Peptides that specifically bind HGF receptor (cMet) and uses thereof

1 . A polypeptide or multimeric peptide construct which binds cMet or a complex comprising cMet and HGF.

2 . A polypeptide or multimeric polypeptide according to claim 1 , comprising an amino acid sequence: X 1 -X 2 -X 3 -Cys-X 4 -X 5 -X 6 -X 7 -Cys-X 8 -X 9 -X 10 , wherein

X 1 is Phe, Leu, Ser, Trp, Tyr or Met;

X 2 is Ile, Tyr, His, Thr or Asn;

X 3 is Ile, Leu, Asp, Met, Phe or Ser;

X 4 is Arg, Asn, Glu, Pro or Trp;

X 5 is Glu, Gly, Leu, Pro, Thr, Trp or Tyr;

X 6 is Asp, Gln, Glu, Gly, Phe, Ser, Thr, or Trp;

X 7 is Ala, Arg, Asn, Gln, Glu, Gly, Phe or Trp;

X 8 is Gly, Asn, His, Arg, Met, Ile, Asp, Val, or Thr;

X 9 is Ser, Lys, Phe, Met, Thr, Asp or Leu; and

X 10 is Ser, Pro, Thr, Leu, Tyr, Asn, His, Glu or Trp.

3 . A polypeptide or multimeric polypeptide according to claim 2 , comprising an amino acid sequence selected from the group consisting of: SEQ ID NO:1; SEQ ID NO:2; SEQ ID NO:3; SEQ ID NO:4, SEQ ID NO:5; SEQ ID NO:6; SEQ ID NO:7; SEQ ID NO:9 AND SEQ ID NO:10.

4 . A polypeptide or multimeric polypeptide according to claim 1 , comprising an amino acid sequence: X 1 -X 2 -X 3 -Cys-X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -Cys-X 10 -X 11 -X 12 , wherein

X 1 is Gly, Val, Trp, Thr, Lys or Gln;

X 2 is Trp, Tyr, Leu, Phe or Thr;

X 3 is Trp, Glu, Phe, Ile, Leu or Ser;

X4 is Asn, Gln or Glu;

X 5 is Leu, Glu or Trp;

X 6 is Glu, Ser or Tyr;

X 7 is Glu, Met or Pro;

X 8 is Met, Ser or Trp;

X 9 is Leu, Phe or Val;

X 10 is Asp, Glu or Trp;

X 11 is Met, Phe or Trp; and

X 12 Gln, Leu, or Trp.

5 . A polypeptide or multimeric polypeptide according to claim 4 , comprising an amino acid sequence selected from the group consisting of: SEQ ID NO:11; SEQ D NO:12; SEQ ID NO:13; SEQ ID NO:14; SEQ ID NO:15; SEQ ID NO: 16; SEQ ID NO:17; SEQ ID NO:18; SEQ ID NO:19; SEQ ID NO:20; SEQ ID NO:21; SEQ ID NO:22; SEQ ID NO:23; SEQ ID NO:24; SEQ ID NO:25; SEQ ID NO:26; SEQ ID NO:27; SEQ ID NO:28; SEQ ID NO:29; SEQ ID NO:30; SEQ ID NO:31; SEQ ID NO:32; SEQ ID NO:33; SEQ ID NO:34; SEQ ID NO:35; SEQ ID NO:36; SEQ ID NO:37; SEQ ID NO:38; SEQ ID NO:39; and SEQ ID NO:40.

6 . A polypeptide or multimeric polypeptide according to claim 1 , comprising an amino acid sequence: X 1 -X 2 -X 3 -Cys-X 4 -Gly-X 5 -Pro-X 6 -Phe-X 7 -Cys-X 8 -X 9 , wherein

X 1 is Glu, Ser, or Trp;

X 2 is Phe-Thr or Trp;

X 3 is His, Phe or Trp;

X 4 is Ala, Lys, Ser or Thr;

X 5 is Pro or Trp;

X 6 is Ser or Thr;

X 7 is Glu or Ser;

X 8 is Ile, Trp or Tyr; and

X 9 is Glu, Met or Tyr.

