US2013197191A1PendingUtilityA1
Binding Proteins That Bind to Human FGFR1c, Human Beta-Klotho and Both Human FGFR1c and Human Beta-Klotho
Est. expiryDec 2, 2029(~3.4 yrs left)· nominal 20-yr term from priority
A61P 3/10A61P 9/10A61P 3/06A61P 3/00A61P 3/04C07K 2319/70A61P 1/18A61K 38/00C07K 14/705A61P 1/16C07K 2319/75C07K 14/001C07K 14/50
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Claims
Abstract
Binding proteins that specifically bind to β-Klotho or portions thereof, FGFR1c or portions thereof, or both FGFR1c and β-Klotho, and optionally other proteins as well are provided. Coding sequences, methods of treatment and pharmaceutical compositions are also provided.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A binding protein that selectively binds β-Klotho, wherein the binding protein comprises one or more of:
(SEQ ID NO: 254)
C [AGP][APS][DGN][EQ]F[QRT] C [GNRS][GNS][GT][GKQS][-
IK] C [ILV]P[LQRV][AEHP]W[LRV] C DG[DLV][DN]D C GD[GN]
SDE[AEKPS][GLPS][-AEV][-IT] C ;
(SEQ ID NO: 597)
C LPDEFQ C [SG]SGR C IPQ[HT]W[VL] C DGLND C GDGSDE[PS]PA
[HT] C ;
and
(SEQ ID NO: 249)
C [AGPR][AP][DGNS][EQ]F[QRT] C [GSK]N[GT][GHR][R] C
[ILV][PS][ALQ][NST]W[LRV] C DG[DEV]DD C [GL]DGSDE[AET]
[DNS][-A][-T] C ;
wherein amino acids in brackets indicate alternative amino acids at a specified position and “-” indicates no amino acid at the specified position.
2 . The binding protein of claim 1 , wherein the binding protein comprises one or more of:
(SEQ ID NO: 255)
CGPDQFRCSSGKCIPQHWLCDGLNDCGDGSDESPATC;
(SEQ ID NO: 256)
CGANEFQCRSTGICVPVEWVCDGDNDCGDGSDEPPVC;
(SEQ ID NO: 257)
CGADQFRCGNGSCVPRAWRCDGVDDCGDGSDEAPEIC;
(SEQ ID NO: 258)
CGPDEFRCNNGQCIPLPWRCDGVDDCGDNSDEPLEIC;
(SEQ ID NO: 259)
CASGEFTCNNGQCVPLAWRCDGVNDCQDGSDEKGC;
(SEQ ID NO: 260)
CGPDEFRCNNGQCIPLPWRCDGVDDCGDNSDEPLEIC;
(SEQ ID NO: 261)
CPPDEFQCRGTKKCLPLAWVCDGDNDCEDDSDEESC;
(SEQ ID NO: 1237)
CLPDEFQCGSGRCIPQHWLCDGLNDCGDGSDEPPAHC;
(SEQ ID NO: 1326)
CLPDEFQCGSGRCIPQHWLCDGLNDCGDGSDEPPAHC;
(SEQ ID NO: 1327)
CAPGEFTCKNTGRCIPLNWRCDGDDDCGDGSDETDC;
and
(SEQ ID NO: 1328)
CGPDEFRCNNGQCIPLPWRCDGVDDCGDNSDEPLEIC.
3 . A binding protein that selectively binds β-Klotho, wherein the binding protein comprises one or more of:
(SEQ ID NO: 394)
C QSNEFR C RSGR C IPQHWL C DGLND C GDGSD
E[PS][PQ][AQ][-H]C;
(SEQ ID NO: 217)
C [ELPQR][APS][DGIN][EGQ][FQ][FKPQRT][-
E] C [GNRS][NS]G[HNQR] C [IV]P[AELPQRV][AHPQRT]W
[LRV] C DG[DEV][DNP]D C [GLQ]D[DGNS]SDE[AEKT]
[DGLNS][-A][-H] C ;
and
(SEQ ID NO: 254)
C [AGP][APS][DGN][EQ]F[QRT] C [GNRS][GNS][GT][GKQS][-
IK] C [ILV]P[LQRV][AEHP]W[LRV] C DG[DLV][DN]D C GD
[GN]SDE[AEKPS][GLPS][-AEV][-IT] C ;
wherein amino acids in brackets indicate alternative amino acids at a specified position and “-” indicates no amino acid at the specified position.
4 . The binding protein of claim 3 , wherein the binding protein comprises one or more of: CQSNEFRCRSGRCIPQHWLCDGLNDCGDGSDESQQC (SEQ ID NO: 159);
CRAGEFRCSNGRCVPLTWLCDGEDDCQDNSDEKNC (SEQ ID NO:1323); CPSNQFPCRSTGICIPLAWVCDGLNDCGDGSDESPAHC (SEQ ID NO:1324); and CQSNEFRCRSGRCIPQHWLCDGLNDCGDGSDEPPAHC (SEQ ID NO:1325).
