Isolated protein processed to peptides which form complexes...

Details Isolated protein processed to peptides which form complexes... Isolated protein processed to peptides which form complexes...

1998-10-26

2001-06-12

Myers, Carla J. (Department: 1655)

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Amino acid sequence disclosed in whole or in part; or...

C424S277100, C530S350000, C536S023500

Reexamination Certificate

active

06245333

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to isolated peptides, derived from tumor rejection antigen precursors and presented by HLA molecules, such as HLA-A24, HLA-A28, HLA-B13, HLA-B44, and HLA-Cw6 molecules and uses thereof. In addition, it relates to the ability to identify those individuals diagnosed with conditions characterized by cellular abnormalities whose abnormal cells present complexes of these peptides and HLA molecules, the presented peptides, and the ramifications thereof. Also a part of the invention are the nucleic acid molecules which code for the tumor rejection antigen precursor, the tumor rejection antigen precursor, and uses thereof.
BACKGROUND AND PRIOR ART
The process by which the mammalian immune system recognizes and reacts to foreign or alien materials is a complex one. An important facet of the system is the T cell response. This response requires that T cells recognize and interact with complexes of cell surface molecules, referred to as human leukocyte antigens (“HLA”), or major histocompatibility complexes (“MHCs”), and peptides. The peptides are derived from larger molecules which are processed by the cells which also present the HLA/MHC molecule. See in this regard Male et al.,
Advanced Immunology
(J.P. Lipincott Company, 1987), especially chapters 6-10. The interaction of T cell and complexes of HLA/peptide is restricted, requiring a T cell specific for a particular combination of an HLA molecule and a peptide. If a specific T cell is not present, there is no T cell response even if its partner complex is present. Similarly, there is no response if the specific complex is absent, but the T cell is present. This mechanism is involved in the immune system's response to foreign materials, in autoimmune pathologies, and in responses to cellular abnormalities. Recently, much work has focused on the mechanisms by which proteins are processed into the HLA binding peptides. See, in this regard, Barinaga, Science 257: 880 (1992); Fremont et al., Science 257: 919 (1992); Matsumura et al., Science 257: 927 (1992); Latron et al., Science 257: 964 (1992).
The mechanism by which T cells recognize cellular abnormalities has also been implicated in cancer. For example, in PCT application PCT/US92/04354, filed May 22, 1992, published on Nov. 26, 1992, and incorporated by reference, a family of genes is disclosed, which are processed into peptides which, in turn, are expressed on cell surfaces, which can lead to lysis of the tumor cells by specific CTLs. The genes are said to code for “tumor rejection antigen precursors” or “TRAP” molecules, and the peptides derived therefrom are referred to as “tumor rejection antigens” or “TRAs”. See Traversari et al., Immunogenetics 35: 145 (1992); van der Bruggen et al., Science 254: 1643 (1991), for further information on this family of genes.
In U.S. patent application Ser. No. 938,334now U.S. Pat. No. 5.405,940, the disclosure of which is incorporated by reference, nonapeptides are taught which bind to the HLA-Al molecule. The reference teaches that given the known specificity of particular peptides for particular HLA molecules, one should expect a particular peptide to bind one HLA molecule, but not others. This is important, because different individuals possess different HLA phenotypes. As a result, while identification of a particular peptide as being a partner for a specific HLA molecule has diagnostic and therapeutic ramifications, these are only relevant for individuals with that particular HLA phenotype. There is a need for further work in the area, because cellular abnormalities are not restricted to one particular HLA phenotype, and targeted therapy requires some knowledge of the phenotype of the abnormal cells at issue.
The enzyme tyrosinase catalyzes the reaction converting tyrosine to dehydroxyphenylalanine or “DOPA” and appears to be expressed selectively in melanocytes (Muller et al., EMBO J 7: 2715 (1988)). An early report of cDNA for the human enzyme is found in Kwon, U.S. Pat. No. 4,898,814. A later report by Bouchard et al., J. Exp. Med. 169: 2029 (1989) presents a slightly different sequence. A great deal of effort has gone into identifying inhibitors for this enzyme, as it has been implicated in pigmentation diseases. Some examples of this literature include Jinbow, W09116302; Mishima et al., U.S. Pat. No. 5,077,059, and Nazzaropor, U.S. Pat. No. 4,818,768. The artisan will be familiar with other references which teach similar materials.
U.S. patent application Ser. No. 08/081,673, filed Jun. 23, 1993 now U.S. Pat. No. 5,487,974 and incorporated by reference, teaches that tyrosinase may be treated in a manner similar to a foreign antigen or a TRAP molecule—i.e., it was found that in certain cellular abnormalities, such as melanoma, tyrosinase is processed and a peptide derived therefrom forms a complex with HLA molecules on certain abnormal cells. These complexes were found to be recognized by cytolytic T cells (“CTLs”), which then lyse the presenting cells. The ramifications of this surprising and unexpected phenomenon were discussed. Additional peptides have now been found which also act as tumor rejection antigens presented by HLA-A2 molecules. These are described in Ser. No. 08/203,054, filed Feb. 28, 1994 now U.S. Pat. No. 5,530,096 and incorporated by reference.
U.S. patent application Ser. No. 08/233,305 filed Apr. 26, 1994 now U.S. Pat. No. 5,519,118 and incorporated by reference, disclosed that tyrosinase is also processed to an antigen presented by HLA-B44 molecules. The finding was of importance, because not all individuals are HLA-A2
+
. The fact that tyrosinase is processed to an HLA-B44 presented peptide, however, does not provide for a universal approach to diagnosis and treatment of all HLA-B44
+
tumors, because tyrosinase expression is not universal. Further, the fact that tyrosinase is expressed by normal cells as well as tumor cells may suggest some caution in the therapeutic area.
It has now been found that a non-tyrosinase coding gene also expresses a tumor rejection antigen precursor which is processed to at least one tumor rejection antigen presented by HLA-B44 molecules and to other antigens presented by HLA-A24, HLA-B13, HLA-Cw6 and HLA-A28. This, inter alia, is the subject of the invention disclosure which follows.


