c-MET kinase binding proteins

1. An isolated polypeptide comprising at least one monomer domain that binds to c-MET, wherein the at least one monomer domain comprises a sequence selected from the group consisting of (i) SEQ ID NO:8, (ii) SEQ ID NO:13, (iii) at least amino acids 1-34 of SEQ ID NO:15 and (iv) a sequence that is at least 95% identical to a sequence defined by any of (i), (ii) or (iii), as defined herein:

Cxxx[EQ]FxCxSTxRC[IV]xxxWxCDGDNDCEDxSDEx (SEQ ID NO:8),

wherein the first x is an amino acid chosen from A, L, E, R, P, and Q,

the second x is an amino acid chosen from P, A, and S,

the third x is an amino acid chosen from S, N, and G,

the fourth x is an amino acid chosen from T, Q, and K,

the fifth x is an amino acid chosen from N, R, S, and H,

the sixth x is an amino acid chosen from G, N, D, and E,

the seventh x is an amino acid chosen from P and S,

the eighth x is an amino acid chosen from Q, L, and A,

the ninth x is an amino acid chosen from E, T, Q, A, S, G, and D

the tenth x is an amino acid chosen from V and L,

the eleventh x is an amino acid chosen from S and G,

the twelfth x is an amino acid chosen from A, S, and K, and

amino acids in brackets are alternative amino acids at a single position;

Cxxx[EQ]FxCxSTGRCxPxxWxCxGxNDCEDxSDEx (SEQ ID NO:13),

wherein the first x is an amino acid chosen from A, E, V, R, L, P, and Q,

the second x is an amino acid chosen from A, S, P, T, and L,

the third x is an amino acid chosen from D, S, N, and G,

the fourth x is an amino acid chosen from Q, T, and R,

the fifth x is an amino acid chosen from N, H, and R,

the sixth x is any amino acid,

the seventh x is an amino acid chosen from V, Q, L, R, A, and G,

the eighth x is an amino acid chosen from S, E, D, Q, and A,

the ninth x is any amino acid,

the tenth x is amino acid chosen from D and H,

the eleventh amino acid is V and D,

the twelfth x is an amino acid chosen from S and G,

the thirteenth x is an amino acid chosen from A, T, S, and E,

and amino acids in brackets are alternative amino acids at a single position; and

at least amino acids 1-34 of

Cxxx[EQ]FxCxxxxxC[ILV]xxxWxCDGxNDCxDxSxExxxxC (SEQ ID NO:15),

wherein the first x is an amino acid chosen from P, Q, V, L, and E,

the second x is an amino acid chosen from A, S, and P,

the third x is an amino acid chosen from G, S, N, and D,

the fourth x is an amino acid chosen from Q, R, T, and M,

the fifth x is any amino acid,

the sixth x is any amino acid,

the seventh x is an amino acid chosen from T, G, and N,

the eighth x is any amino acid,

the ninth x is an amino acid chosen from R and Q,

the tenth x is amino acid chosen from P and S,

the eleventh amino acid is any amino acid,

the twelfth x is an amino acid chosen from T, P, N, D, A, and H,

the thirteenth x is an amino acid chosen from L, G, and V,

the fourteenth x is an amino acid chosen from D, V, and E,

the fifteenth x is an amino acid chosen from E and G,

the sixteenth x is an amino acid chosen from G and S,

the seventeenth x is any amino acid,

the eighteenth x is any amino acid,

the nineteenth x is any amino acid,

the twentieth x is any amino acid,

the twenty first x is any amino acid,

and amino acids in brackets are alternative amino acids at a single position.

2. The polypeptide of claim 1 comprising at least two monomer domains that bind to c-MET wherein each of the at least two monomer domains comprises a sequence selected from the group consisting of SEQ ID NO:8, a sequence that is at least 95% identical to SEQ ID NO:8, SEQ ID NO:13, a sequence that is at least 95% identical to SEQ ID NO:13, at least amino acids 1-34 of SEQ ID NO:15, and a sequence that is at least 95% identical to at least amino acids 1-34 of SEQ ID NO:15, as defined in claim 1 .

3. The polypeptide of claim 1 comprising at least three monomer domains that bind to c-MET wherein each of the monomer domains comprises a sequence selected from the group consisting of SEQ ID NO:8, a sequence that is at least 95% identical to SEQ ID NO:8, SEQ ID NO:13, a sequence that is at least 95% identical to SEQ ID NO:13, at least amino acids 1-34 of SEQ ID NO:15, and a sequence that is at least 95% identical to at least amino acids 1-34 of SEQ ID NO:15, as defined in claim 1 .

