Antibody directed against S. aureus clumping factor A (ClfA)
Inventors
Tkaczyk, Christine • Sellman, Bret • BORROK, III, MARTIN • Corti, Davide • MINOLA, ANDREA
Assignees
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Publication Number
US-11970527-B2
Publication Date
2024-04-30
Expiration Date
Abstract
The present disclosure is directed to a monoclonal antibody, or antigen-binding fragment thereof, that specifically binds to a Staphylococcus aureus clumping factor A protein (ClfA), as well as compositions comprising the monoclonal antibody. The disclosure also is directed to methods of treating a Staphylococcus aureus infection by administering the anti-ClfA monoclonal antibody alone, or in combination with a monoclonal antibody that specifically binds to S. aureus alpha toxin (AT) protein to a subject. Bispecific monoclonal antibodies that specifically bind to both ClfA and AT and methods of using the same also are provided.
Core Innovation
The invention provides anti-Staphylococcus aureus antibodies that specifically bind clumping factor A (ClfA) and anti-Staphylococcus aureus alpha toxin (AT) antibodies, including compositions that comprise both activities in a single composition. The ClfA-binding antibody is defined by a variable heavy chain (VH) comprising the amino acid sequence of SEQ ID NO:13, a variable light chain (VL) comprising the amino acid sequence of SEQ ID NO:14, and a heavy chain constant domain comprising the amino acid sequence of CSYHLC (SEQ ID NO:21).
The disclosed antibodies include fully specified sequence embodiments and constant-region embodiments, such as constant-region variants comprising a YTE mutation and embodiments where the ClfA-binding constant domain sequence is specified as CSYHLC (SEQ ID NO:21) or MHEACSYHLCQKSLSLS (SEQ ID NO:23). For the AT-binding component, the invention includes embodiments where the antibody is an IgG1 antibody with a VH comprising the amino acid sequence of SEQ ID NO:15 and a VL comprising the amino acid sequence of SEQ ID NO:16.
The invention further describes performance improvements of ClfA-binding antibodies, including picomolar-affinity binding to key ClfA genotypes (ClfA001/002/004), inhibition of fibrinogen binding/agglutination, and opsonophagocytic killing. Fc-engineered variants, including SAR114-N3, SAR114-N3F, and SAR114-N3Y, are described as extending half-life and improving light stability with preserved activity, and the invention also describes combined and bispecific constructs that bind both ClfA and AT.
Claims Coverage
The identified independent claim covers a two-antibody composition with inventive sequence-defined targeting of both S. aureus ClfA and S. aureus alpha toxin (AT). Across dependent claims in the provided excerpt, inventive coverage is refined by specifying alternative fully defined VH/VL sequences, selecting specific heavy-chain constant-domain sequences, and optionally introducing a YTE mutation and specific IgG/IgG1 antibody formats.
Two-antibody ClfA and alpha toxin targeting composition
A composition comprising an antibody or antigen-binding fragment specifically binding to S. aureus ClfA protein with a VH comprising SEQ ID NO:13, a VL comprising SEQ ID NO:14, and a heavy chain constant domain comprising CSYHLC (SEQ ID NO:21), and an antibody or antigen-binding fragment specifically binding to S. aureus alpha toxin (AT) protein.
Specified ClfA VH/VL and constant-region variants
The composition includes antibodies that specifically bind S. aureus ClfA and S. aureus alpha toxin, where the ClfA-binding antibody and/or AT-binding antibody include defined VH and VL amino acid sequences using specified SEQ ID numbers, and embodiments refine the heavy-chain constant domain sequence.
YTE mutation in the heavy chain constant region
The composition of the ClfA and AT targeting composition is defined such that its heavy chain constant region includes a YTE mutation.
IgG format for the ClfA-binding antibody
The ClfA-binding antibody is specified as an IgG antibody or an antigen-binding fragment.
IgG1 AT-binding antibody with defined VH/VL
The anti-S. aureus AT protein antibody is specified as an IgG1 antibody with a VH comprising amino acid sequence SEQ ID NO:15 and a VL comprising amino acid sequence SEQ ID NO:16.
Overall, the claim coverage centers on a composition combining a sequence-defined anti-ClfA antibody with a sequence-defined anti-AT antibody, with dependent coverage refining antibody format, specifying alternative fully defined VH/VL sequence identities via SEQ ID numbers, defining specific heavy-chain constant-domain sequences, and including embodiments with a YTE mutation.
Stated Advantages
Picomolar-affinity binding to key ClfA genotypes (ClfA001/002/004).
Inhibition of fibrinogen binding/agglutination.
Opsonophagocytic killing.
Fc-engineered variants extend half-life.
Fc-engineered variants improve light stability with preserved activity.
Documented Applications
Use for treating or preventing S. aureus infection.
In vitro and in vivo evaluation in lethal bacteremia models, including diabetic db/db mice.
In vivo evaluation in lethal pneumonia models.
Characterization including bispecific construct effects with observed reduced AT neutralization/protection for SAR114-based bispecifics in some settings.
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