5 . A binding protein that selectively binds FGFR1c, wherein the binding protein comprises:
(SEQ ID NO: 108)
CG [AE][GS] LFTC [GR][NRS][AST][KN] ICIS [EHQS][AV]W
[IV] CDG [IV] DDC [DE] DNSDE [DKMNT][NSY] C ;
wherein amino acids in brackets indicate alternative amino acids at a specified position and “-” indicates no amino acid at the specified position.
6 . The binding protein of claim 5 , wherein the binding protein comprises one or more of:
(SEQ ID NO: 109)
CGAGLFTCRS TNICISQVWV CDGVDDCEDN SDEDSC;
(SEQ ID NO: 110)
CGAGLFTCRS TNICISQAWV CDGVDDCEDN SDENYC;
(SEQ ID NO: 111)
CGAGLFTCRS TNICISQAWV CDGVDDCEDN SDETNC;
(SEQ ID NO: 112)
CGEGLFTCGS TNICISSAWV CDGVDDCEDN SDENNC;
(SEQ ID NO: 113)
CGEGLFTCRS TNICISHAWV CDGVDDCEDN SDENNC;
(SEQ ID NO: 114)
CGEGLFTCRS TNICISEAWI CDGVDDCEDN SDEKNC;
(SEQ ID NO: 115)
CGAGLFTCRS AKICISHAWV CDGIDDCEDN SDENNC;
(SEQ ID NO: 116)
CGAGLFTCRN SKICISQAWV CDGVDDCDDN SDEKYC;
(SEQ ID NO: 117)
CGASLFTCRR SNICISQAWV CDGVDDCEDN SDEMNC;
and
(SEQ ID NO: 118)
CGAGLFTCRS TKICISQAWV CDGVDDCEDN SDEKNC.
7 . The binding protein of claim 6 , wherein the binding protein further comprises a linker comprising the sequence SAPASEPPGSL (SEQ ID NO: 12).
8 . The binding protein of claim 7 , wherein the binding protein comprises one or more of:
(SEQ ID NO: 293)
CGAGLFTCRSTNICISQVWVCDGVDDCEDNSDEDSCSAPASEPPGSL;
(SEQ ID NO: 294)
CGAGLFTCRSTNICISQAWVCDGVDDCEDNSDENYCSAPASEPPGSL;
(SEQ ID NO: 295)
CGAGLFTCRSTNICISQAWVCDGVDDCEDNSDETNCSAPASEPPGSL;
(SEQ ID NO: 448)
CGEGLFTCGSTNICISSAWVCDGVDDCEDNSDENNCSAPASEPPGSL;
(SEQ ID NO: 297)
CGEGLFTCRSTNICISHAWVCDGVDDCEDNSDENNCSAPASEPPGSL;
(SEQ ID NO: 449)
CGEGLFTCRSTNICISEAWICDGVDDCEDNSDEKNCSAPASEPPGSL;
(SEQ ID NO: 450)
CGAGLFTCRSAKICISHAWVCDGIDDCEDNSDENNCSAPASEPPGSL;
(SEQ ID NO: 464)
CGAGLFTCRNSKICISQAWVCDGVDDCDDNSDEKYCSAPASEPPGSL;
(SEQ ID NO: 296)
CGASLFTCRRSNICISQAWVCDGVDDCEDNSDEMNCSAPASEPPGSL;
and
(SEQ ID NO: 287)
CGAGLFTCRSTKICISQAWVCDGVDDCEDNSDEKNCSAPASEPPGSL.
9 . The binding protein of claim 8 , wherein the binding protein comprises the sequence:
(SEQ ID NO: 297)
CGEGLFTCRSTNICISHAWVCDGVDDCEDNSDENNCSAPASEPPGSL.
10 . A binding protein that selectively binds β-Klotho, wherein the binding protein comprises:
(a) a first β-Klotho binding domain comprising a sequence selected from the group represented by the sequences:
(SEQ ID NO: 254)
C [AGP][APS][DGN][EQ]F[QRT] C [GNRS][GNS][GT][GKQS][-
IK] C [ILV]P[LQRV][AEHP]W[LRV] C DG[DLV][DN]D C GD
[GN]SDE[AEKPS][GLPS][-AEV][-IT] C ;
(SEQ ID NO: 597)
C LPDEFQ C [SG]SGR C IPQ[HT]W[VL] C DGLND C GDGSDE[PS]PA
[HT] C ;
(SEQ ID NO: 249)
C [AGPR][AP][DGNS][EQ]F[QRT] C [GSK]N[GT][GHR][-
R] C [ILV][PS][ALQ][NST]W[LRV] C DG[DEV]DD C [GL]DGSDE
[AET][DNS][-A][-T] C ;
and
(b) a second β-Klotho binding domain comprising a sequence selected from the group represented by the sequences:
(SEQ ID NO: 394)
C QSNEFR C RSGR C IPQHWL C DGLND C GDGSD
E[PS][PQ][AQ][-H]C;
(SEQ ID NO: 217)
C [ELPQR][APS][DGIN][EGQ][FQ][FKPQRT][-
E] C [GNRS][NS]G[HNQR] C [IV]P[AELPQRV][AHPQRT]W
[LRV] C DG[DEV][DNP]D C [GLQ]D[DGNS]SDE[AEKT]
[DGLNS][-A][-H] C ;
and
(SEQ ID NO: 254)
C [AGP][APS][DGN][EQ]F[QRT] C [GNRS][GNS][GT][GKQS][-
IK] C [ILV]P[LQRV][AEHP]W[LRV] C DG[DLV][DN]D C GD[GN]
SDE[AEKPS][GLPS][-AEV][-IT] C ;
wherein amino acids in brackets indicate alternative amino acids at a specified position and “-” indicates no amino acid at the specified position.