7 . A polypeptide or multimeric polypeptide according to claim 6 , comprising an amino acid sequence selected from the group consisting of: SEQ IID NO:48; SEQ D NO:49; SEQ ID NO:50; SEQ ID NO:51; SEQ ID NO:52; SEQ ID NO:53; SEQ ID NO:54; SEQ ID NO:55; SEQ ID NO:56; SEQ ID NO:57; SEQ ID NO:58; SEQ ID NO:59; SEQ ID NO:60; SEQ ID NO:61; SEQ ID NO:62; SEQ ID NO:63; SEQ ID NO:64; SEQ ID NO:65; SEQ ID NO:66; SEQ ID NO:67; SEQ ID NO:68; SEQ ID NO:69; SEQ ID NO:70; SEQ ID NO:71; SEQ ID NO:72; SEQ ID NO:73; SEQ ID NO:74; SEQ ID NO:75; SEQ ID NO:76; SEQ ID NO:79; SEQ ID NO:80; SEQ ID NO:81; SEQ ID NO:82; SEQ ID NO:83; SEQ ID NO:84; SEQ ID NO:85; SEQ ID NO:86; SEQ ID NO:87; SEQ ID NO:88; SEQ ID NO:89; SEQ ID NO:90; SEQ ID NO:91; SEQ ID NO:92; SEQ ID NO:93; SEQ ID NO:94; SEQ ID NO:95; SEQ ID NO:96; SEQ ID NO:97; SEQ ID NO:98; SEQ ID NO:99; SEQ ID NO:100; and SEQ ID NO:101.

9 . A polypeptide or multimeric polypeptide according to claim 1 , comprising an amino acid sequence: X 1 -X 2 -X 3 -Cys-X 4 -Gly-Pro-Pro-X 5 -Phe-X 6 -Cys-Trp-X 7 -X 8 -X 9 -X 10 -X 11 , wherein

X 1 is Arg, Asp, Asn, Ile or Ser;

X 2 is Leu, Ile, Phe, Trp or Val;

X 3 is Asn, Gln, His, Leu, Tyr or Val;

X 4 is Leu, Lys or Ser;

X 5 is Ala, Ser, Thr or Trp;

X 6 is Glu or Ser;

X 7 is Leu, Ser or Trp;

X 8 is Phe or Tyr;

X 9 is Asp, Glu, Gly or Val;

X 10 is Met, Pro, Thr or Ser; and

X 11 is Glu or Gly.

