The Texas A&m University System

Inhibitex, Inc.

Other

The Uab Research Foundation

Universitá Degli Studi Di Pavia

The Provost Fellows and Scholars of the College of the Holy and Undivided Trinity of Queen Elizabeth, Near Dublin

University of Florida Research Foundation, Incorporated

University of Manitoba

Bioresearch Ireland

Wyeth Holdings Corporation

University Degli Studi Di Pavia

The Provost Fellows and Scholars of the College of the Holy and Undivived Trinity of Queen Elizabeth Near Dublin

Joseph M Patti

Timothy James Foster

Magnus A Hook

Jeff T Hutchins

Pietro Speziale

Andrea Hall

Magnus A O Hook

Deidre Ni Eidhin

Samuel E Perkins

Elisabet Josefsson

Karen L House-Pompeo

Paul Domanski

Yi Xu

Narayana Sthanam

Pratiksha Patel

Maria G Bowden

Martin J McGavin

Danny Joh

Ann Progulske-Fox

Magnus Höök

Jouko V Sillanpaa

Guylaine Lepine

Karthe Ponnuraj

Naiming Han

Mark Pallen

Fiona Roche

Marilyn Lantz

Magnus H&ouml;&ouml;k

Somying Tumwasorn

Viliam Pavliak

Steven Morris Baker

Subramonia Padmanaba Pillai

Livia Visal

Klas Jonsson

Sivashankarappa Gurusiddappa

Peter Syribeys

Pratisksha Patel

Fabrizia Casolini

Elizabet Joseffson

Bradley D Prater

Linda Santos

Jindrich Symersky

Jeff T c/o Inhibitex Inc Hutchins

Andrea c/o Inhibitex Inc Hall

Elizabet Josefsson

Fiona c/o The Provost Fellows & Scholars Roche

G Maria Bowden

Karthe The Uab Research Foundation Ponnuraj

Andrea Inhibitex Inc Hall

Yi The Texas A&M Univ System Xu

Jouko V The Texas A&M Univ System Sillanpaa

Narayana The Uab Research Foundation Sthanam

Jeff T Inhibitex Inc Hutchins

Timothy J Foster

Magnus Hook

Monoclonal antibodies which can bind to the SdrF protein ofare provided which can be useful in the treatment and protection against infection from staphylococcal bacteria such as. The monoclonal antibodies of the invention are advantageous in that they can also recognize binding domains and subdomains of theSdrF protein in addition to the protein itself. Suitable compositions and passive vaccines based on the monoclonal antibodies of the invention, as well as methods for their use, are also provided.

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Immunogenic polysaccharide-protein conjugates having a polysaccharide antigen (or its oligosaccharide fragment representing one or more antigenic epitopes) derived from a nosocomial pathogen conjugated to a staphylococcal surface adhesin carrier protein are used in immunogenic compositions to elicit antibody responses to both the polysaccharide antigen and the staphylococcal surface adhesin carrier protein. Such immunogenic compositions are used to immunize against diseases caused byor other nosocomial pathogens.

Polysaccharide-staphylococcal surface adhesin carrier protein conjugates for immunization against nosocomial infections

Disclosed are antibodies that block the binding of fibronectin protein to fibronectin. Also disclosed are site specifically-mutated and truncated peptide epitopes derived from the fnbA and fnbB genes of, the fnbA and fnbB genes of, and the sfb gene of, and nucleic acid segments encoding these peptides and epitopes. The anti-(fibronectin binding site) antibodies, peptides and epitopes that give rise to antibodies that block the binding of fibronectin binding proteins to fibronectin, and DNA segments encoding these proteins and are of use in various screening, diagnostic and therapeutic applications including active and passive immunization and methods for the prevention of streptococcal and staphylococcal colonization in animals or humans. These. DNA segments and the peptides derived therefrom are proposed to be of use directly in the preparation of vaccines and also for use as carrier proteins in vaccine formulations.

Multicomponent vaccines are provided which aid in the prevention and treatment of staphylococcal infections and which include certain selected combinations of bacterial binding proteins or fragments thereof, or antibodies to those proteins or fragments. By careful selection of the proteins, fragments, or antibodies, a vaccine is provided that imparts protection against a broad spectrum ofand other bacterial strains and against proteins that are expressed at different stages of the logarithmic growth curve. In one embodiment of the invention, a composition is provided that includes a fibrinogen binding domain of a fibrinogen binding protein and a bacterial component such as a capsular polysaccharide, and both active and passive vaccines based on these components are also provided, along with methods of treating infection using these compositions and vaccines.

