Bicyclic peptide ligands specific for gfral

Abstract

The present invention relates to polypeptides which are covalently bound to molecular scaffolds such that two or more peptide loops are subtended between attachment points to the scaffold. In particular, the invention describes peptides which bind to GFRAL. The invention also includes pharmaceutical compositions comprising said peptide ligands and the use of said peptide ligands and pharmaceutical compositions in preventing, suppressing or treating a disease or disorder mediated by GFRAL.

Description

[0001] BICYCLIC PEPTIDE LIGANDS SPECIFIC FOR GFRAL

[0002] RELATED APPLICATIONS

[0003] The present application claims priority to United States of America Patent Application No.

[0004] 63 / 756,496 filed 10 February 2025 and United States of America Patent Application No.

[0005] 63 / 787,227 filed 11 April 2025, the entire contents of each of which are hereby incorporated by reference in their entirety.

[0006] FIELD OF THE INVENTION

[0007] The present invention relates to polypeptides which are covalently bound to molecular scaffolds such that twO Or more peptide loops are subtended between attachment points to the scaffold. In particular, the invention describes peptides which bind to GFRAL. The invention also includes pharmaceutical compositions comprising said peptide ligands and the use of said peptide ligands and pharmaceutical compositions in preventing, suppressing or treating a disease or disorder mediated by GFRAL.

[0008] BACKGROUND OF THE INVENTION

[0009] Cyclic peptides are able to bind with high affinity and specificity to protein targets and hence are an attractive molecule class for the development of therapeutics. In fact, several cyclic peptides are already successfully used in the clinic, as for example the antibacterial peptide vancomycin, the immunosuppressant drug cyclosporine or the anti-cancer drug octreotide (Driggers et al. (2008), Nat. Rev. Drug. Discov. 7(7), 608-24). Good binding properties result from a relatively large interaction surface formed between the peptide and the target as well as the reduced conformational flexibility of the cyclic structures. Typically, macrocycles bind to surfaces of several hundred square angstrom, as for example the cyclic peptide CXCR4 antagonist CVX15 (400 A2; Wu et al. (2007), Science 330, 1066-71), a cyclic peptide with the Arg-Gly-Asp motif binding to integrin aVb3 (355 A2) (Xiong et al. (2002), Science 296(5565), 151-5) or the cyclic peptide inhibitor upain-1 binding to urokinase- type plasminogen activator (603 A2; Zhao etal. (2007), J. Struct. Biol. 160(1), 1-10).

[0010] Due to their cyclic configuration, peptide macrocycles are less flexible than linear peptides, leading to a smaller loss of entropy upon binding to targets and resulting in a higher binding affinity. The reduced flexibility also leads to locking target-specific conformations, increasing binding specificity compared to linear peptides. This effect has been exemplified by a potent and selective inhibitor of matrix metalloproteinase 8 (MM P-8) which lost its selectivity over other MMPs when its ring was opened (Cherney et al. (1998), J. Med. Chem. 41(11), 1749-51). The favourable binding properties achieved through macrocyclization are even morepronounced in multicyclic peptides having more than one peptide ring as for example in vancomycin, nisin and actinomycin.

[0011] Different research teams have previously tethered polypeptides with cysteine residues to a synthetic molecular structure (Kemp and McNamara (1985), J. Org. Chem; Timmerman et al. (2005), ChemBioChem). Meloen and co-workers had used tris(bromomethyl)benzene and related molecules for rapid and quantitative cyclisation of multiple peptide loops onto synthetic scaffolds for structural mimicry of protein surfaces (Timmerman etal. (2005), ChemBioChem). Methods for the generation of candidate drug compounds wherein said compounds are generated by linking cysteine containing polypeptides to a molecular scaffold as for example 1,1',1"-(1,3,5-triazinane-1,3,5-triyl)triprop-2-en-1-one (TATA) (Heinis et al. (2014) Angewandte Chemie, International Edition 53(6) 1602-1606).

[0012] Phage display-based combinatorial approaches have been developed to generate and screen large libraries of bicyclic peptides to targets of interest (Heinis et al. (2009), Nat. Chem. Biol.

[0013] 5(7), 502-7 and WO 2009 / 098450). Briefly, combinatorial libraries of linear peptides containing three cysteine residues and two regions of six random amino acids (Cys-(Xaa)6-Cys-(Xaa)6-Cys) were displayed on phage and cyclised by covalently linking the cysteine side chains to a small molecule scaffold.

[0014] SUMMARY OF THE INVENTION

[0015] GFRAL is also known as “GDNF family receptor alpha like” and is a protein which in humans in encoded by the GFRAL gene. GFRAL is associated with a number of disorders including obesity and other cardiometabolic disorders, and is a therapeutic target for both tumour and chemotherapy induced cachexia. There is a need for new ligands capable of binding GFRAL.

[0016] According to a first aspect of the invention, there is provided a peptide ligand specific for GFRAL 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.

[0017] According to a further aspect of the invention, there is provided a multimeric binding complex comprising a plurality of peptide ligands as described herein. In some embodiments themultimeric binding complex comprises two, three or four peptide ligands as described herein, which may be the same or different.

[0018] According to a yet further aspect of the invention, there is provided a pharmaceutical composition comprising a peptide ligand as defined herein in combination with one or more pharmaceutically acceptable excipients.

[0019] According to a further aspect of the invention, there is provided a peptide ligand or pharmaceutical composition as defined herein for use in preventing, suppressing or treating a disease or disorder mediated by GFRAL.

[0020] DETAILED DESCRIPTION OF THE INVENTION

[0021] Definitions

[0022] Unless specifically defined herein, all terms used herein have the same meaning as they would tO One skilled in the art of the present invention. Practitioners are particularly directed to Sambrook et al., Molecular Cloning: A Laboratory Manual, 4th ed., Cold Spring Harbor Press, Plainsview, New York (2012); and Ausubel et al., Current Protocols in Molecular Biology (Supplement 114), John Wiley & Sons, New York (2016), for definitions and terms of the art.

[0023] The term “amino acid” in the context of the present disclosure is used in its broadest sense and is meant to include organic compounds containing amine (NH2) and carboxyl (COOH) functional groups, along with a side chain (e.g., a R group) specific to each amino acid. In some embodiments, the amino acids refer to naturally occurring L a-amino acids or residues. The commonly used one and three letter abbreviations for naturally occurring amino acids are used herein: A=Ala; C=Cys; D=Asp; E=Glu; F=Phe; G=Gly; H=His; I=Ile; K=Lys; L=Leu; M=Met; N=Asn; P=Pro; Q=Gln; R=Arg; S=Ser; T=Thr; V=Val; W=Trp; and Y=Tyr (Lehninger, A. L., (1975) Biochemistry, 2d ed., pp. 71-92, Worth Publishers, New York). The general term “amino acid” further includes D-amino acids, retro-inverso amino acids as well as chemically modified amino acids such as amino acid analogues, naturally occurring amino acids that are not usually incorporated into proteins such as norleucine, and chemically synthesised compounds having properties known in the art to be characteristic of an amino acid, such as p-amino acids. For example, analogues or mimetics of phenylalanine or proline, which allow the same conformational restriction of the peptide compounds as do natural Phe or Pro, are included within the definition of amino acid. Such analogues and mimetics are referred to herein as "functional equivalents" of the respective amino acid. Other examples of amino acids are listed by Roberts and Vellaccio, The Peptides: Analysis, Synthesis, Biology, Gross and Meiehofer, eds., Vol. 5 p. 341, Academic Press, Inc., N. Y.1983, which is incorporated herein by reference. The chemical properties of the 20 main amino acids are provided in Table A below.

[0024] Table A - Chemical properties of amino acid s

[0025] Ala aliphatic, hydrophobic, neutral Met hydrophobic, neutral

[0026] Cys polar, hydrophobic, neutral Asn polar, hydrophilic, neutral

[0027] Asp polar, hydrophilic, charged (-) Pro hydrophobic, neutral

[0028] Glu polar, hydrophilic, charged (-) Gin polar, hydrophilic, neutral

[0029] Phe aromatic, hydrophobic, neutral Arg polar, hydrophilic, charged (+) Gly aliphatic, neutral Ser polar, hydrophilic, neutral

[0030] His aromatic, polar, hydrophilic, Thr polar, hydrophilic, neutral charged (+)

[0031] lie aliphatic, hydrophobic, neutral Vai aliphatic, hydrophobic, neutral Lys polar, hydrophilic, charged(+) Trp aromatic, hydrophobic, neutral

[0032]

[0033] Leu aliphatic, hydrophobic, neutral Tyr aromatic, polar, hydrophobic

[0034] The terms “polypeptide”, and “peptide” are interchangeably used herein to refer to a polymer of amino acid residues and to variants and synthetic analogues of the same. Thus, these terms apply to amino acid polymers in which one or more amino acid residues is a synthetic non-naturally occurring amino acid, such as a chemical analogue of a corresponding naturally occurring amino acid, as well as to naturally-occurring amino acid polymers. Polypeptides can also undergo maturation or post-translational modification processes that may include, but are not limited to: glycosylation, proteolytic cleavage, lipidization, signal peptide cleavage, propeptide cleavage, phosphorylation, and such like.

[0035] As used herein, Ac represents an acetyl group; Abu represents aminobutyric acid, Aib represents aminoisobutyric acid, Aze represents azetidine, B-Melle represents betamethyl isoleucine, C5g represents cyclopentyl glycine, Cba represents p-cyclobutylalanine, Cbg represents cyclobutyl glycine, Chg represents cyclohexyl glycine, Cpg represents cyclopropryl glycine, dPEG represents discrete PEG (representing PEG having a dispersity, D = 1; in some embodiments dPEG is used synonymously with PEG, also in some embodiments written Peg); EPA represents 2-amino-3-ethyl-pentanoic acid, HyP represents trans-4-hydroxy-L-proline, [K(Na)] 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; AzPro represents azidopropyl, Aze represents azetidine, 1Nal represents 1-naphthylalanine, NMeTrp represents N-methyl-tryptophan, K(PYA) represents lysine, £-4-pentynoyl, Peg represents polyethylene glycol, Pip represents pipecolic acid, Sar representssarcosine, Fl represents fluorescein and [K(N3)(PYA-Maleimide)] represents a modified

[0036] lysine having the following structure:

[0037]

[0038] Peptide ligands

[0039] According to a first aspect of the invention, there is provided a peptide ligand specific for GFRAL 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.

[0040] In some embodiments, said reactive groups are selected from cysteine, d-cysteine (dC), cysteamine (Cysam), homocysteine (hCys, (S)-2-Amino-4-sulfanylbutanoic acid), pCys ((R)-3-amino-3-mercaptopropanoic acid), penicillamine (Pen, (R)-2-amino-3-mercapto-3-methylbutanoic acid), Dap ((S)-2,3-diaminopropanoic acid) and N-alkyl-Dap (e.g. N-methyl-Dap, (S)-2-amino-3-(methylamino)propanoic acid. In some embodiments, said reactive groups are selected from cysteine, d-cysteine (dC), and cysteamine (Cysam). In some embodiments said reactive groups are isoelectronic and / or isosteric with cysteine. In one embodiment, said reactive groups comprise cysteine residues.

[0041] It will be appreciated that the term “specific for GFRAL” refers to the ability of the peptide ligand to bind to GFRAL.

[0042] In a further embodiment, said loop sequences comprise 2, 3, 4, 5, 6, 7, 8, or 9 amino acids. In some embodiments the peptide ligand comprises a polypeptide comprising a first loop sequence comprising 2, 3, 4, 5, 6, 7, or 8 amino acids and a second loop sequence comprising 2, 3, 4, 5, 6, 7, or 8 amino acids. In some embodiments the length of the polypeptide comprising the first and second loop sequences and the reactive groups (e.g. from the first reactive group to the third reactive group) is from about 12 to about 16 amino acids, e.g. 13, 14 or 15 amino acids. In a yet further embodiment, the combined number of amino acids in both loop sequences comprises between 8 and 12 amino acids.In one embodiment, said polypeptide comprises three reactive groups as defined herein (e.g. three cysteine residues) separated by two loop sequences the first of which consists of 2 amino acids and the second of which consists of 8 amino acids.

[0043] In some embodiments the polypeptide comprises an amino acid sequence:

[0044] Z-Xl a-X2a-Z-X3a-X4a-X5a-X6a-X7a-X8a-X9a-Xl Oa’Z

[0045] wherein each of X1a to X10a are any amino acid and Z is a reactive group as defined herein; e.g. wherein Z is cysteine.

[0046] In some embodiments X1a and X2a are each independently selected from S, T, N, and Q. In some embodiments X1a and X2a are each independently selected from S and N. In some embodiments X1a is S and X2a is N. In some embodiments the moiety of formula -X1a-X2a- is -SN-.

[0047] In some embodiments X3a to X10a are each independently selected from P, N, W, Y, I, H, L and M. In some embodiments X3a is P. In some embodiments X4a is N. In some embodiments X5a is W. In some embodiments X6a is Y. In some embodiments X7a is I. In some embodiments X8a is H. In some embodiments X9a is L. In some embodiments X10a is M. In some embodiments the moiety of formula -X3a-X4a-X5a-X6a-X7a-X8a-X9a-X10a- is -PNWYIHLM-.

[0048] In some embodiments the peptide ligand comprises an amino acid sequence:

[0049] Z-SN-Z-PNWYIHLM-Z

[0050] or a variant thereof as defined herein, wherein each Z is independently a reactive group as defined herein; or a pharmaceutically acceptable salt thereof.

[0051] In a further embodiment, said loop sequences comprise three cysteine residues separated by two loop sequences the first of which consists of 2 amino acids and the second of which consists of 8 amino acids and comprise an amino acid sequence which is:

[0052] CSNCPNWYIHLMCi (SEQ ID NO: 1);

[0053] wherein the three cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof.

[0054] In a further embodiment, the molecular scaffold is a derivative of TATA (1,1',1"-(1,3,5-triazinane-1,3,5-triyl)triprop-2-en-1-one) which has the following structure:

[0055]

[0056] wherein * denotes the point of attachment of the three reactive groups (e.g. cysteine residues).

[0057] In some embodiments the peptide ligand comprises N- and / or C-terminal additions as described herein. In some embodiments the peptide ligand is:

[0058] A-(SEQ ID NO: 1)-A (herein referred to as BCY10120).

[0059] In an alternative embodiment, said polypeptide comprises three reactive groups as defined herein (e.g. three cysteine residues) separated by two loop sequences the first of which consists of 3 amino acids and the second of which consists of 7 amino acids.

[0060] In some embodiments the polypeptide comprises an amino acid sequence

[0061] Z-X1b-X2b-X3b-Z-X4b-X5b-X6b-X7b-X8b-X9b-X10b-Z

[0062] wherein each of X1b to X10b are any amino acid and Z is a reactive group as defined herein; e.g. wherein Z is cysteine.

[0063] In some embodiments X1b is selected from A, D and P. In some embodiments X1b is P. In some embodiments X2b is selected from A, D, E, F, G, H, I, K, N, R, S, and T. In some embodiments X3b is selected from A and W. In some embodiments X3b is W. In some embodiments of the moiety -X1b-X2b-X3b-: X1b is P, D, or A; X2b is any amino acid; and X3b is W or A. In some embodiments the moiety -X1b-X2b-X3b- is -P-X2b-W- wherein X2b is any amino acid.

[0064] In some embodiments X4b is S, A, E, G, H, N, T, or Y. In some embodiments X4b is S or A. In some embodiments X4b is S. In some embodiments X5b is A, D, H, K, L, N, Q, R, T, or V. In some embodiments X6b is L, I, Y, or A. In some embodiments X6b is L. In some embodiments X7b is G, [dA], A, I, L or S. In some embodiments X7b is G. In some embodiments X8b is I, A, D, F, G, N, S, or V. In some embodiments X8b is I. In some embodiments X9b is W, A, F, M,N, S, or T. In some embodiments X9b is W. In some embodiments X10b is D, E, A, N, L, S, or T. In some embodiments X10b is D, E, A, or N.

[0065] In some embodiments of the moiety -X4a-X5a-X6a-X7a-X8a-X9a-X10a-: X4a. X5a. X7a. X8a. X9a. and X10a are any amino acid and X6b is I, L, Y or A. In some embodiments X4a is S or A; X5a is any amino acid; X6 is L; X7b is G; X8b is I; X9b is W and X10b is D, E, A, or N. In some embodiments X4a is S; X5a is any amino acid; X6 is L; X7b is G; X8b is I; X9b is W and X10b is D, E, A, or N.

[0066] In some embodiments, therefore, the polypeptide comprises an amino acid sequence

[0067] Z-X1b-X2b-X3b-Z-X4b-X5b-X6b-X7b-X8b-X9b-X10b-Z

[0068] wherein Z is a reactive group; X2b, X4b, X5b, X7b, X8b, X9b, X10b are each independently any amino acid; X1b is P, D, or A; X3b is W or A; and X6b is I, Y, L, or A.

[0069] In some embodiments the polypeptide comprises an amino acid sequence

[0070] Z-P-X2b-W-Z-X4b-X5b-X6b-X7b-X8b-X9b-X10b-Z

[0071] wherein Z is a reactive group; X2b, X4b, X5b, X7b, X8b, X9b, X10b are each independently any amino acid; and X6b is I, Y, L, or A.

[0072] In some embodiments the polypeptide comprises an amino acid sequence

[0073] Z-P-X2b-W-Z-X4b-X5b-LGIW-X10b-Z

[0074] wherein Z is a reactive group; X2b and X5b are each independently any amino acid; X4b is S or A; and X10b is D, E, A or N.

[0075] In some embodiments the polypeptide comprises an amino acid sequence

[0076] Z-P-X2b-W-Z-S-X5b-LGIW-X10b-Z

[0077] wherein Z is a reactive group; X2b and X5b are each independently any amino acid; and X10b is D, E, A or N.

[0078] In some embodiments the polypeptide comprises an amino acid sequence:

[0079] Z-PKW-Z-EHYSSFL-ZZ-PNW-Z-HDIGIWS-ZZ-PAW-Z-YRLIDST-ZZ-PSW-Z-GRLLGNA-ZZ-PDW-Z-SDIGVWN-ZZ-PIW-Z-SRLGIWD-ZZ-PDW-Z-SKLGIWE-ZZ-PNW-Z-SVLGIWD-Zor a variant thereof as defined herein, wherein each Z is independently a reactive group as defined herein; or a pharmaceutically acceptable salt thereof.

[0080] In a further embodiment, said loop sequences comprise three cysteine residues separated by two loop sequences the first of which consists of 3 amino acids and the second of which consists of 7 amino acids and comprise an amino acid sequence which is selected from:

[0081] CPKWCEHYSSFLC (SEQ ID NO: 2);

[0082] CPNWCHDIGIWSC (SEQ ID NO: 3);

[0083] CPAWCYRLIDSTC (SEQ ID NO: 4);

[0084] CPSWCGRLLGNAC (SEQ ID NO: 5);

[0085] CPDWCSDIGVWNC (SEQ ID NO: 6);

[0086] CPIWCSRLGIWDC (SEQ ID NO: 7);

[0087] CPDWCSKLGIWEC (SEQ ID NO: 8);

[0088] CPNWCSVLGIWDC (SEQ ID NO: 9) herein referred to as BCY20418 when complexed with a derivative of TATA which has the following structure O O

[0089]

[0090] wherein * denotes the point of attachment of the three cysteine residues;

[0091] CPGWCSRLGIWAC (SEQ ID NO: 10)

[0092] CPSWCNRLLGFAC (SEQ ID NO: 11)

[0093] CPEWCGRLLGFAC (SEQ ID NO: 12)

[0094] CPAWCTRLLGTAC (SEQ ID NO: 13)

[0095] CPAWCYRLLGTAC (SEQ ID NO: 14)

[0096] CPEWCSRLLFSAC (SEQ ID NO: 15)

[0097] CPGWCARLLNSAC (SEQ ID NO: 16)

[0098] CPRWCSLLLDWAC (SEQ ID NO: 17)

[0099] CDRWCTNLLFMAC (SEQ ID NO: 18)

[0100] CPAWCSQLGIWDC (SEQ ID NO: 19)

[0101] CPEWCSRLGIWAC (SEQ ID NO: 20)

[0102] CPAWCSRLGIWDC (SEQ ID NO: 21)CPHWCSTLGIWDC (SEQ ID NO: 22);

[0103] CPFWCSKLGIWDC (SEQ ID NO: 23);

[0104] CPGWCSRLGIWDC (SEQ ID NO: 24);

[0105] CPTWCSRLGIWNC (SEQ ID NO: 25);

[0106] CPNWCSVLAIWDC (SEQ ID NO: 26);

[0107] CPNWCSVL[dA]IWDC (SEQ ID NO: 27);

[0108] CPNWCAVLGIWDC (SEQ ID NO: 28);

[0109] CANWCSVLGIWDC (SEQ ID NO: 29);

[0110] CPNWCSALGIWDC (SEQ ID NO: 30);

[0111] CPAWCSVLGIWDC (SEQ ID NO: 31); and

[0112] CPNWCSVLGIWAC (SEQ ID NO: 32);

[0113] wherein the three cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof.

[0114] In a further embodiment, the molecular scaffold is a derivative of TATA which has the following structure:

[0115]

[0116] wherein * denotes the point of attachment of the three reactive groups (e.g. cysteine residues).

[0117] In some embodiments the peptide ligand comprises N- and / or C-terminal additions as described herein. In some embodiments the peptide ligand is selected from:

[0118] A-(SEQ ID NO: 2)-A (herein referred to as BCY8978);

[0119] A-(SEQ ID NO: 3)-A (herein referred to as BCY8989);

[0120] A-(SEQ ID NO: 4)-A (herein referred to as BCY9189);

[0121] A-(SEQ ID NO: 5)-A (herein referred to as BCY9190);

[0122] A-(SEQ ID NO: 6)-A (herein referred to as BCY9195);

[0123] A-(SEQ ID NO: 7)-A (herein referred to as BCY9794);

[0124] A-(SEQ ID NO: 8)-A (herein referred to as BCY10107);

[0125] A-(SEQ ID NO: 9)-A (herein referred to as BCY10108);Ac-(SEQ ID NO: 9) (herein referred to as BCY10385);

[0126] Ac-(SEQ ID NO: 9)-K (herein referred to as BCY20416);

[0127] Ac-(SEQ ID NO: 9)-[K(Ac)] (herein referred to as BCY20417);

[0128] Ac-(SEQ ID NO: 9)-[K(dPEG(25))] (herein referred to as BCY20544);

[0129] [PA]-(SEQ ID NO: 9) (herein referred to as BCY20545);

[0130] [Ts]-(SEQ ID NO: 9) (herein referred to as BCY20555);

[0131] [PhtCOOH]-(SEQ ID NO: 9) (herein referred to as BCY20556);

[0132] [PheCOOH]-(SEQ ID NO: 9) (herein referred to as BCY20557); [Succinate]-(SEQ ID NO: 9) (herein referred to as BCY20558);

[0133] [n-Hex]-(SEQ ID NO: 9) (herein referred to as BCY20559);

[0134] [Piv]-(SEQ ID NO: 9) (herein referred to as BCY20560);

[0135] A-(SEQ ID NO: 10)-A (herein referred to as BCY10109);

[0136] A-(SEQ ID NO: 11)-A (herein referred to as BCY10215);

[0137] A-(SEQ ID NO: 12)-A (herein referred to as BCY10216);

[0138] A-(SEQ ID NO: 13)-A (herein referred to as BCY10217);

[0139] A-(SEQ ID NO: 14)-A (herein referred to as BCY10218);

[0140] A-(SEQ ID NO: 15)-A (herein referred to as BCY10219);

[0141] A-(SEQ ID NO: 16)-A (herein referred to as BCY10220);

[0142] A-(SEQ ID NO: 17)-A (herein referred to as BCY10221);

[0143] A-(SEQ ID NO: 18)-A (herein referred to as BCY10222);

[0144] A-(SEQ ID NO: 19)-NTS (herein referred to as BCY10771);

[0145] A-(SEQ ID NO: 20)-GRV (herein referred to as BCY10772);

[0146] SGQ-(SEQ ID NO: 21)-A (herein referred to as BCY10773);

[0147] AKG-(SEQ ID NO: 22)-A (herein referred to as BCY10775);

[0148] YGA-(SEQ ID NO: 23)-A (herein referred to as BCY10869);

[0149] AGP-(SEQ ID NO: 24)-A (herein referred to as BCY10870);

[0150] A-(SEQ ID NO: 25)-AHTA (herein referred to as BCY10871);

[0151] A-(SEQ ID NO: 26)-A (herein referred to as BCY20419);

[0152] A-(SEQ ID NO: 27)-A (herein referred to as BCY20420);

[0153] A-(SEQ ID NO: 28)-A (herein referred to as BCY20421);

[0154] A-(SEQ ID NO: 29)-A (herein referred to as BCY20422);

[0155] A-(SEQ ID NO: 30)-A (herein referred to as BCY20423);

[0156] A-(SEQ ID NO: 31)-A (herein referred to as BCY20426); and

[0157] A-(SEQ ID NO: 32)-A (herein referred to as BCY20427).In an alternative embodiment, said polypeptide comprises three reactive groups as defined herein (e.g. three cysteine residues) separated by two loop sequences the first of which consists of 3 amino acids and the second of which consists of 8 amino acids.

