Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1995-08-03
2000-04-25
Chin, Christopher L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 231, 435 691, 435 693, 435 711, 4351721, 4353201, 530350, C07H 2104
Patent
active
060545720
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to novel polypeptides and monoclonal antibodies, their preparation and their use to combat infection at the site of wounds, surgical implants and other in-dwelling devices such as catheters. The present invention also relates to isolated nucleic acids encoding the polypeptide and to recombinant host cells transformed with DNA encoding the polypeptide.
BACKGROUND OF THE INVENTION
One of the major complications associated with the clinical use of implanted materials and in-dwelling devices is bacterial infection. In particular, staphylococci have frequently been implicated in medical device-related infections (Dankert et al 1986, CRC Rev Biocompatability 2, 219-301). Once established the infection is virtually impossible to treat resulting in implant failure.
It has been suggested that the adhesion of a microorganism to a surface is an initial stop in the development of such infections (Quie and Belani, 1987, J. Infec. Dis. 156: 543-547) and there is now evidence to suggest that a specific adhesion mechanism is involved in the pathogenesis of foreign body infections (Vaudaux et al. 1990, J. Biomat. Appl. 5: 134-153). Soon after coming into contact with blood, inert materials, such as used for intravenous cannulae and prosthetic implants, are almost immediately coated with a layer of extracellular matrix proteins, (Cottanaro et al 1981, Transactions of the American Society for Artificial Internal Organs 27: 391-395). In particular this layer includes the plasma protein fibronectin and it is believed that staphylococci are able to bind to fibronectin through bacterial cell surface receptor proteins known as fibronectin binding protein (Fbp). However, some studies have suggested that blood proteins do not promote adherence of staphylococci to biomaterial (eg. Muller et al 1991, Infect.Immun. 59: 3323-3326) thereby discouraging research into the interaction of these bacteria with these proteins as an approach in the prevention of adhesion to biomaterials.
Fibronectin binding proteins have been isolated from Staphylococcus aureus and the nucleotide sequence subsequently established [Signas, C. et al. (1989) Proc. Nat. Acad. Sci 86, 699-703; Jonsson, K. et al. (1991) Eur. J Biochem. 202, 1041-1048] (FbpA and FbpB respectively). The primary fibronectin binding domain of this protein has been identified as a homologous unit (usually of 38 amino acids) that is repeated three times (D1-D3 region) and partially repeated a fourth time (D4 region).
Previous attempts to combat staphylococcal adhesion to implants have involved modification of the surface of the prosthetic material to discourage adhesion of proteins; e.g. coating with a "non-stick" material such as PTFE, or bonding antibiotics to the surface (Kamal et al., 1991, J. Amer. Med. Assoc. 265, 2364-2368).
There have also been proposals to use non-steroidal anti-inflammatory drugs to prevent adhesion of staphylococci to medical polymers (Farber and Wolff 1992, J. Infect. Dis. 166: 861-865).
EP0163623, EP0294349, EP0397633 and WO92/02555 disclose certain fibronectin binding polypeptides from S. aureus.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
One approach adopted in he present invention is to use a monoclonal antibody that binds to matrix binding proteins such as fibronectin binding protein, to block the adhesion of bacteria to matrix proteins.
Accordingly, in one broad aspect the present invention is directed to the use of a monoclonal antibody (Mab), or a fragment thereof, that binds to one or more epitopes of a matrix binding protein in the prevention of adhesion of bacteria, in particular gram positive bacteria, to extracellular matrix proteins on in-dwelling devices or to extracellular matrix proteins in wounds. The invention particularly relates to the manufacture of a medicament for such uses.
The effect of the Mab or fragment is to block the site on the matrix binding protein that is associated with binding to the matrix protein.
In-dwelling devices include surgical implants, prosthetic devices and
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Burnham Martin Karl Russel
Chopra Ian
Critchley Ian Alfred
Knowles David Justin Charles
Chin Christopher L.
Gimmi Edward R.
Graser Jennifer
King William T.
Kinzig Charles M.
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