Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues
Reexamination Certificate
1998-03-30
2002-04-30
Carlson, Karen Cochrane (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
C530S350000, C530S300000, C530S324000, C514S012200, C514S016700, C514S053000, C424S450000, C424S400000, C424SDIG008
Reexamination Certificate
active
06380359
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to liposomes comprising novel peptide antigens which play a role in regulating human immunity against hepatitis B virus(“HBV”), more specifically, to peptide groups corresponding to epitopes of antigens derived from X protein of HBV which induce cytotoxic T lymphocytes(“CTL”) against the virus or immunological tolerance to the virus, and pH-sensitive liposomes comprising said peptide groups to induce cellular immunity so that CTLs specific to the virus can be produced.
2. Description of the Prior Art
When human body is infected with HBV, various physiological responses occurs to remove the virus. Among the responses, one of most important ones is to destroy and remove the infected cells, which finally results in recovery from viral infection. Destruction of the infected cells is accomplished by another kind of cell having cytotoxicity, which is called as CTL. To exhibit cytotoxicity, CTL has to, first of all, recognize some of peptides derived from invading viral proteins. In general, viral proteins are synthesized within the infected cells, and then, they are converted to short peptides consisting of 8 to 15 amino acids through intracellular degradation process. When some of the peptides thus produced appear at cell surface in a combined form with intracellular major histocompatibility complex molecule(“MHC”), CTL recognizes them to destroy the infected cells. On the other hand, MHC is classified into Class I and Class II, and it has been known that MHC of Class I plays an important role in induction of CTL, compared with MHC of Class II. However, it has been reported that sites of protein(peptides) recognized by CTL are restricted to only ones having specific amino acid sequences among the peptides produced by degradation of viral proteins(see: Fremont, D. et al., Science, 257:919-926(1992); Matsumura, M. et al., Science, 257:929-934(1992)).
Accordingly, finding of amino acid sequences of those specific sites permits chemical synthesis and production of peptides corresponding to the amino acid sequences, thus employment of the peptides allows artificial induction of CTL specifically recognizing hepatitis virus in human body or regulation of other immune responses such as immunosuppression, which results in effective prevention and treatment of diseases caused by the hepatitis virus.
Based on the knowledge, many researchers have made efforts to find amino acid sequences of peptides recognized by CTL among the peptides produced by degradation of hepatitis viral proteins. As a result, several specific amino acid sequences have been found, and it has been expected that several sequences would be further discovered. In addition, to employ such peptides in prevention and treatment of hepatitis-associated diseases, it is necessary that peptides as many as possible are used at the same time, and their effects may vary, depending on the kinds of peptides. Therefore, discovery of amino acid sequences of such peptides has very important significance.
Peptides for prevention and treatment of hepatitis B which have been reported to be recognized by CTL are mainly derived from S(surface antigen) protein and C(core) protein of HBV. However, peptides derived from X protein, one of antigenic proteins of HBV have not been reported so far, even though a series of studies using transgenic mice clearly revealed that X protein is directly involved in HBV-associated liver cancer(see: Hoyhne et al., EMBO J., 9:1137-1145(1990); Kim et al., Nature, 351:317-320(1991)).
On the other hand, when phospholipids are dispersed in water, polar head groups are oriented to water and hydrophobic tails aggregate by hydrophobic interaction, spontaneously to form spherical closed vesicles of bilayer which are called as “liposomes”. Such a liposome has been widely used as a carrier in drug delivery system as well as a modelling study of biological membrane(see: Lee, J. W. and Kim, H., Arch. Biochem. Biophys., 297:354(1992); Hahn, K. H. and Kim, H., J. Biochem., 110:635(1991); Yun, C. H. and Kim, H., J. Biochem., 105:406(1989); Kim, J. and Kim, H., Biochemistry, 25:7867(1986); Kim, J. and Kim, H., Korean Biochem. J., 18:403(1985)).
Recently, it has been reported that liposomes can be applied in the field of immunology, which accelerated studies on the liposomes as carriers of vaccines or adjuvants(see: Rooijen, N. V., Vaccine, 11:1170(1993)). In general, when liposomes are injected intravenously, they are easily captured by macrophage(“MO”) which is present abundantly in blood, which plays very important roles in processing of liposomal antigen as well as immunological processing of antigen.
Also, methods for inducing CTL response specific to a certain proteins or peptides employing pH-sensitive liposomes have been recently developed(see: Readdy, R. et al., J. Immunol. Methods, 141:157(1991); Zhou, F. et al., J. immunol. Methods, 145:143(1991); Nair, S. et al., J. Exp. Med., 175:609(1992); Harding, C. V. et al., J. Immunol. 147:2860(1991); Zhou, F. and Huang, L., Vaccine, 11:1139(1993)), and pH-sensitive liposomes have been widely used as carriers and adjuvant systems of the protein or peptide antigen for the development of subunit vaccine. In this connection, the present inventors have reported a process for preparing a pH-sensitive liposome which permits selective transportation of anti-cancer drugs(see: Chol, M. J. et al., J. Biochem., 112:694(1992))
SUMMARY OF THE INVENTION
In accordance with the present invention, a series of peptides specifically recognized by CTL, among peptides derived from HBV X protein, are provided. And, pH-sensitive liposomes comprising the peptide antigens derived from HBV X protein are also provided. The present inventors found that the liposomes may be used for the development of proposed therapeutic agents for the prevention and treatment of HBV-associated diseases by inducing cellular immunity so that CTLs specific to she peptide antigens of HBV can be produced.
A primary object of the invention is, therefore, to provide peptide antigens derived from HBV X protein which can be recognized by CTL and show cytotoxicity to the virus.
The other object of the invention is to provide pH-sensitive liposomes comprising the said peptide antigens which can induce celluar immunity.
REFERENCES:
patent: WO85/03950 (1985-09-01), None
patent: WO93/03753 (1993-03-01), None
patent: WO94/20127 (1994-09-01), None
W. I. White et al., “Antibody and Cytotoxic T-lymphocyte Responses to a Single Liposome-Assiciated Peptide Antigen”,Vaccine, 13(12):1111-1122 (1995).
F. Zhou and L. Huang, Monophosphoryl Lipid A Enhances Specific CTL Induction by a Soluble Protein Antigen Entrapped in Liposomes,Vaccine, 11(11):1139-1144 (1993).
Barbara Rehermann et al., “Cytotoxic Lymphocyte Responsiveness after Resolution of Chronic Hepatitis B Virus Infection”,The Journal of Clinical Investigation, 97(7): 1655-1665 (1996).
Ramin Nayersina et al., “HLA A2 Resitrcted Cytotoxic T Lymphocyte Responses to Multiple Hepatitis B Surface Antigen Epitopes during Hepatitis B Virus Infection”,The Journal of Immunology, 150(10):4659-4671 (1993).
Chang Jin-Soo
Cheong Hong-Seok
Cho Sung-Yoo
Choi Myeong-Jun
Hwang Yu-Kyeong
Carlson Karen Cochrane
Mogam Biotechnology Research Institute
Robinson Hope A.
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