Multicomponent vaccines

Surface proteins are provided which generate polyclonal and monoclonal antibodies which are cross-reactive to both coagulase-positivebacteria, such asand to coagulase-negative bacteria, such asand. The antibodies may be generated from surface proteins that have been isolated on the basis of characteristics that may be common betweenand coagulase-negative staphylococci, or the A domains of those surface proteins, and these recombinant surface proteins are used to generate the cross-reactive antibodies. Vaccines comprising an immunologically effective amount of the proteins are also provided, and these vaccines are used in methods for the treatment or protection against a wide variety of staphylococcal infections.

An isolated extracellular matrix-binding protein, designated as SdrE and its corresponding amino acid and nucleic acid sequences and motifs are described. The proteins, peptides, fragments thereof or antigenic portions thereof are useful for the prevention, inhibition, treatment and diagnosis ofinfection and as scientific research tools. Further, antibodies or antibody fragments to the proteins, peptides, fragments thereof or antigenic portions thereof are also useful for the prevention, inhibition, treatment and diagnosis ofinfection. In particular, the proteins or antibodies thereof may be administered to wounds or used to coat biomaterials to act as blocking agents to prevent or inhibit the binding ofto wounds or biomaterials.

A bioinformatic method for identifying and isolating proteins and peptides with MSCRAMM&#xae;-like characteristics from Gram positive bacteria, such asandbacteria, and proteins and peptides obtained thereby are provided which can be utilized in methods to prevent and treat infections caused by Gram-positive bacteria. The method involves identifying from sequence information those proteins with a putative C-terminal LPXTG (SEQ ID NO:1) cell wall sorting signal and other structural similarities to MSCRAMM&#xae; proteins having the LPXTG-anchored cell wall proteins. The MSCRAMM&#xae; proteins and immunogenic regions therein that are identified and isolated using the present invention may be useful in the diagnosis, treatment or prevention of Gram positive bacterial infections.

Bioinformatic method for identifying surface-anchored proteins from gram-positive bacteria and proteins obtained thereby

An isolated extracellular matrix-binding protein, designated as SdrD and its corresponding amino acid and nucleic acid sequences and motifs are described. The proteins, peptides, fragments thereof or antigenic portions thereof are useful for the prevention, inhibition, treatment and diagnosis ofinfection and as scientific research tools. Further, antibodies or antibody fragments to the proteins, peptides, fragments thereof or antigenic portions thereof are also useful for the prevention, inhibition, treatment and diagnosis ofinfection. In particular, the proteins or antibodies thereof may be administered to wounds or used to coat biomaterials to act as blocking agents to prevent or inhibit the binding ofto wounds or biomaterials.

An isolated extracellular matrix-binding protein, designated as SdrC and its corresponding amino acid and nucleic acid sequences and motifs are described. The proteins, peptides, fragments thereof or antigenic portions thereof are useful for the prevention, inhibition, treatment and diagnosis ofinfection and as scientific research tools. Further, antibodies or antibody fragments to the proteins, peptides, fragments thereof or antigenic portions thereof are also useful for the prevention, inhibition, treatment and diagnosis ofinfection. In particular, the proteins or antibodies thereof may be administered to wounds or used to coat biomaterials to act as blocking agents to prevent or inhibit the binding ofto wounds or biomaterials.

Multicomponent vaccines are provided which aid in the prevention and treatment of staphylococcal infections and which include certain selected combinations of bacterial binding proteins or fragments thereof, or antibodies to those proteins or fragments. By careful selection of the proteins, fragments, or antibodies, a vaccine is provided that imparts protection against a broad spectrum ofand other bacterial strains and against proteins that are expressed at different stages of the logarithmic growth curve. In one embodiment of the invention, a composition is provided that includes a fibrinogen binding domain of a fibrinogen binding protein and a bacterial component such as ca capsular polysaccharide, and both active and passive vaccines based on these components are also provided, along with methods of treating infection using these compositions and vaccines.

