US 11,696,956 B2 · Bicyclic peptide ligands specific for EphA2

Abstract

The present invention relates to polypeptides which are covalently bound to non-aromatic molecular scaffolds such that two or more peptide loops are subtended between attachment points to the scaffold. In particular, the invention describes peptides which are high affinity binders of the Eph receptor tyrosine kinase A2 (EphA2). The invention also includes drug conjugates comprising said peptides, conjugated to one or more effector and/or functional groups, to pharmaceutical compositions comprising said peptide ligands and drug conjugates and to the use of said peptide ligands and drug conjugates in preventing, suppressing or treating a disease or disorder characterised by overexpression of EphA2 in diseased tissue (such as a tumour).

A peptide ligand specific for EphA2, or a pharmaceutically acceptable salt or modified derivative thereof, the peptide ligand comprising a polypeptide comprising at least three cysteine residues, separated by at least two loop sequences, and a non-aromatic molecular scaffold which forms covalent bonds with the cysteine residues of the polypeptide such that at least two polypeptide loops are formed on the molecular scaffold, wherein the polypeptide comprises an amino acid sequence selected from

(SEQ ID NO:
1)
C(HyP)LVNPLCLHP(D-Asp)W(HArg)C;
(SEQ ID NO:
2)
(β-Ala)-Sar10-A(HArg)DC(HyP)LVNPLCLHP(D-
Asp)W(HArg)C;
(SEQ ID NO:
3)
ACMNDWWCAMGWKCA;
(SEQ ID NO:
4)
ACVPDRRCAYMNVCA;
(SEQ ID NO:
5)
ACVVDGRCAYMNVCA;
(SEQ ID NO:
6)
ACVVDSRCAYMNVCA;
(SEQ ID NO:
7)
ACVPDSRCAYMNVCA;
(SEQ ID NO:
8)
ACYVGKECAIRNVCA;
(SEQ ID NO:
9)
ACYVGKECAYMNVCA;
(SEQ ID NO:
10)
ARDCPLVNPLCLHPGWTC;
(SEQ ID NO:
11)
A(HArg)DCPLVNPLCLHPGWTC;
(SEQ ID NO:
12)
CPLVNPLCLHPGWTCLHG;
(SEQ ID NO:
13)
CPLVNPLCLHPGWTCL(D-His)G;
(SEQ ID NO:
14)
CPLVNPLCLHPGWSCRGQ;
(SEQ ID NO:
15)
CPLVNPLCLHPGWSC(HArg)GQ;
(SEQ ID NO:
16)
ACVPDRRCAYMNVC;
(SEQ ID NO:
17)
DLRCGGDPRCAYMNVCA;
(SEQ ID NO:
18)
SRPCVIDSRCAYMNVCA;
(SEQ ID NO:
19)
ESRCSPDARCAYMNVCA;
(SEQ ID NO:
20)
HSGCRPDPRCAYMNVCA;
(SEQ ID NO:
21)
GSGCKPDSRCAYMNVCA;
(SEQ ID NO:
22)
ETVCLPDSRCAYMNVCA;
(SEQ ID NO:
23)
GQVCIVDARCAYMNVCA;
(SEQ ID NO:
24)
ACVPDRRCAFENVCVDH;
(SEQ ID NO:
25)
ACVPDRRCAFMNVCEDR;
(SEQ ID NO:
26)
ACVPDRRCAFQDVCDHE;
(SEQ ID NO:
27)
ACVPDRRCAFRDVCLTG;
(SEQ ID NO:
28)
ACQPSNHCAFMNYCA;
(SEQ ID NO:
29)
ACSPTPACAVQNLCA;
(SEQ ID NO:
30)
ACTSCWAYPDSFCA;
(SEQ ID NO:
31)
ACTKPTGFCAYPDTICA;
(SEQ ID NO:
32)
ACRGEWGYCAYPDTICA;
(SEQ ID NO:
33)
ACRNWGMYCAYPDTICA;
(SEQ ID NO:
34)
ACPDWGKYCAYPDTICA;
(SEQ ID NO:
35)
ACRVYGPYCAYPDTICA;
(SEQ ID NO:
36)
ACSSCWAYPDSVCA;
(SEQ ID NO:
37)
ACQSCWAYPDTYCA;
(SEQ ID NO:
38)
ACGFMGLEPCETFCA;
(SEQ ID NO:
39)
ACGFMGLVPCEVHCA;
(SEQ ID NO:
40)
ACGFMGLEPCEMVCA;
(SEQ ID NO:
41)
ACGFMGLEPCVTYCA;