10 . A polypeptide or multimeric polypeptide according to claim 9 , comprising an amino acid sequence selected from the group consisting of: SEQ ID NO:103; SEQ D NO:104; SEQ ID NO:106; SEQ ID NO:108; SEQ ID NO:111; SEQ ID NO:114; SEQ ID NO:117; SEQ ID NO:119; SEQ ID NO:120; SEQ ID NO:121; SEQ ID NO:128; SEQ ID NO:130; SEQ ID NO:132; SEQ ID NO:133; SEQ ID NO:140; SEQ ID NO:143; SEQ ID NO:145; SEQ ID NO:146; SEQ ID NO:147; SEQ ID NO:150; SEQ ID NO:151; SEQ ID NO:153; SEQ ID NO:155-SEQ ID NO:158; SEQ ID NO:163; SEQ ID NO:165; SEQ ID NO:167; SEQ ID NO:169; SEQ ID NO:170; SEQ ID NO:172; SEQ ID NO:173; SEQ ID NO:178; SEQ ID NO:179; SEQ ID NO:184; SEQ ID NO:185; SEQ ID NO:188; SEQ ID NO:189; SEQ ID NO:190; SEQ ID NO:192; SEQ ID NO:195; SEQ ID NO:198; SEQ ID NO:201-SEQ ID NO:204; SEQ ID NO:208; SEQ ID NO:209; SEQ ID NO:211; SEQ ID NO:215; SEQ ID NO:216; SEQ ID NO:217;SEQ ID NO:219;SEQ ID NO:221; SEQ ID NO:224; SEQ ID NO:226; SEQ ID NO:227; SEQ ID NO:230-SEQ ID NO:234; SEQ ID NO:236; SEQ ID NO:237; SEQ ID NO:238; SEQ ID NO:242; SEQ ID NO:246-SEQ ID NO:254; SEQ ID NO:256; SEQ ID NO:259-SEQ ID NO:264; SEQ ID NO:266; SEQ ID NO:267; SEQ ID NO:269-SEQ ID NO:271; SEQ ID NO:273; SEQ ID NO:275-SEQ ID NO:282; SEQ ID NO:284; SEQ ID NO:285; SEQ ID NO:287; SEQ ID NO:288; SEQ ID NO:293-SEQ ID NO:295; SEQ ID NO:297; SEQ ID NO:298; SEQ ID NO:301-SEQ ID NO:303; SEQ ID NO:305-SEQ ID NO:308; SEQ ID NO:311; SEQ ID NO:313-SEQ ID NO:320; SEQ ID NO:323; SEQ ID NO:324; SEQ ID NO:326-SEQ ID NO:328; SEQ ID NO:331-SEQ ID NO:335; SEQ ID NO:337-SEQ ID NO:341; SEQ ID NO:345; SEQ ID NO:347; SEQ ID NO:349; SEQ ID NO:352; SEQ ID NO:354-SEQ ID NO:357; and SEQ ID NO:361-SEQ ID NO:364.

11 . A polypeptide or multimeric polypeptide according to claim 1 , comprising an amino acid sequence: X 1 -X 2 -X 3 -X 4 -Trp-X 5 -Cys-X 6 -Gly-Pro-Pro-Thr-Phe-Glu-Cys-Trp-X 7 -X 8 , wherein

X 1 is Asp, Glu or Val;

X 2 is Ala, Asp, Gly, Ser or Val;

X 3 is Asp, Gly, Ser or Val;

X 4 is Arg, Asn, Gly, Ser or Thr;

X 5 is Gln or His;

X 6 is Asn, Lys or Ser; and

X 7 is Ser or Trp.

12 . A polypeptide or multimeric polypeptide according to claim 1 , comprising an amino acid sequence: X 1 -X 2 -X 3 -Cys-X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -Cys-X 12 -X 13 -X 14 , wherein

X 1 is His, Phe, Pro, Thr or Trp;

X 2 is Ala, Arg, Glu, His, Lys or Phe;

X 3 is Met, Phe, Pro, Thr or Val;

X 4 is His, Leu, Met, Phe or Trp;

X 5 is Arg, Asp, Glu, Gly, Met or Trp;

X 6 is Glu, Gly, Ile, Lys, Phe or Pro;

X 7 is Asp, Phe, Pro, Ser, Trp or Tyr;

X 8 is Ala, Arg, Asn, Phe or Ser;

X 9 is Ala, Gln, Gly, Leu or Phe;

X 10 is Gln, Gly, Ile, Leu, Trp or Tyr;

X 11 is Arg, Asp, Phe, Pro, Tyr or Val;

X 12 is Asn, Gln, His, Ile or Thr;

X 13 is Ala, Asn, Asp, Glu or His; and

X 14 is Asn, Gln, Glu, His or Val.

13 . A polypeptide or multimeric polypeptide according to claim 12 , comprising an amino acid sequence selected from the group consisting of: SEQ ID NO:365; SEQ ID NO:366; SEQ ID NO:367; SEQ ID NO:368; SEQ ID NO:369; and SEQ ID NO:370.

