting key secreted toxins or bacterial surface molecules such as capsular polysaccharides; the former aiming to harness neutralizing antibodies, the latter, complement-fixing antibodies. However, many clinical isolates of S. aureus do not produce capsular polysaccharides, and several failed clinical trials have taught us that toxin-neutralization is not sufficient to ameliorate disease (NCT02940626, NCT01589185, NCT03816956). Here, we propose to pursue monoclonal antibodies, 3F6 and 2A12, that target the surface proteins, SpA and ClfA, respectively. Why these antigens? SpA is conserved and extremely abundant on the bacterial cell surface where it binds the constant region (Fcg) of IgG thereby blocking the effector functions of antibodies. ClfA is the agglutinating factor of S. aureus, it promotes the shielding of bacteria in fibrin cables and their physical escape from phagocytes. Our earlier work demonstrated that the constant region of humanized 3F6-hIgG1 can be optimized with Fcg amino acid substitutions to escape inhibition by SpA. Further, Fc g interactions with complement component 1q (C1q) or Fc g-receptors to promote complement- dependent or antibody-dependent cell-mediated phagocytosis, respectively, can be controlled by engineering Fcg glycans at Asn 297. Here, we will compare antibodies for their ability to reduce bacterial replication in freshly drawn blood and in blood stream models of infection and re-infection in adult and neonatal mice. We will ask if S. aureus clearance by 3F6 antibodies is augmented when agglutination is simultaneously inhibited by anti-ClfA antibodies (2A12) and whether phagocytic uptake is more efficient when antibodies engage C1q or Fc g-receptors. We will also generate 3F6 and 2A12 IgM variants as multimeric IgM is the most potent activator of C1q. Using this collection of antibodies, we propose to identify the cells that promote the clearance of antibody-bound bacteria and the pathways activated by these immune complexes. A future goal of this research is to exploit monoclonal antibodies to promote both the clearance and uptake of this pathogen by antigen presenting cells to improve immune outcomes and curb the problem of recurring infections.


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 = $2,855,920 )
2026	2026	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	6	2/6/2026	COMPETING CONTINUATION	$2,855,920
														Subtotal = $2,855,920

Issue Date FY: 2025 ( Subtotal = -$232,329 )
2025	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	5	9/8/2025	NON-COMPETING CONTINUATION	-$232,329
														Subtotal = -$232,329

Issue Date FY: 2024 ( Subtotal = $540,443 )
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	001	5	5/15/2024	NON-COMPETING CONTINUATION	$54,044
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	5	10/30/2023	NON-COMPETING CONTINUATION	$486,399
														Subtotal = $540,443

Issue Date FY: 2023 ( Subtotal = $524,243 )
2023	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	4	11/3/2022	NON-COMPETING CONTINUATION	$524,243
														Subtotal = $524,243

Issue Date FY: 2022 ( Subtotal = $524,243 )
2022	2022	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	3	11/12/2021	NON-COMPETING CONTINUATION	$524,243
														Subtotal = $524,243

Issue Date FY: 2021 ( Subtotal = $522,623 )
2021	2021	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	2	11/24/2020	NON-COMPETING CONTINUATION	$522,623
														Subtotal = $522,623

Issue Date FY: 2020 ( Subtotal = $536,503 )
2020	2020	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	001	1	6/1/2020	NEW	$0
2020	2020	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	1	12/13/2019	NEW	$536,503
														Subtotal = $536,503

Grand Total All Awards = $5,271,646

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Engineering monoclonal antibodies against Staphylococcus aureus

Award Number: R01AI148543

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: 12/13/2019

PERIOD OF PERFORMANCE END DATE: 01/31/2030

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