11 . The binding protein of claim 10 further comprising at least one linker joining (a) and (b).
12 . The binding protein of claim 11 , wherein the linker is one or more of: ETPT (SEQ ID NO: 1319), GDSHILPFSTPGPST (SEQ ID NO: 14), SAPASEPPGSL (SEQ ID NO:12), PAPT (SEQ ID NO:1320), QAPT (SEQ ID NO:1321), AQPT (SEQ ID NO:1322), AHT, PERT (SEQ ID NO: 7), TTRT (SEQ ID NO: 8), GTTGPT (SEQ ID NO: 9), ETSGPT (SEQ ID NO: 10), SQDPEFHKVS (SEQ ID NO: 11), and GRPGPGATSAPAA (SEQ ID NO: 13).
13 . The binding protein of claim 10 , wherein the β-Klotho binding domain of (a) comprises one or more of:
(SEQ ID NO: 255)
CGPDQFRCSSGKCIPQHWLCDGLNDCGDGSDESPATC;
(SEQ ID NO: 256)
CGANEFQCRSTGICVPVEWVCDGDNDCGDGSDEPPVC;
(SEQ ID NO: 257)
CGADQFRCGNGSCVPRAWRCDGVDDCGDGSDEAPEIC;
(SEQ ID NO: 258)
CGPDEFRCNNGQCIPLPWRCDGVDDCGDNSDEPLEIC;
(SEQ ID NO: 259)
CASGEFTCNNGQCVPLAWRCDGVNDCQDGSDEKGC;
(SEQ ID NO: 260)
CGPDEFRCNNGQCIPLPWRCDGVDDCGDNSDEPLEIC;
(SEQ ID NO: 261)
CPPDEFQCRGTKKCLPLAWVCDGDNDCEDDSDEESC;
(SEQ ID NO: 1237)
CLPDEFQCGSGRCIPQHWLCDGLNDCGDGSDEPPAHC;
(SEQ ID NO: 1326)
CLPDEFQCGSGRCIPQHWLCDGLNDCGDGSDEPPAHC;
(SEQ ID NO: 1327)
CAPGEFTCKNTGRCIPLNWRCDGDDDCGDGSDETDC;
and
(SEQ ID NO: 1328)
CGPDEFRCNNGQCIPLPWRCDGVDDCGDNSDEPLEIC.
14 . The binding protein of claim 10 , wherein the β-Klotho binding domain of (b) comprises one or more of:
(SEQ ID NO: 159)
CQSNEFRCRSGRCIPQHWLCDGLNDCGDGSDESQQC;
(SEQ ID NO: 1323)
CRAGEFRCSNGRCVPLTWLCDGEDDCQDNSDEKNC;
(SEQ ID NO: 1324)
CPSNQFPCRSTGICIPLAWVCDGLNDCGDGSDESPAHC;
and
(SEQ ID NO: 1325)
CQSNEFRCRSGRCIPQHWLCDGLNDCGDGSDEPPAHC.
15 . A binding protein that selectively binds β-Klotho and FGFR1c comprising (a) one or more domains that selectively bind β-Klotho, and (b) one or more domains that selectively bind FGFR1c, wherein the binding protein comprises:
(a) a β-Klotho binding domain comprising one or more of:
(SEQ ID NO: 254)
C [AGP][APS][DGN][EQ]F[QRT] C [GNRS][GNS][GT][GKQS][-
IK] C [ILV]P[LQRV][AEHP]W[LRV] C DG[DLV][DN]D C GD[GN]S
DE[AEKPS][GLPS][-AEV][-IT] C ;
(SEQ ID NO: 597)
C LPDEFQ C [SG]SGR C IPQ[HT]W[VL] C DGLND C GDGSDE[PS]PA
[HT] C ;
(SEQ ID NO: 249)
C [AGPR][AP][DGNS][EQ]F[QRT] C [GSK]N[GT][GHR][-
R] C [ILV][PS][ALQ][NST]W[LRV] C DG[DEV]DD C [GL]DGSDE
[AET][DNS][-A][-T] C ;
(b) an FGFR1c binding domain comprising one or more of:
(SEQ ID NO: 108)
CG [AE][GS] LFTC [GR][NRS][AST][KN] ICIS [EHQS][AV]W
[IV] CDG [IV] DDC [DE] DNSDE [DKMNT][NSY] C ;
and
wherein amino acids in brackets indicate alternative amino acids at a specified position and “-” indicates no amino acid at the specified position.
