Methods and compositions for treating staphylococcal infections
Inventors
Missiakas, Dominique M. • Schneewind, Olaf • Chen, Xinhai
Assignees
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Publication Number
US-12528882-B2
Publication Date
2026-01-20
Expiration Date
Abstract
The current disclosure provides novel compositions for treating bacterial infections. Accordingly, aspects of the disclosure relate to an engineered antibody comprising: LCDR1, LCDR2, and LCDR3 of the light chain variable region of the 3F6 antibody and HCDR1, HCDR2, and HCDR3 of the heavy chain variable region of the 3F6 antibody. Also provided are compositions comprising the antibodies and nucleic acids encoding either the heavy chain or light chain (or both) of the antibodies. Other aspects relate to host cells comprising the antibodies and/or nucleic acids of the disclosure. Further aspects relate to a method of preventing or treating staphylococcal infection comprising the step of administering the antibody of the disclosure to a subject in need thereof. Yet further aspects relate to a method of making the antibody comprising expressing the nucleic acid(s) of the disclosure in a cell and isolating the expressed protein.
Core Innovation
The invention relates to engineered human IgG1 antibodies based on monoclonal antibody clone 3F6, with light chain variable region complementarity-determining regions and heavy chain variable region complementarity-determining regions linked to defined sequence identity to specified SEQ ID NOS. The antibodies further include an Fc region with Fcγ amino-acid substitutions intended to abolish staphylococcal protein A (SpA)/Sbi interference while retaining FcRn binding.
A further aspect is a constant region Fc glycosylation modification at the Fc Asn297 site, described with galactosylated Fc glycans and variants including afucosylation and de-sialylation. The Fcγ modifications are described as improving complement C1q binding and enhancing opsonophagocytic killing (OPK), and glycan remodeling identifies Fcγ glycan structures associated with effective MRSA OPK and protection.
The engineered antibodies are presented in relation to staphylococcal infection and colonization, including MRSA bloodstream infection and colonization. The content describes antibodies targeting Staphylococcus aureus-associated factors including SpA and Sbi, with functional readouts including complement pathway dependence via C1q recruitment and complement inhibition.
Claims Coverage
The independent claims cover three engineered antibody variants characterized by specific light- and heavy-chain CDRs defined by sequence identity to SEQ ID NOS, specific constant-region sequence identity to SEQ ID NO:8 including defined amino-acid substitutions, and a glycosylation-modified amino acid at position 77 of SEQ ID NO:8.
Specified CDRs and Fc constant-region substitutions with position 77 glycosylation modification
An engineered antibody comprising a light chain with LCDR1, LCDR2, and LCDR3 having at least 95% sequence identity to SEQ ID NOS: 5, 6, and 7; a heavy chain variable region with HCDR1, HCDR2, and HCDR3 having at least 95% sequence identity to SEQ ID NOS: 2, 3, and 4; and a constant region having at least 95% sequence identity to SEQ ID NO:8 and having a glutamine at position 87, a valine at position 91, a valine at position 158, and an arginine at position 215, wherein the constant region comprises a glycosylation-modified amino acid at position 77 of SEQ ID NO:8.
Specific CDR identity with arginine 215 and position 77 glycosylation modification
An engineered antibody comprising a light chain with LCDR1, LCDR2, and LCDR3 having at least 95% sequence identity to SEQ ID NOS: 5, 6, and 7; a heavy chain variable region with HCDR1, HCDR2, and HCDR3 having at least 95% sequence identity to SEQ ID NOS: 2, 3, and 4; and a constant region having at least 95% sequence identity to SEQ ID NO:8 and having an arginine at position 215, wherein the constant region comprises a glycosylation-modified amino acid at position 77 of SEQ ID NO:8.
Distinct constant-region substitutions with position 77 glycosylation modification
An engineered antibody comprising a light chain with LCDR1, LCDR2, and LCDR3 having at least 95% sequence identity to SEQ ID NOS: 5, 6, and 7; a heavy chain variable region with HCDR1, HCDR2, and HCDR3 having at least 95% sequence identity to SEQ ID NOS: 2, 3, and 4; and a constant region having at least 95% sequence identity to SEQ ID NO:8 and having an alanine at position 34, a glutamic acid at position 91, a serine at position 212, and a proline at position 214, wherein the constant region comprises a glycosylation-modified amino acid at position 77 of SEQ ID NO:8.
Across the independent claims, the core coverage is an engineered antibody with light-chain and heavy-chain CDRs meeting at least 95% sequence identity to specified SEQ ID NOS, together with a constant region meeting at least 95% sequence identity to SEQ ID NO:8 containing defined amino-acid substitutions and including a glycosylation-modified amino acid at position 77 of SEQ ID NO:8.
Stated Advantages
Galactosylation of Fc is indispensable for protection against Staphylococcus aureus bloodstream infection.
G1F and especially G2F support in vivo protection, while no protection is observed for G0F.
Enhanced C1q recruitment and complement activation via the classical pathway correlate with therapeutic activity.
Loss of protection upon complement depletion supports a complement-dependent therapeutic effect.
Afucosylated variants can promote therapeutic control and whole-blood MRSA killing even when C1q binding is reduced.
Improved complement (C1q) binding.
Enhanced opsonophagocytic killing (OPK).
Protection against MRSA bloodstream infection and colonization in mouse models.
Documented Applications
Protection against Staphylococcus aureus bloodstream infection in mice, assessed using engineered glycoforms of an anti-SpA IgG1 antibody.
Whole-blood MRSA killing in relation to fucosylation-dependent FcγR binding and complement activity.
Use of the engineered antibodies to prevent/treat staphylococcal infection/colonization, including MRSA bloodstream infection and colonization, with mouse model efficacy described.
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