Human monoclonal antibody against S. aureus derived alpha-toxin and its use in treating or preventing abscess formation
Inventors
Rudolf, Michael • Koch, Holger
Assignees
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Publication Number
US-9249215-B2
Publication Date
2016-02-02
Expiration Date
Abstract
The present invention includes a human monoclonal antibody specific for the alpha-toxin of S. aureus, a hybridoma producing it, nucleic acids encoding it, and host cells transfected therewith. Further, the present invention includes methods for producing the monoclonal antibody. In addition, the present invention includes pharmaceutical compositions comprising at least one antibody or at least one nucleic acid encoding the antibody. Further, the present invention includes the use of the monoclonal antibody for treating or preventing abscess formation.
Core Innovation
A monoclonal antibody (mAb 243-4) specific for Staphylococcus aureus alpha-toxin is described. The antibody includes variable-region features defined by sequence information, including light-chain CDRs and heavy-chain CDRs, and corresponding variants or muteins with sequence-defined characteristics. Binding specificity for alpha-toxin of S. aureus is described for the antibody or its binding fragments.
The variable region of the light chain and the variable region of the heavy chain are defined using sequence identifiers, and the antibody is provided as an antibody or a binding fragment. Binding fragments include Fab, F(ab')2, single chain, or domain antibody formats, each retaining specific binding to S. aureus alpha-toxin. The described sequence-defined features are used to characterize the binding activity to alpha-toxin.
The document further characterizes binding specificity and affinity using toxin-panel specificity and binding assays, and it provides characterization of binding across epidemic strains. The antibody is also described as protecting cells in a toxin challenge context and as reducing bacterial load and abscess formation in vivo in a multiorgan infection model. Pharmaceutical composition and diagnostic kit concepts are also described in connection with detecting alpha-toxin or S. aureus infection.
Claims Coverage
The provided independent claim set includes one independent claim directed to a sequence-defined monoclonal antibody or binding fragment that specifically binds S. aureus alpha-toxin, with further independent claim coverage for specified fragment formats and uses. The main inventive features are grounded in the defined light- and heavy-chain variable-region sequences and the specified binding to S. aureus alpha-toxin.
Sequence-defined light- and heavy-chain variable regions for alpha-toxin binding
A monoclonal antibody or binding fragment thereof specific for alpha-toxin of S. aureus, wherein the variable region of the light chain comprises the amino acid sequence of SEQ ID NO: 27 and the variable region of the heavy chain comprises the amino acid sequence of SEQ ID NO: 8.
Specific binding to S. aureus alpha-toxin
The antibody or the binding fragment specifically binds to alpha-toxin of S. aureus.
Alpha-toxin-binding antibody in antibody fragment formats
The antibody binding fragment is a Fab, F(ab')2, single chain or domain antibody.
Human antibody format
The monoclonal antibody or fragment is specified such that the antibody is a human antibody.
Lambda-type light chain
The monoclonal antibody or fragment has a lambda-type light chain.
Binding to monomeric and oligomeric alpha-toxin forms
The monoclonal antibody or fragment thereof specifically binds monomeric and oligomeric forms of Staphylococcus aureus alpha-toxin.
Administration to promote prophylaxis or treatment of abscess formation
A method for treating an abscess or providing prophylaxis to promote abscess formation in an organ by administering to the organ a monoclonal antibody of claim 1.
Diagnostic test kit for detecting S. aureus infection
A diagnostic test kit for detecting Staphylococcus aureus infection in a sample using at least one monoclonal antibody or fragment.
Overall, the claims coverage centers on a monoclonal antibody or binding fragment defined by specific light- and heavy-chain variable-region sequences that specifically binds S. aureus alpha-toxin, with further refinements including specified fragment formats, human/lambda characteristics, binding to monomeric and oligomeric alpha-toxin forms, and downstream uses in abscess prophylaxis or treatment and in a diagnostic test kit.
Stated Advantages
Reduces bacterial load and absence of kidney abscess formation in treated mice in a multiorgan infection context.
Provides cell protection in a toxin challenge context.
Provides specificity and binding characterization to alpha-toxin, including binding across epidemic strains.
Supports diagnostic concepts for detecting S. aureus infection in a sample.
Documented Applications
Prophylaxis or treatment of abscess formation in an organ by administering the monoclonal antibody of claim 1.
Diagnostic test kit for detecting Staphylococcus aureus infection in a sample using at least one monoclonal antibody or fragment.
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