Treatment and diagnosis of infections of gram positive cocci

Details Treatment and diagnosis of infections of gram positive cocci Treatment and diagnosis of infections of gram positive cocci

1999-01-04

2003-04-08

Housel, James (Department: 1648)

Drug, bio-affecting and body treating compositions

Immunoglobulin, antiserum, antibody, or antibody fragment,...

Monoclonal antibody or fragment thereof

C424S163100, C424S164100, C530S388400, C530S389500

Reexamination Certificate

active

06544516

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention concerns the treatment and diagnosis of infections of bacteria and fungi, particularly of gram positive cocci, in particular enterococci and staphylococci.
The widespread use of antibiotics and other agents (for example penicillin, vancomycin, methicillin, cephalosporin, tetracycline, chloramphenicol, glycopeptides and aminoglycosides) to treat bacterial infections has led to the rapid development of bacteria resistant to the agents (see for example CDC, 1993, JAMA, 270: 1796; IDCP, 1996, Infect Dis. Clin. Pract., 51-2; Spera, R. V. and Farber, B. F., 1994, Drugs, 48: 678-688) and many bacteria have multiple drug resistance. This proves a particular problem in clinical environments (Norris, J. G. et al., 1995, Ann. Intern. Med., 123: 250-259; Boyce, J. M. et al., 1994, J. Clin Micro., 32: 1148-1153). Bacteria which are particularly problematic are Enterococci and Staphylococci.
Enterococci are the second most common hospital-acquired infections in the USA, causing intra-abdominal abcesses, endocarditis, infections of the urinary tract and soft tissues and septicaemia (with a high mortality of 34-68%). They are now resistant to ampicillin, gentamicin and, increasingly, vancomycin. VRE (vancomycin-resistant enterococci) are currently untreatable and are responsible for 14% of sepsis in intensive care units. There has been a 20 fold increase in VRE between 1989 and 1993 (CDC National Nosocomial Infection Surveillance; WHO Report, 1996).
Staphylococccus aureus
is one of the commonest causes of skin infection, septicaemia, osteomyelitis and endocarditis. 26% of
S. aureus
isolates in France (1989), and in the USA (1991) 38.3%, were multi-resistant MRSA (methicillin resistant
S. aureus
). The MRSA is resistant to all antibiotics except vancomycin and mortality from MRSA septicaemia is 40%. However, the use of vancomycin is one of last resort since it may cause nephrotoxicity, ototoxicity, bone marrow toxicity and the red man syndrome. Transfer of vancomycin-resistance from a VRE to
S. aureus
has been demonstrated in the laboratory and clinically with certain species of staphylococcus. There is a significant possibility that this may occur with
S.aureus
in patients, and would lead to the creation of a bacterium untreatable by current therapies.
SUMMARY OF THE INVENTION
According to the present invention there is provided a bacterial or fungal ABC transporter protein or an immunogenic fragment thereof for use in a method of treatment of the human or animal body. There is also provided a bacterial or fungal ABC transporter protein or an immunogenic fragment thereof used in the manufacture of a medicament.
ABC transporters are well known (Faith, M. J. and Kolter, R., 1993, Microbiological Reviews, 57(4): 995-1017; Borenkamp, S. J. and St. Geme, J. W. III, 1994, Infection and Immunity 62: 3320-3328 ). However, they have no known therapeutic application, nor has one been suggested. Similarly, agents which neutralise their activity have not been proposed for a therapeutic application.
Frosch, M et al. (1992, Infection and Immunity, 60 (3): 798-803) disclose a diagnostic use for a
Neisseria meningitidis
ABC transporter system outer membrane protein termed Ctr A and suggests a possible therapeutic use for same. No diagnostic or therapeutic application is disclosed or suggested for the ABC transporter protein of the system, termed Ctr D (Frosch, M. et al., 1991, Molecular Microbiology, 5 (5): 1251-1263). Particular uses of the ABC transporter protein or immunogenic fragment include their use as immunogens, for example as vaccines.
Reference to ABC transporter proteins is to both importer and exporter proteins. Reference to immunogenic fragment is also reference to analogues of immunogenic fragments, particularly mimotopes (Geysen, H. M. et al, 1987, Journal of Immunological Methods, IU:259-274; Geysen, H.M. et al., 1988, J. Mol. Recognit., 1 (1):32-41).
