US 11,970,555 B2
Bicyclic peptide ligands specific for transferrin receptor 1 (TfR1)
Ellen Gowans, Cambridge (GB); Gemma Elizabeth Mudd, Cambridge (GB); Michael Rigby, Cambridge (GB); Punit Seth, Carlsbad, CA (US); Michael Skynner, Cambridge (GB); Steven Stanway, Cambridge (GB); Liudvikas Urbonas, Cambridge (GB); and Katerine Van Rietschoten, Cambridge (GB)
Assigned to BicycleTx Limited, Cambridge (GB)
Filed by BicycleTx Limited, Cambridge (GB)
Filed on Nov. 12, 2021, as Appl. No. 17/454,665.
Claims priority of provisional application 63/261,820, filed on Sep. 29, 2021.
Claims priority of application No. 2017927 (GB), filed on Nov. 13, 2020; and application No. 2106903 (GB), filed on May 14, 2021.
Prior Publication US 2022/0194988 A1, Jun. 23, 2022
Int. Cl. C07K 7/64 (2006.01); A61K 47/55 (2017.01); A61K 47/64 (2017.01); C07K 1/107 (2006.01)
CPC C07K 7/64 (2013.01) [A61K 47/55 (2017.08); A61K 47/64 (2017.08); C07K 1/1075 (2013.01)] 20 Claims
 
1. A peptide ligand specific for transferrin receptor 1 (TfR1) comprising a polypeptide comprising at least three reactive groups, separated by at least two loop sequences, and a molecular scaffold which forms covalent bonds with the reactive groups of the polypeptide such that at least two polypeptide loops are formed on the molecular scaffold, wherein said polypeptide comprises an amino acid sequence selected from:
 
 (SEQ ID NO: 1)
 
 CiALCiiNDWTLPWHHCiii;
 
 
 
 (SEQ ID NO: 2)
 
 CiREFFDTCiiGLAFIECiii;
 
 
 
 (SEQ ID NO: 3)
 
 CiLEACiiYDGVYWYSCiii;
 
 
 
 (SEQ ID NO: 4)
 
 CiSADDWLGCiiISWCiii;
 
 
 
 (SEQ ID NO: 5)
 
 CiSSDAYLGCiiISWCiii;
 
 
 
 (SEQ ID NO: 6)
 
 CiPPDAHLGCiiISWCiii;
 
 
 
 (SEQ ID NO: 7)
 
 CiPQDAYLGCiiISWCiii;
 
 
 
 (SEQ ID NO: 8)
 
 CiPPDSWQGCiiISYCiii;
 
 
 
 (SEQ ID NO: 9)
 
 CiSPDAHLGCiiISYCiii;
 
 
 
 (SEQ ID NO: 10)
 
 CiPGDAHLGCiiISYCiii;
 
 
 
 (SEQ ID NO: 11)
 
 CiPPDSHLGCiiISYCiii;
 
 
 
 (SEQ ID NO: 12)
 
 CiSADDWLGCiiISYCiii;
 
 
 
 (SEQ ID NO: 13)
 
 CiP[HyP]DAYLGCii[tBuGly]SYCiii;
 
 
 
 (SEQ ID NO: 14)
 
 CiP[HyP]DAYLGCiiISYCiii;
 
 
 
 (SEQ ID NO: 15)
 
 CiS[HyP]DAHLGCiiISYCiii;
 
 
 
 (SEQ ID NO: 16)
 
 CiP[Aib]DAHLGCii[tBuGly]SYCiii;
 
 
 
 (SEQ ID NO: 17)
 
 CiPPDAHLGCiiISYCiii;
 
 
 
 (SEQ ID NO: 18)
 
 CiP[Aib]DAYLGCii[tBuGly]SYCiii;
 
 
 
 (SEQ ID NO: 19)
 
 CiSADAHLGCiiISYCiii;
 
 
 
 (SEQ ID NO: 20)
 
 CiS[Aib]DAHLGCii[tBuGly]SYCiii;
 
 
 
 (SEQ ID NO: 21)
 
 CiSPDAHLGCii[EPA]SYCiii;
 
 
 
 (SEQ ID NO: 22)
 
 CiPPDAYLGCii[tBuGly]SYCiii;
 
 
 
 (SEQ ID NO: 23)
 
 CiS[Aib]DAYLGCii[tBuGly]SYCiii;
 
 
 
 (SEQ ID NO: 24)
 
 CiAPDAHLGCiiISYCiii;
 
 
 
 (SEQ ID NO: 25)
 
 CiP[Aib]DAHLGCiiISYCiii;
 
 
 
 (SEQ ID NO: 26)
 
 CiSPDAYLGCii[tBuGly]SYCiii;
 
 
 
 (SEQ ID NO: 27)
 
 CiSPDAHLGCii[tBuGly]SYCiii;
 
 
 
 (SEQ ID NO: 28)
 
 CiPNDAHLGCiiISYCiii;
 
 
 
 (SEQ ID NO: 29)
 
 CiPIDAHLGCiiISYCiii;
 
 
 
 (SEQ ID NO: 30)
 
 CiSPDAYLGCiiISYCiii;
 
 
 
 (SEQ ID NO: 31)
 