[0158] In some embodiments the polypeptide comprises an amino acid sequence

[0159] Z-X1c-X2c-X3c-Z-X4c-X5c-X6c-X7c-X8c-X9c-X10c-X11c-Z

[0160] wherein each of Xicto Xncare any amino acid and Z is a reactive group as defined herein; e.g. wherein Z is cysteine.

[0161] In some embodiments Xicis selected from P, S, or T. In some embodiments Xicis P or S. In some embodiments X2Cis selected from D, N, P, S, T, and V. In some embodiments X2Cis D. In some embodiments X2Cis P, S or T. In some embodiments X3cis selected from F, S, orW. In some embodiments Xsc is W or F. In some embodiments Xsc is W.

[0162] In some embodiments of the moiety -Xic-X2c-X3c-: Xicis P, S or T; X2Cis D, N, P or V; and X3cis W, F or S. In some embodiments the moiety -Xic-X2c-X3C- is -PDW-. In some embodiments the moiety -Xic-X2c-X3C- is -S-X2C-F- wherein X2Cis P, S or T.

[0163] In some embodiments X4c is D, E, M, P, S or T. In some embodiments X4c is S, D or P, such as S. In some embodiments X4Cis D, T, M or E, such as D. In some embodiments Xscis F, A, H, Q, R, or Y. In some embodiments Xscis F. In some embodiments X6cis L, F, Y or W. In some embodiments X6cis L, F, or Y. In some embodiments X6cis L. In some embodiments X?c is A, D, F, M, N, P, Q, R, S, or Y. In some embodiments Xscis D, E, G, H, I, L, N, Q, or T. In some embodiments Xgcis H, N, D, I, Q or V. In some embodiments X9c is H or N. In some embodiments Xcis W, G, H, L, D, K, N, Q, or S. In some embodiments Xcis W, G, H, or L. In some embodiments X c is W. In some embodiments Xncis L, D, G, H, K, M or S. In some embodiments Xncis L.

[0164] In some embodiments of the moiety ^c-Xsc-Xec-Xyc-Xsc-Xgc-X c-Xnc-: Xsc, X?c, Xsc, Xgcand Xnc are any amino acid; X4Cis S, D, or P; Xecis L, F, W, or Y; and X10c is W, G, H, or L. In some embodiments Xsc, X?c, Xsc, Xgcand Xncare any amino acid; X4Cis S; X6cis L, F, or Y; and X c is W. In some embodiments X?c, Xscand X c are any amino acid; X4cis D, T, M, or E; Xsc is F; Xecis L; Xgcis H or N and Xncis L. In some embodiments X?c, Xscand X c are any amino acid; X4cis D; Xscis F; Xecis L; Xgcis H or N and Xncis L.

[0165] In some embodiments, therefore, the polypeptide comprises an amino acid sequence

[0166] Z-Xlc-X2c-X3c-Z-X4c-X5c-X6c-X7c-X8c-Xgc-Xl Oc'Xl 1 c" Zwherein Z is a reactive group; X5c, X7c, X8c, X9c and X11c are each independently any amino acid; Xicis P, S, or T; X2Cis D, N, P, or V; X3cis W, F, or S; X4Cis S, D, or P; X6cis L, F, W, or Y, and X10c is W, G, H, or L.

[0167] In some embodiments the polypeptide comprises an amino acid sequence:

[0168] Z-PDW-Z-S-Xsc-Xec-Xyc-Xsc-Xgc-W-Xnc-Z

[0169] wherein Z is a reactive group; X5c, X7c, X8c, X9c and X11c are each independently any amino acid; and X6cis L, F or Y.

[0170] In some embodiments the polypeptide comprises an amino acid sequence

[0171] Z-S-X2C-F-Z-X4C-FL-X7C-X8C-X9C-X10C-L-Z

[0172] wherein Z is a reactive group; X7C, Xsc, Xcare each independently any amino acid; X2Cis P, S or T; Xfc is D, T, M or E; and X9c is H or N.

[0173] In some embodiments the polypeptide comprises an amino acid sequence

[0174] Z-S-X2C-F-Z-DFL-X7C-X8C-X9C-XIOC-L-Z

[0175] wherein Z is a reactive group; X7C, Xsc, X c are each independently any amino acid; X2Cis P, S or T; and X9c is H or N.

[0176] In some embodiments the polypeptide comprises an amino acid sequence:

[0177] Z-PDW-Z-SALDINWH-Z

[0178] Z-PNW-Z-SQFPGVWS-Z

[0179] Z-SPF-Z-DFLMTQGL-Z

[0180] Z-SVW-Z-DFLRENHL-Z

[0181] Z-TDS-Z-PHWYINLM-Z

[0182] Z-PDW-Z-SRLDIDWG-Z

[0183] Z-PDW-Z-SHYPEIWD-Z

[0184] Z-PDW-Z-SHYSQIWK-Z

[0185] Z-PDW-Z-SRLPGVWD-Z

[0186] Z-PDW-Z-SYYADIWG-Z

[0187] Z-ETY-Z-ALNWYRELV-Z

[0188] Z-SPF-Z-DFLQEHDL-Z

[0189] Z-SPF-Z-DFLNLNGL-Z

[0190] Z-SSF-Z-DFLQTHDL-Z

[0191] Z-STF-Z-DFLRNNHL-Z

[0192] Z-SPF-Z-DFLFQHQL-Z

[0193] Z-SPF-Z-DFLSENNL-ZZ-SSF-Z-DFLRGNNL-Z

[0194] Z-SSF-Z-DFLRTNSL-Z

[0195] Z-SSF-Z-DFLRDNDL-Z

[0196] Z-SSF-Z-DFLRENDL-Z

[0197] Z-SSF-Z-DFLRDNNL-Z

[0198] Z-SPF-Z-TFLQQHGL-Z

[0199] Z-SPF-Z-MFLREHDL-Z

[0200] Z-SPF-Z-EFLRHHKL-Z

[0201] or a variant thereof as defined herein, wherein each Z is independently a reactive group as defined herein; or a pharmaceutically acceptable salt thereof.

[0202] In a further embodiment, said loop sequences comprise three cysteine residues separated by two loop sequences the first of which consists of 3 amino acids and the second of which consists of 8 amino acids and comprise an amino acid sequence which is selected from:

[0203] CPDWCSALDINWHC (SEQ ID NO: 33);

[0204] CPNWCSQFPGVWSC (SEQ ID NO: 34);

[0205] CSPFCDFLMTQGLC (SEQ ID NO: 35);

[0206] CSVWCDFLRENHLC (SEQ ID NO: 36);

[0207] CTDSCPHWYINLMC (SEQ ID NO: 37);

[0208] CPDWCSRLDIDWGC (SEQ ID NO: 38);

[0209] CPDWCSHYPEIWDC (SEQ ID NO: 39);

[0210] CPDWCSHYSQIWKC (SEQ ID NO: 40);

[0211] CPDWCSRLPGVWDC (SEQ ID NO: 41);

[0212] CPDWCSYYADIWGC (SEQ ID NO: 42);

[0213] CETYCALNWYRELVC (SEQ ID NO: 43);

[0214] CSPFCDFLQEHDLC (SEQ ID NO: 44);

[0215] CSPFCDFLNLNGLC (SEQ ID NO: 45);

[0216] CSSFCDFLQTHDLC (SEQ ID NO: 46);

[0217] CSTFCDFLRNNHLC (SEQ ID NO: 47);

[0218] CSPFCDFLFQHQLC (SEQ ID NO: 48);

[0219] CSPFCDFLSENNLC (SEQ ID NO: 49);

[0220] CSSFCDFLRGNNLC (SEQ ID NO: 50);

[0221] CSSFCDFLRTNSLC (SEQ ID NO: 51);

[0222] CSSFCDFLRDNDLC (SEQ ID NO: 52);

[0223] CSSFCDFLRENDLC (SEQ ID NO: 53);

[0224] CSSFCDFLRDNNLC (SEQ ID NO: 54);

[0225] CSPFCTFLQQHGLC (SEQ ID NO: 55);CSPFCMFLREHDLC (SEQ ID NO: 56); and

[0226] CSPFCEFLRHHKLC (SEQ ID NO: 57);

[0227] wherein the three cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof.

[0228] In a further embodiment, the molecular scaffold is a derivative of TATA which has the following structure:

[0229] N

[0230]

[0231] wherein * denotes the point of attachment of the three reactive groups (e.g. cysteine residues).

[0232] In some embodiments the peptide ligand comprises N- and / or C-terminal additions as described herein. In some embodiments the peptide ligand is selected from:

[0233] A-(SEQ ID NO: 33)-A (herein referred to as BCY9196);

[0234] A-(SEQ ID NO: 34)-A (herein referred to as BCY9197);

[0235] A-(SEQ ID NO: 35)-A (herein referred to as BCY9198);

[0236] A-(SEQ ID NO: 36)-A (herein referred to as BCY9199);

[0237] A-(SEQ ID NO: 37)-A (herein referred to as BCY9200);

[0238] A-(SEQ ID NO: 38)-A (herein referred to as BCY10111);

[0239] A-(SEQ ID NO: 39)-A (herein referred to as BCY10112);

[0240] A-(SEQ ID NO: 40)-A (herein referred to as BCY10113);

[0241] A-(SEQ ID NO: 41)-A (herein referred to as BCY10114);

[0242] A-(SEQ ID NO: 42)-A (herein referred to as BCY10115);

[0243] A-(SEQ ID NO: 43)-A (herein referred to as BCY10261);

[0244] A-(SEQ ID NO: 44)-A (herein referred to as BCY10277);

[0245] A-(SEQ ID NO: 45)-A (herein referred to as BCY10278);

[0246] A-(SEQ ID NO: 46)-A (herein referred to as BCY10279);

[0247] A-(SEQ ID NO: 47)-A (herein referred to as BCY10280);

[0248] A-(SEQ ID NO: 48)-A (herein referred to as BCY10281);

[0249] A-(SEQ ID NO: 49)-A (herein referred to as BCY10282);A-(SEQ ID NO: 50)-A (herein referred to as BCY10283);

[0250] [dPEG(25)]A-(SEQ ID NO: 50)-A (herein referred to as BCY20561);

[0251] A-(SEQ ID NO: 51)-PKV (herein referred to as BCY11129);

[0252] A-(SEQ ID NO: 52)-PIA (herein referred to as BCY11130);

[0253] A-(SEQ ID NO: 53)-SVS (herein referred to as BCY11131);

[0254] A-(SEQ ID NO: 54)-KKE (herein referred to as BCY11132);

[0255] A-(SEQ ID NO: 55)-A (herein referred to as BCY11624);

[0256] A-(SEQ ID NO: 56)-A (herein referred to as BCY11625); and

[0257] A-(SEQ ID NO: 57)-A (herein referred to as BCY11626).

[0258] In an alternative embodiment, said polypeptide comprises three reactive groups as defined herein (e.g. three cysteine residues) separated by two loop sequences the first of which consists of 3 amino acids and the second of which consists of 9 amino acids.

[0259] In some embodiments the polypeptide comprises an amino acid sequence

[0260] Z-X1d-X2d-X3d-Z-X4d-X5d-X6d-X7d-X8d-X9d-X10d-X11d-X12d-Z

[0261] wherein each of Xicto Xi2d are any amino acid and Z is a reactive group as defined herein; e.g. wherein Z is cysteine.

[0262] In some embodiments Xid is selected from A, D, E, G, P, Q, R, S, T, or Y. In some embodiments X2d is selected from D, G, L, P, Q, S, or T. In some embodiments X3d is selected from Y, N, E, H, K, or L. In some embodiments X3d is Y or N, such as Y.

[0263] In some embodiments of the moiety -Xid-X2d-X3d-: Xid is any amino acid; X2d is any amino acid; and X3d is N or Y, such as Y.

[0264] In some embodiments X4d is selected from A, D, F, G, H, N, P, or R. In some embodiments Xsd is selected from L, P, E, K, N, S orT. In some embodiments Xsd is L or P, such as L. In some embodiments Xed is selected from D, E, F, L, M, N, P, R, S, T, or W. In some embodiments X?d is selected from W, A, Y, or P. In some embodiments X?d is W. In some embodiments Xsd is selected from Y, E, N, or V. In some embodiments Xsd is Y. In some embodiments Xgd is selected from D, G, H, I, N, Q, R, S, T or Y. In some embodiments X d is selected from D, E, L, M, N, R or S. In some embodiments Xnd is selected from L, K, M or S. In some embodiments Xnd is L. In some embodiments Xi2d is selected from I, V, M, A, D, or Y. In some embodiments Xi2d is I, V or M, such as I or V.In some embodiments of the moiety -X4d-X5d-Xed-X7d-X8d-Xgd-Xiod-Xnd-Xi2d-: X4d, Xsd, Xed, Xgd, X d, and Xi2d are any amino acid; X?d is W, A, Y, or P; X8d is Y, E, or N; and X11d is L, S, M, or K. In some embodiments, X4d, Xed, Xgd, and X d are any amino acid; Xsd is P or L; X?d is W; Xsdis Y; Xnd is L; and Xi2d is M, I, or V. In some embodiments, X4d, Xed, Xgd, and X d are any amino acid; Xsd is L; X?d is W; Xsdis Y; Xnd is L; and Xi2d is I or V.

[0265] In some embodiments, therefore, the polypeptide comprises an amino acid sequence:

[0266] Z-Xl d-X2d-X3d-Z-X4d-Xsd-Xed-X7d-X8d-Xgd-Xl Od-Xl 1 d-Xl 2d-Z

[0267] wherein Z is a reactive group; Xid, X2d, Xsd, X4d, Xsd, Xed, Xgd, X d, and Xi2d are any amino acid; X7d is W, A, Y, or P; X8d is Y, E, or N; and X11d is L, S, M, or K.

[0268] In some embodiments the polypeptide comprises an amino acid sequence:

[0269] Z-X1d-X2d-X3d-Z-X4d-X5d-X6d-WY-X9d-X10d-L-X12d-Z

[0270] wherein Z is a reactive group; Xid, X2d, X4d, Xed, Xgd, and X d are any amino acid; Xsd is N or Y; X5d is P or L; and X12d is M, I or V.

[0271] In some embodiments the polypeptide comprises an amino acid sequence:

[0272] Z-Xid-X2d-Y-Z-X4d-L-X6d-WY-Xgd-Xiod-L-Xi2d-Z

[0273] wherein Z is a reactive group; Xid, X2d, X4d, Xed, Xgd, and X d are any amino acid; and Xi2d is I orV.

[0274] In some embodiments the polypeptide comprises an amino acid sequence:

[0275] Z-DDY-Z-HLSWYNRLV-Z

[0276] Z-GPY-Z-HLTWYHDLV-Z

[0277] Z-GSY-Z-NLPWYTRLV-Z

[0278] Z-ASY-Z-DLPWYQDLV-Z

[0279] Z-DPY-Z-DLSWYYNLV-Z

[0280] Z-DDY-Z-HLEWYSNLI-Z

[0281] Z-PLY-Z-DLPWYQSLV-Z

[0282] Z-QQE-Z-PKWYVDLMD-Z

[0283] Z-RDN-Z-RPDWYIRLM-Z

[0284] Z-SGL-Z-FTRAEGLSY-Z

[0285] Z-YDK-Z-PNMAEGLSY-Z

[0286] Z-SGL-Z-FTRPNHMKA-Z

[0287] Z-RGK-Z-GELAEGLSY-Z

[0288] Z-TGH-Z-RSFAEGLSY-Zor a variant thereof as defined herein, wherein each Z is independently a reactive group as defined herein; or a pharmaceutically acceptable salt thereof.

[0289] In a further embodiment, said loop sequences comprise three cysteine residues separated by two loop sequences the first of which consists of 3 amino acids and the second of which consists of 9 amino acids and comprise an amino acid sequence which is selected from:

[0290] CDDYCHLSWYNRLVC (SEQ ID NO: 58);

[0291] CGPYCHLTWYHDLVC (SEQ ID NO: 59);

[0292] CGSYCNLPWYTRLVC (SEQ ID NO: 60);

[0293] CASYCDLPWYQDLVC (SEQ ID NO: 61);

[0294] CDPYCDLSWYYNLVC (SEQ ID NO: 62);

[0295] CDDYCHLEWYSNLIC (SEQ ID NO: 63);

[0296] CPLYCDLPWYQSLVC (SEQ ID NO: 64);

[0297] CQQECPKWYVDLMDC (SEQ ID NO: 65);

[0298] CRDNCRPDWYIRLMC (SEQ ID NO: 66);

[0299] CSGLCFTRAEGLSYC (SEQ ID NO: 67);

[0300] CYDKCPNMAEGLSYC (SEQ ID NO: 68);

[0301] CSGLCFTRPNHMKAC (SEQ ID NO: 69);

[0302] CRGKCGELAEGLSYC (SEQ ID NO: 70); and

[0303] CTGHCRSFAEGLSYC (SEQ ID NO: 71);

[0304] wherein the three cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof.

[0305] In a further embodiment, the molecular scaffold is a derivative of TATA which has the following structure:

[0306] N N

[0307] N

[0308]

[0309] wherein * denotes the point of attachment of the three reactive groups (e.g. cysteine residues).In some embodiments the peptide ligand comprises N- and / or C-terminal additions as described herein. In some embodiments the peptide ligand is selected from:

[0310] A-(SEQ ID NO: 58)-A (herein referred to as BCY10262);

[0311] A-(SEQ ID NO: 59)-A (herein referred to as BCY10263);

[0312] A-(SEQ ID NO: 60)-A (herein referred to as BCY10264);

[0313] A-(SEQ ID NO: 61)-A (herein referred to as BCY10266);

[0314] A-(SEQ ID NO: 62)-A (herein referred to as BCY10267);

[0315] A-(SEQ ID NO: 63)-A (herein referred to as BCY9201);

[0316] A-(SEQ ID NO: 64)-A (herein referred to as BCY9204);

[0317] A-(SEQ ID NO: 65)-A (herein referred to as BCY9205);

[0318] A-(SEQ ID NO: 66)-A (herein referred to as BCY8983);

[0319] A-(SEQ ID NO: 67)-A (herein referred to as BCY8984);

[0320] A-(SEQ ID NO: 68)-A (herein referred to as BCY10326);

[0321] A-(SEQ ID NO: 69)-A (herein referred to as BCY10328);

[0322] A-(SEQ ID NO: 70)-A (herein referred to as BCY10329); and

[0323] A-(SEQ ID NO: 71)-A (herein referred to as BCY10330).

[0324] In an alternative embodiment, said polypeptide comprises three reactive groups as defined herein (e.g. three cysteine residues) separated by two loop sequences both of which consist of 4 amino acids.

[0325] In some embodiments the polypeptide comprises an amino acid sequence

[0326] Z-X1e-X2e-X3e-X4e-Z-X5e-X6e-X7e-X8e-Z

[0327] wherein each of Xieto Xseare any amino acid and Z is a reactive group as defined herein; e.g. wherein Z is cysteine.

[0328] In some embodiments Xie, X2e, Xse and X4e are each independently selected from L, R, W and M. In some embodiments Xieis L. In some embodiments X2eis R. In some embodiments X8eis W. In some embodiments X4e is M. In some embodiments the moiety of formula -Xie-X2e-X3e-X4e- is -LRWM-.

[0329] In some embodiments Xse, X8e, X?eand Xseare each independently selected from E, L, G and I. In some embodiments Xseis E. In some embodiments X8eis L. In some embodiments X?eis G. In some embodiments X8eis I. In some embodiments the moiety of formula -Xse-Xee-X7e-X8e- is -ELGI-.

[0330] In some embodiments the peptide ligand comprises an amino acid sequence:Z-LRWM-Z-ELGIZ

[0331] or a variant thereof as defined herein, wherein each Z is independently a reactive group as defined herein; or a pharmaceutically acceptable salt thereof.

[0332] In a further embodiment, said loop sequences comprise three cysteine residues separated by two loop sequences both of which consist of 4 amino acids and comprise an amino acid sequence which is:

[0333] CLRWMCELGIC (SEQ ID NO: 72);

[0334] wherein the three cysteine residues within the peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof.

[0335] In a further embodiment, the molecular scaffold is a derivative of TATA which has the following structure:

[0336] O O

[0337]

[0338] *

[0339] wherein * denotes the point of attachment of the three reactive groups (e.g. cysteine residues).

[0340] In some embodiments the peptide ligand comprises N- and / or C-terminal additions as described herein. In some embodiments the peptide ligand is:

[0341] A-(SEQ ID NO: 72)-A (herein referred to as BCY8991).

[0342] In an alternative embodiment, said polypeptide comprises three reactive groups as defined herein (e.g. cysteine residues) separated by two loop sequences the first of which consists of 4 amino acids and the second of which consists of 6 amino acids.

[0343] In some embodiments the polypeptide comprises an amino acid sequence

[0344] Z-Xlf-X2f-X3f-X4f-Z-X5f-X6f-X7f-Xsf-Xgf-Xl0f-Z

[0345] wherein each of XH to X f are any amino acid and Z is a reactive group as defined herein; e.g. wherein Z is cysteine.In some embodiments XH is selected from E, G, L and Q. In some embodiments X2f is selected from L and P. In some embodiments X3f is selected from D, N and S. In some embodiments X4f is W. In some embodiments of the moiety -Xif-X2f-X3f-X4f-, XH and X3f are any amino acids, X2f is L or P and X4f is W.

[0346] In some embodiments Xsf is selected from A, G, K, N and R. In some embodiments X6f is selected from R, E and P. In some embodiments X?f is L. In some embodiments X3f is F. In some embodiments Xgf is P. In some embodiments X is selected from D, E, N and R. In some embodiments of the moiety -Xsf-Xef-Xyf-Xsf-Xgf-X f-, Xsf and X f are any amino acids; Xef is selected from R, E and P; Xyf is L; Xsf is F; and Xgf is P.

[0347] In some embodiments the polypeptide comprises an amino acid sequence

[0348] Z-Xif-X2f-X3f-W-Z-X5f-X6f-LFP-Xiof-Z

[0349] wherein X, X3f, Xsf and X f are any amino acids; X2f is L or P; and X6f is selected from R, E and P.

[0350] In some embodiments the polypeptide comprises an amino acid sequence:

[0351] Z-ELDW-Z-KRLFPE-Z

[0352] Z-QLDW-Z-NELFPN-Z

[0353] Z-LPNW-Z-GPLFPR-Z

[0354] Z-QLSW-Z-RELFPD-Z

[0355] Z-GLSW-Z-AELFPD-Z

[0356] Z-QLDW-Z-NELFPN-Z

[0357] or a variant thereof as defined herein, wherein each Z is independently a reactive group as defined herein; or a pharmaceutically acceptable salt thereof.

[0358] In a further embodiment, said loop sequences comprise three cysteine residues separated by two loop sequences the first of which consists of 4 amino acids and the second of which consists of 6 amino acids and comprise an amino acid sequence which is selected from:

[0359] CELDWCKRLFPEC (SEQ ID NO: 73);

[0360] CQLDWCNELFPNC (SEQ ID NO: 74);

[0361] CLPNWCGPLFPRC (SEQ ID NO: 75);

[0362] CQLSWCRELFPDC (SEQ ID NO: 76);

[0363] CGLSWCAELFPDC (SEQ ID NO: 77); and

[0364] CQLDW[dC]NELFPNC (SEQ ID NO: 78);

[0365] wherein the three cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof.In a further embodiment, the molecular scaffold is a derivative of TATA which has the following structure:

[0366]

[0367] wherein * denotes the point of attachment of the three reactive groups (e.g. cysteine residues).

[0368] In some embodiments the peptide ligand comprises N- and / or C-terminal additions as described herein. In some embodiments the peptide ligand is selected from:

[0369] A-(SEQ ID NO: 73)-A (herein referred to as BCY8970);

[0370] A-(SEQ ID NO: 74)-A (herein referred to as BCY9206);

[0371] A-(SEQ ID NO: 75)- A (herein referred to as BCY10087);

[0372] A-(SEQ ID NO: 76)-A (herein referred to as BCY10285);

[0373] A-(SEQ ID NO: 77)- A (herein referred to as BCY10286); and

[0374] [-FI][NH-Peg6-CO]A-(SEQ ID NO: 78)-A (herein referred to as BCY20522).

[0375] In an alternative embodiment, said polypeptide comprise three reactive groups as defined herein (e.g. three cysteine residues) separated by two loop sequences the first of which consists of 4 amino acids and the second of which consists of 8 amino acids.

[0376] In some embodiments the polypeptide comprises an amino acid sequence

[0377] Z-X1g-X2g-X3g-X4g-Z-X5g-X6g-X7g-X8g-X9g-X10g-X11g-X12g-Z

[0378] wherein each of Xigto Xi2g are any amino acid and Z is a reactive group as defined herein; e.g. wherein Z is cysteine.