4. The polypeptide of claim 1 wherein at least one monomer domain comprises at least amino acids 1-38 of the following sequence:

CQPNEFQCHSTGRCIPASWLCDGDNDCEDSSDESPANCATPTHT (SEQ ID NO:641).

5. An isolated polypeptide comprising at least three monomer domains that bind to c-MET, wherein

one monomer domain comprises a sequence selected from the group consisting of

(1) Cxxx[EQ]FxCxSTGRCxPxxWxCxGxNDCEDxSDEx (SEQ ID NO:13),

wherein the first x is an amino acid chosen from A, E, V, R, L, F, and Q,

the second x is an amino acid chosen from A, S, P, T, and L,

the third x is an amino acid chosen from D, S, N, and G,

the fourth x is an amino acid chosen from Q, T, and R,

the fifth x is an amino acid chosen from N, H, and R,

the sixth x is any amino acid,

the seventh x is an amino acid chosen from V, Q, L, R, A, and G,

the eighth x is an amino acid chosen from S, E, D, Q, and A,

the ninth x is any amino acid,

the tenth x is amino acid chosen from D and H,

the eleventh amino acid is V and D,

the twelfth x is an amino acid chosen from S and G,

the thirteenth x is an amino acid chosen from A, T, S, and E,

and amino acids in brackets are alternative amino acids at a single position, and

(ii) a sequence that is at least 95% identical to a sequence defined by (i);

another monomer domain comprises a sequence selected from the group consisting of

(iii) at least amino acids 1-34 of:

Cxxx[EQ]FxCxxxxxC[ILV]xxxWxCDGxNDCxDxSxExxxxC (SEQ ID NO:15),

wherein the first x is an amino acid chosen from P, Q, V, L, and E,

the second x is an amino acid chosen from A, S, and P,

the third x is an amino acid chosen from G, S, N, and D,

the fourth x is an amino acid chosen from Q, R, T, and M,

the fifth x is an amino acid chosen from any amino acid,

the sixth x is any amino acid,

the seventh x is an amino acid chosen from T, G, and N,

the eight x is any amino acid,

the ninth x is an amino acid chosen from R and Q,

the tenth x is amino acid chosen from P and S,

the eleventh amino acid is any amino acid,

the twelfth x is an amino acid chosen from T, P, N, D, A, and H,

the thirteenth x is an amino acid chosen from L, G, and V,

the fourteenth x is an amino acid chosen from D, V, and E,

the fifteenth x is an amino acid chosen from E and G,

the sixteenth x is an amino acid chosen from G and S,

the seventeenth x is any amino acid,

The eighteenth x is any amino acid,

the nineteenth x is any amino acid,

the twentieth x is any amino acid,

the twenty first x is any amino acid,

and amino acids in brackets are alternative amino acids at a single position, and

(iv) a sequence that is at least 95% identical to a sequence defined by (iii); and

yet another monomer domain comprises a sequence selected from the group consisting of

(v) at least amino acids 1-34 of:

Cxxx[EQ]FxCxxxxxC[ILV]xxxWxCDGxNDCxDxSxExxxxC (SEQ ID NO:15),

wherein the first x is an amino acid chosen from P, Q, V, L, and E,

the second x is an amino acid chosen from A, S, and P,

the third x is an amino acid chosen from G, S, N, and D,

the fourth x is an amino acid chosen from Q, R, T, and M,

the fifth x is an amino acid chosen from any amino acid,

the sixth x is any amino acid,

the seventh x is an amino acid chosen from T, G, and N,

the eighth x is any amino acid,

the ninth x is an amino acid chosen from R and Q,

the tenth x is amino acid chosen from P and S,

the eleventh amino acid is any amino acid,

the twelfth x is an amino acid chosen from T, P, N, D, A, and H,

the thirteenth x is an amino acid chosen from L, G, and V,

the fourteenth x is an amino acid chosen from D, V, and E,

the fifteenth x is an amino acid chosen from E and G,

the sixteenth x is an amino acid chosen from G and S,

the seventeenth x is any amino acid,

the eighteenth x is any amino acid,

the nineteenth x is any amino acid,

the twentieth x is any amino acid,

the twenty first x is any amino acid,

and amino acids in brackets are alternative amino acids at a single position; and

(vi) a sequence that is at least 95% identical to a sequence defined by (v).