 CiPPDAYLGCiiISYCiii;
 
 
 
 (SEQ ID NO: 32)
 
 CiS[Aib]DAHLGCiiISYCiii;
 
 
 
 (SEQ ID NO: 33)
 
 CiSPDAHLGCii[Chg]SYCiii;
 
 
 
 (SEQ ID NO: 34)
 
 CiAPDAHLGCiiISYCiii;
 
 
 
 (SEQ ID NO: 35)
 
 CiYLPDW[tBuAla]CiiGDEYCiii;
 
 
 
 (SEQ ID NO: 36)
 
 CiSPDAHLGCiiIS[2Nal]Ciii;
 
 
 
 (SEQ ID NO: 37)
 
 CiSPDAHLGCiiIS[3tBuTyr]Ciii;
 
 
 
 (SEQ ID NO: 38)
 
 CiSPD[Aib]HLGCiiISYCiii;
 
 
 
 (SEQ ID NO: 39)
 
 CiSPDAHLGCiiIS[1Nal]Ciii;
 
 
 
 (SEQ ID NO: 40)
 
 CiSPDAH[tBuAla]GCiiISYCiii;
 
 
 
 (SEQ ID NO: 41)
 
 CiSPDAH[Cba]GCiiISYCiii;
 
 
 
 (SEQ ID NO: 42)
 
 CiSPDAHLGCiiISWCiii;
 
 
 
 (SEQ ID NO: 43)
 
 CiSPD[Abu]HLGCiiISYCiii;
 
 
 
 (SEQ ID NO: 44)
 
 CiS[Aze]DAHLGCiiISYCiii;
 
 
 
 (SEQ ID NO: 45)
 
 CiSPDDHLGCiiISYCiii;
 
 
 
 (SEQ ID NO: 46)
 
 CiSPDSHLGCiiISYCiii;
 
 
 
 (SEQ ID NO: 47)
 
 CiSPDAH[Abu]GCiiISYCiii;
 
 
 
 (SEQ ID NO: 48)
 
 CiSPDAHLGCiiIS[4Pal]Ciii;
 
 
 
 (SEQ ID NO: 49)
 
 CiP[dA]DAHLGCiiISYCiii;
 
 
 
 (SEQ ID NO: 50)
 
 CiSPDAYLGCii[tBuAla]SYCiii;
 
 
 
 (SEQ ID NO: 51)
 
 CiSPDAHLGCii[C5g]SYCiii;
 
 
 
 (SEQ ID NO: 52)
 
 CiSPDAHLGCii[Cbg]SYCiii;
 
 
 
 (SEQ ID NO: 53)
 
 CiSPDAHL[dA]CiiISYCiii;
 
 
 
 (SEQ ID NO: 54)
 
 CiSPDAH[Aib]GCiiISYCiii;
 
 
 
 (SEQ ID NO: 55)
 
 CiSPDAHLGCii[Cpg]SYCiii;
 
 
 
 (SEQ ID NO: 56)
 
 CiSPDAHLGCii[B-Melle]SYCiii;
 
 
 
 (SEQ ID NO: 57)
 
 CiSADAHLGCiiISYCiii;
 
 
 
 (SEQ ID NO: 58)
 
 CiSPAAHLGCiiISYCiii;
 
 
 
 (SEQ ID NO: 59)
 
 CiSPDAALGCiiISYCiii;
 
 
 
 (SEQ ID NO: 60)
 
 CiSPDAHAGCiiISYCiii;
 
 
 
 (SEQ ID NO: 61)
 
 CiSPDAHLACiiISYCiii;
 
 
 
 (SEQ ID NO: 62)
 
 CiSPDAHLGCiiASYCiii;
 
 
 
 (SEQ ID NO: 63)
 
 CiSPDAHLGCiiIAYCiii;
 
 
 
 (SEQ ID NO: 64)
 
 CiSPDAHLGCiiISACiii;
 
 
 
 (SEQ ID NO: 65)
 
 Ci[K(N3)]PDAHLGCiiISYCiii;
 
 
 
 (SEQ ID NO: 66)
 
 CiS[K(N3)]DAHLGCiiISYCiii;
 
 and
 
 
 
 (SEQ ID NO: 67)
 
 CiSPD[K(N3)]HLGCiiISYCiii;
wherein Abu represents aminobutyric acid, Aib represents aminoisobutyric acid, Aze represents azetidine, B-MeIle represents beta-methyl isoleucine, C5g represents cyclopentyl glycine, Cba represents β-cyclobutylalanine, Cbg represents cyclobutyl glycine, Chg represents cyclohexyl glycine, Cpg represents cyclopropryl glycine, EPA represents 2-amino-3-ethyl-pentanoic acid, HyP represents trans-4-hydroxy-L-proline, [K(N3)] represents 6-azido lysine, 1Nal represents 1-naphthylalanine, 2Nal represents 2-naphthylalanine, 4Pal represents 4-pyridylalanine, tBuAla represents t-butyl-alanine, tBuGly represents t-butyl-glycine, 3tBuTyr represents 3-t-Butyl-tyrosine, and Ci, Cii, and Ciii, represent first, second, and third cysteine residues, respectively; or a modified derivative thereof, or a pharmaceutically acceptable salt thereof.