[0379] In some embodiments Xigis selected from S, Y, T, A, D, and G. In some embodiments, Xigis S, Y, or T; such as S. In some embodiments X2gis selected from D, G, A, E, H, K, L, P, Q, S, [Cys(Bn)], [dA] and [K(Bz)]. In some embodiments X2gis D or G; such as D. In some embodiments X3gis selected from A, P, E, F, K, L, M, N, Q and R. In some embodiments X3gis A or P; such as A. In some embodiments X4gis selected from L, F, W, A, Q, and S. In some embodiments X4gis L, F, W or A; such as L.

[0380] In some embodiments of the moiety -Xig-X2g-X3g-X4g-: Xigis S; X2gis D; X3gis A; and X4gis L. In some embodiments, Xigis Y; X2gis G; X3gis P; and X4gis F. In some embodiments X1gis S or T; X2gand X3gare any amino acid; and X4gis W. In some embodiments Xigis S; X2gis G; X3gis A or P; and X4gis L or A.

[0381] In some embodiments Xsgis selected from A, D, E, G, H, I, K, N, Q, S, Y, [Agb], [Bpa], [HArg], and K or a derivative thereof (e.g. [K(AS-triaz-DBCO-BA)], [K(DBCO)], [K(Ahx)], [K(Ahx, Ahx)], [K(Bz)J, [K(CO-PEG5-CO)], [K(dPEG(25))J and [K(W)]). In some embodiments Xsgis S, A, K, N, I, [HArg] or Q; such as K. In some embodiments X6gis selected from F or a derivative thereof, A, K, L, W, [Agb], [aMePhe], and [HArg], In some embodiments X6gis F or a derivative thereof, A K, [Agb], [HArg], or L; such as [aMePhe], In some embodiments X?gis selected from F or a derivative thereof, L, A, D, G, H, K, N, Q, R, and [aMePhe], In some embodiments X?gis F or a derivative thereof, L, or A; such as F. In some embodiments X8gis selected from D, G, S, A, E, H, K, M, Q, R, and V. In some embodiments Xsgis R, D, G or S; such as R. In some embodiments Xggis selected from E, I, K, L, A, D, H, N, Q, R, S, T, V, [Agb], [AzaTrp] and [HArg], In some embodiments Xggis E, I, K or L; such as E. In some embodiments Xgis selected from N, L, A, H, M, S and T. In some embodiments Xgis N or L; such as N. In some embodiments Xngis selected from H, T, A, F, G, I, Q, V, and Y. In some embodiments Xngis H, T or A; such as T. In some embodiments Xi2gis selected from W, M, D, N, G, H, K, L, R, S, T, Y, [Agb], [dK], [HArg] and [K(Ahx, Ahx)]. In some embodiments Xi2gis [HArg], W, M, D, N or G; such as [HArg],

[0382] In some embodiments of the moiety -X5g-X6g-X7g-X8g-Xgg-Xiog-Xiig-Xi2g-: Xsg, X8gand Xi2gare any amino acid; X6gis F or a derivative thereof; X?gis F or a derivative thereof; Xggis E, I, K, or L; Xgis N; and Xngis T. In some embodiments X?g, Xggand Xngare any amino acid; Xsgis S; Xegis A, K, Agb, or HArg; Xsgis D, G, or S; Xgis L; and Xi2gis W or M. In some embodiments Xsg, Xgg, Xgand Xi2gare any amino acid; Xsgis A, K or N; Xegis L; X?gis L; and X11gis H or T. In some embodiments X8gand Xggare any amino acid; Xsgis A, I, or Q; X6gis F or A; X?gis F, L, or A; Xgis N; X11gis T or A; and Xi2gis D, N or G.

[0383] In some embodiments, therefore, the polypeptide comprises an amino acid sequence

[0384] Z-SDAL-Z-X5g-X6g-X7g-X8g-X9g-NT-Xi2g-Zwherein Xsgis any amino acid, such as K; X8gis F or a derivative thereof, such as [aMePhe]; X7gis F or a derivative thereof, such as F; X8gis any amino acid, such as R; Xggis E, I, K, or L, such as E; and Xi2gis any amino acid, such as [HArg],

[0385] In some embodiments the polypeptide comprises an amino acid sequence

[0386] Z-YGPF-Z-S-X6g-X7g-X8g-X9g-L-X11g-X12g-Z

[0387] wherein X6gis A, K, Agb, or HArg; X7gis any amino acid; X8gis D, G or S; X9gis any amino acid; X11gis any amino acid; and Xi2gis W or M.

[0388] In some embodiments the polypeptide comprises an amino acid sequence

[0389] Z-X1g-X2g-X3g-W-Z-X5g-LL-X8g-X9g-X10g-X11g-X12g-Z

[0390] wherein X2g, X8g, Xsg, Xgg, Xgand Xi2gare each any amino acid; X1gis S or T; Xsgis A, K or N; and X11gis H or T.

[0391] In some embodiments the polypeptide comprises an amino acid sequence

[0392] Z-SG-X3g-X4g-Z-X5g-X6g-X7g-X8g-Xgg-N-Xng-Xi2g-Z

[0393] wherein X8gand Xggare each any amino acid; X8gis A or P; X4gis L or A; Xsgis A, I or Q; X8gis F or A; X7gis F, L or A; X11gis T or A; and Xi2gis D, N or G.

[0394] In some embodiments the polypeptide comprises an amino acid sequence:

[0395] Z-THEW-Z-ALLQANTG-Z

[0396] Z-SDEW-Z-ALLHQTTY-Z

[0397] Z-SEAW-Z-NLLMSSHT-Z

[0398] Z-SEAW-Z-ALLQTHTN-Z

[0399] Z-SGNW-Z-KLLQSSTN-Z

[0400] Z-SGPW-Z-ALLRDATD-Z

[0401] Z-SSRW-Z-ALLQETTS-Z

[0402] Z-SLPW-Z-ALLQSNTH-Z

[0403] Z-SAEW-Z-ALLGSTTH-Z

[0404] Z-DDFQ-Z-SWKQLMGL-Z

[0405] Z-SAML-Z-GFLSEHTH-Z

[0406] Z-SGAL-Z-AFFRANTD-Z

[0407] Z-SGPL-Z-IFFQKNTG-Z

[0408] Z-SQML-Z-SFLQSHTR-Z

[0409] Z-YGPF-Z-SKGGILQW-Z

[0410] Z-SPAL-Z-DFLMLHTG-Z

[0411] Z-GDFS-Z-EWKMLMGL-ZZ-DDFL-Z-NWRELLGL-Z

[0412] Z-DDFS-Z-SWRQLMGL-Z

[0413] Z-SGAL-Z-QFLKENTN-Z

[0414] Z-SPML-Z-AFLKENTH-Z

[0415] Z-SPAL-Z-EFLAVNTH-Z

[0416] Z-SDAL-Z-KFFRENTK-Z

[0417] Z-SDQL-Z-AFFSTNTG-Z

[0418] Z-SPLL-Z-AFFADNTG-Z

[0419] Z-SPRL-Z-SFFQANTS-Z

[0420] Z-YGPF-Z-SKHDRLIW-Z

[0421] Z-YGPF-Z-SKDDKLFW-Z

[0422] Z-YGPF-Z-SKNDKLVW-Z

[0423] Z-YGPF-Z-SKDGKLYM-Z

[0424] Z-YGPF-Z-SKQGKLHW-Z

[0425] Z-YGPF-Z-SKDSHLVW-Z

[0426] Z-SQAL-Z-AFFAENTD-Z

[0427] Z-SPAL-Z-AFFRTNTD-Z

[0428] Z-SGAL-Z-AFFVQNTG-Z

[0429] Z-SGAL-Z-AFFRENTN-Z

[0430] Z-SDAL-Z-QFFKENTK-Z

[0431] Z-SDAL-Z-QFFSLNTK-Z

[0432] Z-SDAL-Z-HFFRENTK-Z

[0433] Z-SDAL-Z-KFFGINTG-Z

[0434] Z-SDAL-Z-KFFKENTG-Z

[0435] Z-SPLL-Z-AFFRNNTG-Z

[0436] Z-SPLL-Z-AFFSQNTG-Z

[0437] Z-SPLL-Z-AFFQDNTG-Z

[0438] Z-SPQL-Z-SFFAQNTS-Z

[0439] Z-SPQL-Z-SFFKTNTS-Z

[0440] Z-SPRL-Z-SFFQSNTN-Z

[0441] Z-SPRL-Z-SFFQSNTG-Z

[0442] Z-S[K(Bz)]AL-Z-[Bpa]FFS[AzaTrp]NTK-Z Z-S[K(Bz)]AL-Z-[Bpa]FFSKNT[HArg]-Z Z-SDKL-Z-[K(Bz)]FFRENT[HArg]-Z

[0443] Z-SKAL-Z-[K(Bz)]FFRENT[HArg]-Z

[0444] Z-SDAL-Z-[K(Bz)]FFRKNT[HArg]-Z

[0445] Z-SDKL-Z-[HArg]FFRENT[HArg]-ZZ-S[Cys(Bn)]AL-Z-KFFRENT[HArg]-Z

[0446] Z-SDAL-Z-[K(Bz)]FFRENTK-Z

[0447] Z-SKAL-Z-[HArg]FFRENT[HArg]-Z

[0448] Z-SDAL-Z-YFFRKNT[HArg]-Z

[0449] Z-SDAL-Z-K[aMePhe]FRENT[HArg]-Z

[0450] Z-SDAL-Z-KF[aMePhe]RENT[HArg]-Z

[0451] Z-SDAL-Z-HFFRKNT[HArg]-Z

[0452] Z-SDAL-Z-[HArg]FFRENTK-Z

[0453] Z-SDAL-Z-KFFRENT[HArg]-Z

[0454] Z-SDAL-Z-[HArg]FFRENT[dK]-Z

[0455] Z-SDAL-Z-KFFHENT[HArg]-Z

[0456] Z-SDAL-Z-[Agb]FFRENTK-Z

[0457] Z-SDAL-Z-KFFRENT[Agb]-Z

[0458] Z-SDAL-Z-HFFSKNT[HArg]-Z

[0459] Z-SDAL-Z-KFFSENT[HArg]-Z

[0460] Z-SDAL-Z-KFFAENT[HArg]-Z

[0461] Z-SAAL-Z-AFFRANTD-Z

[0462] Z-S[dA]AL-Z-AFFRANTD-Z

[0463] Z-AGAL-Z-AFFRANTD-Z

[0464] Z-SGAL-Z-AFFRANAD-Z

[0465] Z-SGAA-Z-AFFRANTD-Z

[0466] Z-SGAL-Z-AAFRANTD-Z

[0467] Z-YGPF-Z-S[HArg]DD[HArg]LFW-Z

[0468] Z-YGPF-Z-SKDD[HArg]LFW-Z

[0469] Z-YGPF-Z-S[HArg]DDKLFW-Z

[0470] Z-YGPF-Z-S[Agb]DD[Agb]LFW-Z

[0471] Z-YGPF-Z-SKDD[Agb]LFW-Z

[0472] Z-YGPF-Z-S[Agb]DDKLFW-Z

[0473] Z-YGPF-Z-SKDDALFW-Z

[0474] Z-YGPF-Z-SADDKLFW-Z

[0475] Z-YGPF-Z-SADDALFW-Z

[0476] Z-SDAL-Z-YFFRKNT[HArg]-Z

[0477] Z-SDAL-Z-KFFRENT[HArg]-Z

[0478] Z-SDAL-Z-KFFAENT[HArg]-Z

[0479] Z-SDAL-Z-[K(dPEG(25))]FFRENT[HArg]-Z

[0480] Z-SDAL-Z-[K(AS-triaz-DBCO-BA)]FFRENT[HArg]-Z Z-SDAL-Z-[K(CO-PEG5-CO)]FFRENT[HArg]-ZZ-SDAL-Z-[K(Ahx, Ahx)]FFRENT[HArg]-Z

[0481] Z-SDAL-Z-[Agb]FFRENT[K(Ahx, Ahx]-Z

[0482] Z-SDAL-Z-[K(W)]FFRENT[HArg]-Z

[0483] Z-SDAL-Z-[K(Ahx)]FFRENT[HArg]-Z

[0484] Z-SDAL-Z-[HArg]FFRENT[HArg]-Z

[0485] Z-SDAL-Z-[HArg]FFRKNT[HArg]-Z

[0486] Z-SDAL-Z-[K(DBCO)]FFRENT[HArg]-Z

[0487] or a variant thereof as defined herein, wherein each Z is independently a reactive group as defined herein; or a pharmaceutically acceptable salt thereof.

[0488] In a further embodiment, said loop sequences comprise three cysteine residues separated by two loop sequences the first of which consists of 4 amino acids and the second of which consists of 8 amino acids and comprise an amino acid sequence which is selected from:

[0489] CTHEWCALLQANTGC (SEQ ID NO: 79);

[0490] CSDEWCALLHQTTYC (SEQ ID NO: 80);

[0491] CSEAWCNLLMSSHTC (SEQ ID NO: 81);

[0492] CSEAWCALLQTHTNC (SEQ ID NO: 82);

[0493] CSGNWCKLLQSSTNC (SEQ ID NO: 83);

[0494] CSGPWCALLRDATDC (SEQ ID NO: 84);

[0495] CSSRWCALLQETTSC (SEQ ID NO: 85);

[0496] CSLPWCALLQSNTHC (SEQ ID NO: 86);

[0497] CSAEWCALLGSTTHC (SEQ ID NO: 87);

[0498] CDDFQCSWKQLMGLC (SEQ ID NO: 88);

[0499] CSAMLCGFLSEHTHC (SEQ ID NO: 89);

[0500] CSGALCAFFRANTDC (SEQ ID NO: 90);

[0501] CSGPLCIFFQKNTGC (SEQ ID NO: 91);

[0502] CSQMLCSFLQSHTRC (SEQ ID NO: 92);

[0503] CYGPFCSKGGILQWC (SEQ ID NO: 93);

[0504] CSPALCDFLMLHTGC (SEQ ID NO: 94);

[0505] CGDFSCEWKMLMGLC (SEQ ID NO: 95);

[0506] CDDFLCNWRELLGLC (SEQ ID NO: 96);

[0507] CDDFSCSWRQLMGLC (SEQ ID NO: 97);

[0508] CSGALCQFLKENTNC (SEQ ID NO: 98);

[0509] CSPMLCAFLKENTHC (SEQ ID NO: 99);

[0510] CSPALCEFLAVNTHC (SEQ ID NO: 100);

[0511] CSDALCKFFRENTKC (SEQ ID NO: 101);CSDQLCAFFSTNTGC (SEQ ID NO: 102);

[0512] CSPLLCAFFADNTGC (SEQ ID NO: 103);

[0513] CSPRLCSFFQANTSC (SEQ ID NO: 104);

[0514] CYGPFCSKHDRLIWC (SEQ ID NO: 105);

[0515] CYGPFCSKDDKLFWC (SEQ ID NO: 106);

[0516] CYGPFCSKNDKLVWC (SEQ ID NO: 107);

[0517] CYGPFCSKDGKLYMC (SEQ ID NO: 108);

[0518] CYGPFCSKQGKLHWC (SEQ ID NO: 109);

[0519] CYGPFCSKDSHLVWC (SEQ ID NO: 110);

[0520] CSQALCAFFAENTDC (SEQ ID NO: 111);

[0521] CSPALCAFFRTNTDC (SEQ ID NO: 112);

[0522] CSGALCAFFVQNTGC (SEQ ID NO: 113);

[0523] CSGALCAFFRENTNC (SEQ ID NO: 114);

[0524] CSDALCQFFKENTKC (SEQ ID NO: 115);

[0525] CSDALCQFFSLNTKC (SEQ ID NO: 116);

[0526] CSDALCHFFRENTKC (SEQ ID NO: 117);

[0527] CSDALCKFFGINTGC (SEQ ID NO: 118);

[0528] CSDALCKFFKENTGC (SEQ ID NO: 119);

[0529] CSPLLCAFFRNNTGC (SEQ ID NO: 120);

[0530] CSPLLCAFFSQNTGC (SEQ ID NO: 121);

[0531] CSPLLCAFFQDNTGC (SEQ ID NO: 122);

[0532] CSPQLCSFFAQNTSC (SEQ ID NO: 123);

[0533] CSPQLCSFFKTNTSC (SEQ ID NO: 124);

[0534] CSPRLCSFFQSNTNC (SEQ ID NO: 125);

[0535] CSPRLCSFFQSNTGC (SEQ ID NO: 126);

[0536] CS[K(Bz)]ALC[Bpa]FFS[AzaTrp]NTKC (SEQ ID NO: 127); CS[K(Bz)]ALC[Bpa]FFSKNT[HArg]C (SEQ ID NO: 128); CSDKLC[K(Bz)]FFRENT[HArg]C (SEQ ID NO: 129);

[0537] CSKALC[K(Bz)]FFRENT[HArg]C (SEQ ID NO: 130);

[0538] CSDALC[K(Bz)]FFRKNT[HArg]C (SEQ ID NO: 131);

[0539] CSDKLC[HArg]FFRENT[HArg]C (SEQ ID NO: 132);

[0540] CS[Cys(Bn)]ALCKFFRENT[HArg]C (SEQ ID NO: 133);

[0541] CSDALC[K(Bz)]FFRENTKC (SEQ ID NO: 134);

[0542] CSKALC[HArg]FFRENT[HArg]C (SEQ ID NO: 135);

[0543] CSDALCYFFRKNT[HArg]C (SEQ ID NO: 136);

[0544] CSDALCK[aMePhe]FRENT[HArg]C (SEQ ID NO: 137); CSDALCKF[aMePhe]RENT[HArg]C (SEQ ID NO: 138);CSDALCHFFRKNT[HArg]C (SEQ ID NO: 139);

[0545] CSDALC[HArg]FFRENTKC (SEQ ID NO: 140);

[0546] CSDALCKFFRENT[HArg]C (SEQ ID NO: 141);

[0547] CSDALC[HArg]FFRENT[dK]C (SEQ ID NO: 142);

[0548] CSDALCKFFHENT[HArg]C (SEQ ID NO: 143);

[0549] CSDALC[Agb]FFRENTKC (SEQ ID NO: 144);

[0550] CSDALCKFFRENT[Agb]C (SEQ ID NO: 145);

[0551] CSDALCHFFSKNT[HArg]C (SEQ ID NO: 146);

[0552] CSDALCKFFSENT[HArg]C (SEQ ID NO: 147);

[0553] CSDALCKFFAENT[HArg]C (SEQ ID NO: 148);

[0554] CSAALCAFFRANTDC (SEQ ID NO: 149);

[0555] CS[dA]ALCAFFRANTDC (SEQ ID NO: 150);

[0556] CAGALCAFFRANTDC (SEQ ID NO: 151);

[0557] CSGALCAFFRANADC (SEQ ID NO: 152);

[0558] CSGAACAFFRANTDC (SEQ ID NO: 153);

[0559] CSGALCAAFRANTDC (SEQ ID NO: 154);

[0560] CYGPFCS[HArg]DD[HArg]LFWC (SEQ ID NO: 155);

[0561] CYGPFCSKDD[HArg]LFWC (SEQ ID NO: 156);

[0562] CYGPFCS[HArg]DDKLFWC (SEQ ID NO: 157);

[0563] CYGPFCS[Agb]DD[Agb]LFWC (SEQ ID NO: 158);

[0564] CYGPFCSKDD[Agb]LFWC (SEQ ID NO: 159);

[0565] CYGPFCS[Agb]DDKLFWC (SEQ ID NO: 160);

[0566] CYGPFCSKDDALFWC (SEQ ID NO: 161);

[0567] CYGPFCSADDKLFWC (SEQ ID NO: 162);

[0568] CYGPFCSADDALFWC (SEQ ID NO: 163);

[0569] CSDALCYFFRKNT[HArg][Cysam] (SEQ ID NO: 164);

[0570] CSDALCKFFRENT[HArg][Cysam] (SEQ ID NO: 165);

[0571] CSDALCKFFAENT[HArg][Cysam] (SEQ ID NO: 166);

[0572] CSDALC[K(dPEG(25))]FFRENT[HArg]C (SEQ ID NO: 167);

[0573] CSDALC[K(AS-triaz-DBCO-BA)]FFRENT[HArg]C (SEQ ID NO: 168); CSDALC[K(CO-PEG5-CO)]FFRENT[HArg]C (SEQ ID NO: 169); CSDALC[K(Ahx, Ahx)]FFRENT[HArg]C (SEQ ID NO: 170);

[0574] CSDALC[Agb]FFRENT[K(Ahx, Ahx]C (SEQ ID NO: 171);

[0575] CSDALC[K(W)]FFRENT[HArg]C (SEQ ID NO: 172);

[0576] CSDALC[K(Ahx)]FFRENT[HArg]C (SEQ ID NO: 173);

[0577] CSDALC[HArg]FFRENT[HArg]C (SEQ ID NO: 303);

[0578] CSDALC[HArg]FFRKNT[HArg]C (SEQ ID NO: 304) andCSDALC[K(DBCO)]FFRENT[HArg]C (SEQ ID NO: 305)

[0579] wherein the cysteine and Cysam residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof.

[0580] In a further embodiment, the molecular scaffold is a derivative of TATA which has the following structure:

[0581] O O

[0582]

[0583] wherein * denotes the point of attachment of the three reactive groups (e.g. cysteine residues).

