Use of peptides derived from the melanoma antigen MAGE-A1, or their derivatives, as vaccines and reagents for prevention, treatment and diagnosis of MAGE-associated cancers

摘要

#CMT# #/CMT# Use of a peptide (I), derived from the MAGE-A1 antigen, for preparing (a) a vaccine for prevention and treatment of MAGE-associated cancer in an individual carrying a DP4 allele and (b) a diagnostic reagent for the immune status of such an individual with respect to the cancer, is new. #CMT# : #/CMT# Use of a peptide (I), derived from the MAGE-A1 antigen, for preparing (a) a vaccine for prevention and treatment of MAGE-associated cancer in an individual carrying a DP4 allele and (b) a diagnostic reagent for the immune status of such an individual with respect to the cancer, is new. (I) (i) contains a T CD4 +>epitope that can be presented by HLA-DP4; (ii) can induce T lymphocytes specific for at least one MAGE antigen expressed by tumor cells and (iii) consists of (a) fragments containing 13-50, preferably 13-25, consecutive amino acids (aa) of the MAGE-A1 antigen, containing at least one of the sequences between aa 93-101, 271-279, 68-76, 107-115, 123-131, 139-147, 150-158, 215-223 and 274-282 or (b) variants of (a) of the same size and with binding activity for HLA-DP4 not over 1000 nM, able to induce CD4 +>T cells that recognize the epitopes defined in (a). Independent claims are included for the following: (1) similar use of a polyepitopic fragment (II) consisting of a concatenation of at least two epitopes (same or different) of at least one (I); (2) similar use of a fusion protein (III) containing a protein (or its fragment) fused to (I); (3) similar use of a lipopeptide (IV) prepared by adding a lipid to the alpha -amino group or reactive sidechain in (I); (4) similar use of an expression vector that encodes (I)-(IV); (5) immunogenic or vaccinating compositions that contain at least one of (I)-(IV) as antigen, plus a vehicle, carrier or adjuvant; (6) diagnostic reagent that contains the antigen of (5); (7) method for diagnosing the immune status of an individual with respect to a MAGE-related cancer by contact with (I) and detecting specific CD4 +>lymphocytes, in vitro; (8) method for selecting CD4 +>T cells that are specific for MAGE expressed in tumor cells; (9) (I) as new peptides (Ia) except for MAGE-A2 127-139; A3 111-125, 111-126, 113-126, 113-127, 113-128, 114-126, 114-127, 114-128, 127-142, 146-160, 156-170 and 281-295; A6 121-144, 140-158, 140-170, 150-165, 155-170 and 219-236; (10) new polyepitopic fragments (IIa) that include at least one (Ia); (11) new fusion proteins (IIIa) that include (Ia) or (IIa); (12) new lipopeptide (IVa) that includes (Ia) or (IIa); (13) new polynucleotides (NA) that encode (Ia), (IIa) or (IIIa); (14) expression vectors containing NA and regulatory sequences; and (15) host cells that contain NA or the vector of (15). #CMT#ACTIVITY : #/CMT# Cytostatic. No details of tests for cytostatic activity are given. #CMT#MECHANISM OF ACTION : #/CMT# Vaccine. #CMT#USE : #/CMT# (I), and related polyepitopic fragments, fusion proteins, lipoproteins and nucleic acids, are useful (a) for treatment and prevention of MAGE-associated cancers and (b) for diagnosis of the immune status of a subject with such a cancer (all claimed). #CMT#ADVANTAGE : #/CMT# (I) has strong affinity for HLA-DP4 and induces MAGE-specific CD4 +>T cells that recognize the epitope of the native antigen on dendritic cells. #CMT#BIOTECHNOLOGY : #/CMT# Preferred Peptides: (I) of (a) are MAGE-A1 sequences 90-104; 268-282;65-79; 104-118; 120-134; 136-150; 147-161; 212-226 or 271-285; and (I) of (b) are (i) fragments of different MAGE antigens expressed by tumor cells and homologous with (a), or (ii) synthetic peptides in which at least one residue at specified locations has been altered. (I) may be labeled or complexed, particularly to a labeled HLA-DP4 molecule and most especially one in which the beta chain is encoded by allele DPB1*0401 or 0402. (II) is particularly a concatenation of (I) and at least one CD8 +>T cell epitope of MAGE and in (III) the protein (fragment) is (part of) the alpha or beta chain of HLA-DP4 or a sequence that targets the endosome. Synthetic 15-mer peptides derived from the MAGE antigens were tested for ability to bind HLA-DP4 and any that were active tested for ability to stimulate T cells in vitro. #CMT#ADMINISTRATION : #/CMT# Compositions containing (I), or related molecules, are administered parenterally (subcutaneously, intramuscularly or intravenously), orally, sublingually, rectally or vaginally. No doses are suggested.