MAGE-3 peptides presented by HLA class II molecules

Details MAGE-3 peptides presented by HLA class II molecules MAGE-3 peptides presented by HLA class II molecules

1999-07-07

2002-04-09

Bansal, Geetha P. (Department: 1642)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S023100, C536S023400, C435S320100, C435S350000, C435S363000, C435S325000

Reexamination Certificate

active

06369211

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to fragments of the tumor associated gene product MAGE-3 which bind to and are presented to T lymphocytes by HLA class II molecules. The peptides, nucleic acid molecules which code for such peptides, as well as related antibodies and CD4
+
T lymphocytes, are useful, inter alia, in diagnostic and therapeutic contexts.
BACKGROUND OF THE INVENTION
The process by which the mammalian immune system recognizes and reacts to foreign or alien materials is complex. An important facet of the system is the T cell response, which in part comprises mature T lymphocytes which are positive for either CD4 or CD8 cell surface proteins. T cells can recognize and interact with other cells via cell surface complexes on the other cells of peptides and molecules referred to as human leukocyte antigens (“HLAs”) or major histocompatibility complexes (“MHCs”). The peptides are derived from larger molecules which are processed by the cells which also present the HLA/MHC molecule. See Male et al.,
Advanced Immunology
(J.P. Lipincott Company, 1987), especially chapters 6-10. The interaction of T cells and complexes of HLA/peptide is restricted, requiring a specific T cell for a specific complex 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. The mechanisms described above are involved in the immune system's response to foreign materials, in autoimmune pathologies, and in responses to cellular abnormalities.
The T cell response to foreign antigens includes both cytolytic T lymphocytes and helper T lymphocytes. CD8
+
cytotoxic or cytolytic T cells (CTLs) are T cells which, when activated, lyse cells that present the appropriate antigen presented by HLA class I molecules. CD4
+
T helper cells are T cells which secrete cytokines to stimulate macrophages and antigen-producing B cells which present the appropriate antigen by HLA class II molecules on their surface.
The mechanism by which T cells recognize alien materials also has been implicated in cancer. A number of cytolytic T lymphocyte (CTL) clones directed against autologous melanoma have been described. In some instances, the antigens recognized by these clones have been characterized. In De Plaen et al.,
Immunogenetics
40:360-369 (1994), the “MAGE” family, a family of genes encoding tumor specific antigens, is described. (See also PCT application PCT/US92/04354, published on Nov. 26, 1992.) The expression products of these genes are processed into peptides which, in turn, are expressed on cell surfaces. This 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. Also, see U.S. Pat. No. 5,342,774.
In U.S. Pat. No. 5,405,940, MAGE nonapeptides are taught which are presented by the HLA-A1 molecule. 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.
In U.S. Pat. No. 5,591,430, additional isolated MAGE-3 peptides are taught which are presented by the HLA-A2 molecule. Therefore, a given TRAP can yield a plurality of TRAs.
The foregoing references describe isolation and/or characterization of tumor rejection antigens which are presented by HLA class I molecules. These TRAs can induce activation and proliferation of CD8
+
cytotoxic T lymphocytes (CTLs) which recognize tumor cells that express the tumor associated genes (e.g. MAGE genes) which encode the TRAs.
The importance of CD4
+
T lymphocytes (helper T cells) in antitumor immunity has been demonstrated in animal models in which these cells not only serve cooperative and effector functions, but are also critical in maintaining immune memory (reviewed by Topalian,
Curr. Opin. Immunol
. 6:741-745, 1994). Moreover, several studies support the contention that poor tumor-specific immunity is due to inadequate activation of T helper cells.
It has recently been demonstrated that the tyrosinase gene encodes peptides which are presented by HLA class II molecules to stimulate CD4
+
T lymphocytes (Topalian et al., 1994; Yee et al.,
J. Immunol
. 157:4079-4086, 1996; Topalian et al.,
J. Exp. Med
. 183:1965-1971, 1996).
It now has been discovered that the MAGE-3 gene encodes additional tumor rejection antigens which are HLA class II binding peptides. These peptides, when presented by an antigen presenting cell having an HLA class II molecule, effectively induce the activation and proliferation of CD4
+
T lymphocytes.
The invention is elaborated upon in the disclosure which follows.
SUMMARY OF THE INVENTION
The invention provides isolated MAGE-3 peptides, and functional variants thereof, which bind HLA class II molecules. The invention also provides isolated nucleic acid molecules encoding such peptides, expression vectors containing those nucleic acid molecules, host cells transfected with those nucleic acid molecules, and antibodies to those peptides and complexes of the peptides and HLA class II antigen presenting molecules. T lymphocytes which recognize complexes of the peptides and HLA class II antigen presenting molecules are also provided. Kits containing the foregoing molecules additionally are provided. The foregoing can be used in the diagnosis or treatment of conditions characterized by the expression of MAGE-3.
According to one aspect of the invention, an isolated HLA class II-binding peptide is provided. The isolated peptide comprises the amino acid sequence of SEQ ID NO:11, or a functional variant thereof. In certain embodiments, the isolated HLA class II-binding peptide comprises the amino acid sequence of SEQ ID NO:9. In preferred embodiments, the isolated HLA class II-binding peptide consists essentially of an amino acid sequence selected from the group consisting of SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:9, SEQ ID NO:10 and SEQ ID NO:11. In particularly preferred embodiments, the isolated peptide consists of an amino acid sequence selected from the group consisting of SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:9, SEQ ID NO:10 and SEQ ID NO:11. More preferably, the isolated peptide consists of an amino acid sequence selected from the group consisting of SEQ ID NO:3 and SEQ ID NO:4. In other embodiments of the invention, the isolated HLA class II-binding peptide is non-hydrolyzable. Preferred non-hydrolyzable peptides are selected from the group consisting of peptides comprising D-amino acids, peptides comprising a -psi[CH
2
NH]-reduced amide peptide bond, peptides comprising a -psi[COCH
2
]-ketomethylene peptide bond, peptides comprising a-psi[CH(CN)NH]-(cyanomethylene)amino peptide bond, peptides comprising a-psi[CH
2
CH(OH)]-hydroxyethylene peptide bond, peptides comprising a -psi[CH
2
O]-peptide bond, and peptides comprising a -psi[CH
2
S]-thiomethylene peptide bond.
According to another aspect of the invention, a composition comprising an isolated MAGE-3 HLA class I-binding peptide and an isolated MAGE-3 HLA class II-binding peptide is provided. In certain embodiments the isolated MAGE-3 HLA class II-binding p

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