VEGFR-3 inhibitor materials and methods
AssigneeVegenics Limited
InventorsKari Alitalo, Erkki Koivunen, Hajime Kubo
Life of this patent
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Abstract
The present invention relates to the diagnosis, evaluation, and therapeutic intervention of disorders mediated by the activity of cell surface receptor VEGFR-3, which activity often is stimulated by VEGFR-3 ligands VEGF-C and VEGF-D. More particularly, the present invention identifies novel methods and compositions for the inhibition of VEGF-C/D binding to VEGFR-3. The compositions of the present invention will be useful in the inhibition of angiogenesis and lymphangiogenesis.
Claims74
An isolated peptide comprising the formula:
- X1X2X3X4X5X6X7X8 (SEQ ID NO:
- 32), wherein X1 through X8 are amino acid residues, wherein said peptide binds to VEGFR3, and wherein
- the amino acid residue at X1 is a glycine residue or a conservative substitution thereof;
- the amino acid residue at X2 is a tyrosine residue or a conservative substitution thereof;
- the amino acid residue at X3 is a tryptophan residue or a conservative substitution thereof;
- the amino acid residue at X4 is a leucine residue or a conservative substitution thereof;
- the amino acid residue at X5 is a threonine residue or a conservative substitution thereof;
- the amino acid residue at X6 is an isoleucine residue or a conservative substitution thereof;
- the amino acid residue at X7 is a tryptophan residue or a conservative substitution thereof;
- and
- the amino acid residue at X8 is a glycine residue or a conservative substitution thereof.
The isolated peptide of any one of claims 1 through 9, wherein the conservative substitution at position X6 is selected from the group consisting of valine, leucine, alanine, cysteine, glycine, phenylalanine, proline, tryptophan, tyrosine, norleucine or methionine.
An isolated peptide comprising an amino acid sequence selected from the group consisting of:
- SGYWWDTWF (SEQ ID NO:
- 36), SCYWRDTWF (SEQ ID NO:
- 37), KVGWSSPDW (SEQ ID NO:
- 38), FVGWTKVLG (SEQ ID NO:
- 39), YSSSMRWRH (SEQ ID NO:
- 40), RWRGNAYPG (SEQ ID NO:
- 41), SAVFRGRWL (SEQ ID NO:
- 42), WFSASLRFR (SEQ ID NO:
- 43), and conservative substitution-analogs thereof, wherein said peptide binds human VEGFR-3.
An isolated peptide comprising an amino acid sequence selected from the group consisting of:
- SGYWWDTWF (SEQ ID NO:
- 36), SCYWRDTWF (SEQ ID NO:
- 37), KVGWSSPDW (SEQ ID NO:
- 38), FVGWTKVLG (SEQ ID NO:
- 39), YSSSMRWRH (SEQ ID NO:
- 40), RWRGNAYPG (SEQ ID NO:
- 41), SAVFRGRWL (SEQ ID NO:
- 42), WFSASLRFR (SEQ ID NO:
- 43), wherein said peptide binds human VEGFR-3.
An isolated peptide comprising an amino acid sequence selected from the group consisting of:
- WQLGRNWI (SEQ ID NO:
- 44), VEVQITQE (SEQ ID NO:
- 45), AGKASSLW (SEQ ID NO:
- 46), RALDSALA (SEQ ID NO:
- 47), YGFEAAW (SEQ ID NO:
- 48), YGFLWGM (SEQ ID NO:
- 49), SRWRILG (SEQ ID NO:
- 50), HKWQKRQ (SEQ ID NO:
- 51), MDPWGGW (SEQ ID NO:
- 52), RKVWDIR (SEQ ID NO:
- 53), VWDHGV (SEQ ID NO:
- 54), and conservative substitution-analogs thereof, wherein said peptide binds human VEGFR-3.
A peptide comprising an amino acid sequence selected from the group consisting of:
- WQLGRNWI (SEQ ID NO:
- 44), VEVQITQE (SEQ ID NO:
- 45), AGKASSLW (SEQ ID NO:
- 46), RALDSALA (SEQ ID NO:
- 47), YGFEAAW (SEQ ID NO:
- 48), YGFLWGM (SEQ ID NO:
- 49), SRWRILG (SEQ ID NO:
- 50), HKWQKRQ (SEQ ID NO:
- 51), MDPWGGW (SEQ ID NO:
- 52), RKVWDIR (SEQ ID NO:
- 53), VWDHGV (SEQ ID NO:
- 54), wherein said peptide binds human VEGFR-3.
An isolated peptide that binds VEGFR-3, comprising an amino acid sequence selected from the group consisting of:
- CWQLGRNWIC (SEQ ID NO:
- 55), CVEVQITQEC (SEQ ID NO:
- 56), CAGKASSLWC (SEQ ID NO:
- 57), CRALDSALAC (SEQ ID NO:
- 58), CYGFEAAWC (SEQ ID NO:
- 59), CYGFLWGMC (SEQ ID NO:
- 60), CSRWRILGC (SEQ ID NO:
- 61), CHKWQKRQC (SEQ ID NO:
- 62), CMDPWGGWC (SEQ ID NO:
- 63), CRKVWDIRC (SEQ ID NO:
- 64), CVWDHGVC (SEQ ID NO:
- 65).
An isolated peptide that binds VEGFR-3, comprising the amino acid sequence CGQMCTVWCSSGC (SEQ ID NO:
- 66).
An isolated peptide comprising the amino acid sequence GYWX1X2X3W (SEQ ID NO:
- 67), wherein X1, X2, and X3 compise amino acids, and wherein the peptide binds VEGFR-3
A method for inhibiting proliferation of a cell that expresses VEGFR-3, comprising a step of contacting the cell with a nucleic acid comprising a nucleotide sequence encoding the peptide and further comprising a promoter active in said cell, wherein said promoter is operably linked to the nucleotide sequence encoding said peptide, under conditions permitting the uptake of said nucleic acid and expression of said peptide by said cell in an amount effective to inhibit the proliferation of said cell.
A method according to any one of claims 49-63, wherein the subject has a cancer of a tissue, organ, or cell selected from the group consisting of brain, lung, liver, spleen, kidney, lymph node, small intestine, blood cells, pancreas, colon, stomach, breast, endometrium, prostate, testicle, ovary, skin, head and neck, esophagus, bone marrow and blood.
Dependencies are inferred from the claim text.