REFERENCES:
patent: 5342774 (1994-08-01), Boon et al.
patent: 5405940 (1995-04-01), Boon et al.
patent: 5620886 (1997-04-01), Brichard et al.
patent: 92/20356 (1992-11-01), None
Lehninger, A.L. et al. Principles of Biochemistry, 2nd ed., Worth Publishers, New York, p. 134, 898, 1993.*
Traversari, C. et al. Immunogenetics 35:145-152, 1992.*
Coulie, P.G. et al. Proc. Natl. Acad. Sci. USA 92:7976-7980, Aug. 1995.*
Van der Bruggen, et al., “A Gene Encoding an Antigen Recognized By Cytolytic T Lymphocytes On a Human Melanoma”, Science 254: 1643-1647 (Dec. 1991).
Khanna et al., “Localization of Epstein-Barr Virus Cytotoxic T Cell Epitopes Using Recombinant Vaccinia: Implications for Vaccine Devlopment”, J. Exp. Med. 176: 169-176 (Jul. 1992).
Kita, et al., “HLA-B44-restricted Cytolytic T Lymphocytes Recognizing an Epitope on Hepatitis C Virus Nucleocapsid Protein”, Hepatolgy 18(5): 1039-1044 (1993)..
Thorpe, et al., “Prediction of an HLA-B44 Binding Motif By The Alignment of Known Epitopes And Molecular Modeling of the Antigen Binding Cleft”, Immunogenetics 40: 303-305 (1994).
Fleischauer, et al., “Characterization of Natural Peptide Ligands for HLA-B4402 and -B4403: implications for peptide involvement in allorecognition of a single amino acid change in the HLA-B44 heavy chain”, Tissue Antigens 44: 311-317 (1994).
Burgess, et al., “Possible Dissociation of the Heparin-binding and Mitogenic Activities of Heparin-binding (Acidic Fibroblast) Growth Factor-1 from Its Receptor-binding Activities by Site-Directed Mutagenesis of a Single Lysine Residue,” J. Cell Biol 111:2129-2138 (1990).
Salgaller, et al., “Generation of specific anti-melanoma reactivity by stimulation of human tumor-infiltrating lymphocytes with MAGE-1 synthetic peptide” Canc. Immun

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