[0584] In some embodiments the peptide ligand comprises N- and / or C-terminal additions as described herein. In some embodiments the polypeptide ligand is selected from:

[0585] A-(SEQ ID NO: 79)-A (herein referred to as BCY8969);

[0586] A-(SEQ ID NO: 80)-A (herein referred to as BCY10205);

[0587] A-(SEQ ID NO: 81)-A (herein referred to as BCY10206);

[0588] A-(SEQ ID NO: 82)-A (herein referred to as BCY10207);

[0589] A-(SEQ ID NO: 83)-A (herein referred to as BCY10208);

[0590] A-(SEQ ID NO: 84)-A (herein referred to as BCY10209);

[0591] A-(SEQ ID NO: 85)-A (herein referred to as BCY10210);

[0592] A-(SEQ ID NO: 86)-A (herein referred to as BCY10212);

[0593] A-(SEQ ID NO: 87)-A (herein referred to as BCY10214);

[0594] A-(SEQ ID NO: 88)-A (herein referred to as BCY11331);

[0595] A-(SEQ ID NO: 89)-A (herein referred to as BCY11333);

[0596] A-(SEQ ID NO: 90)-A (herein referred to as BCY11335);

[0597] A-(SEQ ID NO: 90)-[dA] (herein referred to as BCY20464);

[0598] Ac-(SEQ ID NO: 90)-[K(Ac)] (herein referred to as BCY20487);

[0599] Ac-(SEQ ID NO: 90)-K (herein referred to as BCY20491);

[0600] Ac-(SEQ ID NO: 90)-[dK] (herein referred to as BCY20492);

[0601] A-(SEQ ID NO: 90) (herein referred to as BCY20494);Ac-(SEQ ID NO: 90) (herein referred to as BCY20497);

[0602] A-(SEQ ID NO: 91)-A (herein referred to as BCY11336);

[0603] A-(SEQ ID NO: 92)-A (herein referred to as BCY11337);

[0604] A-(SEQ ID NO: 93)-A (herein referred to as BCY11340);

[0605] Ac-(SEQ ID NO: 93) (herein referred to as BCY20506);

[0606] A-(SEQ ID NO: 94)-A (herein referred to as BCY11342);

[0607] A-(SEQ ID NO: 95)-A (herein referred to as BCY11628);

[0608] A-(SEQ ID NO: 96)-A (herein referred to as BCY11629);

[0609] A-(SEQ ID NO: 97)-A (herein referred to as BCY11630);

[0610] A-(SEQ ID NO: 98)-A (herein referred to as BCY11635);

[0611] A-(SEQ ID NO: 99)-A (herein referred to as BCY11636);

[0612] A-(SEQ ID NO: 100)-A (herein referred to as BCY11637);

[0613] A-(SEQ ID NO: 101)-A (herein referred to as BCY11638);

[0614] Ac-(SEQ ID NO: 101) (herein referred to as BCY12152);

[0615] Ac-(SEQ ID NO: 101)-[K(N3)] (herein referred to as BCY20470);

[0616] [AzPnt]-(SEQ ID NO: 101) (herein referred to as BCY20661);

[0617] A-(SEQ ID NO: 102)-A (herein referred to as BCY11639);

[0618] Ac-(SEQ ID NO: 102) (herein referred to as BCY12153);

[0619] A-(SEQ ID NO: 103)-A (herein referred to as BCY11640);

[0620] Ac-(SEQ ID NO: 103) (herein referred to as BCY20503);

[0621] A-(SEQ ID NO: 104)-A (herein referred to as BCY11641);

[0622] A-(SEQ ID NO: 105)-A (herein referred to as BCY11973);

[0623] A-(SEQ ID NO: 106)-A (herein referred to as BCY11974);

[0624] A-(SEQ ID NO: 106)-[K(N3)] (herein referred to as BCY20509); A-(SEQ ID NO: 106)-[PG] (herein referred to as BCY20513);

[0625] [Aib]-(SEQ ID NO: 106) (herein referred to as BCY20516);

[0626] [dA]-(SEQ ID NO: 106) (herein referred to as BCY20519);

[0627] A-(SEQ ID NO: 107)-A (herein referred to as BCY11975);

[0628] A-(SEQ ID NO: 108)-A (herein referred to as BCY11976);

[0629] A-(SEQ ID NO: 109)-A (herein referred to as BCY11977);

[0630] A-(SEQ ID NO: 110)-A (herein referred to as BCY11978);

[0631] SRT-(SEQ ID NO: 111)-A (herein referred to as BCY12100);

[0632] RTS-(SEQ ID NO: 112)-A (herein referred to as BCY12101);

[0633] A-(SEQ ID NO: 113)-AHM (herein referred to as BCY12102);

[0634] A-(SEQ ID NO: 114)-LKN (herein referred to as BCY12103);

[0635] A-(SEQ ID NO: 115)-A (herein referred to as BCY12104);

[0636] Ac-(SEQ ID NO: 115) (herein referred to as BCY20504);ATG-(SEQ ID NO: 116)-A (herein referred to as BCY12105);

[0637] SPH-(SEQ ID NO: 117)-A (herein referred to as BCY12106); Ac-(SEQ ID NO: 117) (herein referred to as BCY20486);

[0638] A-(SEQ ID NO: 118)-RMS (herein referred to as BCY12107); A-(SEQ ID NO: 119)-SEM (herein referred to as BCY12108); Ac-(SEQ ID NO: 119) (herein referred to as BCY20505);

[0639] DIG-(SEQ ID NO: 120)-A (herein referred to as BCY12109); Ac-(SEQ ID NO: 120) (herein referred to as BCY20493);

[0640] A-(SEQ ID NO: 121)-A (herein referred to as BCY12110);

[0641] A-(SEQ ID NO: 122)-LGS (herein referred to as BCY12111); EGG-(SEQ ID NO: 123)-A (herein referred to as BCY12112); SVG-(SEQ ID NO: 124)-A (herein referred to as BCY12113); A-(SEQ ID NO: 125)-EPT (herein referred to as BCY12114); A-(SEQ ID NO: 126)-AST (herein referred to as BCY12115); Ac-(SEQ ID NO: 127) (herein referred to as BCY20466);

[0642] Ac-(SEQ ID NO: 128) (herein referred to as BCY20467);

[0643] Ac-(SEQ ID NO: 129) (herein referred to as BCY20468);

[0644] Ac-(SEQ ID NO: 130) (herein referred to as BCY20469);

[0645] Ac-(SEQ ID NO: 131) (herein referred to as BCY20471);

[0646] Ac-(SEQ ID NO: 132) (herein referred to as BCY20472);

[0647] Ac-(SEQ ID NO: 133) (herein referred to as BCY20473);

[0648] Ac-(SEQ ID NO: 134) (herein referred to as BCY20474);

[0649] Ac-(SEQ ID NO: 135) (herein referred to as BCY20475);

[0650] Ac-(SEQ ID NO: 136) (herein referred to as BCY20476);

[0651] Ac-(SEQ ID NO: 137) (herein referred to as BCY20477);

[0652] Ac-(SEQ ID NO: 138) (herein referred to as BCY20478);

[0653] Ac-(SEQ ID NO: 139) (herein referred to as BCY20479);

[0654] Ac-(SEQ ID NO: 140) (herein referred to as BCY20480);

[0655] Ac-(SEQ ID NO: 141) (herein referred to as BCY20481);

[0656] Ac-(SEQ ID NO: 142) (herein referred to as BCY20482);

[0657] Ac-(SEQ ID NO: 143) (herein referred to as BCY20483);

[0658] Ac-(SEQ ID NO: 144) (herein referred to as BCY20484);

[0659] Ac-(SEQ ID NO: 145) (herein referred to as BCY20485);

[0660] Ac-(SEQ ID NO: 146) (herein referred to as BCY20488);

[0661] Ac-(SEQ ID NO: 147) (herein referred to as BCY20489);

[0662] Ac-(SEQ ID NO: 148) (herein referred to as BCY20490);

[0663] Ac-(SEQ ID NO: 149) (herein referred to as BCY20495);Ac-(SEQ ID NO: 150) (herein referred to as BCY20496);

[0664] Ac-(SEQ ID NO: 151) (herein referred to as BCY20498);

[0665] Ac-(SEQ ID NO: 152) (herein referred to as BCY20499);

[0666] Ac-(SEQ ID NO: 153) (herein referred to as BCY20500);

[0667] Ac-(SEQ ID NO: 154) (herein referred to as BCY20501);

[0668] Ac-(SEQ ID NO: 155)-K (herein referred to as BCY20507);

[0669] A-(SEQ ID NO: 155)-A (herein referred to as BCY20508);

[0670] A-(SEQ ID NO: 156)-A (herein referred to as BCY20510);

[0671] A-(SEQ ID NO: 157)-A (herein referred to as BCY20511);

[0672] A-(SEQ ID NO: 158)-A (herein referred to as BCY20512);

[0673] A-(SEQ ID NO: 159)-A (herein referred to as BCY20514);

[0674] A-(SEQ ID NO: 160)-A (herein referred to as BCY20515);

[0675] A-(SEQ ID NO: 161)-A (herein referred to as BCY20517);

[0676] A-(SEQ ID NO: 162)-A (herein referred to as BCY20518);

[0677] A-(SEQ ID NO: 163)-A (herein referred to as BCY20520);

[0678] Ac-(SEQ ID NO: 164) (herein referred to as BCY20523);

[0679] Ac-(SEQ ID NO: 165) (herein referred to as BCY20524);

[0680] Ac-(SEQ ID NO: 166) (herein referred to as BCY20525);

[0681] Ac-(SEQ ID NO: 167) (herein referred to as BCY20578);

[0682] Ac-(SEQ ID NO: 168) (herein referred to as BCY20579);

[0683] Ac-(SEQ ID NO: 169) (herein referred to as BCY20655);

[0684] Ac-(SEQ ID NO: 170) (herein referred to as BCY20656);

[0685] Ac-(SEQ ID NO: 171) (herein referred to as BCY20657);

[0686] Ac-(SEQ ID NO: 172) (herein referred to as BCY20658);

[0687] Ac-(SEQ ID NO: 173) (herein referred to as BCY20659);

[0688] A-(SEQ ID NO: 303)-A (herein referred to as BCY_A1);

[0689] Ac-(SEQ ID NO: 304) (herein referred to as BCY_A2); and

[0690] Ac-(SEQ ID NO: 305) (herein referred to as BCY_A3).

[0691] In an alternative embodiment, said polypeptide comprises three reactive groups as defined herein (e.g. three cysteine residues) separated by two loop sequences the first of which consists of 5 amino acids and the second of which consists of 4 amino acids.

[0692] In some embodiments the polypeptide comprises an amino acid sequence

[0693] Z-X1h-X2h-X3h-X4h-X5h-Z-X6h-X7h-X8h-X9h-Z

[0694] wherein each of X1h to X9h are any amino acid and Z is a reactive group as defined herein; e.g. wherein Z is cysteine.In some embodiments X1h, X2h, X3h, X4h, and X5h are each independently selected from Y, P, E, W, and Y. In some embodiments X1h is Y. In some embodiments X2h is P. In some embodiments X3h is E. In some embodiments X4h is W. In some embodiments X5h is Y. In some embodiments the moiety -X1h-X2h-X3h-X4h-X5h- is -YPEWY-.

[0695] In some embodiments X6h, X7h, X8h and X9h are each independently selected from R, L and P. In some embodiments X6h is R. In some embodiments X7h is L. In some embodiments X8h is L. In some embodiments X9h is P. In some embodiments the moiety -X6h-X7h-X8h-X9h- is -RLLP-.

[0696] In some embodiments the peptide ligand comprises an amino acid sequence:

[0697] Z-YPEWY-Z-RLLP-Z

[0698] or a variant thereof as defined herein, wherein each Z is independently a reactive group as defined herein; or a pharmaceutically acceptable salt thereof.

[0699] In a further embodiment, said loop sequences comprise three cysteine residues separated by two loop sequences the first of which consists of 5 amino acids and the second of which consists of 4 amino acids and comprise an amino acid sequence which is:

[0700] CYPEWYCRLLPC (SEQ ID NO: 174);

[0701] wherein the three cysteine residues within the peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof.

[0702] In a further embodiment, the molecular scaffold is a derivative of TATA which has the following structure:

[0703] O O

[0704]

[0705] wherein * denotes the point of attachment of the three reactive groups (e.g. cysteine residues).In some embodiments the peptide ligand comprises N- and / or C-terminal additions as described herein. In some embodiments the peptide ligand is:

[0706] A-(SEQ ID NO: 174)-A (herein referred to as BCY8980).

[0707] In an alternative embodiment, said polypeptide comprises three cysteine residues separated by two loop sequences the first of which consists of 5 amino acids and the second of which consists of 7 amino acids.

[0708] In some embodiments the polypeptide comprises an amino acid sequence

[0709] Z-X1i-X2i-X3i-X4i-X5i-Z-X6i-X7i-X8i-X9i-X10i-X11i-X12i-Z

[0710] wherein each of X1i to X12i are any amino acid and Z is a reactive group as defined herein; e.g. wherein Z is cysteine.

[0711] In some embodiments X1i is selected from L, P, S, Y, K, A, E, G, M, N, R, and T. In some embodiments X1i is L, P, S, Y or K. In some embodiments X2i is selected from D, P, N, E, G, and S. In some embodiments X2i is D, P or N. In some embodiments X3i is selected from P, L, D, K, N, S, T, and W. In some embodiments X3i is P or L. In some embodiments X4i is selected from A, F, G, L, M, P, Q, R, and W. In some embodiments X4i is A, G, P, R, M or Q. In some embodiments X5i is selected from W, L, N, S and Y. In some embodiments X5i is W.

[0712] In some embodiments of the moiety -X1i-X2i-X3i-X4i-X5i-: X1i to X5i are each any amino acid. In some embodiments X1i is L, P, S, or Y; X2i is D or P; X3i is L; X4i is A, G, P, or R; and X5i is W. In some embodiments X1i is K; X2i is N; X3i is P; X4i is M; and X5i is W. In some embodiments X1i, X2i and X5i are any amino acid; X3i is L; X4i is Q; and X5i is W.

[0713] In some embodiments X6i is selected from A, D, F, H, K, M, N, Q, R and W. In some embodiments X6i is A. In some embodiments X7i is selected from E, L, M and Q. In some embodiments X8i is selected from F, L, M and Y. In some embodiments X9i is selected from A, D, G, K, M, Q, T, W and [Nle]. In some embodiments X9i is M, G, [Nle], A, G, T, or W. In some embodiments X10i is selected from L, A, D, V, E, H, I, K, Q, R, T, and Y. In some embodiments X10i is L, A, D or V. In some embodiments X11i is selected from D, Q, G, K, M, P, T, W and [Nle]. In some embodiments X11i is D, Q, or G. In some embodiments X12i is selected from H, N, W, D, G, M, R, S, and T. In some embodiments X12i is H, N or W.

[0714] In some embodiments of the moiety -X6i-X7i-X8i-X9i-X10i-X11i-X12i-: X6i, X9i, X10i, X11i and X12i are each any amino acid; X7i is E, L, M, or Q; and X8i is F, L, M, or Y. In some embodiments X6i and X11i are each any amino acid; X7i is E; X8i is L; X9i is M, G, or Nle; X10i is A, D, L, or V; andX12i is H or N. In some embodiments X10i and X12i are each any amino acid; X6i is A; X7i is M; X8i is F; X9i is A, G, or T; and X11i is D or Q. In some embodiments X6i is A; X7i is E or Q; X8i is Y; X9i is W; X10i is L; X11i is G and X12i is W.

[0715] In some embodiments, therefore, the polypeptide comprises an amino acid sequence

[0716] Z-X1i-X2i-X3i-X4i-X5i-Z-X6i-X7i-X8i-X9i-X10i-X11i-X12i-Z

[0717] wherein Z is a reactive group; Xu, X2j, Xai, X4i, Xsi, Xei, Xgi, X i, Xm and Xi2i are any amino acid; X?i is E, L, M, or Q; and Xsi is F, L, M, or Y.

[0718] In some embodiments the polypeptide comprises an amino acid sequence

[0719] Z-X1i-X2i-L-X4i-W-Z-X6i-EL-X9i-X10i-X11i-X12i-Z

[0720] wherein Z is a reactive group; Xu is L, P, S, or Y; X2j is D or P; X4i is A, G, P, or R; Xei is any amino acid; X9i is M, G, or Nle; X i is A, D, L, or V; X is any amino acid; and Xi2iis H or N.

[0721] In some embodiments the polypeptide comprises an amino acid sequence

[0722] Z-KN PM W-Z-AM F-Xgj-Xioi-Xm-X^i-Z

[0723] wherein Z is a reactive group; Xgi is A, G, or T; X i is any amino acid; Xm is D or Q: and X-i2iis any amino acid.

[0724] In some embodiments the polypeptide comprises an amino acid sequence

[0725] Z-Xi i-X2i- LQ-Xsi-Z-A-Xyj-YWLG W-Z

[0726] wherein Z is a reactive group; Xu, X2j and Xsi are each any amino acid; and X7i is E or Q.

[0727] In some embodiments the polypeptide comprises an amino acid sequence:

[0728] Z-KNPMW-Z-AMFAKDD-Z

[0729] Z-YDLPW-Z-KELMLQH-Z

[0730] Z-YPDWY-Z-QLM KLPT-Z

[0731] Z-MPKWY-Z-DLMGTPM-Z

[0732] Z-YDLAW-Z-NELMATH-Z

[0733] Z-YDLPW-Z-NELMAQH-Z

[0734] Z-YDLRW-Z-HELMDQH-Z

[0735] Z-YDLAW-Z-RELGVWN-Z

[0736] Z-PPLAW-Z-RELMLQH-Z

[0737] Z-YDLAW-Z-KELMLMN-Z

[0738] Z-SPLGW-Z-AELMLQH-Z

[0739] Z-KNPMW-Z-AMFGEDS-Z

[0740] Z-KNPMW-Z-AMFGDQS-ZZ-KNPMW-Z-AMFTTQG-ZZ-KNPMW-Z-AMFGYDR-Z

[0741] Z-EGTLW-Z-WMFAKDD-Z

[0742] Z-GSSFW-Z-AMFAKDD-Z

[0743] Z-TDPFW-Z-FMFAKDD-Z

[0744] Z-SPLWY-Z-ALMKRKT-Z

[0745] Z-APWWY-Z-NLMAQPT-Z

[0746] Z-MPDWY-Z-RLMDIDT-Z

[0747] Z-APNWY-Z-MLMQHTT-Z

[0748] Z-PDLAW-Z-KELMLKN-Z

[0749] Z-TELAW-Z-KELMLTN-Z

[0750] Z-LDLAW-Z-KELMLMN-Z

[0751] Z-TN LQL-Z-AQYWLGW-Z

[0752] Z-PDLQN-Z-AQYWLGW-Z

[0753] Z-NDLQY-Z-AEYWLGW-Z

[0754] Z-RELQS-Z-AQYWLGW-Z

[0755] Z-YDLAW-Z-RELMLMN-Z

[0756] Z-YDLPW-Z-KELMLMN-Z

[0757] Z-YDLAW-Z-KELMLMH-Z

[0758] Z-YDLAW-Z-KELMLQN-Z

[0759] Z-YDLAW-Z-KEL[Nle]LMN-Z

[0760] Z-YDLAW-Z-KELML[Nle]N-Z

[0761] Z-YDLAW-Z-KEL[Nle]L[Nle]N-Z

[0762] Z-PPLAW-Z-RELMLMN-Z

[0763] Z-PPLAW-Z-KELMLMN-Z

[0764] or a variant thereof as defined herein, wherein each Z is independently a reactive group as defined herein; or a pharmaceutically acceptable salt thereof.

[0765] In a further embodiment, said loop sequences comprise three cysteine residues separated by two loop sequences the first of which consists of 5 amino acids and the second of which consists of 7 amino acids and comprise an amino acid sequence which is selected from:

[0766] CKNPMWCAMFAKDDC (SEQ ID NO: 175);

[0767] CYDLPWCKELMLQHC (SEQ ID NO: 176);

[0768] CYPDWYCQLMKLPTC (SEQ ID NO: 177);

[0769] CMPKWYCDLMGTPMC (SEQ ID NO: 178);

[0770] CYDLAWCNELMATHC (SEQ ID NO: 179);

[0771] CYDLPWCNELMAQHC (SEQ ID NO: 180);CYDLRWCHELMDQHC (SEQ ID NO: 181);

[0772] CYDLAWCRELGVWNC (SEQ ID NO: 182);

[0773] CPPLAWCRELMLQHC (SEQ ID NO: 183);

[0774] CYDLAWCKELMLMNC (SEQ ID NO: 184);

[0775] CSPLGWCAELMLQHC (SEQ ID NO: 185);

[0776] CKNPMWCAMFGEDSC (SEQ ID NO: 186);

[0777] CKNPMWCAMFGDQSC (SEQ ID NO: 187);

[0778] CKNPMWCAMFTTQGC (SEQ ID NO: 188);

[0779] CKNPMWCAMFGYDRC (SEQ ID NO: 189);

[0780] CEGTLWCWMFAKDDC (SEQ ID NO: 190);

[0781] CGSSFWCAMFAKDDC (SEQ ID NO: 191);

[0782] CTDPFWCFMFAKDDC (SEQ ID NO: 192);

[0783] CSPLWYCALMKRKTC (SEQ ID NO: 193);

[0784] CAPWWYCNLMAQPTC (SEQ ID NO: 194);

[0785] CMPDWYCRLMDIDTC (SEQ ID NO: 195);

[0786] CAPNWYCMLMQHTTC (SEQ ID NO: 196);

[0787] CPDLAWCKELMLKNC (SEQ ID NO: 197);

[0788] CTELAWCKELMLTNC (SEQ ID NO: 198);

[0789] CLDLAWCKELMLMNC (SEQ ID NO: 199);

[0790] CTNLQLCAQYWLGWC (SEQ ID NO: 200);

[0791] CPDLQNCAQYWLGWC (SEQ ID NO: 201);

[0792] CNDLQYCAEYWLGWC (SEQ ID NO: 202);

[0793] CRELQSCAQYWLGWC (SEQ ID NO: 203);

[0794] CYDLAWCRELMLMNC (SEQ ID NO: 204);

[0795] CYDLPWCKELMLMNC (SEQ ID NO: 205);

[0796] CYDLAWCKELMLMHC (SEQ ID NO: 206);

[0797] CYDLAWCKELMLQNC (SEQ ID NO: 207);

[0798] CYDLAWCKEL[Nle]LMNC (SEQ ID NO: 208);

[0799] CYDLAWCKELML[Nle]NC (SEQ ID NO: 209);

[0800] CYDLAWCKEL[Nle]L[Nle]NC (SEQ ID NO: 210);

[0801] CPPLAWCRELMLMNC (SEQ ID NO: 211); and

[0802] CPPLAWCKELMLMNC (SEQ ID NO: 212);

[0803] wherein the cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof.

[0804] In a further embodiment, the molecular scaffold is a derivative of TATA which has the following structure:

[0805]

[0806] wherein * denotes the point of attachment of the three reactive groups (e.g. cysteine residues).

[0807] In some embodiments the peptide ligand comprises N- and / or C-terminal additions as described herein. In some embodiments the peptide ligand is selected from:

[0808] A-(SEQ ID NO: 175)-A (herein referred to as BCY8982);

[0809] A-(SEQ ID NO: 176)-A (herein referred to as BCY9209);

[0810] A-(SEQ ID NO: 177)-A (herein referred to as BCY9210);

[0811] A-(SEQ ID NO: 178)-A (herein referred to as BCY10096);

[0812] A-(SEQ ID NO: 179)-A (herein referred to as BCY10269);

[0813] A-(SEQ ID NO: 180)-A (herein referred to as BCY10270);

[0814] A-(SEQ ID NO: 181)-A (herein referred to as BCY10272);

[0815] A-(SEQ ID NO: 182)-A (herein referred to as BCY10273);

[0816] A-(SEQ ID NO: 183)-A (herein referred to as BCY10274);

[0817] A-(SEQ ID NO: 184)-A (herein referred to as BCY10275);

[0818] Ac-(SEQ ID NO: 184) (herein referred to as BCY20433);

[0819] Ac-[NH-Peg6-CO]-(SEQ ID NO: 184) (herein referred to as BCY20562);

[0820] A-(SEQ ID NO: 185)-A (herein referred to as BCY10276);

[0821] A-(SEQ ID NO: 186)-A (herein referred to as BCY10317);

[0822] A-(SEQ ID NO: 187)-A (herein referred to as BCY10318);

[0823] A-(SEQ ID NO: 188)-A (herein referred to as BCY10319);

[0824] A-(SEQ ID NO: 189)-A (herein referred to as BCY10320);

[0825] A-(SEQ ID NO: 190)-A (herein referred to as BCY10322);

[0826] A-(SEQ ID NO: 191)-A (herein referred to as BCY10323);

[0827] A-(SEQ ID NO: 192)-A (herein referred to as BCY10325);

[0828] A-(SEQ ID NO: 193)-A (herein referred to as BCY10583);

[0829] A-(SEQ ID NO: 194)-A (herein referred to as BCY10584);

[0830] A-(SEQ ID NO: 195)-A (herein referred to as BCY10585);

[0831] A-(SEQ ID NO: 196)-A (herein referred to as BCY10586);SYP-(SEQ ID NO: 197)-A (herein referred to as BCY11119);

[0832] SSW-(SEQ ID NO: 198)-A (herein referred to as BCY11120);

[0833] A-(SEQ ID NO: 199)-TQK (herein referred to as BCY11124);

[0834] A-(SEQ ID NO: 200)-A (herein referred to as BCY11328);

[0835] A-(SEQ ID NO: 201)-A (herein referred to as BCY11619);

[0836] A-(SEQ ID NO: 202)-A (herein referred to as BCY11620);

[0837] A-(SEQ ID NO: 203)-A (herein referred to as BCY11621);

[0838] Ac-(SEQ ID NO: 204) (herein referred to as BCY20430);

[0839] Ac-(SEQ ID NO: 205) (herein referred to as BCY20431);

[0840] Ac-(SEQ ID NO: 206) (herein referred to as BCY20432);

[0841] Ac-(SEQ ID NO: 207) (herein referred to as BCY20434);

[0842] Ac-(SEQ ID NO: 208) (herein referred to as BCY20435);

[0843] Ac-(SEQ ID NO: 209) (herein referred to as BCY20436);

[0844] Ac-(SEQ ID NO: 210) (herein referred to as BCY20437);

[0845] Ac-(SEQ ID NO: 211) (herein referred to as BCY20438); and

[0846] Ac-(SEQ ID NO: 212) (herein referred to as BCY20439).

[0847] In an alternative embodiment, said polypeptide comprises three reactive groups as defined herein (e.g. three cysteine residues) separated by two loop sequences the first of which consists of 6 amino acids and the second of which consists of 3 amino acids.

[0848] In some embodiments the polypeptide comprises an amino acid sequence

[0849] Z-X1j-X2j-X3j-X4j-X5j-X6j-Z-X7j-X8j-X9j-Z

[0850] wherein each of X1j to X9j are any amino acid and Z is a reactive group as defined herein; e.g. wherein Z is cysteine.

[0851] In some embodiments X1j is selected from A, D, E, G, H, M, N, Q, S, and T. In some embodiments X2j is selected from A, H, N, [1Nal], [2Nal] and [4FPhe]. In some embodiments X2j is A, H or N. In some embodiments X3j is selected from A, E and P. In some embodiments X4j is selected from A and L. In some embodiments X5j is selected from W, A, E, G, K, R, S, [1Nal], [2Nal] and [4FPhe]. In some embodiments X5j is W. In some embodiments X6j is selected from A, W, [1Nal], [2Nal] and [4FPhe].

[0852] In some embodiments of the moiety -X1j-X2j-X3j-X4j-X5j-X6j-: X1j, X2j, X5j and X6j are any amino acid; X3j is A, E or P; and X4j is A or L. In some embodiments X1j and X5j are any amino acid; X2j is A, H or N; X3j is A, E or P; and X4j is A or L; and X6j is W.In some embodiments X?j is selected from A, E, R, [Cit], [dR], and [HArg], In some embodiments X?j is A, E or R. In some embodiments Xsj is selected from A, D, E, S and T. In some embodiments X9jis selected from A, I, L and V. In some embodiments of the moiety -Xyj-Xsj-Xgj-: X?j and Xsj are any amino acid; and X9jis A, I, L or V. In some embodiments X?j is A, E or R; Xsj is any amino acid; and X9jis A, I, L or V

[0853] In some embodiments, therefore, the polypeptide comprises an amino acid sequence

[0854] Z-X1j-X2j-X3j-X4j-X5j-X6j-Z-X7j-X8j-X9j-Z

[0855] wherein Z is a reactive group; Xij, X2j, Xsj, Xej, Xyj and Xsj are any amino acid; X3j is A, E or P; X4j is A or L; and Xgj is A, I, L or V.