16 . The binding protein of claim 10 further comprising at least one linker joining (a) and (b).
17 . The binding protein of claim 16 , wherein the linker is one or more of: ETPT (SEQ ID NO: 1319), GDSHILPFSTPGPST (SEQ ID NO: 14), SAPASEPPGSL (SEQ ID NO:12), PAPT (SEQ ID NO:1320), QAPT (SEQ ID NO:1321), AQPT (SEQ ID NO:1322), AHT, PERT (SEQ ID NO: 7), TTRT (SEQ ID NO: 8), GTTGPT (SEQ ID NO: 9), ETSGPT (SEQ ID NO: 10), SQDPEFHKVS (SEQ ID NO: 11), and GRPGPGATSAPAA (SEQ ID NO: 13).
18 . The binding protein of claim 15 , wherein
(i) the β-Klotho binding domain of (a) comprises one or more of:
(SEQ ID NO: 255)
CGPDQFRCSSGKCIPQHWLCDGLNDCGDGSDESPATC;
(SEQ ID NO: 256)
CGANEFQCRSTGICVPVEWVCDGDNDCGDGSDEPPVC;
(SEQ ID NO: 257)
CGADQFRCGNGSCVPRAWRCDGVDDCGDGSDEAPEIC;
(SEQ ID NO: 258)
CGPDEFRCNNGQCIPLPWRCDGVDDCGDNSDEPLEIC;
(SEQ ID NO: 259)
CASGEFTCNNGQCVPLAWRCDGVNDCQDGSDEKGC;
(SEQ ID NO: 260)
CGPDEFRCNNGQCIPLPWRCDGVDDCGDNSDEPLEIC;
(SEQ ID NO: 261)
CPPDEFQCRGTKKCLPLAWVCDGDNDCEDDSDEESC;
(SEQ ID NO: 1237)
CLPDEFQCGSGRCIPQHWLCDGLNDCGDGSDEPPAHC;
(SEQ ID NO: 1326)
CLPDEFQCGSGRCIPQHWLCDGLNDCGDGSDEPPAHC;
(SEQ ID NO: 1327)
CAPGEFTCKNTGRCIPLNWRCDGDDDCGDGSDETDC;
and
(SEQ ID NO: 1328)
CGPDEFRCNNGQCIPLPWRCDGVDDCGDNSDEPLEIC;
and
19 . The binding protein of claim 18 , wherein the FGFR1c binding domain of (b) further comprises a linker comprising the sequence SAPASEPPGSL (SEQ ID NO: 12).
20 . The binding protein of claim 19 , wherein the FGFR1c binding domain comprises one or more of:
(SEQ ID NO: 293)
CGAGLFTCRSTNICISQVWVCDGVDDCEDNSDEDSCSAPASEPPGSL;
(SEQ ID NO: 294)
CGAGLFTCRSTNICISQAWVCDGVDDCEDNSDENYCSAPASEPPGSL;
(SEQ ID NO: 295)
CGAGLFTCRSTNICISQAWVCDGVDDCEDNSDETNCSAPASEPPGSL;
(SEQ ID NO: 448)
CGEGLFTCGSTNICISSAWVCDGVDDCEDNSDENNCSAPASEPPGSL;
(SEQ ID NO: 297)
CGEGLFTCRSTNICISHAWVCDGVDDCEDNSDENNCSAPASEPPGSL;
(SEQ ID NO: 449)
CGEGLFTCRSTNICISEAWICDGVDDCEDNSDEKNCSAPASEPPGSL;
(SEQ ID NO: 450)
CGAGLFTCRSAKICISHAWVCDGIDDCEDNSDENNCSAPASEPPGSL;
(SEQ ID NO: 464)
CGAGLFTCRNSKICISQAWVCDGVDDCDDNSDEKYCSAPASEPPGSL;
(SEQ ID NO: 296)
CGASLFTCRRSNICISQAWVCDGVDDCEDNSDEMNCSAPASEPPGSL;
and
(SEQ ID NO: 287)
CGAGLFTCRSTKICISQAWVCDGVDDCEDNSDEKNCSAPASEPPGSL.
