Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Amino acid sequence disclosed in whole or in part; or...
Patent
1994-10-17
1997-02-04
Housel, James C.
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
4242481, 530350, 436 57, 435 35, A61K 3902, A61K 3704, C07K 100
Patent
active
055995411
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a new antigenic protein capable of causing delayed hypersensitivity reactions of different intensity in the presence of living or dead bacteria of the Mycobacterium tuberculosis complex, its diagnostic and therapeutic applications especially as vaccine.
This Mycobacterium tuberculosis complex comprises four species: Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium africanum, Mycobacterium microti (le Minor et Veron; bacteriologie Madicale 1990, 2nd ed. p. 1966).
2. Discussion of the Background
The delayed-type hypersensitivity reaction to tuberculin is used commonly as means of diagnosing tuberculosis. This tuberculin challenge is particularly used as diagnostic means in the United States and in the Netherlands, countries where BCG vaccination does not or no longer exists. A recent development (1990) by the American Thoracic Society recommends in particular the use of this diagnostic test and specifies its limits for the national campaign for the total eradication of tuberculosis which is being put in place in the United States. For France, the medical practice is a little different because of the wide use of BCG and the still relatively high frequency of tuberculosis. The reaction to tuberculin is used to monitor secondary sensitization to the vaccination and also to provide arguments in favor of the existence of a tubercular infection. This diagnostic indication is based on the clear increase in the intensity of the reaction in a given subject or on the very high intensity of the reaction. But this quantitative notion is difficult to assess accurately when the tuberculin reactions are performed and/or read by different people.
In fact, the delayed-type hypersensitivity skin reaction to tuberculin does not currently allow sick subjects having a developing tuberculosis to be differentiated with certainty from previously sensitized subjects. Indeed, subjects carrying numerous living bacilli (patients suffering from tuberculosis or recently vaccinated subjects) may present the same skin reactivity to tuberculin as subjects who have been previously sensitized by a primary infection cured spontaneously or having suffered a tuberculosis which is now cured.
SUMMARY OF THE INVENTION
The inventors have isolated and purified a new protein called LIP-DTH from BCG culture medium which is found to be capable of causing a delayed-type hypersensitivity in guinea pigs with no consanguinity which are immunized with living bacilli (BCG), without in contrast causing a substantial reaction in guinea pigs immunized with dead bacilli (BCG).
This difference in reactivity was also observed in mice from two different lines (C57BI/6 and C3H/He).
Likewise, guinea pigs and mice having received virulent tuberculosis bacilli (strain H37Rv) show a reactivity towards this protein which is identical to the reaction observed in animals having received living BCG.
A study of the amino acid composition of LIP-DTH revealed a protein having a very unusual amino acid composition, numerous amino acids such as tyrosine, phenylalanine, methionine, histidine, arginine and cysteine being absent or being present in undetectable quantities.
The subject of the present invention is thus a peptide sequence capable of initiating delayed hypersensitivity reactions of different intensity in the presence of living bacteria as opposed to dead bacteria of the Mycobacterium tuberculosis complex, characterized in that it contains not more than 0.5% by weight of the amino acids tyrosine, phenylalanine, methionine, histidine, arginine and cysteine.
The subject of the invention is also a peptide or a protein capable of inducing an immune response in the human or animal host to which it is administered, having peptide sequence as defined above and characterized in that its overall amino acid composition, expressed in percentage relative to the total molecular weight is essentially the following:
Asp/Ash 1.2
Thr 12.2
Set: 2.5
Glu/Gln: 11.5
Gly: 7.7
Ala: 8.9
Val:
REFERENCES:
patent: 4619828 (1986-10-01), Gordon
patent: 4876193 (1989-10-01), Gottlieb
Sevier et al. Clin. Chem. (1981) 27(11): 1797-1806.
Damle et al. J. Immunol. (1984) 132(2): 644-650.
DeBruyn et al. Infection & Immunity (1987) 55(1): 245-252.
Marchal Gilles
Romain Felix
Housel James C.
Institut Pasteur
Shaver Jennifer
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