[0856] In some embodiments the polypeptide comprises an amino acid sequence

[0857] Z-X1j-X2j-X3j-X4j-X5j-W-Z-X7j-X8j-X9j-Z

[0858] wherein Z is a reactive group; Xij, Xsj, and Xsj are any amino acid; X2j is A, H or N; Xgj is A, E or P; and X4j is A or L; X^ is W; X?j is A, E or R; and X9jis A, I, L or V.

[0859] In some embodiments the polypeptide comprises an amino acid sequence:

[0860] -Z-SHPLEW-Z-RTL-Z

[0861] -Z-MNPLGW-Z-RTL-Z

[0862] -Z-DHPLEW-Z-RSL-Z

[0863] -Z-NHPLAW-Z-REV-Z

[0864] -Z-SHELKW-Z-RDL-Z

[0865] -Z-SHPLGW-Z-REL-Z

[0866] -Z-DHPLWW-Z-REI-Z

[0867] -Z-HHPLWW-Z-REI-Z

[0868] -Z-THPLWW-Z-REV-Z

[0869] -Z-GHPLRW-Z-REL-Z

[0870] -Z-NHPLRW-Z-REV-Z

[0871] -Z-HHPLRW-Z-REL-Z

[0872] -Z-DHPLGW-Z-REL-Z

[0873] -Z-QHPLSW-Z-REL-Z

[0874] -Z-SHPLRW-Z-REI-Z

[0875] -Z-EHPLAW-Z-REL-Z

[0876] -Z-D[1 Nal]PLWW-Z-REI-Z

[0877] -Z-D[2Nal]PLWW-Z-REI-Z

[0878] -Z-D[4FPhe]PLWW-Z-REI-Z

[0879] -Z-DHPLWW-Z-[HArg]EI-Z-Z-DHPLW[1Nal]-Z-REI-Z

[0880] -Z-DHPL[1Nal]W-Z-REI-Z

[0881] -Z-DHPL[2Nal]W-Z-REI-Z

[0882] -Z-DHPLW[2Nal]-Z-REI-Z

[0883] -Z-DHPLWW-Z-[Cit]EI-Z

[0884] -Z-DHPLWW-Z-[dR]EI-Z

[0885] -Z-DHPLW[4FPhe]-Z-REI-Z

[0886] -Z-DHPL[4FPhe]W-Z-REI-Z

[0887] -Z-DHALWW-Z-REI-Z

[0888] -Z-DHPLWW-Z-REA-Z

[0889] -Z-DHPAWW-Z-REI-Z

[0890] -Z-DHPLWW-Z-RAI-Z

[0891] -Z-DAPLWW-Z-REI-Z

[0892] -Z-DHPLWW-Z-AEI-Z

[0893] -Z-DHPLAW-Z-REI-Z; and

[0894] -Z-AHPLWW-Z-REI-Z

[0895] or a variant thereof as defined herein, wherein each Z is independently a reactive group as defined herein; or a pharmaceutically acceptable salt thereof.

[0896] In a further embodiment, said loop sequences comprise three cysteine residues separated by two loop sequences the first of which consists of 6 amino acids and the second of which consists of 3 amino acids and comprise an amino acid sequence which is selected from:

[0897] CSHPLEWCRTLC (SEQ ID NO: 213);

[0898] CMNPLGWCRTLC (SEQ ID NO: 214);

[0899] CDHPLEWCRSLC (SEQ ID NO: 215);

[0900] CNHPLAWCREVC (SEQ ID NO: 216);

[0901] CSHELKWCRDLC (SEQ ID NO: 217);

[0902] CSHPLGWCRELC (SEQ ID NO: 218);

[0903] CDHPLWWCREIC (SEQ ID NO: 219);

[0904] CHHPLWWCREIC (SEQ ID NO: 220);

[0905] CTHPLWWCREVC (SEQ ID NO: 221);

[0906] CGHPLRWCRELC (SEQ ID NO: 222);

[0907] CNHPLRWCREVC (SEQ ID NO: 223);

[0908] CHHPLRWCRELC (SEQ ID NO: 224);

[0909] CDHPLGWCRELC (SEQ ID NO: 225);

[0910] CQHPLSWCRELC (SEQ ID NO: 226);

[0911] CSHPLRWCREIC (SEQ ID NO: 227);CEHPLAWCRELC (SEQ ID NO: 228);

[0912] CD[1Nal]PLWWCREIC (SEQ ID NO: 229);

[0913] CD[2Nal]PLWWCREIC (SEQ ID NO: 230);

[0914] CD[4FPhe]PLWWCREIC (SEQ ID NO: 231);

[0915] CDHPLWWC[HArg]EIC (SEQ ID NO: 232);

[0916] CDHPLW[1Nal]CREIC (SEQ ID NO: 233);

[0917] CDHPL[1Nal]WCREIC (SEQ ID NO: 234);

[0918] CDHPL[2Nal]WCREIC (SEQ ID NO: 235);

[0919] CDHPLW[2Nal]CREIC (SEQ ID NO: 236);

[0920] CDHPLWWC[Cit]EIC (SEQ ID NO: 237);

[0921] CDHPLWWC[dR]EIC (SEQ ID NO: 238);

[0922] CDHPLW[4FPhe]CREIC (SEQ ID NO: 239);

[0923] CDHPL[4FPhe]WCREIC (SEQ ID NO: 240);

[0924] CDHALWWCREIC (SEQ ID NO: 241);

[0925] CDHPLWWCREAC (SEQ ID NO: 242);

[0926] CDHPAWWCREIC (SEQ ID NO: 243);

[0927] CDHPLWWCRAIC (SEQ ID NO: 244);

[0928] CDAPLWWCREIC (SEQ ID NO: 245);

[0929] CDHPLWWCAEIC (SEQ ID NO: 246);

[0930] CDHPLAWCREIC (SEQ ID NO: 247); and

[0931] CAHPLWWCREIC (SEQ ID NO: 248);

[0932] wherein the cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof.

[0933] In a further embodiment, the molecular scaffold is a derivative of TATA which has the following structure:

[0934] N N

[0935] N

[0936]

[0937] wherein * denotes the point of attachment of the three reactive groups (e.g. cysteine residues).In some embodiments the peptide ligand comprises N- and / or C-terminal additions as described herein. In some embodiments the peptide ligand is selected from:

[0938] A-(SEQ ID NO: 213)-A (herein referred to as BCY8973);

[0939] A-(SEQ ID NO: 214)-A (herein referred to as BCY8976);

[0940] A-(SEQ ID NO: 215)-A (herein referred to as BCY8979);

[0941] A-(SEQ ID NO: 216)-A (herein referred to as BCY9211);

[0942] A-(SEQ ID NO: 217)-A (herein referred to as BCY9212);

[0943] A-(SEQ ID NO: 218)-A (herein referred to as BCY9213);

[0944] [MeO-dPEG12]-A-(SEQ ID NO: 219)-A (herein referred to as BCY10303); Ac-(SEQ ID NO: 219) (herein referred to as BCY10387);

[0945] Ac-(SEQ ID NO: 219)-[K(Ac)] (herein referred to as BCY20440);

[0946] Ac-(SEQ ID NO: 219)-K (herein referred to as BCY20441);

[0947] [-FI][NH-Peg6-CO]A-(SEQ ID NO: 219)-A (herein referred to as BCY20577); A-(SEQ ID NO: 219)-A (herein referred to as BCY9795);

[0948] A-(SEQ ID NO: 220)-A (herein referred to as BCY9796);

[0949] A-(SEQ ID NO: 221)-A (herein referred to as BCY9797);

[0950] A-(SEQ ID NO: 222)-A (herein referred to as BCY9798);

[0951] A-(SEQ ID NO: 223)-A (herein referred to as BCY10116);

[0952] A-(SEQ ID NO: 224)-A (herein referred to as BCY10118);

[0953] A-(SEQ ID NO: 225)-DSY (herein referred to as BCY10776);

[0954] A-(SEQ ID NO: 226)-STN (herein referred to as BCY10777);

[0955] SQP-(SEQ ID NO: 227)-A (herein referred to as BCY10778);

[0956] RAQ-(SEQ ID NO: 228)-A (herein referred to as BCY10779);

[0957] A-(SEQ ID NO: 229)-A (herein referred to as BCY20442);

[0958] A-(SEQ ID NO: 230)-A (herein referred to as BCY20443);

[0959] A-(SEQ ID NO: 231)-A (herein referred to as BCY20444);

[0960] A-(SEQ ID NO: 232)-A (herein referred to as BCY20445);

[0961] A-(SEQ ID NO: 233)-A (herein referred to as BCY20446);

[0962] A-(SEQ ID NO: 234)-A (herein referred to as BCY20447);

[0963] A-(SEQ ID NO: 235)-A (herein referred to as BCY20448);

[0964] A-(SEQ ID NO: 236)-A (herein referred to as BCY20449);

[0965] A-(SEQ ID NO: 237)-A (herein referred to as BCY20450);

[0966] A-(SEQ ID NO: 238)-A (herein referred to as BCY20451);

[0967] A-(SEQ ID NO: 239)-A (herein referred to as BCY20452);

[0968] A-(SEQ ID NO: 240)-A (herein referred to as BCY20453);

[0969] A-(SEQ ID NO: 241)-A (herein referred to as BCY20454);

[0970] A-(SEQ ID NO: 242)-A (herein referred to as BCY20456);A-(SEQ ID NO: 243)-A (herein referred to as BCY20457);

[0971] A-(SEQ ID NO: 244)-A (herein referred to as BCY20458);

[0972] A-(SEQ ID NO: 245)-A (herein referred to as BCY20459);

[0973] A-(SEQ ID NO: 246)-A (herein referred to as BCY20460);

[0974] A-(SEQ ID NO: 247)-A (herein referred to as BCY20461); and A-(SEQ ID NO: 248)-A (herein referred to as BCY20463).

[0975] In an alternative embodiment, said polypeptide comprises three reactive groups as defined herein (e.g. there cysteine residues) separated by two loop sequences the first of which consists of 6 amino acids and the second of which consists of 4 amino acids.

[0976] In some embodiments the polypeptide comprises an amino acid sequence

[0977] Z-Xl k-X2k-X3k-X4k-X5k-X6k-Z-X7k-X8k-Xgk-Xl Ok’Z

[0978] wherein each of X1k to X10k are any amino acid and Z is a reactive group as defined herein; e.g. wherein Z is cysteine.

[0979] In some embodiments X1k is selected from A, E, N and Y. In some embodiments X1k is Y. In some embodiments X2k is selected from A, D, N, E, K and W. In some embodiments X2k is A, D or N; such as D. In some embodiments X3k is selected from A, L, D, N and P. In some embodiments X3k is A or L; such as L. In some embodiments X4k is selected from A, D, E, G, H, K, P, Q, S, and [dA]. In some embodiments X5k is selected from W, A and R. In some embodiments X5k is W or A; such as W. In some embodiments X6k is selected from Y, A, and L. In some embodiments X6k is Y or A; such as Y.

[0980] In some embodiments of the moiety -X1k-X2k-X3k-X4k-X5k-X6k-: X1k is A, E, N or Y; X2k, X3k and X4k are any amino acid; X5k is W, A or R; and X6k is Y, A, or L. In some embodiments, X1k is Y; X2k is A, D or N; X3k is A or L; X4k is any amino acid; X5k is W or A; and X6k is Y or A. In some embodiments X1k is Y; X2k is D; X3k is L; X4k is any amino acid; X5k is W; and X6k is Y.

[0981] In some embodiments X7k is selected from A, D, E, K, Q, R, S, T, [Agb], [Cit], [dR] and [HArg]. In some embodiments X8k is selected from L, A and Y. In some embodiments X8k is L. In some embodiments X9k is selected from F, A and I. In some embodiments X9k is F. In some embodiments X10k is selected from P, G and T. In some embodiments X10k is P.

[0982] In some embodiments of the moiety -X7k-X8k-X9k-X10k-: X7k is any amino acid; X8k is L, A or Y; X9k is F, A or I; and X10k is P, G or T. In some embodiments X7k is any amino acid; X8k is L orA; X9k is F or A; and X10k is P. In some embodiments X7k is any amino acid; X8k is L; X9k is F; and X10k is P.

[0983] In some embodiments, therefore, the polypeptide comprises an amino acid sequence

[0984] Z-Xl k-X2k-X3k-X4k-Xsk-X6k-Z-X7k-X8k-Xgk-Xl Ok’Z

[0985] wherein Z is a reactive group; X2k, X3k, X4k, and X7k are each any amino acid; X1k is A, E, Y, or N; X5k is A, R, or W; X6k is A, Y, or L; X8k is A, Y, or L; X9k is A, F, or I; and X10k is G, P, or T.

[0986] In some embodiments, therefore, the polypeptide comprises an amino acid sequence

[0987] Z-Y-X2k-X3k-X4k-X5k-X6k-Z-X7k-X8k-X9k-P-Z

[0988] wherein Z is a reactive group; X4k and X7k are each any amino acid; X2k is A, D, or N; X3k is A or L; Xsk is A or W; Xek is A or Y; Xsk is A or L; and Xgk is A or F.

[0989] In some embodiments, therefore, the polypeptide comprises an amino acid sequence

[0990] Z-YDL-X4k-WY-Z-X7k-LFP-Z

[0991] wherein Z is a reactive group; X4k and X7k are each any amino acid.

[0992] In some embodiments the polypeptide comprises an amino acid sequence

[0993] -Z-EENEWY-Z-RLFG-Z

[0994] -Z-NKPAWY-Z-SLFP-Z

[0995] -Z-NWDPRL-Z-KYIT-Z

[0996] -Z-YDLAWY-Z-RLFP-Z

[0997] -Z-YDLKWY-Z-DLFP-Z

[0998] -Z-YDLDWY-Z-TLFP-Z

[0999] -Z-YDLEWY-Z-KLFP-Z

[1000] -Z-YNLEWY-Z-QLFP-Z

[1001] -Z-YDLEWY-Z-ALFP-Z

[1002] -Z-YDLGWY-Z-QLFP-Z

[1003] -Z-YDLQWY-Z-SLFP-Z

[1004] -Z-YDLDWY-Z-RLFP-Z

[1005] -Z-YDLDWY-Z-KLFP-Z

[1006] -Z-YDLSWY-Z-QLFP-Z

[1007] -Z-YDLHWY-Z-TLFP-Z

[1008] -Z-YDLAWY-Z-[HArg]LFP-Z

[1009] -Z-YDLAWY-Z-[Cit]LFP-Z

[1010] -Z-YDLAWY-Z-[dR]LFP-Z

[1011] -Z-YDL[dA]WY-Z-RLFP-Z-Z-YDLAWY-Z-[Agb]LFP-Z

[1012] -Z-YDLAWY-Z-ELFP-Z

[1013] -Z-YDLAWY-Z-RAFP-Z

[1014] -Z-YDAAWY-Z-RLFP-Z

[1015] -Z-YALAWY-Z-RLFP-Z

[1016] -Z-YDLAWY-Z-RLAP-Z

[1017] -Z-YDLAWY-Z-ALFP-Z

[1018] -Z-ADLAWY-Z-RLFP-Z

[1019] -Z-YDLAWA-Z-RLFP-Z

[1020] -Z-YDLAWY-Z-RLFP-Z

[1021] or a variant thereof as defined herein, wherein each Z is independently a reactive group as defined herein; or a pharmaceutically acceptable salt thereof.

[1022] In a further embodiment, said loop sequences comprise three cysteine residues separated by two loop sequences the first of which consists of 6 amino acids and the second of which consists of 4 amino acids and comprise an amino acid sequence which is selected from:

[1023] CEENEWYCRLFGC (SEQ ID NO: 249);

[1024] CNKPAWYCSLFPC (SEQ ID NO: 250);

[1025] CNWDPRLCKYITC (SEQ ID NO: 251);

[1026] CYDLAWYCRLFPC (SEQ ID NO: 252);

[1027] CYDLKWYCDLFPC (SEQ ID NO: 253);

[1028] CYDLDWYCTLFPC (SEQ ID NO: 254);

[1029] CYDLEWYCKLFPC (SEQ ID NO: 255);

[1030] CYNLEWYCQLFPC (SEQ ID NO: 256);

[1031] CYDLEWYCALFPC (SEQ ID NO: 257);

[1032] CYDLGWYCQLFPC (SEQ ID NO: 258);

[1033] CYDLQWYCSLFPC (SEQ ID NO: 259);

[1034] CYDLDWYCRLFPC (SEQ ID NO: 260);

[1035] CYDLDWYCKLFPC (SEQ ID NO: 261);

[1036] CYDLSWYCQLFPC (SEQ ID NO: 262);

[1037] CYDLHWYCTLFPC (SEQ ID NO: 263);

[1038] CYDLAWYC[HArg]LFPC (SEQ ID NO: 264);

[1039] CYDLAWYC[Cit]LFPC (SEQ ID NO: 265);

[1040] CYDLAWYC[dR]LFPC (SEQ ID NO: 266);

[1041] CYDL[dA]WYCRLFPC (SEQ ID NO: 267);

[1042] CYDLAWYC[Agb]LFPC (SEQ ID NO: 268);

[1043] CYDLAWYCELFPC (SEQ ID NO: 269);CYDLAWYCRAFPC (SEQ ID NO: 270);

[1044] CYDAAWYCRLFPC (SEQ ID NO: 271);

[1045] CYALAWYCRLFPC (SEQ ID NO: 272);

[1046] CYDLAWYCRLAPC (SEQ ID NO: 273);

[1047] CYDLAWYCALFPC (SEQ ID NO: 274);

[1048] CADLAWYCRLFPC (SEQ ID NO: 275);

[1049] CYDLAWACRLFPC (SEQ ID NO: 276); and

[1050] CYDLAWY[dC]RLFPC (SEQ ID NO: 277);

[1051] wherein the cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof.

[1052] In a further embodiment, the molecular scaffold is a derivative of TATA which has the following structure:

[1053] N N

[1054]

[1055] wherein * denotes the point of attachment of the three reactive groups (e.g. cysteine residues).

[1056] In some embodiments the peptide ligand comprises N- and / or C-terminal additions as described herein. In some embodiments the peptide ligand is selected from:

[1057] A-(SEQ ID NO: 249)-A (herein referred to as BCY8981);

[1058] A-(SEQ ID NO: 250)-A (herein referred to as BCY8986);

[1059] A-(SEQ ID NO: 251)-A (herein referred to as BCY8992);

[1060] A-(SEQ ID NO: 252)-A (herein referred to as BCY9792);

[1061] A-(SEQ ID NO: 252)-A[MeO-dPEG12] (herein referred to as BCY10301); Ac-(SEQ ID NO: 252) (herein referred to as BCY10384);

[1062] Ac-(SEQ ID NO: 252)-[K(Ac)] (herein referred to as BCY20413);

[1063] Ac-(SEQ ID NO: 252)-K (herein referred to as BCY20414);

[1064] A-(SEQ ID NO: 253)-A (herein referred to as BCY9793);

[1065] A-(SEQ ID NO: 254)-A (herein referred to as BCY10088);

[1066] A-(SEQ ID NO: 255)-A (herein referred to as BCY10089);A-(SEQ ID NO: 256)-A (herein referred to as BCY10090);

[1067] A-(SEQ ID NO: 257)-A (herein referred to as BCY10091);

[1068] A-(SEQ ID NO: 258)-A (herein referred to as BCY10092);

[1069] A-(SEQ ID NO: 259)-SNR (herein referred to as BCY10765);

[1070] A-(SEQ ID NO: 260)-MVT (herein referred to as BCY10767);

[1071] HGP-(SEQ ID NO: 261)-A (herein referred to as BCY10768);

[1072] HTQ-(SEQ ID NO: 262)-A (herein referred to as BCY10769);

[1073] A-(SEQ ID NO: 263)-A (herein referred to as BCY10770);

[1074] A-(SEQ ID NO: 264)-A (herein referred to as BCY20398);

[1075] A-(SEQ ID NO: 265)-A (herein referred to as BCY20399);

[1076] A-(SEQ ID NO: 266)-A (herein referred to as BCY20400);

[1077] A-(SEQ ID NO: 267)-A (herein referred to as BCY20401);

[1078] A-(SEQ ID NO: 268)-A (herein referred to as BCY20402);

[1079] A-(SEQ ID NO: 269)-A (herein referred to as BCY20404);

[1080] A-(SEQ ID NO: 270)-A (herein referred to as BCY20405);

[1081] A-(SEQ ID NO: 271)-A (herein referred to as BCY20406);

[1082] A-(SEQ ID NO: 272)-A (herein referred to as BCY20407);

[1083] A-(SEQ ID NO: 273)-A (herein referred to as BCY20408);

[1084] A-(SEQ ID NO: 274)-A (herein referred to as BCY20409);

[1085] A-(SEQ ID NO: 275)-A (herein referred to as BCY20410);

[1086] A-(SEQ ID NO: 276)-A (herein referred to as BCY20411); and [-FI][NH-Peg6-CO]A-(SEQ ID NO: 277)-A (herein referred to as BCY20521).

[1087] In an alternative embodiment, said polypeptide comprises three reactive groups (e.g. three cysteine residues) separated by two loop sequences both of which consist of 6 amino acids.

[1088] In some embodiments the polypeptide comprises an amino acid sequence

[1089] Z-X1al-X2al-X3al-X4al-X5al-X6al-Z-X7al-X8al-X9al-X10al-X11l-X12l-Z

[1090] wherein each of X1l to X12l are any amino acid and Z is a reactive group as defined herein; e.g. wherein Z is cysteine.

[1091] In some embodiments X1l is selected from N, P and R. In some embodiments X2al is selected from G and S. In some embodiments X3al is selected from P, L and S; such as P or L. In some embodiments X4al is selected from F, P and S. In some embodiments X5al is selected from T and A. In some embodiments X6al is selected from V and W; such as W. In some embodiments the moiety -X1l-X2al-X3al-X4al-X5al-X6al- is selected from -NGPFTV-, -RGLPAW- and -PSSSAW-.In some embodiments X7al is selected from N, Y and S. In some embodiments X8al is selected from G and S. In some embodiments X9al is selected from R and L. In some embodiments X10al is selected from V and F. In some embodiments X11l is selected from R and P. In some embodiments X12l is selected from L, D and S. In some embodiments the moiety -X7al-X8al-X9al-X10al-X11l-X12l- is selected from -NGRVRL-, -YSLFPD- and -SSLFPS-.

[1092] In some embodiments the polypeptide comprises an amino acid sequcne

[1093] Z-NGPFTV-Z-NGRVRL-Z

[1094] Z-RGLPAW-Z-YSLFPD-Z

[1095] Z-PSSSAW-Z-SSLFPS-Z

[1096] or a variant thereof as defined herein, wherein each Z is independently a reactive group as defined herein; or a pharmaceutically acceptable salt thereof.

[1097] In a further embodiment, said loop sequences comprise three cysteine residues separated by two loop sequences both of which consist of 6 amino acids and comprise an amino acid sequence which is selected from:

[1098] CNGPFTVCNGRVRLC (SEQ ID NO: 278);

[1099] CRGLPAWCYSLFPDC (SEQ ID NO: 279); and

[1100] CPSSSAWCSSLFPSC (SEQ ID NO: 280);

[1101] wherein the cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof.

[1102] In a further embodiment, the molecular scaffold is a derivative of TATA which has the following structure:

[1103] O O

[1104]

[1105] wherein * denotes the point of attachment of the three reactive groups (e.g. cysteine residues).In some embodiments the peptide ligand comprises N- and / or C-terminal additions as described herein. In some embodiments the peptide ligand is selected from:

[1106] A-(SEQ ID NO: 278)-A (herein referred to as BCY8985);

[1107] A-(SEQ ID NO: 279)-A (herein referred to as BCY8988); and

[1108] A-(SEQ ID NO: 280)-A (herein referred to as BCY10094).

[1109] In an alternative embodiment, said polypeptide comprises three reactive groups as defined herein (e.g. three cysteine residues) separated by two loop sequences the first of which consists of 7 amino acids and the second of which consists of 3 amino acids.

[1110] In some embodiments the polypeptide comprises an amino acid sequenc

[1111] Z-X1m-X2m-X3m-X4m-X5m-X6m-X7m-Z-X8m-X9m-X10m-Z

[1112] wherein each of Ximto X10mare any amino acid and Z is a reactive group as defined herein; e.g. wherein Z is cysteine.

[1113] In some embodiments Ximis selected from A, D, G, I, L, M, P, R, S, T, V, and Y. In some embodiments X2m is selected from D, H, N, P, R, and Y. In some embodiments X3mis selected from E, K, M, R, G, I, and L. In some embodiments X3mis E, K, M or R. In some embodiments X4m is selected from P, H, N and W. In some embodiments X4m is P. In some embodiments Xsm is selected from D, E, L, Q, R and S. In some embodiments Xemis selected from W, L and Q. In some embodiments Xemis W. In some embodiments X?mis selected from Y, L, N, and W. In some embodiments X?mis Y.