21 . A binding protein that selectively binds β-Klotho and FGFR1c comprising (a) one or more domains that selectively bind β-Klotho, and (b) one or more domains that selectively bind FGFR1c, wherein the binding protein comprises:
(a) a β-Klotho binding domain comprising one or more of:
(SEQ ID NO: 394)
C QSNEFR C RSGR C IPQHWL C DGLND C GDGSD
E[PS][PQ][AQ][-H]C;
(SEQ ID NO: 217)
C [ELPQR][APS][DGIN][EGQ][FQ][FKPQRT][-
E] C [GNRS][NS]G[HNQR] C [IV]P[AELPQRV][AHPQRT]W[LRV] C
DG[DEV][DNP]D C [GLQ]D[DGNS]SDE[AEKT][DGLNS][-A]
[-H] C ;
(SEQ ID NO: 254)
C [AGP][APS][DGN][EQ]F[QRT] C [GNRS][GNS][GT][GKQS][-
IK] C [ILV]P[LQRV][AEHP]W[LRV] C DG[DLV][DN]D C GD[GN]SD
E[AEKPS][GLPS][-AEV][-IT] C ;
and
(b) an FGFR1c binding domain comprising a sequence selected from the group represented by the sequence:
(SEQ ID NO: 108)
CG [AE][GS] LFTC [GR][NRS][AST][KN] ICIS [EHQS][AV]W
[IV] CDG [IV] DDC [DE] DNSDE [DKMNT][NSY] C ;
wherein amino acids in brackets indicate alternative amino acids at a specified position and “-” indicates no amino acid at the specified position.
22 . The binding protein of claim 10 further comprising at least one linker joining (a) and (b).
23 . The binding protein of claim 22 , wherein the linker is one or more of: ETPT (SEQ ID NO: 1319), GDSHILPFSTPGPST (SEQ ID NO: 14), SAPASEPPGSL (SEQ ID NO:12), PAPT (SEQ ID NO:1320), QAPT (SEQ ID NO:1321), AQPT (SEQ ID NO:1322), AHT, PERT (SEQ ID NO: 7), TTRT (SEQ ID NO: 8), GTTGPT (SEQ ID NO: 9), ETSGPT (SEQ ID NO: 10), SQDPEFHKVS (SEQ ID NO: 11), and GRPGPGATSAPAA (SEQ ID NO: 13).
24 . The binding protein of claim 21 , wherein
(i) the β-Klotho binding domain of (a) comprises one or more of:
(SEQ ID NO: 159)
CQSNEFRCRSGRCIPQHWLCDGLNDCGDGSDESQQC;
(SEQ ID NO: 1323)
CRAGEFRCSNGRCVPLTWLCDGEDDCQDNSDEKNC;
(SEQ ID NO: 1324)
CPSNQFPCRSTGICIPLAWVCDGLNDCGDGSDESPAHC;
and
(SEQ ID NO: 1325)
CQSNEFRCRSGRCIPQHWLCDGLNDCGDGSDEPPAHC;
and
(ii) the FGFR1c binding domain of (b) comprises one or more of:
(SEQ ID NO: 109)
CGAGLFTCRS TNICISQVWV CDGVDDCEDN SDEDSC;
(SEQ ID NO: 110)
CGAGLFTCRS TNICISQAWV CDGVDDCEDN SDENYC;
(SEQ ID NO: 111)
CGAGLFTCRS TNICISQAWV CDGVDDCEDN SDETNC;
(SEQ ID NO: 112)
CGEGLFTCGS TNICISSAWV CDGVDDCEDN SDENNC;
(SEQ ID NO: 113)
CGEGLFTCRS TNICISHAWV CDGVDDCEDN SDENNC;
(SEQ ID NO: 114)
CGEGLFTCRS TNICISEAWI CDGVDDCEDN SDEKNC;
(SEQ ID NO: 115)
CGAGLFTCRS AKICISHAWV CDGIDDCEDN SDENNC;
(SEQ ID NO: 116)
CGAGLFTCRN SKICISQAWV CDGVDDCDDN SDEKYC;
(SEQ ID NO: 117)
CGASLFTCRR SNICISQAWV CDGVDDCEDN SDEMNC;
and
(SEQ ID NO: 118)
CGAGLFTCRS TKICISQAWV CDGVDDCEDN SDEKNC.
25 . The binding protein of claim 24 , wherein the FGFR1c binding domain of (b) further comprises a linker comprising the sequence SAPASEPPGSL (SEQ ID NO: 12).
26 . The binding protein of claim 25 , wherein the FGFR1c binding domain comprises one or more of:
(SEQ ID NO: 293)
CGAGLFTCRSTNICISQVWVCDGVDDCEDNSDEDSCSAPASEPPGSL;
(SEQ ID NO: 294)
CGAGLFTCRSTNICISQAWVCDGVDDCEDNSDENYCSAPASEPPGSL;
(SEQ ID NO: 295)
CGAGLFTCRSTNICISQAWVCDGVDDCEDNSDETNCSAPASEPPGSL;
(SEQ ID NO: 448)
CGEGLFTCGSTNICISSAWVCDGVDDCEDNSDENNCSAPASEPPGSL;
(SEQ ID NO: 297)
CGEGLFTCRSTNICISHAWVCDGVDDCEDNSDENNCSAPASEPPGSL;
(SEQ ID NO: 449)
CGEGLFTCRSTNICISEAWICDGVDDCEDNSDEKNCSAPASEPPGSL;
(SEQ ID NO: 450)
CGAGLFTCRSAKICISHAWVCDGIDDCEDNSDENNCSAPASEPPGSL;
(SEQ ID NO: 464)
CGAGLFTCRNSKICISQAWVCDGVDDCDDNSDEKYCSAPASEPPGSL;
(SEQ ID NO: 296)
CGASLFTCRRSNICISQAWVCDGVDDCEDNSDEMNCSAPASEPPGSL;
and
(SEQ ID NO: 287)
CGAGLFTCRSTKICISQAWVCDGVDDCEDNSDEKNCSAPASEPPGSL.
