Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Amino acid sequence disclosed in whole or in part; or...
Reexamination Certificate
1996-04-02
2002-10-15
Caputa, Anthony C. (Department: 1642)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
C424S184100, C424S277100, C514S002600, C514S014800, C514S015800, C514S021800, C530S300000, C530S324000, C530S326000, C530S327000, C530S328000
Reexamination Certificate
active
06464980
ABSTRACT:
BACKGROUND OF THE INVENTION
Tumor cells express certain antigens which are absent from, or present in small amounts on, their normal cellular counterparts. Most of these are differentiation antigens, shared by the tumor and various embryonic cells. Some of the antigens that appear with sufficient selectivity may serve as possible targets for therapeutic agents.
More than 40 different melanoma antigens have been defined with monoclonal antibodies, resulting in several major antigenic families with immunologically and biologically distinct characteristics. Among these families are: (1) the high molecular weight oncofetal proteins; (2) the gangliosides; (3) receptors for growth factors such as EGF, PDGF, TGF-alpha and TGF-beta, and nerve growth factor; (4) cation transport and binding proteins such as p97; (5) HLA class II antigens; (6) pigmentation-associated antigens; and (7) extracellular matrix proteins. Herlyn and Koproski,
Ann. Rev. Immunol
. 6: 283-308 (1988).
While preliminary studies with monoclonal antibody-based therapy and diagnosis directed toward various of these antigens are encouraging, work continues unabated in the hope that better agents and antigenic targets can be identified. Cutaneous malignant melanoma is increasing in prevalence at an alarming rate, particularly in the United States.
More recently a new family of antigens has been described on melanoma tumors. These antigens, now termed the “melanoma antigen,” or MAGE family of antigens, were identified in a melanoma cell line which was lysed by a panel of autologous cytotoxic T lymphocytes (“CTLs”). Cells which did not express a MAGE-type antigen were not killed by the CTL, and by selecting these “antigen-loss” variants, six independent antigens were identified. Van den Eynde et al.,
Int. J. Cancer
, 44: 634 (1989). A gene encoding one of the antigens, designated MZ2-E (“E”), has been cloned and sequenced. Van der Bruggen et al.,
Science
254: 1643 (1991). The sequence was deposited in GenBank (accession #M77481), and comparison of the nucleotide sequence, designated “MAGE-1,” failed to reveal any significant homology with any sequence in data banks, including GenBank. Two additional nonidentical cDNAs were also found (MAGE-2 and MAGE-3) which were more closely related to each other than to MAGE-1, but the three were approximately equally expressed.
Smaller regions of the MAGE-1 gene were cloned and transfected into cells. These transfectants expressed antigen which was recognized by the anti-E CTLS. Thus, it appears that the gene does not encode a protein which further activates an antigen-encoding gene. Van der Bruggen, id. The sequence encoding the antigenic peptide was speculated to be within the region of overlap of the segments. See Traversari et al.,
J. Exp. Med
. 176: 1453-1457 (1992). The cDNAs of MAGE-2 and MAGE-3 were unable to transfer the expression of antigen E in transfection experiments. The presenting molecule for the E-antigen was thought to be HLA-A1.
The MAGE gene family has been shown by Van der Bruggen et al., id., to be expressed by a variety of different tumors and are not limited to melanomas, but they are not expressed by most normal cells. Thus, the MAGE antigens may have important implications for cancer immunotherapy. The sequence of the MAGE-1 gene was thought to be identical in both normal tissues and in tumors.
What is needed in the art is a more thorough understanding of the immunogenic tumor-rejecting epitopes of the MAGE antigens. Once the immunodominant epitopes are identified, along with their HLA restriction, more effective therapeutic protocols can be devised. The present invention fulfills these and other related needs.
SUMMARY OF THE INVENTION
This invention is based in part on the novel and unexpected observation that the previously reported gene encoding the human MAGE-1 protein encodes an additional fifty-eight amino acids at the C-terminal end. The complete human MAGE-1 protein and peptides thereof can be produced by recombinant or synthetic means and may or may not have the biological activity of the native MAGE-1 antigen, depending on the intended use. Accordingly, isolated and purified polynucleotides are described which code for the complete human MAGE-1 protein. The cDNA which codes for the fall length human MAGE-1 protein may be incorporated into a recombinant DNA vector; which in turn may be used to transform a suitable host; the host cell transformed with the vector including the cDNA can express full length human MAGE-1 protein, and the full length human MAGE-1 protein can be recovered.