A bioinformatic method is provided for identifying and isolating proteins with MSCRAMM&#xae;&#x2014;like characteristics from Gram positive bacteria, such asandbacteria, which can then be utilized in methods to prevent and treat infections caused by Gram-positive bacteria. The method involves identifying from sequence information those proteins with a putative C-terminal LPXTG (SEQ ID NO:1) cell wall sorting signal and other structural similarities to MSCRAMM&#xae; proteins having the LPXTG-anchored cell wall proteins. The MSCRAMM&#xae; proteins and immunogenic regions therein that are identified and isolated using the present invention may be used to generate antibodies useful in the diagnosis, treatment or prevention of Gram positive bacterial infections.

Isolated extracellular matrix-binding proteins, designated ClfB, SdrC, SdrD and SdrE, and their corresponding amino acid and nucleic acid sequences and motifs are described. The proteins, peptides, fragments thereof or antigenic portions thereof are useful for the prevention, inhibition, treatment and diagnosis ofinfection and as scientific research tools. Further, antibodies or antibody fragments to the proteins, peptides, fragments thereof or antigenic portions thereof are also useful for the prevention, inhibition, treatment and diagnosis ofinfection. In particular, the proteins or antibodies thereof may be administered to wounds or used to coat biomaterials to act as blocking agents to prevent or inhibit the binding ofto wounds or biomaterials. ClfB is a cell-wall associated protein having a predicted molecular weight of approximately 88 kDa and an apparent molecular weight of approximately 124 kDa, which binds both soluble and immobilized fibrinogen. ClfB binds both the alpha and beta chains of fibrinogen and acts as a clumping factor. SdrC, SdrD and SdrE are cell-wall associated proteins that exhibit cation-dependent ligand binding to the extracellular matrix. It has been discovered that in the A region of SdrC, SdrD, SdrE, ClfA and ClfB, there is a highly conserved amino acid sequence that can be used to derive a consensus motif of TYTFTDYVD.

Monoclonal antibodies which can bind to the ClfA protein and which are generated from binding subdomains or active fragments of the ClfA protein from, including the active fragments proteins from its fibrinogen binding domain such as Clf40 protein, the Clf33 protein, or ClfA N3, are provided which can be useful in the treatment and protection against infection from staphylococcal bacteria such as. In addition, medical instruments can be treated using the monoclonal antibodies of the invention in order to reduce or eliminate the possibility of their becoming infected or further spreading the infection. In particular, the antibodies of the present invention are advantageous because they can prevent adherence of the bacteria to host cells by impairing or inhibiting the ability ofClfA to bind to fibrinogen or fibrin, and thus can be utilized in methods or treating or preventing staphylococcal inventions.

Monoclonal antibodies to the CLFA protein and method of use in treating infections

Antibodies to the CNA protein and to other regions from the collagen binding domain, including domain CNA19, are provided, and antibodies produced in this manner have been shown to be cross reactive to bothandbacteria and which can thus be used in the prevention and treatment of infections caused by both of these types of bacteria. In addition, medical instruments can be treated using the antibodies of the invention in order to reduce or eliminate the possibility of their becoming infected or further spreading the infection. In particular, the proteins are advantageous because they are cross-reactive and may thus be administered to patients so as to reduce or prevent severe infection by staphylococcal bacteria of more than one species. Antibodies generated in this manner have also been shown to exhibit displacement activity and can thus be utilized advantageously in methods wherein these antibodies will be administered to patients having pre-existing staphylococcal infections because of the ability to displace bacterial proteins from binding sites on the extracellular matrix. Finally, a method of identifying, isolating and utilizing displacing antibodies is also provided.

Cross-reactive displacing antibodies from collagen-binding proteins and method of identification and use

Disclosed are antibodies that block the binding of fibronectin protein to fibronectin. Also disclosed are site specifically-mutated and truncated peptide epitopes derived from the fnbA and fnbB genes of, the fnbA and fnbB genes of, and the sfb gene of, and nucleic acid segments encoding these peptides and epitopes. The anti-(fibronectin binding site) antibodies, peptides and epitopes that give rise to antibodies that block the binding of fibronectin binding proteins to fibronectin, and DNA segments encoding these proteins and are of use in various screening, diagnostic and therapeutic applications including active and passive immunization and methods for the prevention of streptococcal and staphylococcal colonization in animals or humans. These DNA segments and the peptides derived therefrom are proposed to be of use directly in the preparation of vaccines and also for use as carrier proteins in vaccine formulations.

Fibronectin binding protein compositions and methods of use

Growing community of inventors

Cumming, GA, United States of America

Joseph M Patti