27 . A binding protein that selectively binds β-Klotho and FGFR1c comprising (a) one or more domains that selectively bind β-Klotho, and (b) one or more domains that selectively bind FGFR1c, wherein the binding protein comprises:
(a) a β-Klotho binding domain comprising:
(i) a first binding domain comprising one or more of:
(SEQ ID NO: 254)
C [AGP][APS][DGN][EQ]F[QRT] C [GNRS][GNS][GT][GKQS][-
IK] C [ILV]P[LQRV][AEHP]W[LRV] C DG[DLV][DN]D C GD[GN]SD
E[AEKPS][GLPS][-AEV][-IT] C ;
(SEQ ID NO: 597)
C LPDEFQ C [SG]SGR C IPQ[HT]W[VL] C DGLND C GDGSDE[PS]PA
[HT] C ;
(SEQ ID NO: 249)
C [AGPR][AP][DGNS][EQ]F[QRT] C [GSK]N[GT][GHR][-
R] C [ILV][PS][ALQ][NST]W[LRV] C DG[DEV]DD C [GL]DGSDE[A
ET][DNS][-A][-T] C ;
(ii) a second binding domain comprising one or more of:
(SEQ ID NO: 394)
C QSNEFR C RSGR C IPQHWL C DGLND C GDGSD
E[PS][PQ][AQ][-H]C;
(SEQ ID NO: 217)
C [ELPQR][APS][DGIN][EGQ][FQ][FKPQRT][-E] C [GNRS]
[NS]G[HNQR] C [IV]P[AELPQRV][AHPQRT]W[LRV] C DG
[DEV][DNP]D C [GLQ]D[DGNS]SDE[AEKT][DGLNS][-A][-H] C ;
(SEQ ID NO: 254)
C [AGP][APS][DGN][EQ]F[QRT] C [GNRS][GNS][GT][GKQS][-
IK] C [ILV]P[LQRV][AEHP]W[LRV] C DG[DLV][DN]D C GD[GN]SD
E[AEKPS][GLPS][-AEV][-IT] C ;
and
(iii) a linker joining the first binding domain and the second binding domain; and
(b) an FGFR1c binding domain comprising a sequence selected from the group represented by the sequence:
(SEQ ID NO: 108)
CG [AE][GS] LFTC [GR][NRS][AST][KN] ICIS [EHQS][AV]W
[IV] CDG [IV] DDC [DE] DNSDE [DKMNT][NSY] C ;
and
(c) a linker joining the sequences of (a) and (b),
wherein amino acids in brackets indicate alternative amino acids at a specified position and “-” indicates no amino acid at the specified position.
28 . The binding protein of claim 27 , wherein the first binding domain of (a) comprises one or more of:
(SEQ ID NO: 255)
CGPDQFRCSSGKCIPQHWLCDGLNDCGDGSDESPATC;
(SEQ ID NO: 256)
CGANEFQCRSTGICVPVEWVCDGDNDCGDGSDEPPVC;
(SEQ ID NO: 257)
CGADQFRCGNGSCVPRAWRCDGVDDCGDGSDEAPEIC;
(SEQ ID NO: 258)
CGPDEFRCNNGQCIPLPWRCDGVDDCGDNSDEPLEIC;
(SEQ ID NO: 259)
CASGEFTCNNGQCVPLAWRCDGVNDCQDGSDEKGC;
(SEQ ID NO: 260)
CGPDEFRCNNGQCIPLPWRCDGVDDCGDNSDEPLEIC;
(SEQ ID NO: 261)
CPPDEFQCRGTKKCLPLAWVCDGDNDCEDDSDEESC;
(SEQ ID NO: 1237)
CLPDEFQCGSGRCIPQHWLCDGLNDCGDGSDEPPAHC;
(SEQ ID NO: 1326)
CLPDEFQCGSGRCIPQHWLCDGLNDCGDGSDEPPAHC;
(SEQ ID NO: 1327)
CAPGEFTCKNTGRCIPLNWRCDGDDDCGDGSDETDC;
and
(SEQ ID NO: 1328)
CGPDEFRCNNGQCIPLPWRCDGVDDCGDNSDEPLEIC.