6. An isolated polypeptide comprising at least three monomer domains that bind to c-MET, wherein

one monomer domain comprises at least amino acids 1-38 of:

CQPNEFQCHSTGRCIPASWLCDGDNDCEDSSDESPANCATPTHT (SEQ ID NO:641);

another monomer domain comprises a sequence selected from the group consisting of

(i) at least amino acids 1-34 of:

Cxxx[EQ]FxCxxxxxC[ILV]xxxWxCDGxNDCxDxSxExxxC (SEQ ID NO:15),

wherein the first x is an amino acid chosen from P, Q, V, L, and E,

the second x is an amino acid chosen from A, S, and P,

the third x is an amino acid chosen from G, S, N, and D,

the fourth x is an amino acid chosen from Q, R, T, and M,

the fifth x is an amino acid chosen from any amino acid,

the sixth x is any amino acid,

the seventh x is an amino acid chosen from T, G, and N,

the eighth x is any amino acid,

the ninth x is an amino acid chosen from R and Q,

the tenth x is amino acid chosen from P and S,

the eleventh amino acid is any amino acid,

the twelfth x is an amino acid chosen from T, P, N, D, A, and H,

the thirteenth x is an amino acid chosen from L, G, and V,

the fourteenth x is an amino acid chosen from D, V, and E,

the fifteenth x is an amino acid chosen from E and G,

the sixteenth x is an amino acid chosen from G and S,

the seventeenth x is any amino acid,

the eighteenth x is any amino acid,

the nineteenth x is any amino acid,

the twentieth x is any amino acid,

the twenty first x is any amino acid,

and amino acids in brackets are alternative amino acids at a single position, and

(ii) a sequence that is at least 95% identical to a sequence defined by (i); and

yet another monomer domain comprises a sequence selected from the group consisting of

(iii) at least amino acids 1-34 of:

Cxxx[EQ]FxCxxxxxC[ILV]xxxWxCDGxNDCxDxSxExxxxC (SEQ ID NO:15),

wherein the first x is an amino acid chosen from P, Q, V, L, and E,

the second x is an amino acid chosen from A, S, and P,

the third x is an amino acid chosen from G, S, N, and D,

the fourth x is an amino acid chosen from Q, R, T, and M,

the fifth x is an amino acid chosen from any amino acid,

the sixth x is any amino acid,

the seventh x is an amino acid chosen from T, G, and N,

the eighth x is any amino acid,

the ninth x is an amino acid chosen from R and Q,

the tenth x is amino acid chosen from P and S,

the eleventh amino acid is any amino acid,

the twelfth x is an amino acid chosen from T, P, N, D, A, and H,

the thirteenth x is an amino acid chosen from L, G, and V,

the fourteenth x is an amino acid chosen from D, V, and E,

the fifteenth x is an amino acid chosen from E and G,

the sixteenth x is an amino acid chosen from G and S,

the seventeenth x is any amino acid,

the eighteenth x is any amino acid,

the nineteenth x is any amino acid,

the twentieth x is any amino acid,

the twenty first x is any amino acid,

and amino acids in brackets are alternative amino acids at a single position; and

(iv) a sequence that is at least 95% identical to a sequence defined by (iii).

7. A polynucleotide encoding the polypeptide of claim 1 .

8. A polynucleotide encoding the polypeptide of claim 2 .

9. A polynucleotide encoding the polypeptide of claim 3 .

10. A polynucleotide encoding the polypeptide of claim 5 .

11. A polynucleotide encoding the polypeptide of claim 6 .

12. The polypeptide of claim 2 wherein at least one monomer domain comprises at least amino acids 1-38 of the following sequence:

CQPNEFQCHSTGRCIPASWLCDGDNDCEDSSDESPANCATPTHT (SEQ ID NO:641).

13. The polypeptide of claim 3 wherein at least one monomer domain comprises at least amino acids 1-38 of the following sequence:

CQPNEFQCHSTGRCIPASWLCDGDNDCEDSSDESPANCATPTHT (SEQ ID NO:641).

14. A polynucleotide encoding the polypeptide of claim 12 .

15. A polynucleotide encoding the polypeptide of claim 13 .

16. The polypeptide of any of claims 1 - 6 , 12 or 13 , further comprising a monomer domain having a binding specificity for a blood factor, thereby increasing the serum half-life of the polypeptide when the polypeptide is injected into an animal compared to the serum half-life of a polypeptide lacking the blood factor-binding monomer domain.

17. The polypeptide of claim 16 , wherein the blood factor is selected from the group consisting of serum albumin, an immunoglobulin and an erythrocyte.

18. The polypeptide of claim 17 , wherein the monomer domain having a binding specificity for a blood factor comprises a sequence selected from the group consisting of:

CHPTGQFRCRSSGRCVSPTWVCDGDNDCGDNSDEENCSAPASEPPGSL (SEQ ID NO:6), and

CHPTGQFRCRSSGRCVSPTWVCDGDNDCGDNSDEENC (SEQ ID NO:7).

19. The polypeptide of any of claims 1 - 6 , 12 or 13 , wherein the polypeptide hither polyethylene glycol (PEG).