A bacterium may be an entercoccus, for example selected from the group of
E.faecium, E.faecalis, E.avium, E.gallinarium, E.durans, E.mundtii
and
E.casseflavus.
The experimental section (below) describes particular enteroccal ABC transporter proteins having weights of 97 and 54 kDa. Hence the ABC transporter protein may be an enteroccal protein selected from the group of 97 and 54 kDa immunodominant conserved antigens.
The 97 and 54 kDa enteroccal immunodominant conserved antigens are not novel per se (Clark, I. M. and Burnie, J. P., 1993, Serodiagn. Immunother. Infect. Disease, 5: 85-92; Sulaiman, A. et al, 1996, Eur. J. Clin. Microbiol Infect Dis., l:826-829). However, they have not been previously identified or suggested as being ABC transporter proteins, nor have they been suggested for a therapeutic application nor have agent which neutralise them.
An immunogenic fragment may comprise an AT? binding site or a part thereof Specific (therapeutically useful) epitopes have been determined to be displayed by the ATP binding sites of ABC transporters, and so they or neutralising agents specific to them may be used therapeutically. Si y, agents which bind to them may be used diagnostically.
An enteroccal immunogenic fragment may have the sequence of SEQ ID NO: 3, and is displayed by the ABC transporters of e.g.
E.faecium
and
E.faecalis.
An
E.faecium
immunogenic fragment may have the sequence of SEQ ID NO: 4.
A number of
E.faecium
specific epitopes have been found, and so the immunogenic fragment may have the sequence of any one of SEQ ID NOs: 5-8.
Also provided according to the present invention are neutralising agents specific to a bacterial or fungal ABC transporter protein or immunogenic fragment thereof for use in a method of treatment of the human or animal body.
A neutralising agent may be used in the manufacture of a medicament.
Neutralising agents are well known and may include antibodies and antigen binding fragments thereof (Harlow, E. and Lane, D., “Antibodies—A Laboratory Mannual”, Cold Spring Harbor Laboratory, Cold Spring Harbor Press, N.Y., 1988), ribozymes and antisense nucleic acid chains. Other neutralising agents will be readily apparent to one skilled in the art.
Also provided according to the present invention is a method of treatment of the human or animal body comprising treating a patient with a bacterial or fungal ABC transporter protein or an immunogenic fragment thereof or a neutralising agent specific thereto according to the present invention.
Medicaments according to the present invention may additionally comprise a pharmaceutically acceptable carrier, diluent or excipient (Remington's Pharmaceutical Sciences and US Pharmacopea, 1984, Mack Publishing Company, Easton, Pa., USA).
Also provided according to the present invention is a bacterial or fungal ABC transporter protein or an immunogenic fragment thereof for use in a method of diagnosis of the human or animal body. The ABC transporter or immunogenic fragment thereof may be used in a method of diagnosis.
The bacterium may be an enterococcus, for example selected from the grow of
E.faecium, E.faecalis, E.avium, E.gallinarium, E.durans, E.mundtii
and
E.casseflavus.
The ABC transporter protein may be an enterocccal protein selected from the group of 97 and 54 kDa immunodominant conserved antigens.
An immunogenic fragment may comprise an ATP binding site or a part thereof.
The bacterium may be an enterocous, the immunogenic fragment having the sequence of SEQ ID NO: 3. The bacterium may be
E.faecium,
the immunogenic fragment having the sequence of SEQ ID NO: 4
The bacterium may be
E.faecium,
the immunogenic fragment having the sequence of any one of SEQ ID NOs: 5-8.
Also provided according to the present invention is a binding agent specific to a bacterial or fungal ABC transporter protein or immunogenic fragment thereof according to the present invention for use in a method of diagnosis of the human or animal body.
Also provided according to the present invention is a binding agent specific to a bacterial or fungal ABC transporter protein or immunogenic fragment thereof accordi

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