29 . The binding protein of claim 27 , wherein the second binding domain of (a) comprises one or more of:
(SEQ ID NO: 159)
CQSNEFRCRSGRCIPQHWLCDGLNDCGDGSDESQQC;
(SEQ ID NO: 1323)
CRAGEFRCSNGRCVPLTWLCDGEDDCQDNSDEKNC;
(SEQ ID NO: 1324)
CPSNQFPCRSTGICIPLAWVCDGLNDCGDGSDESPAHC;
and
(SEQ ID NO: 1325)
CQSNEFRCRSGRCIPQHWLCDGLNDCGDGSDEPPAHC.
30 . The binding protein of claim 27 , wherein the linker of (a) comprises one or more of: ETPT (SEQ ID NO: 1319), GDSHILPFSTPGPST (SEQ ID NO: 14), SAPASEPPGSL (SEQ ID NO:12), PAPT (SEQ ID NO:1320) and QAPT (SEQ ID NO:1321).
31 . The binding protein of claim 27 , wherein the FGFR1c binding domain comprises one or more of:
(SEQ ID NO: 109)
CGAGLFTCRS TNICISQVWV CDGVDDCEDN SDEDSC;
(SEQ ID NO: 110)
CGAGLFTCRS TNICISQAWV CDGVDDCEDN SDENYC;
(SEQ ID NO: 111)
CGAGLFTCRS TNICISQAWV CDGVDDCEDN SDETNC;
(SEQ ID NO: 112)
CGEGLFTCGS TNICISSAWV CDGVDDCEDN SDENNC;
(SEQ ID NO: 113)
CGEGLFTCRS TNICISHAWV CDGVDDCEDN SDENNC;
(SEQ ID NO: 114)
CGEGLFTCRS TNICISEAWI CDGVDDCEDN SDEKNC;
(SEQ ID NO: 115)
CGAGLFTCRS AKICISHAWV CDGIDDCEDN SDENNC;
(SEQ ID NO: 116)
CGAGLFTCRN SKICISQAWV CDGVDDCDDN SDEKYC;
(SEQ ID NO: 117)
CGASLFTCRR SNICISQAWV CDGVDDCEDN SDEMNC;
and
(SEQ ID NO: 118)
CGAGLFTCRS TKICISQAWV CDGVDDCEDN SDEKNC.
32 . The binding protein of claim 31 , further comprising a linker comprising the sequence SAPASEPPGSL (SEQ ID NO: 12).
33 . The binding protein of claim 32 , wherein the binding protein comprises one or more of:
(SEQ ID NO: 293)
CGAGLFTCRSTNICISQVWVCDGVDDCEDNSDEDSCSAPASEPPGSL;
(SEQ ID NO: 294)
CGAGLFTCRSTNICISQAWVCDGVDDCEDNSDENYCSAPASEPPGSL;
(SEQ ID NO: 295)
CGAGLFTCRSTNICISQAWVCDGVDDCEDNSDETNCSAPASEPPGSL;
(SEQ ID NO: 448)
CGEGLFTCGSTNICISSAWVCDGVDDCEDNSDENNCSAPASEPPGSL;
(SEQ ID NO: 297)
CGEGLFTCRSTNICISHAWVCDGVDDCEDNSDENNCSAPASEPPGSL;
(SEQ ID NO: 449)
CGEGLFTCRSTNICISEAWICDGVDDCEDNSDEKNCSAPASEPPGSL;
(SEQ ID NO: 450)
CGAGLFTCRSAKICISHAWVCDGIDDCEDNSDENNCSAPASEPPGSL;
(SEQ ID NO: 464)
CGAGLFTCRNSKICISQAWVCDGVDDCDDNSDEKYCSAPASEPPGSL;
(SEQ ID NO: 296)
CGASLFTCRRSNICISQAWVCDGVDDCEDNSDEMNCSAPASEPPGSL;
and
(SEQ ID NO: 287)
CGAGLFTCRSTKICISQAWVCDGVDDCEDNSDEKNCSAPASEPPGSL.
34 . The binding protein of claim 33 , wherein the FGFR1c binding domain comprises one or more of:
(SEQ ID NO: 297)
CGEGLFTCRSTNICISHAWVCDGVDDCEDNSDENNCSAPASEPPGSL.
35 . The binding protein of claim 27 , wherein the linker of (c) comprises one or more of: AQPT (SEQ ID NO:1322), AHT, PERT (SEQ ID NO: 7), TTRT (SEQ ID NO: 8), GTTGPT (SEQ ID NO: 9), ETSGPT (SEQ ID NO: 10), SQDPEFHKVS (SEQ ID NO: 11), SAPASEPPGSL (SEQ ID NO: 12), GRPGPGATSAPAA (SEQ ID NO: 13), and GDSHILPFSTPGPST (SEQ ID NO: 14).