(SEQ ID NO:
42)
ACGFMGLEPCELVCA;
(SEQ ID NO:
43)
ACGFMGLVPCNVFCA;
(SEQ ID NO:
44)
ACGFMGLEPCELFCA;
(SEQ ID NO:
45)
ACGFMGLEPCELFCMPK;
(SEQ ID NO:
46)
ACGFMGLEPCELYCA;
(SEQ ID NO:
47)
ACGFMGLEPCELYCAHT;
(SEQ ID NO:
48)
ACGFMGLEPCEMYCA;
(SEQ ID NO:
49)
ACGFMGLVPCELYCADN;
(SEQ ID NO:
50)
ACPLVNPLCLTSGWKCA;
(SEQ ID NO:
51)
ACPMVNPLCLHPGWICA;
(SEQ ID NO:
52)
ACPLVNPLCLHPGWICA;
(SEQ ID NO:
53)
ACPLVNPLCLHPGWRCA;
(SEQ ID NO:
54)
ACPLVNPLCNLPGWTCA;
(SEQ ID NO:
55)
ACPLVNPLCLVPGWSCA;
(SEQ ID NO:
56)
ACPLVNPLCLLDGWTCA;
(SEQ ID NO:
57)
ACPLVNPLCLMPGWGCA;
(SEQ ID NO:
58)
ACPLVNPLCMIGNWTCA;
(SEQ ID NO:
59)
ACPLVNPLCLMTGWSCA;
(SEQ ID NO:
60)
ACPLVNPLCMMGGWKCA;
(SEQ ID NO:
61)
ACPLVNPLCLYGSWKCA;
(SEQ ID NO:
62)
ACPLVNPLCLHPGWTCA;
(SEQ ID NO:
63)
ARDCPLVNPLCLHPGWTCA;
(SEQ ID NO:
64)
RPACPLVNPLCLHPGWTCA;
(SEQ ID NO:
65)
RPPCPLVNPLCLHPGWTCA;
(SEQ ID NO:
66)
KHSCPLVNPLCLHPGWTCA;
(SEQ ID NO:
67)
ACPLVNPLCLHPGWTCLHG;
(SEQ ID NO:
68)
ACPLVNPLCLHPGWTCL(D-His)G;
(SEQ ID NO:
69)
ACPLVNPLCLHPG(2Nal)TCLHG;
(SEQ ID NO:
70)
RHDCPLVNPLCLLPGWTCA;
(SEQ ID NO:
71)
TPRCPLVNPLCLMPGWTCA;
(SEQ ID NO:
72)
ACPLVNPLCLAPGWTCA;
(SEQ ID NO:
73)
ACPLVNPLCLAPGWTCSRS;
(SEQ ID NO:
74)
ACPLVNPLCLEPGWTCA;
(SEQ ID NO:
75)
ACPLVNPLCLEPGWTCAKR;
(SEQ ID NO:
76)
ACPLVNPLCLHPGWSCA;
(SEQ ID NO:
77)
ACPLVNPLCLHPGWSCRGQ;
(SEQ ID NO:
78)
ACPLVNPLCLHPGWSC(HArg)GQ;
(SEQ ID NO:
79)
ACPLVNPLCLHPG(2Nal)SCRGQ;
(SEQ ID NO:
80)
ACPLVNPLCLTPGWTCTNT;
(SEQ ID NO:
81)
ACPMVNPLCLHPGWKCA;
(SEQ ID NO:
82)
ACPMVNPLCLTPGWICA;
(SEQ ID NO:
83)
ACPMVNPLCLHPGWTCA;
(SEQ ID NO:
84)
H(D-Asp)VT-C(Aib)(1Nal)G(Aib)F(1Nal)CP(tBuGly)N
(HArg)P(D-Asp)C;
(SEQ ID NO:
85)
A(HArg)DC(HyP)(Hse(Me))VNPLCLHP(D-Asp)W(HArg)C;
(SEQ ID NO:
86)
A(HArg)DC(HyP)(Hse(Me))VNPLCLHP(D-Asp)WTC;
(SEQ ID NO:
87)
A(HArg)DC(HyP)LVNPLCLHP(D-Ala)WTC;
(SEQ ID NO:
88)
A(HArg)DCPLVNPLCLHP(D-Ala)WTC;
(SEQ ID NO:
89)
ARDC(HyP)LVNPLCLHPGWTC;
(SEQ ID NO:
90)
ARDCPLVNPLCL(D-3,3-DPA)PGWTC;
(SEQ ID NO:
91)
ARDCPLVNPLCLHPGWTCLH;
(SEQ ID NO:
92)
A(HArg)DCPLVNPLCLHP(D-Cya)WTC;
(SEQ ID NO:
93)
A(D-Arg)DC(HyP)LVNPLCL(D-3,3-DPA)P(D-Asp)W(HArg)C;
(SEQ ID NO:
94)
ACPWGPAWCPVNRPGCA;
(SEQ ID NO:
95)
ACPWGPFWCPVNRPGCA;
(SEQ ID NO:
96)
ADVTCPWGPFWCPVNRPGCA;
and
(SEQ ID NO:
97)
CPLVNPLCLHPGWTC;
wherein HyP is hydroxyproline, HArg is homoarginine, Sar is sarcosine, HArg is homoarginine, D-Asp is D-aspartic acid, 2Nal is 2-naphthylalanine, 1Nal is 1-naphthylalanine, Aib is 2-aminoisobutyric acid, tBuGly is tert-leucine, hSerMe is homoserine(methyl), D-Ala is D-alanine, D-3,3-DPA is 3,3-diphenyl-D-alanine, D-Cya is D-cysteic acid, D-Arg is D-arginine, HPhe is homophenylalanine, and D-His is D-histidine.

292 more elements

Bicyclic peptide ligands specific for EphA2

Life of this patent

Bicyclic peptide ligands specific for EphA2

Life of this patent

Abstract

Claims19