Polypeptides and polynucleotides for enhancing immune reactivity to HER-2 protein
Compositions for stimulating the immune system and for treating malignancies associated with overexpression of the HER-2 protein are provided. Such compositions include immunogenic epitopes of the HER-2 proteins and chimeric and multivalent peptides which comprise such epitopes. The present invention also relates to polynucleotides which encode the chimeric peptides. Also provided are pharmaceutical compositions comprising such immunogenic compositions. Methods for stimulating an immune response to HER-2 protein are provided. Methods for treating breast cancer, ovarian cancer, prostate cancer, colon cancer and lung cancer are provided.
1. A chimeric peptide for stimulating an immune response to HER-2 protein comprising a HER-2 B cell epitope, a T helper (Th) epitope, and a linker joining the HER-2 B cell epitope to the Th epitope, wherein:
the HER-2 B cell epitope consists of a sequence selected from the group consisting of:
ALVTYNTDTFESMPNPEGRYT,
SEQ ID NO: 5;
the Th epitope comprises a sequence selected from the group consisting of:
NSVDDALINSTIYSYFPSV,
SEQ ID NO: 13;
PGINGKAIHLVNNQSSE,
SEQ ID NO: 14;
QYIKANSKFIGITEL,
SEQ ID NO: 15;
NNFTVSFWLRVPKVSASHLE,
SEQ ID NO: 16;
LSEIKGVIVHRLEGV,
SEQ ID NO: 17;
FFLLTRILTIPQSLN,
SEQ ID NO: 18;
and
TCGVGVRVRSRVNAANKKPE,
SEQ ID NO: 19;
and
the linker comprises a sequence that is from 1 to 15 amino acids in length.
2. The chimeric peptide of claim 1 wherein the Th epitope comprises NSVDDALINSTIYSYFPSV, SEQ ID NO: 13.
3. The chimeric peptide of claim 1 wherein the Th epitope comprises PGINGKAIHLVNNQSSE, SEQ ID NO: 14.
4. The chimeric peptide of claim 1 wherein the Th epitope comprises QYIKANSKFIGITEL, SEQ ID NO: 15.
5. The chimeric peptide of claim 1 wherein the Th epitope comprises FNNFTVSFWLRVPKVSASHLE, SEQ ID NO: 16.
6. The chimeric peptide of claim 1 wherein the Th epitope comprises LSEIKGVIVHRLEGV, SEQ ID NO: 17.
7. The chimeric peptide of claim 1 wherein the Th epitope comprises FFLLTRILTIPQSLN, SEQ ID NO: 18.
8. The chimeric peptide of claim 1 wherein the Th epitope comprises TCGVGVRVRSRVNAANKKPE, SEQ ID NO: 19.
9. The chimeric peptide of claim 1 wherein the linker comprises a sequence that is from 2 to 15 amino acids in length.
10. The chimeric peptide of claim 9 wherein the linker comprises GPSL, SEQ ID NO: 20.
11. The chimeric peptide of claim 1 further comprising a second HER-2 B cell epitope comprising a sequence selected from the group consisting of:
TGTDMKLRLPASPETHLDM,
SEQ ID NO: 1;
AVLDNGDPLNNTTPVTGASPGG,
SEQ ID NO: 2;
LWKDIFHKINNQLALTLIDTNRS,
SEQ ID NO: 3;
TLIDTNRSRACHPCSPMCKGSRCWGESSEDCQSLT,
SEQ ID NO: 4;
ALVTYNTDTFESMPNPEGRYT,
SEQ ID NO: 5;
PLHNQEVTAEDGTQRAEKCSKPCA,
SEQ ID NO: 6;
PESFDGDPASNTAPLQPE,
SEQ ID NO: 7;
LYISAWPDSLPDLSVFQNLQ,
SEQ ID NO: 8;
LFRNPHQALLHTANRPEDE,
SEQ ID NO: 9;
CLPCHPECQPQNGSVTCFGPEADQCVACAHYKDP,
SEQ ID NO: 10;
KPDLSYMPIWKFPDEEGA,
SEQ ID NO: 11;
and
INGTHSCVDLDDKGCPAEQRAS,
SEQ ID NO: 12.
12. The chimeric peptide of claim 11 further comprising a second linker joining the first HER-2 B cell epitope to the second HER-2 B cell epitope.
13. The chimeric peptide of claim 12 wherein the second linker comprises a sequence that is from 1 to 15 amino acids in length.
14. The chimeric peptide of claim 13 wherein the second linker comprises GPSL, SEQ ID NO: 20.
15. An immunogenic composition comprising a chimeric peptide of claim 1 or claim 11 .