Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Patent
1995-12-13
1999-02-09
Housel, James C.
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Bacterium or component thereof or substance produced by said...
4241851, 4241901, 530350, 536 231, 536 237, A61K 39102
Patent
active
058690654
DESCRIPTION:
BRIEF SUMMARY
This application is a 35 USC 371 of PCT/US94/02550 filed Mar. 15, 1994.
FIELD OF INVENTION
This invention relates to high molecular weight proteins of non-typeable haemophilus.
BACKGROUND TO THE INVENTION
Non-typeable Haemophilus influenzae are non-encapsulated organisms that are defined by their lack of reactivity with antisera against known H. influenzae capsular antigens.
These organisms commonly inhabit the upper respiratory tract of humans and are frequently responsible for infections, such as otitis media, sinusitis, conjunctivitis, bronchitis and pneumonia. Since these organisms do not have a polysaccharide capsule, they are not controlled by the present Haemophilus influenzae type b (Hib) vaccines, which are directed towards Hib bacterial capsular polysaccharides. The non-typeable strains, however, do produce surface antigens that can elicit bactericidal antibodies. Two of the major outer membrane proteins, P2 and P6, have been identified as targets of human serum bactericidal activity. However, it has been shown that the P2 protein sequence is variable, in particular in the non-typeable Haemophilus strains. Thus, a P2-based vaccine would not protect against all strains of the organism.
There have previously been identified by Barenkamp et al (Pediatr. Infect. Dis. J., 9:333-339, 1990) a group of high-molecular-weight (HMW) proteins that appeared to be major targets of antibodies present in human convalescent sera. Examination of a series of middle ear isolates revealed the presence of one or two such proteins in most strains. However, prior to the present invention, the structures of these proteins were unknown as were pure isolates of such proteins.
SUMMARY OF INVENTION
The inventors, in an effort to further characterize the high molecular weight (HMW) Haemophilus proteins, have cloned, expressed and sequenced the genes coding for two immunodominant HMW proteins (designated HMW1 and HMW2) from a prototype non-typeable Haemophilus strain and have cloned, expressed and almost completely sequenced the genes coding for two additional immunodominant HMW proteins (designated HMW3 and HMW4) from another non-typeable Haemophilus strain.
In accordance with one aspect of the present invention, therefore, there is provided an isolated and purified gene coding for a high molecular weight protein of a non-typeable Haemophilus strain, particularly a gene coding for protein HMW1, HMW2, HMW3 or HMW4, as well as any variant or fragment of such protein which retains the immunological ability to protect against disease caused by a non-typeable Haemophilus strain. In another aspect, the invention provides a high molecular weight protein of non-typeable Haemophilus influenzae which is encoded by these genes.
BRIEF DESCRIPTION OF DRAWINGS
FIGS. 1A-1G is a DNA sequence of a gene coding for protein HMW1 (SEQ ID NO: 1);
FIGS. 2A-2B is a derived amino acid sequence of protein HMW1 (SEQ ID NO: 2);
FIGS. 3A-3G is a DNA sequence of a gene coding for protein HMW2 (SEQ ID NO: 3);
FIGS. 4A-4B is a derived amino acid sequence of HMW2 (SEQ ID NO: 4);
FIG. 5A shows restriction maps of representative recombinant phages which contained the HMW1 or HMW2 structural genes, the locations of the structural genes being indicated by the shaded bars;
FIG. 5B shows the restriction map of the T7 expression vector pT7-7;
FIGS. 6A-6L contains the DNA sequence of a gene cluster for the hmw1 gene (SEQ ID NO: 5), comprising nucleotides 351 to 4958 (ORF a) (as in FIG. 1), as well as two additional downstream genes in the 3' flanking region, comprising ORFs b, nucleotides 5114-6748 and c nucleotides 7062-9011;
FIGS. 7A-7L contains the DNA sequence of a gene cluster for the hmw2 gene (SEQ ID NO: 6), comprising nucleotides 792 to 5222 (ORF a) (as in FIG. 3), as well as two additional downstream genes in the 3' flanking region, comprising ORFs b, nucleotides 5375-7009, and c, nucleotides 7249-9198;
FIGS. 8A-8F is a partial DNA sequence of a gene coding for protein HMW3 (SEQ ID NO: 7);
FIGS. 9A-9F is a partial DNA sequence of a gene coding f
REFERENCES:
Barenkamp et al. Infection & Immunity Apr. 1992 60(4): pp. 1302-1313.
Barenkamp (Ped. Res. 1991 29(4) pt. 2., 167A, Abstract No. 985).
Barenkamp et al. (Ped. Inf. Dis. J. 1990 9(5):333-339.
Barenkamp Stephen J.
St. Geme, III Joseph William
Board of Trustees of the Leland Stanford Junior University
Housel James C.
Shaver Jennifer
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