[1114] In some embodiments of the moiety -Xim-X2m-X3m-X4m-X5m-X6m-X7m-: Xim, X2m, X3m, and Xsmare any amino acid; X4m is P, H, N or W; Xemis W, L or Q; and X7m is Y, L, N, or W. In some embodiments Xim, X2m and Xsmare any amino acid; X3mis E, K, M or R; X4m is P; Xemis W; and X7m is Y.

[1115] In some embodiments X8mis selected from D, E, K, L, N, P, Q, R and T. In some embodiments X9mis selected from L, D, F, and H. In some embodiments X9mis L. In some embodiments X10m is selected from M, G, L, S and [MetO]. In some embodiments X10m is M.

[1116] In some embodiments of the moiety -X8m-X9m-X10m-: X8mand X10m are each any amino acid and X9mis selected from L, D, F, and H. In some embodiments X8mis any amino acid; X9mis L; and X10m is M.

[1117] In some embodiments, therefore, the polypeptide comprises an amino acid sequence:Z-X1m-X2m-X3m-X4m-X5m-X6m-X7m-Z-X8m-X9m-X10m-Z

[1118] wherein Z is a reactive group; Xim, X2m, Xsm, Xsm, Xsmand X m are each any amino acid; X4m is P, H, N or W; Xemis W, L or Q; X?mis Y, L, N, or W; and Xgmis selected from L, D, F, and H.

[1119] In some embodiments the polypeptide comprises an amino acid sequence:

[1120] Z-X1m-X2m-X3m-P-X5m-WY-Z-X8m-LM-Z

[1121] wherein Z is a reactive group; Xim, X2m, Xsmand Xsmare each any amino acid; and X3mis E, K, M or R.

[1122] In some embodiments the polypeptide comprises an amino acid sequence:

[1123] Z-GNGHQLN-Z-LFS-Z

[1124] Z-ADRPRWY-Z-DLM-Z

[1125] Z-DPIWELL-Z-PHG-Z

[1126] Z-PYLNLQW-Z-RDL-Z

[1127] Z-SHKPQWY-Z-NLM-Z

[1128] Z-MYEPSWY-Z-QLM-Z

[1129] Z-VDMPDWY-Z-QLM-Z

[1130] Z-YYEPEWY-Z-NLM-Z

[1131] Z-IDMPDWY-Z-TLM-Z

[1132] Z-LYEPSWY-Z-NLM-Z

[1133] Z-RYEPEWY-Z-NLM-Z

[1134] Z-TNMPRWY-Z-DLM-Z

[1135] Z-VDMPDWY-Z-KLM-Z

[1136] Z-VDMPDWY-Z-RLM-Z

[1137] Z-ARMPDWY-Z-NLM-Z

[1138] Z-VDMPDWY-Z-ELM-Z

[1139] Z-RYEPEWY-Z-NL[MetO]-Z

[1140] or a variant thereof as defined herein, wherein each Z is independently a reactive group as defined herein; or a pharmaceutically acceptable salt thereof.

[1141] In a further embodiment, said loop sequences comprise three cysteine residues separated by two loop sequences the first of which consists of 7 amino acids and the second of which consists of 3 amino acids and comprise an amino acid sequence which is selected from:

[1142] CGNGHQLNCLFSC (SEQ ID NO: 281);

[1143] CADRPRWYCDLMC (SEQ ID NO: 282);

[1144] CDPIWELLCPHGC (SEQ ID NO: 283);CPYLNLQWCRDLC (SEQ ID NO: 284);

[1145] CSHKPQWYCNLMC (SEQ ID NO: 285);

[1146] CMYEPSWYCQLMC (SEQ ID NO: 286);

[1147] CVDMPDWYCQLMC (SEQ ID NO: 287);

[1148] CYYEPEWYCNLMC (SEQ ID NO: 288);

[1149] CIDMPDWYCTLMC (SEQ ID NO: 289);

[1150] CLYEPSWYCNLMC (SEQ ID NO: 290);

[1151] CRYEPEWYCNLMC (SEQ ID NO: 291);

[1152] CTNMPRWYCDLMC (SEQ ID NO: 292);

[1153] CVDMPDWYCKLMC (SEQ ID NO: 293);

[1154] CVDMPDWYCRLMC (SEQ ID NO: 294);

[1155] CARMPDWYCNLMC (SEQ ID NO: 295);

[1156] CVDMPDWYCELMC (SEQ ID NO: 296); and

[1157] CRYEPEWYCNL[MetO]C (SEQ ID NO: 297);

[1158] wherein the cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof.

[1159] In a further embodiment, the molecular scaffold is a derivative of TATA which has the following structure:

[1160] N N

[1161] N

[1162]

[1163] wherein * denotes the point of attachment of the three reactive groups (e.g. cysteine residues).

[1164] In some embodiments the peptide ligand comprises N- and / or C-terminal additions as described herein. In some embodiments the peptide ligand is selected from:

[1165] A-(SEQ ID NO: 281)-A (herein referred to as BCY8971);

[1166] A-(SEQ ID NO: 282)-A (herein referred to as BCY9191);

[1167] A-(SEQ ID NO: 283)-A (herein referred to as BCY9192);

[1168] A-(SEQ ID NO: 284)-A (herein referred to as BCY9193);

[1169] A-(SEQ ID NO: 285)-A (herein referred to as BCY9194);A-(SEQ ID NO: 286)-A (herein referred to as BCY10097);

[1170] A-(SEQ ID NO: 287)-A (herein referred to as BCY10098);

[1171] A-(SEQ ID NO: 288)-A (herein referred to as BCY10099);

[1172] A-(SEQ ID NO: 289)-A (herein referred to as BCY10100);

[1173] A-(SEQ ID NO: 290)-A (herein referred to as BCY10101);

[1174] A-(SEQ ID NO: 291)-A (herein referred to as BCY10102);

[1175] Ac-(SEQ ID NO: 291) (herein referred to as BCY10386);

[1176] A-(SEQ ID NO: 292)-A (herein referred to as BCY10103);

[1177] A-(SEQ ID NO: 293)-A (herein referred to as BCY10104);

[1178] A-(SEQ ID NO: 294)-A (herein referred to as BCY10105);

[1179] RPH-(SEQ ID NO: 295)-A (herein referred to as BCY11138);

[1180] A-(SEQ ID NO: 296)-PKK (herein referred to as BCY11139); and A-(SEQ ID NO: 297)-A (herein referred to as BCY20415).

[1181] In an alternative embodiment, said polypeptide comprises three reactive groups as defined herein (e.g. cysteine residues) separated by two loop sequences the first of which consists of 7 amino acids and the second of which consists of 5 amino acids.

[1182] In some embodiments the polypeptide comprises an amino acid sequence

[1183] Z-X1n-X2n-X3n-X4n-X5n-X6n-X7n-Z-X8n-X9n-X10n-X11n-X12n-Z

[1184] wherein each of Xinto X12n are any amino acid and Z is a reactive group as defined herein; e.g. wherein Z is cysteine.

[1185] In some embodiments Xinis selected from G and N. In some embodiments X2n is E. In some embodiments X3nis F. In some embodiments X4n is selected from Q and S. In some embodiments Xsnis selected from K and F. In some embodiments Xenis selected from S and E. In some embodiments X?nis W. In some embodiments the moiety -Xin-X2n-X3n-X4n-X5n-X6n-X7n- is selected from -GEFQFSW- and -NEFSKEW-.

[1186] In some embodiments X8nis selected from M and A. In some embodiments X9nis L. In some embodiments X10n is selected from S and M. In some embodiments X11nis G. In some embodiments X12n is L. In some embodiments the moiety -X8n-X9n-X10n-X11n-X12n- is selected from -MLSGL- and -ALMGL-.

[1187] In some embodiments the polypeptide comprises an amino acid sequence:

[1188] Z-X1n-X2n-X3n-X4n-X5n-X6n-X7n-Z-X8n-X9n-X10n-X11n-X12n-Zwherein Z is a reactive group; Xin, Xm, Xsn, Xsn, Xsnand X n is any amino acid; X2n is E; X3nis F; X?nis W; Xgnis L; Xnnis G and Xi2n is L.

[1189] In some embodiments the polypeptide comprises an amino acid sequence

[1190] Z-GEFQFSW-Z-MLSGL-Z

[1191] Z-NEFSKEW-Z-ALMGL-Z

[1192] or a variant thereof as defined herein, wherein each Z is independently a reactive group as defined herein; or a pharmaceutically acceptable salt thereof.

[1193] In a further embodiment, said loop sequences comprise three cysteine residues separated by two loop sequences the first of which consists of 7 amino acids and the second of which consists of 5 amino acids and comprise an amino acid sequence which is selected from:

[1194] CGEFQFSWCMLSGLC (SEQ ID NO: 298); and

[1195] CNEFSKEWCALMGLC (SEQ ID NO: 299);

[1196] wherein the cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof.

[1197] In a further embodiment, the molecular scaffold is a derivative of TATA which has the following structure:

[1198] O O

[1199]

[1200] *

[1201] wherein * denotes the point of attachment of the three reactive groups (e.g. cysteine residues).

[1202] In some embodiments the peptide ligand comprises N- and / or C-terminal additions as described herein. In some embodiments the peptide ligand is selected from:

[1203] A-(SEQ ID NO: 298)-A (herein referred to as BCY11632); and A-(SEQ ID NO: 299)-A (herein referred to as BCY11633).In an alternative embodiment, said polypeptide comprises three reactive groups as defined herein (e.g. three cysteine residues) separated by two loop sequences the first of which consists of 8 amino acids and the second of which consists of 2 amino acids.

[1204] In some embodiments the polypeptide comprises an amino acid sequence

[1205] Z-X1o-X2o-X3o-X4o-X5o-X6o-X7o-X8o-Z-X9o-X10o-Z

[1206] wherein each of X1oto X10oare any amino acid and Z is a reactive group as defined herein; e.g. wherein Z is cysteine.

[1207] In some embodiments X1o, X2o, X3o, X4o, X5o, X6o, X7oand X8oare each independently selected from R, D, W, A, W, V, F and G. In some embodiments X1ois R. In some embodiments X20 is D. In some embodiments X30, is W. In some embodiments X40 is A. In some embodiments X50 is W. In some embodiments Xe0is V. In some embodiments X?ois F. In some embodiments Xs0is G. In some embodiments the moiety -X1o-X2o-X3o-X4o-X5o-X6o-X7o-X8o- is -RDWAWVFG-.

[1208] In some embodiments Xg0and X100 are selected from D and E. In some embodiments Xg0is D. In some embodiments X100 is E. In some embodiments the moiety -X90-X100- is -DE-.

[1209] In some embodiments the peptide ligand comprises an amino acid sequence

[1210] Z-RDWAWVFG-Z-DE-Z

[1211] or a variant thereof as defined herein, wherein each Z is independently a reactive group as defined herein; or a pharmaceutically acceptable salt thereof.

[1212] In a further embodiment, said loop sequences comprise three cysteine residues separated by two loop sequences the first of which consists of 8 amino acids and the second of which consists of 2 amino acids and comprise an amino acid sequence which is:

[1213] CRDWAWVFGCDEC (SEQ ID NO: 300);

[1214] wherein the cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof.

[1215] In a further embodiment, the molecular scaffold is a derivative of TATA which has the following structure:

[1216]

[1217] wherein * denotes the point of attachment of the three reactive groups (e.g. cysteine residues).

[1218] In some embodiments the peptide ligand comprises N- and / or C-terminal additions as described herein. In some embodiments the peptide ligand is:

[1219] A-(SEQ ID NO: 300)-A (herein referred to as BCY11341).

[1220] In an alternative embodiment, said polypeptide comprises three reactive groups as defined herein (e.g. three cysteine residues) separated by two loop sequences the first of which consists of 8 amino acids and the second of which consists of 4 amino acids.

[1221] In some embodiments the polypeptide comprises an amino acid sequence

[1222] Z-X1p-X2p-X3p-X4p-X5p-X6p-X7p-X8p-Z-X9p-X10p-X11p-X12p-Z

[1223] wherein each of X1pto X12pare any amino acid and Z is a reactive group as defined herein; e.g. wherein Z is cysteine.

[1224] In some embodiments X1pis N or G. In some embodiments X2pis S. In some embodiments X3pis W. In some embodiments X4pis Q or L. In some embodiments X5pis Q or E. In some embodiments X6pis Y. In some embodiments X7pis L or Q. In some embodiments X8pis D or L. In some embodiments the moiety -X1p-X2p-X3p-X4p-X5p-X6p-X7p-X8p- is -NSWQQYLD- or -GSWLEYQL-

[1225] In some embodiments X9pis V or I. In some embodiments X10pis R or D. In some embodiments X11pis G or T. In some embodiments X12pis S or G. In some embodiments the moiety -X9p-X10p-X11p-X12p- is -VRGS- or -IDTG-.

[1226] In some embodiments, therefore, the peptide ligand comprises an amino acid sequence Z-X1p-X2p-X3p-X4p-X5p-X6p-X7p-X8p-Z-X9p-X10p-X11p-X12p-Z

[1227] wherein each of X1pto X12pare any amino acid; X2pis S; X3pis W; and X6pis Y.In some embodiments the peptide ligand comprises an amino acid sequence Z-NSWQQYLD-Z-VRGS-Z

[1228] Z-GSWLEYQL-Z-IDTG-Z

[1229] or a variant thereof as defined herein, wherein each Z is independently a reactive group as defined herein; or a pharmaceutically acceptable salt thereof.

[1230] In a further embodiment, said loop sequences comprise three cysteine residues separated by two loop sequences the first of which consists of 8 amino acids and the second of which consists of 4 amino acids and comprise an amino acid sequence which is selected from:

[1231] CNSWQQYLDCVRGSC (SEQ ID NO: 301); and

[1232] CGSWLEYQLCIDTGC (SEQ ID NO: 302);

[1233] wherein the cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof.

[1234] In a further embodiment, the molecular scaffold is a derivative of TATA which has the following structure:

[1235] O O

[1236]

[1237] wherein * denotes the point of attachment of the three reactive groups (e.g. cysteine residues).

[1238] In some embodiments the peptide ligand comprises N- and / or C-terminal additions as described herein. In some embodiments the peptide ligand is selected from:

[1239] A-(SEQ ID NO: 301)-A (herein referred to as BCY8974); and

[1240] A-(SEQ ID NO: 302)-A (herein referred to as BCY8977).

[1241] As described herein, in some embodiments the polypeptide comprises N- and / or C-terminal additions. In some embodiments the N- and / or C-terminal additions comprise one or more natural or non-natural amino acids. In some embodiments the N- and / or C-terminal additions comprise one or more groups selected from A, D, E, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,Y, [Ac], [Aib], [AzPnt], [CONH2], [dA], [dK], [dPEG] (e.g. dPEG5 to dPEG 30, such as dPEGIO, dPEG12, dPEG14, dPEG16, dPEG18, dPEG20, dPEG22, dPEG24, dPEG25, dPEG26, dPEG28, dPEG30), [Fl], [K(Ac)], [K(dPEG)] (e.g. [K(dPEG5 to dPEG 30, such as dPEGIO, dPEG12, dPEG14, dPEG16, dPEG18, dPEG20, dPEG22, dPEG24, dPEG25, dPEG26, dPEG28, dPEG30)]), [K(N3)], [n-Hex], [NH-PEG-CO] (e.g. [NH-{PEG3 to PEG 20, such as PEG4, PEG5, PEG6, PEG8, PEG10, PEG12, PEG14, PEG16, PEG18, PEG20J-CO], [PA], [PG], [PheCOOH], [PhtCOOH], [Piv], [succinate], and [Ts], In some embodiments the one or more N- and / or C-terminal additions comprise from about 1 to about 10, e.g. from about 2 to about 5 e.g. 2, 3, or 4 such groups. Examples of N-terminal modifications include extension of the peptide by one or more amino acids or amino acid analogues such as alanine (A) or a variant thereof, and / or N-terminal acetylation, represented by “Ac”. Examples of C-terminal modifications include extension of the peptide by one or more amino acids or amino acid analogues such as alanine (A), and / or C-terminal amidation, i.e. the conversion of a C-terminal carboxylic acid group (-CO(O)H or -CO(O)- to an amide -C(O)NH2([CONH2]). In some embodiments the N- and / or C-terminal additions comprise one or more N-terminal additions selected from:

[1242] A-, [Ac]-, [PA]-, [Ts]-, [PhtCOOH]-, [PheCOOH]-, [Succinate]-, [n-Hex]-, [Piv]-, SGQ-, AKG-, YGA-, AGP-, [dPEG(25)]A-, [-FI][NH-Peg6-CO]A-, [AzPnt]-, [Aib]-, [dA]-, SRT-, RTS-, ARY-, ATG-, SPH-, DIG-, APT-, EGG-, SVG-, [Ac][NH-Peg6-CO]-, SYP-, SSW-, [NH-PEG6-CO]A-, SQP-, RAQ-, HGP-, HTQ-, ANT-, and RPH-; and / or one or more C-terminal additions selected from

[1243] -[CONH2], -A[CONH2], -K[CONH2], -[K(Ac)][CONH2], -[K(dPEG(25))][CONH2], -NTS[CONH2], -GRV[CONH2], -AHTA[CONH2], -PKV[CONH2], -PIA[CONH2], -SVS[CONH2], -KKE[CONH2], -[dA][CONH2], -[dK][CONH2], -[K(N3)][CONH2], -[PG][CONH2], -AHM[CONH2], -LKN[CONH2], -RMS[CONH2], -SEM[CONH2], -LGS[CONH2], -EPT[CONH2], -AST[CONH2], -TQK[CONH2], -DSY[CONH2], -STN[CONH2], -SNR[CONH2], -MVT[CONH2], and -PKK[CONH2],

[1244] Typically a polypeptide as described herein is amidated at the C-terminus. Often a polypeptide as described herein is acetylated at the N-terminus.

[1245] The polypeptide may have an amino acid sequence as defined herein (e.g. a polypeptide according to any one of SEQ ID NOs: 1 to 305) wherein one, two, three, four, or five of the amino acids, typically one, twO Or three of the amino acids, are modified as described herein. In some embodiments, the polypeptide may have at least 70% sequence identity with any one of the peptides described herein (e.g. any one of SEQ ID NOs: 1 -305), such as at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity. Itwill be appreciated that references herein to “sequence identity” are to be understood as meaning the percentage identity between two protein sequences, e.g. SEQ ID NO: X and SEQ ID NO: Y, for example as measured using the methods described herein.

[1246] In some embodiments a peptide ligand as described herein comprises a polypeptide as described herein attached (e.g. by being covalently bonded) to a molecular scaffold as described herein. In some embodiments the polypeptide is attached (e.g. covalently bonded) to the molecular scaffold by bonds between the molecular scaffold and each of the reactive groups (e.g. each of the Z groups in the above sequences. When one or more Z group is a cysteine residue, the polypeptide is typically bonded to the molecular scaffold by covalent bonds between the thiol groups of said cysteine residues and the scaffold. In some embodiments the scaffold is 1, T,1"-(1,3,5-triazinane-1,3,5-triyl)triprop-2-en-1-one (TATA).

[1247] For the purpose of this description, the molecular scaffold within each of the bicyclic peptides is a derivative of 1, T,1"-(1,3,5-triazinane-1,3,5-triyl)triprop-2-en-1-one (TATA) which has the following structure:

[1248] O O

[1249] (also depicted as

[1250]

[1251] and yielding a tri-substituted structure, wherein * denotes the point of attachment of the three reactive groups (e.g. cysteine residues). However, as will be clear from the descriptions of the invention presented herein, cyclisation may be performed with any suitable molecular scaffold which forms covalent bonds with the reactive groups of the polypeptide such that atleast two polypeptide loops are formed. Cyclisation occurs on three reactive groups (e.g. cysteine residues).

[1252] In a further embodiment, the pharmaceutically acceptable salt is selected from the free acid or the sodium, potassium, calcium or ammonium salt.

[1253] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art, such as in the arts of peptide chemistry, cell culture and phage display, nucleic acid chemistry and biochemistry. Standard techniques are used for molecular biology, genetic and biochemical methods (see Sambrook etal., Molecular Cloning: A Laboratory Manual, 3rd ed., 2001, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Ausubel etal., Short Protocols in Molecular Biology (1999) 4thed., John Wiley & Sons, Inc.), which are incorporated herein by reference.

[1254] In some embodiments the peptide ligand is a peptide ligand as described in Noisier et al, J. Med Chem. 68 (20) 2025, the entire contents of which are incorporated herein by reference.

[1255] Multimeric Bicyclic Peptide Ligands

[1256] According to a further aspect of the invention, there is provided a multimeric binding complex which comprises at least two bicyclic peptide ligands, wherein said peptide ligands may be the same or different, wherein at least one said ligand is specific for GFRAL. In some embodiments at least one said ligand is a ligand as described herein.

[1257] According to a further aspect of the invention, there is provided a multimeric binding complex which comprises at least two bicyclic peptide ligands, wherein said peptide ligands may be the same or different, each of which comprises a peptide ligand specific for GFRAL 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.

[1258] Thus, in this aspect of the invention the multimeric binding complex comprises at least two (i.e. 2, 3 or 4) of any of the monomeric bicyclic peptide ligands as defined herein.

[1259] This aspect of the invention describes a series of multimerized bicyclic peptides with various chemical linkers and hinges of various lengths and rigidity using different sites of attachments within said bicyclic peptide which bind and activate GFRAL with a wide range of potency and efficacy.It will be appreciated by the skilled person that this aspect of the invention presents multiply arranged (multimeric) bicyclic peptides which provide a synergistic benefit by virtue of the resultant properties of said multimeric binding complexes compared to the corresponding monomeric binding complexes which contain a single bicyclic peptide. For example, the multimeric binding complexes of this aspect of the invention typically have greater levels of binding potency or avidity (as measured herein by Kd values) than their monomeric counterparts. Furthermore, the multimeric binding complexes of the invention are designed to be sufficiently small enough to be cleared by the kidneys.

[1260] Without being bound by theory it is believed that multimerized bicyclic peptides are able to activate receptors by homo-crosslinking more than one of the same receptor. Thus, in one embodiment, said bicyclic peptide ligands are specific for the same target within GFRAL. In a further embodiment, the multimeric binding complex comprises at least two identical bicyclic peptide ligands. By “identical” it is meant bicyclic peptides having the same amino acid sequence, most critically the same amino acid sequence refers to the binding portion of said bicyclic peptide (for example, the sequence may vary in attachment position). In this embodiment, each of the bicyclic peptides within the multimeric binding complex will bind exactly the same epitope upon the same target of GFRAL - the resultant target bound complex will therefore create a homodimer (if the multimeric complex comprises two identical bicyclic peptides), homotrimer (if the multimeric complex comprises three identical bicyclic peptides) or homotetramer (if the multimeric complex comprises four identical bicyclic peptides), etc.

[1261] In an alternative embodiment, the multimeric binding complex comprises at least two differing bicyclic peptide ligands. By “differing” it is meant bicyclic peptides having a different amino acid sequence. In this embodiment, the differing bicyclic peptide ligands within the multimeric binding complex will bind to different epitopes on GFRAL - the resultant target bound complex will therefore create a biparatopic (if the multimeric complex comprises two differing bicyclic peptides), triparatopic (if the multimeric complex comprises three differing bicyclic peptides) or tetraparatopic (if the multimeric complex comprises four differing bicyclic peptides), etc.

[1262] Without being bound by theory it is believed that multimerized bicyclic peptides are able to activate receptors by hetero-crosslinking differing targets, such as differing target receptors on GFRAL. Thus, in one embodiment, said bicyclic peptide ligands are specific for different targets on GFRAL. It will be appreciated that in this embodiment, the multimeric binding complex comprises at least two differing bicyclic peptide ligands (i.e. bicyclic peptide ligands having differing amino acid sequences). In this embodiment, each of the bicyclic peptideswithin the multimeric binding complex will bind a differing epitope upon GFRAL - the resultant target bound complex will therefore create a bispecific multimeric binding complex (if the multimeric complex comprises two differing bicyclic peptides), trispecific multimeric binding complex (if the multimeric complex comprises three differing bicyclic peptides), tetraspecific multimeric binding complex (if the multimeric complex comprises four differing bicyclic peptides), etc.

[1263] It will be appreciated that the multimeric binding complexes of the invention may be designed to be capable of binding to a range of different targets on GFRAL, such as receptors.

[1264] The bicyclic peptides within the multimeric binding complexes of the invention may be assembled via a number of differing options. For example, there may be a central hinge or branching moiety with spacer or arm elements radiating from said hinge or branch point each of which will contain a bicyclic peptide. Alternatively, it could be envisaged that a circular support member may hold a number of inwardly or outwardly projecting bicyclic peptides.

[1265] In one embodiment, each bicyclic peptide ligand is connected to a central hinge moiety by a spacer group.

