US2024000957A1PendingUtilityA1
BICYCLIC PEPTIDE LIGANDS SPECIFIC FOR EphA2
Est. expiryDec 19, 2037(~11.4 yrs left)· nominal 20-yr term from priority
A61K 47/6415C07K 7/08A61K 47/65A61K 47/64A61P 35/00A61K 31/5365A61K 38/07A61K 38/10A61K 38/05A61K 47/62
83
PatentIndex Score
0
Cited by
0
References
0
Claims
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).
Claims
exact text as granted — not AI-modified1 - 31 . (canceled)
32 . A method of preventing, suppressing or treating cancer, the method comprising administering to a patient in need thereof a peptide ligand specific for EphA2, or a pharmaceutically acceptable salt or modified derivative thereof, wherein the peptide ligand comprises 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)-Sar 10 -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.
33 . The method of claim 32 , wherein the polypeptide comprises an amino acid sequence selected from
ACMNDWWCAMGWKCA-Sar 6 -K(FI) ((SEQ ID NO: 3)-Sar 6 -K(FI));
ACVPDRRCAYMNVCA-Sar 6 -K(FI) ((SEQ ID NO: 4)-Sar 6 -K(FI));
ACVVDGRCAYMNVCA-Sar 6 -K(FI) ((SEQ ID NO: 5)-Sar 6 -K(FI));
ACVVDSRCAYMNVCA-Sar 6 -K(FI) ((SEQ ID NO: 6)-Sar 6 -K(FI));
ACVPDSRCAYMNVCA-Sar 6 -K(FI) ((SEQ ID NO: 7)-Sar 6 -K(FI));
ACYVGKECAIRNVCA-Sar 6 -K(FI) ((SEQ ID NO: 8)-Sar 6 -K(FI));
ACYVGKECAYMNVCA-Sar 6 -K(FI) ((SEQ ID NO: 9)-Sar 6 -K(FI));
FI-G-Sar 5 -ACYVGKECAYMNVCA (FI-G-Sar 5 -(SEQ ID NO: 9));
FI-(β-Ala)-Sar 10 -ARDCPLVNPLCLHPGWTC (FI-(β-Ala)-Sar 10 -(SEQ ID NO: 10));
FI-(β-Ala)-Sar 10 -A(HArg)DCPLVNPLCLHPGWTC (FI-(β-Ala)-Sar 10 -(SEQ ID NO: 11);
Ac-CPLVNPLCLHPGWTCLHG-Sar 6 -(D-K[FI]) (Ac-(SEQ ID NO: 12)-Sar 6 -(D-K[FI]));
Ac-CPLVNPLCLHPGWTCL(D-His)G-Sar 6 -(D-K[FI]) (Ac-SEQ ID NO: 13)-Sar 6 -(D-K[FI]));
Ac-CPLVNPLCLHPGWSCRGQ-Sar 6 -(D-K[FI]) (Ac-(SEQ ID NO: 14)- Sar 6 -(D-K[FI]));
Ac-CPLVNPLCLHPGWSC(HArg)GQ-Sar 6 -(D-K[FI]) (Ac-(SEQ ID NO: 15)- Sar 6 -(D-K[FI]));
(β-Ala)-Sar 10 -ACVPDRRCAYMNVC ((β-Ala)-Sar 10 -(SEQ ID NO: 16));
(β-Ala)-Sar 10 -A(HArg)DCPLVNPLCLHPGWTC ((β-Ala)-Sar 10 -(SEQ ID NO: 11);
Ac-ARDCPLVNPLCLHPGWTCA-Sar 6 -(D-K) (Ac-(SEQ ID NO: 63)-Sar 6 -(D-K));
Ac-A(HArg)DCPLVNPLCLHPGWTCA- Sar 6 -(D-K) (Ac-(SEQ ID NO: 11)-A-Sar 6 -(D-K));
Ac-CPLVNPLCLHPGWTCLHG (Ac-(SEQ ID NO: 12));
(β-Ala)-Sar 10 -ACPLVNPLCLHPGWTCLHG ((β-Ala)-Sar 10 -(SEQ ID NO: 67));
(β-Ala)-Sar 10 -ACPLVNPLCLHPGWTCL(D-His)G ((β-Ala)-Sar 10 -(SEQ ID NO: 68));
Ac-CPLVNPLCLHPGWTCLHG-Sar 6 -(D-K) (Ac-(SEQ ID NO: 12)-Sar 6 -(D-K));
Ac-CPLVNPLCLHPGWTCL(D-His)G-Sar 6 -(D-K) (Ac-(SEQ ID NO: 13)- Sar 6 -(D-K));
Ac-CPLVNPLCLHPGWSCRGQ (Ac-(SEQ ID NO: 14));
(β-Ala)-Sar 10 -ACPLVNPLCLHPGWSCRGQ ((β-Ala)-Sar 10 -(SEQ ID NO: 77);
(β-Ala)-Sar 10 -ACPLVNPLCLHPGWSC(HArg)GQ ((β-Ala)-Sar 10 -(SEQ ID NO: 78));
Ac-CPLVNPLCLHPGWSCRGQ-Sar 6 -(D-K) (Ac-(SEQ ID NO: 14)-Sar 6 -(D-K));
Ac-CPLVNPLCLHPGWSC(HArg)GQ-Sar 6 -(D-K) (Ac-(SEQ ID NO: 15) -Sar 6 -(D-K));
(β-Ala)-Sar 10 -H(D-Asp)VT-C(Aib)(1Nal)G(Aib)F(1Nal)CP(tBuGly)N(HArg)P(D-Asp)C ((β-Ala)-
Sar 10 -(SEQ ID NO: 84));
(β-Ala)-Sar 10 -(SEQ ID NO: 10);
(β-Ala)-Sar 10 -(SEQ ID NO: 11)-CONH 2 ;
(β-Ala)-Sar 5 -(SEQ ID NO: 11);
Ac-(SEQ ID NO: 12)-Sar 6 -(D-K);
Ac-(SEQ ID NO: 14)-Sar 6 -(D-K);
Ac-(SEQ ID NO: 12)-Sar 6 -(D-K[Ac]);
(β-Ala)-Sar 10 -(SEQ ID NO: 2)-CONH 2 ;
(β-Ala)-Sar 10 -(SEQ ID NO: 87);
(β-Ala)-Sar 10 -(SEQ ID NO: 88);
(β-Ala)-Sar 10 -(SEQ ID NO: 86);
(β-Ala)-Sar 10 -(SEQ ID NO: 85);
(β-Ala)-Sar 10 -(SEQ ID NO: 91);
(β-Ala)-Sar 10 -(SEQ ID NO: 90);
(β-Ala)-Sar 10 -(SEQ ID NO: 89);
(β-Ala)-Sar 10 -(SEQ ID NO: 93);
(β-AlaSO 3 H)-Sar 10 -(SEQ ID NO: 11);
(β-AlaSO 3 H)-Sar 5 -(SEQ ID NO: 11);
and
(β-AlaSO 3 H)-Sar 4 -(Cya)-Sar 4 -(Cya)-(SEQ ID NO: 92).