14 . A polypeptide or multimeric polypeptide according to claim 1 , comprising an amino acid sequence: X 1 -X 2 -X 3 -Cys-X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -Cys-X 13 -X 14 -X 15 , wherein

X 1 is Gln, Gly, Met, Phe or Ser;

X 2 is Asn, Gln, Leu or Met;

X 3 is Arg, Asn, Gly, His or Ile;

X 4 is Asn, Asp, Leu, Thr or Trp;

X 5 is Arg, Gln, Thr, Tyr or Val;

X 6 is Glu, Gly, Leu, Met or Thr;

X 7 is Ala, Asn, Asp, His, Ile, Leu, or Ser;

X 8 is Arg, Gln, Ser, Thr or Tyr;

X 9 is Asp, Gly, Ile or Phe;

X 10 is Gln, Phe or Thr;

X 11 is Gln, His, Phe, Pro, Ser or Tyr;

X 12 is Asn, Asp, Phe, Pro or Ser;

X 13 is Ala, Asn, Gly, Leu or Ser;

X 14 is Arg, Pro, Ser or Val; and

X 15 is Asp, Glu, Leu or Met.

15 . A polypeptide or multimeric polypeptide according to claim 14 , comprising an amino acid sequence selected from the group consisting of: SEQ ID NO:371; SEQ ID NO:372; SEQ ID NO:373; SEQ ID NO:374; SEQ ID NO:375; SEQ ID NO:376; SEQ ID NO:377; SEQ ID NO:378; SEQ ID NO:379; SEQ ID NO:380; SEQ ID NO:381; SEQ ID NO:382; SEQ ID NO:383; SEQ ID NO:384; SEQ ID NO:385; SEQ ID NO:386; and SEQ ID NO:387.

16 . A polypeptide or multimeric polypeptide according to claim 1 , comprising an amino acid sequence: X 1 -X 2 -X 3 -Cys-X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -Cys-X 14 -X 15 -X 16 , wherein

X 1 is Ala, His, Leu, Pro or Tyr;

X 2 is Arg, Asp, Leu, Ser or Tyr;

X 3 is Glu, Met or Trp;

X 4 is Asp, Gln, Glu, Phe or Ser;

X 5 is Glu, Ile, Phe or Trp;

X 6 is Asn, Asp or Ser;

X 7 is Asn, Asp or Leu;

X 8 is Asp, Glu or Lys;

X 9 is Gly, Phe or Thr;

X 10 is Gly, Phe, Trp or Tyr;

X 11 is Glu, Ser or Trp;

X 12 is Glu, Phe, Tyr or Val;

X 13 is Glu, Lys, Thr or Val;

X 14 is Glu or Trp;

X 15 is Asp, Phe, Pro, Ser or Trp; and

X 16 is Ala, Asn or Ile.

17 . A polypeptide or multimeric polypeptide according to claim 16 , comprising an amino acid sequence selected from the group consisting of: SEQ ID NO:390; SEQ ID NO:391; SEQ ID NO:392; SEQ ID NO:393; SEQ ID NO:394; SEQ ID NO:395; SEQ ID NO:396; SEQ ID NO:397; SEQ ID NO:398; SEQ ID NO:399; SEQ ID NO:400; SEQ ID NO:401; SEQ ID NO:402; SEQ ID NO:403; and SEQ ID NO:404.

18 . A polypeptide or multimeric polypeptide according to claim 1 , comprising an amino acid sequence: Ser-Cys-X 1 -Cys-X 2 -Gly-Pro-Pro-Thr-Phe-Glu-Cys-Trp-Cys-Tyr-X 3 -X 4 -X 5 , wherein

X 1 is Asn, His or Tyr;

X 2 is Gly or Ser;

X 3 is Ala, Asp, Glu, Gly or Ser;

X 4 is Ser or Thr; and

X 5 is Asp or Glu.