[1266] It will be appreciated that the spacer group may be linear and connect a single bicyclic peptide with the central hinge moiety. Thus, in one embodiment, the multimeric binding complex comprises a compound of formula (I):

[1267] m

[1268]

[1269] wherein CHM represents a central hinge moiety;

[1270] Bicycle represents a bicyclic peptide ligand as defined herein; and

[1271] m represents an integer selected from 2 to 10.

[1272] In one embodiment, m represents an integer selected from 2, 3 or 4.

[1273] In a further embodiment, m represents 2.When m represents 2, it will be appreciated that the central hinge moiety will require 2 points of attachment.

[1274] More generally, twO Or more peptide ligands as described herein may be attached together by any suitable linker. As used herein, a linker may also be referred to as a spacer. Some exemplary linkers are described herein.

[1275] In forming a multimeric binding peptide ligand as described herein, the attachment point of a spacer or linker to a peptide ligand may be know as the exit vector. The attachment point (exit vector) in a given peptide ligand may be chosen or determined according to the linker or spacer for use in the production of the construct. In some embodiments the attachment point (exit vector) for attachment of a linker / spacer to a peptide linker is the N-terminal amine group of the polypeptide of the peptide ligand. In some embodiments the attachment point (exit vector) for attachment of a linker / spacer to a peptide linker is the e-amine group of a lysine side chain comprised in the polypeptide of the peptide ligand. The lysine group may be numbered as described herein and the attachment point indicated as LysX wherein X is the position of the lysine residue as numbered herein (e.g. Lys2, Lys3, Lys5 etc). In some embodiments when the attachment point (exit vector) is the e-amine group of a lysine side chain, the N-terminal amine group of the peptide ligand is modified, e.g. by acylation. In some embodiments wherein a peptide sequence comprises a plurality of potential attachment points (exit vectors), such as when the peptide sequence comprises a plurality of lysine residues, the peptide may be modified as described herein (e.g. by exchanging one or more lysine residues for alternative amino acids such as HArg) to control the number of attachment points (exit vectors).

[1276] Linkers

[1277] In embodiments which provide a multimeric binding complex comprising at least one bicycle peptide ligand as described herein (e.g. at least 2, 3, or 4 bicycle peptide ligands as described herein), the peptide ligands may be conjugated together via any suitable linker. Such linkers may also be used to link a bicycle peptide ligand as described herein (or a complex of bicycle peptide ligands as described herein) to a payload such as an effector or functional group as described in more detail herein.

[1278] In one embodiment the linker is a linear linker or a branched linker.

[1279] In some embodiments a linear linker comprises two points of attachment and is capable of binding two bicycle peptide ligands.In some embodiments the linker is a branched linker and comprises three or four branches. In some embodiments the linker is capable of binding to three or four bicyclic peptide ligands. In some embodiments the linker comprises three branches and is capable of binding to three bicyclic peptide ligands. In some embodiments the linker comprises four branches and is capable of binding to four bicyclic peptide ligands. In some embodiments the linker comprises one or more repeating monomer groups.

[1280] In some embodiments, the linker is a bidentate or polydentate group having a length of from about 0.3 nm to about 300 nm. In some embodiments the linker has a length of from about 0.5 nm to about 200 nm, such as from about 1 nm to about 100 nm, e.g. from about 1.5 nm to about 50 nm, e.g. from about 2 nm to about 20 nm, such as from about 3 nm to about 10 nm. In some embodiments the linker length is the persistence length. In some embodiments the length is determined when linker is in aqueous solution under physiological conditions, (e.g. phosphate buffered saline, pH 7.4 at 37 °C) and in some embodiments can be determined using atomic force microscopy.

[1281] In some embodiments, the linker comprises one or more linking moieties such as one or more poly(alkyleneglycol) groups such as poly(ethyleneglycol) or poly(propyleneglycol). In some embodiments the linker may comprise one or more groups such as an amine group, an amide group; an alkylene group; an alkenylene group, an alkynylene group, a carbamate group; an ether group; an ester group; a disulphide bond; a hydrazone group; a sulfonamide group; a thioether group; or a cyclic group, preferably a 4-12 membered carbocyclic or heterocyclic group, a 5-12 membered heteroaryl group or a C6-12 aryl group; wherein said alkylene, alkenylene, alkynylene, poly(alkyleneglycol), amine and cyclic group is each independently optionally substituted.

[1282] In some embodiments the linker comprises one or more amino acids or amino acid analogs. In some embodiments the linker comprises from about 1 to about 5 amino acids or amino acid analogs. In some embodiments the linker comprises from about 1 to about 30 amino acids or amino acid analogs, such as from about 5 to about 25 amino acids or amino acid analogs. In some embodiments the linker comprises a repeating motif of from about 3 to about 10 amino acids or amino acid analogs, such as from about 4 to about 5 amino acids or amino acid analogs. In some embodiments the repeating motif comprises about 5 amino acids or amino acid analogs. In some embodiments the repeating motif is repeated from about 2 to about 10 times, e.g. from about 3 to about 6 times, e.g. about 4 or about 5 times. In some embodiments a repeating motif comprises one or more amino acids selected from E, A, and K. In some embodiments a repeating motif comprises -EXnK- wherein X is any amino acid and n is an integer of from 1 to 4, such as 2 or 3. In some embodiments at least one X is A. In some embodiments each X is A. In some embodiments a repeating motif comprises [EAAAK], In some embodiments a linker comprises -[EAAAK]m- wherein m is an integer from2 to 10, such as from 3 to 6 e.g. 4 or 5. In some embodiments a linker comprises -[EAAAK]s-. In some embodiments such a linker may be attached to a peptide ligand as described herein by a functionalised amino acid such as lysine; in some embodiments the lysine may be functionalised (e.g. on the side chain amine group) to comprise an azide group. In some embodiments the azide group is suitable for reacting with a complementary functional group on the peptide ligand, e.g. to an alkyne group in a DBCO group comprised in the peptide ligand. An example of a compound with such a linker is BCY22766.

[1283] In some embodiments the side chains of two amino acids or amino acid analogs in the linker are attached together. In some embodiments the linker comprises a moiety of form

[1284]

[1285] wherein each R1is H or C1-4 alkyl; each R2is selected from the side chain of an amino acid (e.g. a canonical amino acid) or is CM alkyl which may be substituted e.g. with OH, SH, SC1-4 alkyl, aryl (which may be substituted with OH), heteroaryl, C(O)OH, C(O)NH2, N+H3, NH(C=N+H2)NH2, for example, R2may comprise the side chain of arginine or homo-arginine; and wherein LINK is a linker, wherein LINK is optionally a C2-8 hydrocarbylene (e.g. alkylene) linker optionally terminated by or substituted with one or more groups such as an amine group, an amide group; an alkylene group; a carbamate group; an ether group; an ester group; a disulphide bond; a hydrazone group; a sulfonamide group; a thioether group; or a cyclic group as defined herein; for example, LINK may comprise a C3-6 alkylene group which terminates in or is interrupted by an amide group; e.g. LINK may comprise a moiety of form -Ci-4alkylene-NHC(O)-Ci-4alkylene-, e.g. -C4alkylene-NHC(O)-Cialkylene-. In some embodiments said moiety is attached to a polypeptide comprised in a peptide ligand or bicyclic peptide ligand as defined herein, e.g. at the N- or C- terminus of a polypeptide comprised in a peptide ligand or bicyclic peptide ligand as defined herein.

[1286] In some embodiments the linker comprises one or more reactive groups for reaction with a bicyclic peptide ligand as described herein. Exemplary reactive groups include azide groups (which may react with alkyne groups on a bicyclic peptide ligand as described herein, e.g. in the presence of suitable conditions, for example in the presence of an azide-alkyne cycloaddition catalyst, e.g. thereby forming a 1,2,3-triazole group); carboxylic acids and activated derivatives thereof (such as NHS-esters) (which may react with amine groups on a bicyclic peptide ligand as described herein, e.g. in the presence of suitable conditions, e.g. thereby forming an amide bond), and the like. By way of non-limiting example, azide groupsmay be present on a peptide ligand as described herein in the form of a DBCO (dibenzocyclooctyne) group

[1287] In some embodiments when the linker comprises a poly(alkyleneglycol), the poly(alkyleneglycol) is poly(ethyleneglycol) (PEG) or poly(propyleneglycol) (PPG). In some embodiments the linker comprises one or more group PEGn, wherein n represents the number of contiguous ethyleneglycol units in each said PEG group. In some embodiments n is an integer from about 2 to about 30, such as about 5 to about 25, such as about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25. In some embodiments the linker comprises one or more branches e.g. three branches and each branch comprises a PEGngroup.

[1288] In some embodiments the linker comprises a poly(alkyleneglycol) such as poly(ethyleneglycol) (PEG) or poly(propyleneglycol) (PPG) as described herein; and one or more amino acids. The one or more amino acids may in some embodiments be used to link the poly(alkyleneglycol) to a peptide ligand. Typical amino acids for use in such embodiments include, for example, tryptophan (W).

[1289] In some embodiments a linker is attached to a peptide ligand by an amide group as described herein. In some embodiments the linker is attached to an amine group comprised in the peptide moiety (e.g. to a free N-terminal amino group of a peptide or to a free amino group comprised in e.g. a lysine residue of the peptide). In some such embodiments the linker may be considered as terminating in a -C(O)- group with the -NH- moiety of the amide (-CO-NH-) being comprised in the peptide.

[1290] In some embodiments when the linker comprises an amide group, said amide group is of formula -NHC(O)- or -C(O)NH-. In some embodiments when the linker comprises an amine group, the amine group is of formula N(R)a, wherein each R may be the same or different. In some embodiments each R comprises a bicyclic peptide ligand as described herein, for example attached to the amine nitrogen via a linking moiety comprising one or more group PEGn as described herein. In some embodiments when the linker comprises a cyclic group the cyclic group is a Ge aryl group. In some embodiments when the linker comprises an alkylene group the alkylene group is a C1-3 alkylene group.

[1291] In one embodiment, the linker is a linear linker. Without being bound by theory it is believed that a linear linker has the advantage of allowing the presence of one first peptide ligand at one end and one second peptide ligand at the other end.

[1292] In some embodiments the linear linker is a group of formula

[1293] Q1— (Aik)— Q2

[1294] wherein each Aik is independently a C1-25 alkylene, alkenylene or alkynylene group and Q1 and Q2 are each a linking group such as a carboxylic acid (C(O)OH) or activated derivative thereof (e.g. an NHS-ester group); an amine, an amide, or a carbonyl group.

[1295] Q7In some embodiments the linear linker is a group of formula

[1296] Q1— (Alk)m— PEGn— (Alk)m— Q2

[1297] wherein each Aik is independently a C1-6 alkylene group; each m is independently 0 or 1; n is an integer from about 2 to about 25; and Q1 and Q2 are each a linking group such as a carboxylic acid (C(O)OH) or activated derivative thereof (e.g. an NHS-ester group); an amine, an amide, or a carbonyl group.

[1298] In some embodiments a linker comprises an azide group. Those skilled in the art will appreciate that when conjugated with bicyclic peptide ligands as described herein, the azide group will typically react with an alkyne group on one bicyclic peptide ligand (e.g. to an alkyne group comprised in a K(PYA) moiety as described herein). In some embodiments the linker comprises an azide group and a further linking group such as a carboxylic acid (C(O)OH) or activated derivative thereof (e.g. an NHS-ester group); an amine, an amide, or a carbonyl group. When conjugated to a payload such as an effector group, an azide or carboxylic acid group on the linker may react with a complementary group (such as an alkyne group or an amide group on the payload).

[1299] In some embodiments the linker comprises the products of a click chemistry reaction such as a DBCO group. In some embodiments a linker may comprise a triazole group. A triazole group may be formed as the product of a click chemistry reaction between an azide and an alkyne group as described herein.

[1300] In some embodiments the linker has a formula

[1301] Q1— (A)p— (Alk)m— PEGn— (Alk)m— (A)p— Q2

[1302] wherein each A is independently an amino acid (e.g. W); each p is independently 0 or 1; each Aik is independently a C1-6 alkylene group; each m is independently 0 or 1; n is an integer from about 2 to about 25; and Q1 and Q2 are each a linking group such as a carboxylic acid (C(O)OH) or activated derivative thereof (e.g. an NHS-ester group); an amine, an amide, or a carbonyl group.

[1303] In some embodiments the linker has a formula

[1304] Q1— (Alk)m— (A)p— (Alk)m— Q2

[1305] wherein each A is independently an amino acid (e.g. W); p is an integer from 1 to about 15; each Aik is independently a C1-6 alkylene group; each m is independently 0 or 1; and Q1 and Q2 are each a linking group such as a carboxylic acid (C(O)OH) or activated derivative thereof (e.g. an NHS-ester group); an amine, an amide, or a carbonyl group.

[1306] Examples of suitable spacers are as follows:

[1307] amido-Peg5-amidoamido-Peg7-amido

[1308]

[1309] amido-Peg9-amido

[1310] amido-Peg13-amido

[1311] O

[1312]

[1313] 12 O

[1314] amido-Peg17-amido

[1315] o

[1316] 16 o

[1317] amido-Peg21-amido

[1318] o

[1319]

[1320] 20 o

[1321] amido-Peg25-amido

[1322]

[1323] amido- W-Peg9-W-amidoamido-W-Peg13-W-amido

[1324]

[1325] amido- W-Peg25-W-amido

[1326]

[1327] amido-AS-tria-DBCO-BA-Peg13-AS-tria-DBCO-BA-amido

[1328]

[1329] (mixture of triazole isomers)

[1330] DBCO-KAAAE5-DBCO

[1331] NH2

[1332]

[1333] (mixture of triazole isomers)

[1334] amido-Ahx2-C10-Ahx2-amido

[1335] triazolyl-Peg18-triazolyl

[1336]

[1337] Sebacyl (also referred to as amido-octanyl-amido)

[1338] o

[1339]

[1340] oHomodimers

[1341] In one embodiment, the multimeric binding complex comprises two identical bicyclic peptides and comprises a homodimeric binding complex described in the following Table 1:

[1342] Table 1: Exemplified Homodimeric Binding Complexes of the Invention

[1343] Homodimer Corresponding Number of Central Hinge Moiety Attachment Point Compound Monomer Monomers

[1344] Number

[1345] BCY10304 BCY9795 2 amido-Peg25-amido N-terminus

[1346] BCY22807 BCY10109 2 amido-Peg25-amido N-terminus BCY22812 BCY9796 2 amido-Peg25-amido N-terminus BCY22809 BCY10283 2 amido-Peg25-amido N-terminus BCY22810 BCY10280 2 amido-Peg25-amido N-terminus BCY22813 BCY10105 2 amido-Peg25-amido N-terminus BCY22811 BCY10274 2 amido-Peg25-amido N-terminus BCY22808 BCY10108 2 amido-Peg25-amido N-terminus BCY22815 BCY11335 2 amido-Peg25-amido N-terminus BCY22816 BCY20416 2 amido-Peg25-amido C-terminal Lys BCY22817 BCY20414 2 amido-Peg25-amido C-terminal Lys BCY22818 BCY20441 2 amido-Peg25-amido C-terminal Lys BCY22819 BCY20491 2 amido-Peg25-amido C-terminal Lys BCY22820 BCY20520 2 amido-Peg25-amido N-terminus BCY22821 BCY20508 2 amido-Peg25-amido N-terminus BCY22782 BCY11335 2 amido-Peg17-amido N-terminus BCY22787 BCY11335 2 amido-Peg21-amido N-terminus BCY22822 BCY20512 2 amido-Peg25-amido N-terminus BCY22768 BCY11335 2 amido-Peg13-amido N-terminus BCY22793 BCY11335 2 amido-Peg7-amido N-terminus BCY22791 BCY11335 2 amido-Peg5-amido N-terminus BCY22795 BCY11335 2 amido-Peg9-amido N-terminus BCY22769 BCY20491 2 amido-Peg13-amido C-terminal Lys BCY22796 BCY20491 2 amido-Peg9-amido C-terminal Lys BCY22788 BCY20491 2 amido-Peg21-amido C-terminal Lys

[1347]

[1348] BCY22783 BCY20491 2 amido-Peg17-amido C-terminal Lys BCY22823 BCY20492 2 amido-Peg25-amido C-terminal D-Lys BCY22784 BCY20508 2 amido-Peg17-amido N-terminus BCY22789 BCY20508 2 amido-Peg21-amido N-terminus BCY22824 BCY20507 2 amido-Peg25-amido C-terminal Lys BCY22825 BCY20480 2 amido-Peg25-amido Lys 12 BCY22826 BCY20481 2 amido-Peg25-amido Lys5 BCY22770 BCY20485 2 amido-Peg13-amido Lys5 BCY22797 BCY20508 2 amido-Peg9-amido N-terminus BCY22771 BCY20508 2 amido-Peg13-amido N-terminus BCY22790 BCY20507 2 amido-Peg21-amido C-terminal Lys BCY22785 BCY20507 2 amido-Peg17-amido C-terminal Lys BCY22772 BCY20507 2 amido-Peg13-amido C-terminal Lys BCY22798 BCY20507 2 amido-Peg9-amido C-terminal Lys BCY22773 BCY20481 2 amido-Peg13-amido Lys5 BCY22799 BCY20481 2 amido-Peg9-amido Lys5 BCY22794 BCY20481 2 amido-Peg7-amido Lys5 BCY22792 BCY20481 2 amido-Peg5-amido Lys5 BCY22827 BCY20489 2 amido-Peg25-amido Lys5 BCY22828 BCY20490 2 amido-Peg25-amido Lys5 BCY22829 BCY20483 2 amido-Peg25-amido Lys5 BCY22830 BCY20479 2 amido-Peg25-amido Lys9 BCY22831 BCY20476 2 amido-Peg25-amido Lys9 BCY22832 BCY20488 2 amido-Peg25-amido Lys9 BCY22834 BCY20481 2 amido- W-Peg25-W- Lys5

[1349] amido

[1350] BCY22800 BCY20473 2 amido-Peg9-amido Lys5 BCY22833 BCY20506 2 amido-Peg25-amido Lys6 BCY22774 BCY20479 2 amido-Peg13-amido Lys9 BCY22835 BCY20475 2 amido-Peg17-amido Lys2 BCY22802 BCY20479 2 amido-W-Peg13-W- Lys9

[1351] amido

[1352] BCY22786 BCY20475 2 amido- W-Peg17-W- Lys2

[1353] amido

[1354]

[1355] BCY22761 BCY20484 2 amido-Ahx2-C10-Ahx2- Lys12 amido

[1356] BCY22805 BCY20481 2 amido- W-Peg9-W- Lys5

[1357] amido

[1358] BCY22801 BCY20480 2 amido-Peg9-amido Lys12 BCY22775 BCY20472 2 amido-Peg13-amido Lys3 BCY22806 BCY20480 2 amido- W-Peg9-W- Lys12 amido

[1359] BCY22803 BCY20472 2 amido-W-Peg13-W- Lys3

[1360] amido

[1361] BCY22766 BCY20481 2 DBCO-KAAAE5-DBCO Lys5 BCY22767 BCY20486 2 DBCO-KAAAE5-DBCO Lys12 BCY22762 BCY20481 2 amido-Ahx2-C10-Ahx2- Lys5

[1362] amido

[1363] BCY22776 BCY20477 2 amido-Peg13-amido Lys5 BCY22777 BCY20482 2 amido-Peg13-amido D-Lys12 BCY22778 BCY20478 2 amido-Peg13-amido Lys5 BCY22763 BCY20479 2 amido-Ahx2-C10-Ahx2- Lys9

[1364] amido

[1365] BCY22764 BCY20475 2 amido-Ahx2-C10-Ahx2- Lys2

[1366] amido

[1367] BCY22779 BCY20524 2 amido-Peg13-amido Lys5 BCY22780 BCY20523 2 amido-Peg13-amido Lys9 BCY22781 BCY20525 2 amido-Peg13-amido Lys5 BCY22804 BCY20481 2 amido-AS-tria-DBCO- Lys5

[1368] BA-Peg13-AS-tria- DBCO-BA-amido

[1369] BCY22839 BCY20474 2 amido-Peg13-amido Lys12 BCY10302 BCY9792 2 amido-Peg25-amido N-terminus BCY_B1 BCY_A1 2 amido-Peg25-amido N-terminus BCY_B2 BCY_A2 2 amido-Peg13-amido Lys9 BCY_B3 BCY20656 2 amido-octanyl-amido Lys5 BCY_B4 BCY20475 2 amido-Peg13-amido Lys2 BCY_B5 BCY20472 2 amido-Peg17-amido Lys3

[1370]

[1371] Reference to an attachment point such as Lys2, Lys3, Lys5, Lys6, Lys9, Lys12 etc, indicates that the linker (e.g. an amido-Peg13-amido linker having the form

[1372]

[1373] as described above) is attached to the amine group of the lysine side chain at the indicated position in the polypeptide sequence, counting from the N-terminal reactive group (e.g. N-terminal cysteine residue) and excluding intermediate reactive groups. For example, in BCY 22776, the two BCY20477 ligands each comprise a polypeptide sequence

[1374] Ac-CSDALCK[aMePhe]FRENT[HArg]C (SEQ ID NO: 137);

[1375] the lysine residue is numbered 5 relative to the N-terminal cysteine residue; and in each peptide ligand the amine group of the lysine side chain forms an amide bond with the amido- Peg13-amido linker such that the resulting compound is of the form:

[1376] Ac-CSDALC

[1377]

[1378] wherein the C-terminal of each peptide may be amidated.

[1379] BCY22776 may be depicted as follows:

[1380]

[1381] BCY22762 may be depicted as follows:

[1382]

[1383] BCY22766 may be depicted as follows:

[1384]

[1385] Heterodimers

[1386] In an alternative embodiment, the multimeric binding complex comprises two differing bicyclic peptides and comprises a heterodimeric binding complex described in the following Table 2:

[1387] Table 2: Exemplified Heterodimeric Binding Complexes of the Invention

[1388] Heterodimer First Linker First Second Second Compound Monomer Monomer Monomer Monomer Number Attachment Attachment point point BCY22814 BCY9795 amido- N-terminus BCY9792 N-terminus Peg25-amido

[1389]

[1390] In some embodiments the multimeric binding complex is a complex described in Noisier et al, J. Med Chem. 68 (20) 2025, the entire contents of which are incorporated herein by reference.

[1391] Abbreviations

[1392] Abbreviation Definition / Structure

[1393] Agb 2-amino-4-guanidinobutyric acid

[1394] Aib aminoisobutyric acid

[1395] aMePhe

[1396] Ok

[1397] Hs

[1398] AS-triaz-DBCO-BA

[1399] AzPnt

[1400] o

[1401]

[1402] AzaTrp

[1403] Bpa 0

[1404] z

[1405] AMOV ZZ- Cit citrulline ° \

[1406] CO-PEG5-CO O O

[1407] Cysam cysteamine

[1408] Cys(Bn) 0

[1409] cr-^>

[1410] dA 0

[1411] ;-A

[1412] dC 0

[1413] yNH

[1414] dK 0

[1415] yNH

[1416] dPEG(25) OH

[1417] O 1- 24

[1418] dR NH 0

[1419] H2NAN^ '-^

[1420] n^-NH

[1421] 4FPhe 4- fluoro-phenylalanine

[1422]

[1423] Fl fluorescein

[1424] HArg homoarginine

[1425] K(Ac) acetyl-lysine

[1426] K(Ahx)0H

[1427] yNH 0

[1428] K(Ahx, Ahx) O O yNH o

[1429] K(Bz)

[1430] 0 yNH

[1431] 1

[1432] o

[1433] K(DBCO)

[1434] JWV' 0 \ / / O

[1435] « 1 I

[1436] K(dPEG(25))

[1437] H H r i?H0Jy o t J24K(N3) N3

[1438] ANV

[1439] H0

[1440] K(W)

[1441] HNNNH2^NH

[1442] MeO-dPEG12

[1443]

[1444] MetO

[1445] n-Hex

[1446] 1Nal 1-naphthylalanine

[1447] 2Nal 2-naphthylalanine

[1448] / / /

[1449] iz^

[1450] NH-Peg6-CO o

[1451] x° \ H Nle norleucine

[1452] PA 0

[1453] PEG polyethylene glycol

[1454] PG

[1455] Hs

[1456] PheCOOH

[1457] QF°

[1458] PhtCOOH

[1459] Hi0

[1460] OH

[1461] Piv 0

[1462] Succinate O

[1463] o

[1464] Ts

[1465]

[1466] Xr^Numbering

[1467] When referring to amino acid residue positions within the peptides of the invention, the three reactive groups (e.g. cysteine residues) are omitted from the numbering as they are invariant, therefore, the numbering of amino acid residues within the peptides of the invention is referred to as below:

[1468] -C-S1-N2-C-P3-N4-W5-Y6-I7-H8-L9-M10-C- (SEQ ID NO: 1).

[1469] Molecular Format

[1470] N- or C-terminal extensions to the bicycle core sequence are added to the left or right side of the sequence, separated by a hyphen. For example, an N-terminal biotin-G-Sar5tail would be denoted as:

[1471] [Biot]-G-[Sar5]-A-(SEQ ID NO: X).

[1472] wherein [Biot] represents biotin and Sar represents sarcosine.

