| 摘要 |
#CMT# #/CMT# Peptides (P) derived from the alpha -isoform of survivin (Sa) for use as antigen in prophylactic or therapeutic vaccination; and for diagnosis, prognosis or therapeutic monitoring of cancer. (P) comprise (a) 13-18 consecutive amino acids (aa) between positions 17 and 34 of Sa; (b) 13-30 consecutive aa between positions 84 and 113; (c) 13-21 aa between positions 122 and 142, or (d) variants of (a)-(c). All P have binding activity, to at least one HLA-II molecule preponderant in Caucasians, of below 1000 nM and can induce CD4 +> T lymphocytes specific for survivin. #CMT# : #/CMT# Independent claims are included for the following: (1) polyepitopic fragment (X) comprising the concatenation of at least two epitopes, same or different, at least one being a P, for use as antigen as above; (2) fusion protein (FP) containing a protein (or fragment) fused to P or X, for use as antigen as above; (3) lipopeptide (LP) obtained by adding a lipid to the alpha -amino or reactive sidechains of P or X, for use as antigen as above; (4) expression vector that contains a polynucleotide encoding P, X or LP, under control of appropriate regulators, for use as antigen as above; (5) immunogenic or vaccinating composition containing at least one P, X, FP, LP, vector of (4) plus vehicle, carrier or adjuvant; (6) method for diagnosis, prognosis or monitoring of cancer by contacting, in vitro, a patient sample with P and detecting CD4 +> T cells specific for survivin; (7) method for selecting CD4 +> T cells specific for survivin by contacting, in vitro, a cell sample with labeled multimeric complex formed between HLA-II molecule and at least one P, then isolating cells that have bound the complex; (8) P as new compounds, except for the peptide containing aa 89-101 of alpha -survivin; (9) (X), FP and LP as new compounds; (10) new polynucleotides that encode P, X and FP; (11) the vector of (4) as new; and (12) host cells modified by the nucleic acid/vectors of (11) and (12). #CMT#ACTIVITY : #/CMT# Cytostatic. No details of tests for cytostatic activity are given. #CMT#MECHANISM OF ACTION : #/CMT# Vaccine. Survivin is an apoptosis inhibitor, overexpressed in most tumors, and if its expression is prevented, human cancer cell lines are prevented from dividing and undergo apoptosis. Survivin mRNA is also a good prognostic indicator; high levels being associated with a poor prognosis. The new process induces a tumor-specific CD4 +>/CD8 +> T cell response. #CMT#USE : #/CMT# The specified peptides, also derived polyepitopic fragments, fusion proteins, lipopeptides and nucleic acids encoding them are useful in vaccines for treatment and prevention of cancer, also as reagents for diagnosis, prognosis and therapeutic monitoring of cancer (all claimed). #CMT#ADVANTAGE : #/CMT# Since survivin is overexpressed by most tumors, a single vaccine should be suitable for treating most cancers. #CMT#BIOLOGY : #/CMT# Preferred Materials: The preponderant HLA-II molecules are HLA-DR1, 3, 4,7,11, 13 or 15; -DRB3, 4 or 5; or -DP4; particularly encoded by alleles DRB1*0101, *0301, *0401, *0701, *1101, *1301 and *1501; DRB3*0101; DRB4*0101; DRB5*0101; DP*0401 and DP*0402. Especially P can be presented by at least 3 of these preponderant molecules, including at least one of DP401 and DP402. Preferred P contain 13-25 aa and may be labeled and/or complexed, particularly complexed to a labeled HLA-II molecule. (X) contains at least one P and at least one CD8 +> T epitope of survivin and/or a universal CD4 +> T epitope, and in FP the preferred protein component is an alpha or beta chain of an HLA-II molecule, their fragments or a sequence that targets the endosome, particularly one derived from the invariable chain (Ii) of LAMP-1 protein. Preparation: P, and their derivatives, are produced by standard chemical peptide synthesis or by recombinant DNA techniques. #CMT#ADMINISTRATION : #/CMT# Immunogenic compositions are administered e.g. by subcutaneous or intramuscular injection; orally; rectally or vaginally. No doses are suggested. #CMT#SPECIFIC PEPTIDES : #/CMT# Eleven (P) are specifically claimed, e.g. His-Arg-Ile-Ser-Thr-Phe-Lys-Asn-Trp-Pro-Phe-Leu-Glu-Gly-Cys. |