19 . A polypeptide or multimeric polypeptide according to claim 18 , comprising an amino acid sequence selected from the group consisting of: SEQ ID NO:405; SEQ ID NO:406; SEQ ID NO:407; SEQ ID NO:408; SEQ ID NO:409; SEQ ID NO:410; SEQ ID NO:411; SEQ ID NO:412; SEQ ID NO:413; SEQ ID NO:414; SEQ ID NO:415; SEQ ID NO:416; SEQ ID NO:417; SEQ ID NO:418; SEQ ID NO:419; SEQ ID NO:420; SEQ ID NO:421; SEQ ID NO:422; SEQ ID NO:423; SEQ ID NO:424; SEQ ID NO:425; SEQ ID NO:426; SEQ ID NO:427; SEQ ID NO:428; SEQ ID NO:429; SEQ ID NO:430; SEQ ID NO:431; SEQ ID NO:432; SEQ ID NO:433; SEQ ID NO:434; SEQ ID NO:435; SEQ ID NO:436; SEQ ID NO:437; SEQ ID NO:438; SEQ ID NO:439; SEQ ID NO:440; SEQ ID NO:441; SEQ ID NO:442; SEQ ID NO:443; SEQ ID NO:444; SEQ ID NO:445; SEQ ID NO:446; and SEQ ID NO:447.

20 . A polypeptide or multimeric polypeptide according to claim 1 , comprising an amino acid sequence: Glu-X 1 -Gly-Ser-Cys-His-Cys-Ser-Gly-Pro-Pro-Thr-Phe-Glu-Cys-X 2 -Cys-X 3 , wherein

X 1 is Ala, Glu, Gly or Ser;

X 2 is Phe, Trp or Tyr; and

X 3 is Phe or Tyr.

21 . A polypeptide or multimeric polypeptide according to claim 20 , comprising an amino acid sequence selected from the group consisting of: SEQ ID NO:406; SEQ ID NO:415; SEQ ID NO:427; SEQ ID NO:445 and SEQ ID NO:447.

22 . A polypeptide or multimeric polypeptide according to claim 1 , wherein said polypeptide or multimeric polypeptide has a Kd for cMet of less than about 1.0 μM.

23 . A multimeric polypeptide according to claim 13 , further comprising an amino acid sequence of SEQ ID NO:516 or SEQ ID NO:517.

24 . A multimeric polypeptide according to claim 23 , wherein the multimeric polypeptide comprises an amino acid sequence of SEQ ID NO:514 or SEQ ID NO:515.

25 . A multimeric polypeptide according to claim 13 , wherein the multimeric polypeptide comprises SEQ ID NO:514 and SEQ ID NO:515.

26 . A method of detecting cMet or a complex of cMet and HGF in an animal or human subject comprising:

providing a polypeptide or multimeric polypeptide according to claim 1 , wherein the polypeptide or multimeric polypeptide is labeled;

administering to the subject the labeled polypeptide or multimeric polypeptide; and

detecting the labeled polypeptide or multimeric polypeptide in the subject.

27 . A method according claim 26 , wherein the label is radioactive or paramagnetic.

28 . A method of treating a condition involving activation of cMet, comprising:

administering to an animal or human subject a composition comprising a polypeptide or multimeric polypeptide according to claim 1 .

29 . A method according to claim 28 , wherein the disease is a solid tumor.

30 . A method according to claim 29 , wherein the tumor is selected from the group consisting of: breast, thyroid, glioblastoma, prostate, malignant mesothelioma, colorectal, heptacellular, heptobiliary, renal, osteosarcoma and cervical tumors.

31 . A method of purifying cMet or a cMet and HGF complex from a solution containing it, comprising:

contacting the solution with at least one polypeptide or multimeric polypeptide according to claim 1; and

separating the polypeptide or multimeric polypeptide from the solution.

32 . A recombinant bacteriophage expressing exogenous DNA encoding a polypeptide of claim 1 , wherein the polypeptide is displayed on the surface of the bacteriophage.