Peptides of human P53 protein for use in human T cell response i

Details Peptides of human P53 protein for use in human T cell response i Peptides of human P53 protein for use in human T cell response i

1995-02-06

1997-10-21

Chan, Christina Y.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

530327, 530328, 435325, 4353723, A61K 3800, C07K 500, C12N 500

Patent

active

056796412

DESCRIPTION:

BRIEF SUMMARY
The present application is a 371 of PCT/NL 03/00102, filed May 18, 1993.


FIELD OF THE INVENTION

The invention is concerned with novel peptides derived from the human p53 protein. The invention further concerns the use of said novel peptides in: (1) the induction of primary p53-specific T cells that can be used in a therapeutic treatment, in particular the induction of HLA class I-restricted CD8.sup.+ cytotoxic T cells and (2) pharmaceutical compositions for a prophylactic or therapeutic treatment of human individuals, all against diseases such as a variety of human cancers that show an overexpressed p53 protein.


BACKGROUND OF THE INVENTION

Human protein p53 is a nuclear phosphoprotein that is involved in regulation of the cell cycle. It is expressed by many normal cells (1). Although p53 has been implicated as a proto-oncogene, the molecular mechanisms of p53 action in normal and malignant cells are not well understood. It has been demonstrated, however, that the p53 gene frequently acquires mutations during the development of many human malignancies including colon, breast, lung, leukemias, soft tissue sarcomas, bladder, ovary, brain and neurofibrosarcomas in patients with von Recklinghausen disease (2-9). The p53 mutations which have been noted in these cancers invariably are located in a relatively large region of the gene that has been highly conserved through evolution (10). These mutations, which cause amino acid substitutions, appear to change the conformation of p53 resulting in increased stability and higher steady state levels of this normally short lived protein (11). It is precisely this difference between normal cells and tumor cells that our invention is concerned with, because it would allow the induction of T cell immune responses against this overexpressed p53 protein. Such T cells would subsequently only react against tumor cells with overexpression of p53 protein and not against normal cells with minimal expression of p53. These T cells would not necessarily have to react against the mutated amino acid sequences of p53 (although they could), but this invention is especially concerned with the reaction of T cells against normal amino acid sequences of p53 to which one would expect immunological tolerance. These normal autologous p53 antigens can also be overexpressed in tumors because of mutations elsewhere in the p53 protein sequence.
Cytotoxic T lymphocytes (CTL) are of crucial importance in the resistance against virus infections and the immune surveillance against tumors (reviewed in 12 and 13). CTL specific for viruses or tumors recognize short viral or tumor protein-derived peptides, of about 9 amino acids in length, that are bound to the antigen presenting groove of major histocompatibility complex (MHC) class I molecules (reviewed in 12 and 13). Recently in several systems vaccination with peptides recognized by antigen-specific CTL was shown to prevent lethal virus infections and to delay tumor growth in mice (reviewed in 12 and 14).
We have succeeded in the identification of autologous human p53 peptides that bind to the groove of MHC class I molecules by using the antigen processing defective cell line 174.CEM T2 generated and provided by P. Cresswell (15). This cell line expresses the human MHC class I HLA-A2.1 and HLA-B5 alleles of which only the HLA-A2.1 molecules are expressed as partly empty and unstable molecules that can be stabilized on the cell surface with exogenously added peptides. Addition of human .beta.2-microglobulin enhances peptide-loaded MHC class I expression on 174.CEM T2 cells. Subsequent primary CTL response induction (see further on) can also be enhanced. If incubation with peptide results in an increase in the cell surface expression of this MHC molecule, this implies that the peptide binds to the groove of the HLA-A2.1 molecule and is therefore a possible candidate to be recognized by CTL. The ELA-A2.1 molecule is the most frequent HLA molecule present in the Western European Caucasold population. About 50% of this population expresses this allel

REFERENCES:
Ezzell, J. NIH Research, 7:46-49, 1995 Jan. 1995.
Ikeda et al., Int. J. Oncology, 8: 1045-1052, 1996 Feb. 1996.
Lotze, Cell transplantation, 2: 33-47, 1993 Feb. 1993.
Melief, et al., Res. Immunol., 142: 425-429, 1991 Jun. 1991.
Leder et al., Peptides 1992, Proc. Eur. Pept. Symp. 22nd., pp. 136-138 Sep. 1992.

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