This invention further concerns MAGE-1 immunogenic peptides from the C-terminus of the MAGE-1 protein which induce CTL activity. The immunogenic peptides of this invention may be identified using motifs as described in copending U.S. patent applications Ser. No. 07/926,666 and Ser. No. 08/027,146 for the various MHC class I alleles. Thus, small synthetic or recombinant peptides can be prepared which immunologically mimic MAGE-1 CTL inducing antigenic determinants. The CTL-inducing MAGE-1 peptides of the invention can be used therapeutically, for example, to induce, in the context of an appropriate MHC presenting molecule, an immunological response to tumors which express the corresponding MAGE determinants. In this manner the tumor cells can be killed or inhibited. The induction of CTLs can be accomplished in vivo or ex vivo. Thus, the MAGE-1 peptides described herein also can be formulated and administered as pharmaceutical compositions, especially when used to induce immunological responses in individuals predisposed to developing or already afflicted by a tumor which expresses MAGE-1 determinants.
In yet other embodiments the invention relates to methods for diagnosis, where the peptides of the invention are used to determine the presence in an individual of lymphocytes which are capable of a cytotoxic T cell response to MAGE-1 antigen. Typically the lymphocytes are peripheral blood lymphocytes and the individual of interest is suffering from a tumor associated with MAGE antigen. The diagnostic methods and compositions can be used in conjunction with therapeutic approaches to MAGE related diseases, and particularly the treatment of malignant melanoma.
REFERENCES:
patent: 5342724 (1994-08-01), Boon et al.
Bates et al. Annals of Internal Medicines 115(8):623-638.*
Kumar et al. PNAS 87:1337-1341 1990.*
Cohen Science 262: 841-843 1993.*
Paul, W.E. (Ed) Fundamental Immunology 3rd Ed. Raven Press (NY) 1993 IEE pp. 977, 978, 1222, 1223.*
Lanzavecchia Science 260:937-943 1993.*
Herlyn and Koproski, “Melanoma Antigens: Immunological and Biological Characterization and Clinical Significance”,Ann. Rev. Immunol.6: 283-308 (1988).
Van den Eynde et al., “Presence on a human Melanoma of Multiple Antigens Recognized by Autologous CTL”,Int. J. Cancer, 44: 634 (1989).
Deres et al., “In Vivo Priming of Virus-Specific Cytotoxic T Lymphocytes with Synthetic Lipopeptide Vaccine”,Nature342:561-564 (Nov. 30, 1989).
Van Bleek et al., “Isolation of an Endogenously Processed Immunodominant Viral Peptide from the Class IH-2KbMolecule”,Nature348:213-216 (Nov. 15, 1990).
Rotzschke et al., “Isolation and Analysis of Naturally Processed Viral Peptides as Recognized by Cytotoxic T cells”,Nature348:252-254 (Nov. 15, 1990).
Schmacher et al., “Peptide Selection by MHC Class I Molecules”,Nature350: 703-706 (Apr. 25, 1991).
Falk et al., “Allele-specific Motifs Revealed by Sequencing of Self-peptides Eluted from MHC Molecules”,Nature351:290-296 (May 23, 1991).
Van der Bruggen et al., “A Gene Encoding an Antigen Recognized by Cytolytic T Lymphocytes on a Human Melanoma”,Science254: 1643-1647 (Dec. 13, 1991).
Traversari et al., “A Nonapeptide Encoded by Human Gene MAGE-1 is Recognized on HLA-A1 by Cytolytic T Lymphoctyes Directed Against Tumor Antigen MZ2-E”,J. Exp. Med.176: 1453-1457 (1992).
Brasseur et al., “Human gene MAGE-1, which codes for a tumor-rejecting antigen is expressed by some breast tumors”,Int. J. Cancer, 52:839-841 (1992).
Fikes John D.
Livingston Brian D.
Sette Alessandro D.
Sidney John C.
Caputa Anthony C.
Epimmune Inc.
Hunt Jennifer
Townsend and Townsend / and Crew LLP
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