34 . The method of claim 32 , wherein the polypeptide comprises the amino acid sequence
(SEQ ID NO: 1)
C(HyP)LVNPLCLHP(D-Asp)W(HArg)C.
35 . The method of claim 32 , wherein the polypeptide comprises the amino acid sequence
(β-Ala)-Sar 10 -A(HArg)DC(HyP)LVNPLCLHP(D-Asp)
W(HArg)C (SEQ ID NO: 2);
or
(SEQ ID NO: 2)-CONH 2 .
36 . The method of claim 32 , wherein the polypeptide comprises the amino acid sequence selected from
A(HArg)DCPLVNPLCLHPGWTC (SEQ ID NO: 11);
FI-(β-Ala)-Sar 10 -(SEQ ID NO: 11);
(β-Ala)-Sar 10 -(SEQ ID NO: 11);
Ac-(SEQ ID NO: 11)-A-Sar 6 -(D-K);
(β-Ala)-Sar 10 -(SEQ ID NO: 11)-CONH 2 ;
(β-Ala)-Sar 5 -(SEQ ID NO: 11);
(β-AlaSO 3 H)-Sar 10 -(SEQ ID NO: 11);
and
(β-AlaSO 3 H)-Sar 5 -(SEQ ID NO: 11).
37 . The method of claim 32 , wherein the polypeptide comprises the amino acid sequence
(SEQ ID NO: 97)
CPLVNPLCLHPGWTC
38 . The method of claim 32 , wherein the molecular scaffold is 1,1′,1″-(1,3,5-triazinane-1,3,5-triyl)triprop-2-en-1-one (TATA).
39 . The method of claim 32 , wherein the peptide ligand is selected from
or a pharmaceutically acceptable salt thereof.
40 . The method of claim 32 , wherein the pharmaceutically acceptable salt is selected from a free acid or a sodium, potassium, calcium, or ammonium salt.
41 . The method of claim 32 , wherein the EphA2 is human EphA2.
42 . The method of claim 32 , wherein the peptide ligand is conjugated to one or more effector and/or functional group forming a drug conjugate.
43 . The method of claim 42 , wherein said effector and/or functional group is a cytotoxic agent selected from DM1 and MMAE.
44 . The method of claim 43 , wherein the drug conjugate comprises a linker between said peptide ligand and said cytotoxic agent.
45 . The method of claim 44 , wherein said cytotoxic agent is MMAE and the linker is selected from: -Val-Cit-, -Trp-Cit-, -Val-Lys-, -D-Trp-Cit-, -Ala-Ala-Asn-, D-Ala-Phe-Lys-, and -Glu-Pro-Cit-Gly-hPhe-Tyr-Leu- (SEQ ID NO: 98).
46 . The method of claim 44 , wherein said cytotoxic agent is MMAE and the linker is -Val-Cit-.
47 . The method of claim 44 , wherein said cytotoxic agent is DM1 and the linker is selected from: —S—S—, —SS(SO 3 H)—, —SS-(Me)-, -(Me)-SS-(Me)-, —SS-(Me 2 )-, and —SS-(Me)-SO 3 H—.
48 . The method of claim 42 , wherein the drug conjugate is selected from
and
or a pharmaceutically acceptable salt thereof,
wherein BCY6099 has a structure
wherein BCY6014 has a structure
wherein BCY6104 has a structure
wherein BCY6018 has a structure
wherein BCY 6017 as a structure
wherein BCY6019 has a structure
wherein BCY 6009 has a structure
wherein BCY6152 has a structure
wherein BCY6153 has a structure
wherein BCY6138 has a structure
and wherein BCY6137 has a structure
49 . The method of claim 32 , wherein the cancer is selected from prostate cancer, lung cancer (such as non-small cell lung carcinomas (NSCLC)), breast cancer (such as triple negative breast cancer), gastric cancer, ovarian cancer, oesophageal cancer, multiple myeloma, and fibrosarcoma.
50 . The method of claim 49 , wherein the lung cancer is non-small cell lung carcinomas (NSCLC)), and the breast cancer is triple negative breast cancer.
51 . The method of claim 32 , wherein the patient has an increased copy number variation (CNV) of EphA2.Join the waitlist — get patent alerts
Track US2024000957A1 — get alerts on status changes and closely related new filings.
We store only your email — no account needed. See our privacy policy.