Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Reduced antigenicity – reduced ability to bind complement – or...
Patent
1981-04-30
1984-01-31
Phillips, Delbert R.
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Reduced antigenicity, reduced ability to bind complement, or...
2601125R, C07C10352, A61K 3702
Patent
active
044289413
DESCRIPTION:
BRIEF SUMMARY
The invention relates to a nucleic acid comprising a nucleotide sequence capable of coding an immunogenic peptide sequence corresponding to the surface antigen of the virus of viral hepatitis B, and to the polypeptides and peptides obtained.
It relates also to a process enabling such a nucleic acid to be obtained.
Hepatitis B is a frequent viral disease particularly in Tropical Africa, in South East Asia and in the Far East.
The etiological agent is a virus (HBV) or Dane particle, comprising an envelope (Australia antigen or HBs antigen), a capsid (HBc antigen), and endogenic polymerase and a partly single strand circular DNA molecule; the longest strand of this DNA molecule includes close to 3,200 nucleotides (SUMMERS J., O'CONNELL / A. et MILLMAN I. (1975) Proc. Nat. Acad. Sci. USA 72, 4 597-4 601).
The endogenic DNA polymerase can be used to repair the shorter strand in vitro (T. A. LANDERS, H. B. GREENBERT and J. S. ROBINSON, J. VIROL., 23, 1977, p. 368-376).
Electrophoretic analysis of the proteins of the envelope has shown the presence of 2 to 7 polypeptides of which the principal are called: polypeptide I and polypeptide II (PETERSON D. L., ROBERTS I. M. and VYAS G. N. (1977) Proc. Nat. Acad. Sci., USA, 74, 1,530-1,534, and PETERSON D. L., CHIEN D. Y., VYAS G. N., NITECHKI D. and BOND H. (1978) In viral Hepatitis, ed. G. VYAS, S. COHEN and R. SCHMID, The Franklin Institute Press, Philadelphia, 569-573).
The Polypeptide I has a weight of 22,000 to 26,000 daltons. Polypeptide II is glycosylated and has a molecular weight of 28,000 to 30,000 daltons. The amino acid composition of these two polypeptides is very similar, the sequences which form, respectively, their 15 first amino-acids (from the N-terminal end) and their last 3 amino-acids are identical, so that the hypothesis has formulated that polypeptide II could differ from polypeptide I only by a glycosylation.
Study of the virus is extremely difficult to the extent that no cell culture system is available enabling the propagation of the virus. This difficulty has already in part been overcome, more particularly as regards the ayw serotype. The whole DNA (genome) of the virus has been identified and cloned, notably in E. coli, after its previous insertion in the single EcoRI site of a .lambda.gt.WES. .lambda.B vector, according to the technique by FRITSCH A., POURCEL C., CHARNAY P. and TIOLLAIS P. (1978) C. R. Acad. de Paris, 287, 1,453-1,456).
Until now, the sequence of the I and II polypeptides themselves, and the location in the viral DNA of the sequence coding these peptides have not been done.
It is an object of the invention to provide a much smaller DNA sequence than the viral DNA itself, containing the sequence adapted to code the peptide sequence endowed with immunogenic properties enabling, when it is introduced into the organism of a living host, to induce the formation by the latter of antibodies capable of protecting this same host subsequently with respect to the virus of viral hepatitus B, notably when the latter is in virulent state.
The invention stems not only from the complete nucleotide analysis of the genome of the Dane particle which the inventors have achieved, but to the idea that they have had for identifying the coding gene (called below "S gene") of the abovesaid polypeptides, to search in the complete nucleotide structure thus preestablished of the genome of the Dane particle, for those of the sequences of the nucleotides capable of coding the known proximal and terminal peptide sequences of these polypeptides.
It will be recalled the PETERSON and co-workers have reported, notably in the articles of which the references are recalled above, that the proximal sequence (first N-terminal amino-acid) of the 15 first amino-acids is in principle as follows: met glu asn ile thr ser gly phe leu gly pro leu leu val ser and that the terminal sequence of these same polypeptides (last C-terminal amino-acid) was the following:
FIG. 1 is a diagramatic chart of the genome of the Dane particle;
FIG. 2 is a diagramatic chart of a vector;
REFERENCES:
Murray et al., "European Patent Application", 13828, Aug. 6, 1980.
Galibert et al., Nature, 281, 646-650 (1979).
Pasek et al., Nature, 282, 575-579 (1979).
Valenzuela et al., Nature, 280, 815-819 (1979).
Charnay et al., Nature, 286, 893-895 (1980).
Sninsky et al., Nature, 279, 346-348 (1979).
Burrell et al., Nature, 279, 43-47 (1979).
Charnay Patrick
Galibert Francis
Tiollais Pierre
Institut National de la Sante et de la Recherche Medicale
Institut Pasteur
Moezie F. T.
Phillips Delbert R.
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