36 . The binding protein of claim 27 , wherein the binding protein comprises the sequence:
(SEQ ID NO: 359)
CGADQFRCGNGSCVPRAWRCDGVDDCGDGSDEAPEICETPTCQSNEFRCR
SGRCIPQHWLCDGLNDCGDGSDESQQCSAPASEPPGSLCGEGLFTCRSTN
ICISHAWVCDGVDDCEDNSDENNCSAPASEPPGSL.
37 . The binding protein of claim 27 , wherein the binding protein comprises the sequence:
(SEQ ID NO: 339)
CLPDEFQCGSGRCIPQHWLCDGLNDCGDGSDEPPAHCSAPASEPPGSLCR
AGEFRCSNGRCVPLTWLCDGEDDCQDNSDEKNCAQPTCGEGLFTCRSTNI
CISHAWVCDGVDDCEDNSDENNCSAPASEPPGSL.
38 . The binding protein of claim 27 , wherein the binding protein comprises the sequence:
(SEQ ID NO: 1270)
CAPGEFTCKNTGRCIPLNWRCDGDDDCGDGSDETDCPAPTCPSNQFPCRS
TGICIPLAWVCDGLNDCGDGSDESPAHCSAPASEPPGSLCGEGLFTCRST
NICISHAWVCDGVDDCEDNSDENNCSAPASEPPGSL.
39 . The binding protein of claim 27 , wherein the binding protein comprises the sequence:
(SEQ ID NO: 1271)
CGPDEFRCNNGQCIPLPWRCDGVDDCGDNSDEPLEICQAPTCQSNEFRCR
SGRCIPQHWLCDGLNDCGDGSDEPPAHCSAPASEPPGSLCGEGLFTCRST
NICISHAWVCDGVDDCEDNSDENNCSAPASEPPGSL.
40 . A binding protein comprising:
(B1) a -(L1) x -(B2) b -(L2) y -(1C) c -(L3) z wherein a, b, c, x, y, and z is 0, 1, or 2, provided however that at least one of a, b, and c is 1 or 2; wherein B1 is an amino acid sequence as set forth in claim 1 ; wherein B2 is an amino acid sequence as set forth in claim 3 ; wherein 1C is an amino acid sequence as set forth in claim 5 ; wherein L1 is an amino acid sequence as set forth in claim 12 ; wherein L2 is an amino acid sequence as set forth in claim 17 ; and wherein L3 is SAPASEPPGSL.
41 . The binding protein of claim 1 , 3 , 5 , 10 , 15 , 21 , 27 , 36 , 37 , 38 , or 39 , wherein the binding protein further comprises a half life-extending moiety that increases the serum half-life of the binding protein in a mammal compared to the serum half-life of the binding protein lacking the half life-extending moiety in a mammal.
42 . The binding protein of claim 41 , wherein the half life-extending moiety is one or more of: polyethylene glycol (PEG), human serum albumin (HSA), an immunoglobulin (IgG), and an Fc moeity.
43 . The binding protein of claim 41 , wherein the half life-extending moiety comprises a protein sequence that specifically binds a blood factor.
44 . The binding protein of claim 43 , wherein the blood factor is serum albumin, an immunoglobulin or an erythrocyte.
45 . The binding protein of claim 1 , 3 , 5 , 10 , 15 , 21 , 27 , 36 , 37 , 38 , or 39 , wherein the binding protein comprises an amino acid sequence comprising one or more non-naturally occurring amino acids.
46 . A polynucleotide encoding a binding protein comprising one or more of:
(a) a β-Klotho binding domain; (b) an FGFR1c binding domain; (c) one or more β-Klotho binding domains and an FGFR1c binding domain; and (c) a binding protein of claim 1 , 3 , 5 , 10 , 15 , 21 , 27 , 36 , 37 , 38 , or 39 .
47 . An expression vector comprising the polynucleotide of claim 46 .
48 . A host cell comprising the expression vector of claim 47 .
49 . A method of making a binding protein comprising incubating the host cell of claim 48 under conditions suitable to induce expression of the binding protein, and optionally isolating the expressed polypeptide.
50 . A pharmaceutical composition comprising: (a) a binding protein of claim 1 , 3 , 5 , 10 , 15 , 21 , 27 , 36 , 37 , 38 , or 39 ; and (b) a pharmaceutically acceptable formulation agent.
51 . The pharmaceutical composition of claim 50 , wherein the pharmaceutically acceptable formulation agent is a carrier, adjuvant, solubilizer, stabilizer, or anti-oxidant.
52 . A method for treating a metabolic disorder comprising administering to a human patient in need thereof the pharmaceutical composition of claim 50 .
53 . The method of claim 52 , wherein the metabolic disorder is one or more of: diabetes, obesity, dyslipidimia, hypertension, hepatosteaotosis, non-alcoholic steatohepatitis (NASH), acute pancreatitis, metabolic syndrome, cardiovascular disease, such as atherosclerosis, and aging.
54 . The method of claim 53 , wherein the metabolic disorder is diabetes.
55 . The method of claim 53 , wherein the metabolic disorder is obesity.Cited by (0)
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