[1473] Inversed Peptide Sequences

[1474] In light of the disclosure in Nair et al. (2003) J. Immunol. 170(3), 1362-1373, it is envisaged that the peptide sequences disclosed herein would also find utility in their retro-inverso form. For example, the sequence is reversed (i.e. N-terminus become C-terminus and vice versa) and their stereochemistry is likewise also reversed (i.e. D-amino acids become L-amino acids and vice versa).

[1475] Peptide Ligand Definition

[1476] A peptide ligand, as referred to herein, refers to a peptide, peptidic or peptidomimetic covalently bound to a molecular scaffold. Typically, such peptides, peptidics or peptidomimetics comprise a peptide having natural or non-natural amino acids, twO Or more reactive groups (e.g. cysteine, homocysteine (hCys, (S)-2-Amino-4-sulfanylbutanoic acid), βCys ((R)-3-amino-3-mercaptopropanoic acid), or penicillamine (Pen, (R)-2-amino-3-mercapto-3-methylbutanoic acid), Dap ((S)-2,3-diaminopropanoic acid) or N-alkyl-Dap (e.g. N-methyl-Dap, (S)-2-amino-3-(methylamino)propanoic acid) which are capable of forming covalent bonds to the scaffold, and a sequence subtended between said reactive groups which is referred to as the loop sequence, since it forms a loop when the peptide, peptidic or peptidomimetic is bound to the scaffold. In the present case, the peptides, peptidics or peptidomimetics typically comprise at least three cysteine residues, and form at least two loops on the scaffold.

[1477] Accordingly, in some embodiments the present disclosure provides a peptide ligand or multimeric binding complex comprising peptide ligand as defined herein, wherein one or moreof the cysteine residues of one or more of the polypeptides comprised in said peptide ligand is replaced with homocysteine (hCys), βCys, penicillamine (Pen), Dap or N-methyl-Dap. In some embodiments one or more (e.g. 1, 2 or 3) of the cysteine residues in any one of the polypeptides described herein are replaced with homocysteine (hCys), βCys, penicillamine (Pen), Dap or N-methyl-Dap.

[1478] Peptide specificity

[1479] As explained above, in some embodiments the provided peptide ligands and complexes comprising such (described in more detail herein) are specific for GFRAL.

[1480] As used herein, the term “specific” (“specific binding”, etc) refers in its broadest sense to a peptide ligand which binds to its biological target. In some embodiments the peptide ligand binds to its biological target in a specific manner; that is, the binding to the biological target is not non-specific. In some embodiments a peptide which exhibits non-specific binding is promiscuous; that is the peptide is capable of binding to multiple different biological species, typically including the target of interest and off-target binding sites, such as binding sites on cell types other than a target cell type. Accordingly, in some embodiments a peptide ligand which is chosen or designed to bind specifically to its intended target does not exhibit promiscuous binding tO Off-target binding sites.

[1481] In some embodiments the binding to the target is a binding to a particular epitope on the target. A peptide ligand may be designed to be specific for a particular epitope or may be identified by suitable screening methods, such as display techniques (e.g. phage display) which can be used to develop high-affinity binders against given targets (e.g. epitopes). Alternatively, a peptide ligand can be identified with specific binding to a biological target (such as a cellular target) without knowledge of the specific epitope to which it binds. In some embodiments a peptide ligand which specifically binds to a target or epitope has a high affinity for the target or epitope. In some embodiments the binding affinity of a peptide ligand to its epitope may be expressed in terms of its dissociation constant (KD, also written as Kd). Typically, a peptide ligand which specifically binds to a biological target will have a KD against that target of less than 10 pM, e.g. less than 1 pM. Often, a peptide ligand which specifically binds to a biological target will have a nanomolar KD against that target, such as less than 100 nM, less than 20 nM, less than 10 nM, less than 5 nM or even less than 1 nM. Binding affinities can be determined by methods known in the art, such as SPR and competition assays. Some suitable assays are described in the examples.

[1482] In some embodiments a peptide ligand which specifically binds to a biological target will have a higher affinity (lower KD) for the specific biological binding site than for other biological binding site. For example, a peptide or peptide ligand which specifically binds to GFRAL will typically bind to GFRAL with a higher affinity than tO Other binding sites. In someembodiments a peptide or peptide ligand which specifically binds to a biological target will bind to the desired binding site with an affinity at least twice as strong, e.g. at least 5 times, e.g. at least 10 times, e.g. at least 20 time, e.g. at least 50 times, e.g. at least 100 times, e.g. at least 1000 times or more as strong as the binding of the peptide to any other off-target binding sites.

[1483] Advantages of the Peptide Ligands

[1484] Certain bicyclic peptides of the present invention have a number of advantageous properties which enable them to be considered as suitable drug-like molecules for injection, inhalation, nasal, ocular, oral or topical administration. Such advantageous properties include:

[1485] - Species cross-reactivity. This is a typical requirement for preclinical pharmacodynamics and pharmacokinetic evaluation;

[1486] - Protease stability. Bicyclic peptide ligands should in most circumstances demonstrate stability to plasma proteases, epithelial ("membrane-anchored") proteases, gastric and intestinal proteases, lung surface proteases, intracellular proteases and the like. Protease stability should be maintained between different species such that a bicyclic peptide lead candidate can be developed in animal models as well as administered with confidence to humans;

[1487] - Desirable solubility profile. This is a function of the proportion of charged and hydrophilic versus hydrophobic residues and intra / inter-molecular H-bonding, which is important for formulation and absorption purposes; and

[1488] - An optimal plasma half-life in the circulation. Depending upon the clinical indication and treatment regimen, it may be required to develop a bicyclic peptide with short or prolonged in vivo exposure times for the management of either chronic or acute disease states. The optimal exposure time will be governed by the requirement for sustained exposure (for maximal therapeutic efficiency) versus the requirement for short exposure times to minimise toxicological effects arising from sustained exposure to the agent.

[1489] Pharmaceutically Acceptable Salts

[1490] It will be appreciated that salt forms are within the scope of this invention, and references to peptide ligands include the salt forms of said ligands.

[1491] The salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two.Acid addition salts (mono- or di-salts) may be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include mono- or di-salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic), L-aspartic, benzenesulfonic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric, camphor-sulfonic, (+)-(1S)-camphor-10-sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric, ethane-1,2-disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, formic, fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic), a-oxoglutaric, glycolic, hippuric, hydrohalic acids (e.g. hydrobromic, hydrochloric, hydriodic), isethionic, lactic (e.g. (+)-L-lactic, (±)-DL-lactic), lactobionic, maleic, malic, (-)-L-malic, malonic, (±)-DL-mandelic, methanesulfonic, naphthalene-2-sulfonic, naphthalene-1,5-disulfonic, 1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, pyruvic, L-pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic, (+)-L-tartaric, thiocyanic, p-toluenesulfonic, undecylenicand valeric acids, as well as acylated amino acids and cation exchange resins.

[1492] One particular group of salts consists of salts formed from acetic, hydrochloric, hydriodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, sulfuric, methanesulfonic (mesylate), ethanesulfonic, naphthalenesulfonic, valeric, propanoic, butanoic, malonic, glucuronic and lactobionic acids. One particular salt is the hydrochloride salt. Another particular salt is the acetate salt.

[1493] If the compound is anionic, or has a functional group which may be anionic (e.g. -COOH may be -COO'), then a salt may be formed with an organic or inorganic base, generating a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Li+, Na+and K+, alkaline earth metal cations such as Ca2+and Mg2+, and other cations such as Al3+or Zn+. Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e. NH4+) and substituted ammonium ions (e.g. NH3R+, NH2R2+, NHR3+, NR4+). Examples of some suitable substituted ammonium ions are those derived from: methylamine, ethylamine, diethylamine, propylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4+.

[1494] In one embodiment, the pharmaceutically acceptable salt is selected from the sodium, potassium, calcium or ammonium salt.Where the peptides of the invention contain an amine function, these may form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to the skilled person. Such quaternary ammonium compounds are within the scope of the peptides of the invention.

[1495] The peptide ligands and complexes comprising such of the invention may exist as a zwitterion. Such compounds may also be provided in the form of a pharmaceutically acceptable salt. Suitable salts include those formed with pharmaceutically acceptable acids, which provide a proton to a negatively charged group such as a COO- group, and a counter-ion to balance the positive charge on a positively charged group such as a quaternary nitrogen atom. Suitable pharmaceutically acceptable acids include hydrochloric acid, sulphonic acids including methanesulphonic acid and toluene sulphonic acid, ascorbic acid and citric acid. Hydrochloric acid and sulphonic acids are preferred, in particular hydrochloric acid. Alternatively, zwitterions can be combined with pharmaceutically acceptable bases, for example, alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides.

[1496] Modified Derivatives

[1497] It will be appreciated that modified derivatives of the peptide ligands as defined herein are within the scope of the present invention.

[1498] In some embodiments, modified derivatives include functional fragments, derivatives and variants of sequences provided herein.

[1499] As those skilled in the art will appreciate, fragments of amino acid sequences include deletion variants of such sequences wherein one or more, such as at least 1, 2, 3, 4 or 5 amino acids are deleted. Deletion may occur at the C- terminus or N-terminus of the reference sequence or within the reference sequence.

[1500] Derivatives of amino acid sequences include modified sequences including sequences which are modified in vivO Or ex vivo. Many different protein modifications are known to those skilled in the art and include modifications to introduce new functionalities to amino acid residues, modifications to protect reactive amino acid residues or modifications to couple amino acid residues to chemical moieties such as reactive functional groups on linkers for attachment to such amino acid residues. Exemplary modifications that can be made to the provided peptides and ligands are described in more detail herein.Derivatives of amino acid sequences include addition variants of such sequences wherein one or more, such as at least 1, 2, 3, 4, or 5 amino acids are added or introduced into the reference sequence. Addition may occur at the C- terminus or N-terminus of the reference sequence or within the reference sequence. Variants of amino acid sequences include sequences wherein one or more amino acid such as at least 1, 2, 3, 4, or 5 amino acid residues in the reference sequence are exchanged for one or more alternative residues. Variants of amino acid sequences include sequences carrying naturally occurring amino acids and / or unnatural amino acids.

[1501] Variants, derivatives and fragments of the aforementioned amino acid sequences typically retain at least some of the activity / functionality of the reference sequence. In a preferred embodiment, the variants, derivatives and fragments substantially retain their biological function(s) as described herein. Thus, in one embodiment the variants, derivatives and fragments retain the binding specificity of the reference sequence i.e. the ability to specifically bind to GFRaL. In one such embodiment, the variants, derivatives and fragments bind to the same epitope as the reference sequence. In another embodiment, the variants, derivatives and fragments retain the binding affinity of the reference sequence. Typically, variants, derivatives and fragments of a reference sequence have increased / improved activity / functionality when compared to the reference sequence.

[1502] In some embodiments a variant, derivative or fragment of an amino acid sequence is expressed in terms of its percentage identity to the reference sequence. Protocols to determine percent identity are routine procedures within the scope of those skilled in the art. Suitable methods include CLUSTAL W (Thompson et al., Nucleic Acids Research, 22(22) 4673-4680 (1994)) and iterative refinement (Gotoh, J. Mol. Biol. 264(4) 823-838 (1996)); and methods described by Altschul et al., Bull. Math. Bio. 48: 603-16, 1986 and Henikoff and Henikoff, Proc. Natl. Acad. Sci. USA 89:10915-19, 1992. In an exemplary method, two amino acid sequences are aligned tO Optimize the alignment scores using a gap opening penalty of 10, a gap extension penalty of 1, and the "blosum 62" scoring matrix of Henikoff and Henikoff (ibid.), with percentage identity then calculated as: [100 x (T / L)]; wherein T = total number of identical matches and L = length of the longer sequence plus the number of gaps introduced into the longer sequence in order to align the two sequences.

[1503] In some embodiments a variant, derivative or fragment of a reference sequence has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or more identity to the reference sequence.

[1504] Examples of such suitable modified derivatives include one or more modifications selected from: N-terminal and / or C-terminal modifications; replacement of one or more amino acid residues with one or more non-natural amino acid residues (such as replacement of one or more polar amino acid residues with one or more isosteric or isoelectronic amino acids; replacement of one or more non-polar amino acid residues with other non-natural isosteric or isoelectronic amino acids); addition of a spacer group; replacement of one or more oxidation sensitive amino acid residues with one or more oxidation resistant amino acid residues; replacement of one or more amino acid residues with one or more replacement amino acids, such as an alanine, replacement of one or more L-amino acid residues with one or more D-amino acid residues; N-alkylation of one or more amide bonds within the bicyclic peptide ligand; replacement of one or more peptide bonds with a surrogate bond; peptide backbone length modification; substitution of the hydrogen on the alpha-carbon of one or more amino acid residues with another chemical group; modification of amino acids such as cysteine, lysine, glutamate / aspartate and tyrosine with suitable amine, thiol, carboxylic acid and phenolreactive reagents so as to functionalise said amino acids; and introduction or replacement of amino acids that introduce orthogonal reactivities that are suitable for functionalisation, for example azide or alkyne-group bearing amino acids that allow functionalisation with alkyne or azide-bearing moieties, respectively.

[1505] Amino acid residues may typically be replaced with other amino acid residues of similar chemical structure, similar chemical properties or similar side-chain volume (“conservative substitutions”). The amino acids introduced may have similar polarity, hydrophilicity, hydrophobicity, basicity, acidity, neutrality or charge to the amino acids they replace. Alternatively, the conservative substitution may introduce another amino acid that is aromatic or aliphatic in the place of a pre-existing aromatic or aliphatic amino acid. Conservative amino acid changes are well-known in the art and may be selected in accordance with the properties of the 20 main amino acids as defined in Table A above. Where amino acids have similar polarity, this can also be determined by reference to the hydropathy scale for amino acid side chains, which is well-known the person skilled in the art.

[1506] In one embodiment a modified derivative comprises one or more alpha-methylated amino acids, where the hydrogen atom attached to the a-carbon is replaced with a methyl group. In some embodiments a modified derivative comprises one or more aMePhe residues in placeof one or more phenylalanine residues in the peptide sequence. Without being bound by theory, such modifications are believed to enhance the a-helical conformation of peptides.

[1507] In one embodiment, the modified derivative comprises an N-terminal and / or C-terminal modification. In a further embodiment, wherein the modified derivative comprises an N-terminal modification using suitable amino-reactive chemistry, and / or C-terminal modification using suitable carboxy-reactive chemistry. In a further embodiment, said N-terminal or C-terminal modification comprises addition of an effector group, including but not limited to a cytotoxic agent, a radiochelator or a chromophore.

[1508] Therefore, in some embodiments a peptide ligand as described herein or a multimeric binding complex as described herein comprises one or more effector groups and / or functional groups, such as one or more cytotoxic agents, radiochelators, chromophores and / or fluorophores.

[1509] In a further embodiment, the modified derivative comprises an N-terminal modification. In a further embodiment, the N-terminal modification comprises an N-terminal acetyl group. In this embodiment, the N-terminal residue is capped with acetic anhydride or other appropriate reagents during peptide synthesis leading to a molecule which is N-terminally acetylated. This embodiment provides the advantage of removing a potential recognition point for aminopeptidases and avoids the potential for degradation of the bicyclic peptide.

[1510] In an alternative embodiment, the N-terminal modification comprises the addition of a molecular spacer group which facilitates the conjugation of effector groups and retention of potency of the bicyclic peptide to its target.

[1511] In a further embodiment, the modified derivative comprises a C-terminal modification. In a further embodiment, the C-terminal modification comprises an amide group. In this embodiment, the C-terminal residue is synthesized as an amide during peptide synthesis leading to a molecule which is C-terminally amidated. This embodiment provides the advantage of removing a potential recognition point for carboxypeptidase and reduces the potential for proteolytic degradation of the bicyclic peptide.

[1512] In one embodiment, the modified derivative comprises replacement of one or more amino acid residues with one or more non-natural amino acid residues. In this embodiment, non-natural amino acids may be selected having isosteric / isoelectronic side chains which are neither recognised by degradative proteases nor have any adverse effect upon target potency.Alternatively, non-natural amino acids may be used having constrained amino acid side chains, such that proteolytic hydrolysis of the nearby peptide bond is conformationally and sterically impeded. In particular, these concern proline analogues, bulky sidechains, Ca-disubstituted derivatives (for example, aminoisobutyric acid, Aib), and cyclo amino acids, a simple derivative being amino-cyclopropylcarboxylic acid.

[1513] In one embodiment, the modified derivative comprises the addition of a spacer group. In a further embodiment, the modified derivative comprises the addition of a spacer group to the N-terminal cysteine and / or the C-terminal cysteine.

[1514] In one embodiment, the modified derivative comprises replacement of one or more oxidation sensitive amino acid residues with one or more oxidation resistant amino acid residues. In a further embodiment, the modified derivative comprises replacement of a tryptophan residue with a naphthylalanine or alanine residue. This embodiment provides the advantage of improving the pharmaceutical stability profile of the resultant bicyclic peptide ligand.

[1515] In one embodiment, the modified derivative comprises replacement of one or more charged amino acid residues with one or more hydrophobic amino acid residues. In an alternative embodiment, the modified derivative comprises replacement of one or more hydrophobic amino acid residues with one or more charged amino acid residues. The correct balance of charged versus hydrophobic amino acid residues is an important characteristic of the bicyclic peptide ligands. For example, hydrophobic amino acid residues influence the degree of plasma protein binding and thus the concentration of the free available fraction in plasma, while charged amino acid residues (in particular arginine) may influence the interaction of the peptide with the phospholipid membranes on cell surfaces. The two in combination may influence half-life, volume of distribution and exposure of the peptide drug, and can be tailored according to the clinical endpoint. In addition, the correct combination and number of charged versus hydrophobic amino acid residues may reduce irritation at the injection site (if the peptide drug has been administered subcutaneously).

[1516] In one embodiment, the modified derivative comprises replacement of one or more L-amino acid residues with one or more D-amino acid residues. This embodiment is believed to increase proteolytic stability by steric hindrance and by a propensity of D-amino acids to stabilise p-turn conformations (Tugyi etal. (2005) PNAS, 102(2), 413-418).

[1517] In one embodiment, the modified derivative comprises removal of any amino acid residues and substitution with alanines, such as D-alanines. This embodiment provides the advantageof identifying key binding residues and removing potential proteolytic attack site(s).

[1518] It should be noted that each of the above mentioned modifications serve to deliberately improve the potency or stability of the peptide. Further potency improvements based on modifications may be achieved through the following mechanisms:

[1519] - Incorporating hydrophobic moieties that exploit the hydrophobic effect and lead to lower off rates, such that higher affinities are achieved;

[1520] - Incorporating charged groups that exploit long-range ionic interactions, leading to faster on rates and to higher affinities (see for example Schreiber et al., Rapid, electrostatically assisted association of proteins (1996), Nature Struct. Biol. 3, 427-31); and

[1521] - Incorporating additional constraint into the peptide, by for example constraining side chains of amino acids correctly such that loss in entropy is minimal upon target binding, constraining the torsional angles of the backbone such that loss in entropy is minimal upon target binding and introducing additional cyclisations in the molecule for identical reasons.

[1522] (for reviews see Gentilucci et al., Curr. Pharmaceutical Design, (2010), 16, 3185-203, and Nestor eta / ., Curr. Medicinal Chem (2009), 16, 4399-418).

[1523] Isotopic Variations

[1524] The present invention includes all pharmaceutically acceptable (radio)isotope-labelled peptide ligands of the invention, wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature, and peptide ligands of the invention, wherein metal chelating groups are attached (termed “effector”) that are capable of holding relevant (radio)isotopes, and peptide ligands of the invention, wherein certain functional groups are covalently replaced with relevant (radio)isotopes or isotopically labelled functional groups.

[1525] Examples of isotopes suitable for inclusion in the peptide ligands of the invention comprise isotopes of hydrogen, such as2H (D) and3H (T), carbon, such as11C,13C and14C, chlorine, such as36CI, fluorine, such as18F, iodine, such as123I,125I and131I, nitrogen, such as13N and15N, oxygen, such as150,17O and18O, phosphorus, such as32P, sulphur, such as35S, copper, such as64Cu, gallium, such as67Ga or68Ga, yttrium, such as90Y and lutetium, such as177Lu, and Bismuth, such as213Bi.

[1526] Certain isotopically-labelled peptide ligands of the invention, for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies, and to clinically assess the presence and / or absence of the target on diseased tissues. The peptideligands of the invention can further have valuable diagnostic properties in that they can be used for detecting or identifying the formation of a complex between a labelled compound and other molecules, peptides, proteins, enzymes or receptors. The detecting or identifying methods can use compounds that are labelled with labelling agents such as radioisotopes, enzymes, fluorescent substances, luminous substances (for example, luminol, luminol derivatives, luciferin, aequorin and luciferase), etc. The radioactive isotopes tritium, i.e.3H (T), and carbon-14, i.e.14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

[1527] Substitution with heavier isotopes such as deuterium, i.e.2H (D), may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

[1528] Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining target occupancy.

[1529] Isotopically-labelled compounds of peptide ligands of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously employed.

[1530] Molecular Scaffold

[1531] In one embodiment, the molecular scaffold comprises a non-aromatic molecular scaffold. References herein to “non-aromatic molecular scaffold” refers to any molecular scaffold as defined herein which does not contain an aromatic (i.e. unsaturated) carbocyclic or heterocyclic ring system.

[1532] Suitable examples of non-aromatic molecular scaffolds are described in Heinis et al. (2014) Angewandte Chemie, International Edition 53(6) 1602-1606.

[1533] As noted in the foregoing documents, the molecular scaffold may be a small molecule, such as a small organic molecule.

[1534] In one embodiment the molecular scaffold may be a macromolecule. In one embodiment the molecular scaffold is a macromolecule composed of amino acids, nucleotides or carbohydrates.In one embodiment the molecular scaffold comprises reactive groups that are capable of reacting with functional group(s) of the polypeptide to form covalent bonds.

[1535] The molecular scaffold may comprise chemical groups which form the linkage with a peptide, such as amines, thiols, alcohols, ketones, aldehydes, nitriles, carboxylic acids, esters, alkenes, alkynes, azides, anhydrides, succinimides, maleimides, alkyl halides and acyl halides.

[1536] An example of an αβ unsaturated carbonyl containing compound is 1,1',1"-(1,3,5-triazinane-1,3,5-triyl)triprop-2-en-1-one (TATA) (Angewandte Chemie, International Edition (2014), 53(6), 1602-1606). An alternative example of a suitable molecular scaffold is 1, 1 ', 1 "-(1,3,5-triazinane-1,3,5-triyl)tris(2-bromoethanone) (TATB). Accordingly, also provided herein is a peptide ligand comprising a polypeptide as described herein attached to a molecular scaffold which is TATB, wherein said polypeptide is attached to said scaffold at the three reactive groups of the polypeptide (e.g. at three cysteine residues).

[1537] Synthesis

[1538] The peptides of the present invention may be manufactured synthetically by standard techniques followed by reaction with a molecular scaffold in vitro. When this is performed, standard chemistry may be used. This enables the rapid large scale preparation of soluble material for further downstream experiments or validation. Such methods could be accomplished using conventional chemistry such as that disclosed in Timmerman et al. (supra).

[1539] Thus, the invention also relates to the manufacture of polypeptides or conjugates selected as set out herein, wherein the manufacture comprises optional further steps as explained below. In one embodiment, these steps are carried out on the end product polypeptide / conjugate made by chemical synthesis.

[1540] Optionally amino acid residues in the polypeptide of interest may be substituted when manufacturing a conjugate or complex.

[1541] Peptides can also be extended, to incorporate for example another loop and therefore introduce multiple specificities.To extend the peptide, it may simply be extended chemically at its N-terminus or C-terminus or within the loops using orthogonally protected lysines (and analogues) using standard solid phase or solution phase chemistry. Standard (bio)conjugation techniques may be used to introduce an activated or activatable N- or C-terminus. Alternatively additions may be made by fragment condensation or native chemical ligation e.g. as described in (Dawson etal. 1994. Synthesis of Proteins by Native Chemical Ligation. Science 266:776-779), or by enzymes, for example using subtiligase as described in (Chang etal. Proc Natl Acad Sci U S A. 1994 Dec 20; 91(26): 12544-8 or in Hikari et al. Bioorganic & Medicinal Chemistry Letters Volume 18, Issue 22, 15 November 2008, Pages 6000-6003).

[1542] Alternatively, the peptides may be extended or modified by further conjugation through disulphide bonds. This has the additional advantage of allowing the first and second peptide to dissociate from each other once within the reducing environment of the cell. In this case, the molecular scaffold (e.g. TATA or TATB) could be added during the chemical synthesis of the first peptide so as to react with the three cysteine groups; a further cysteine or thiol could then be appended to the N- or C-terminus of the first peptide, so that this cysteine or thiol only reacted with a free cysteine or thiol of the second peptide, forming a disulphide-linked bicyclic peptide-peptide conjugate.

[1543] Furthermore, addition of other functional groups or effector groups may be accomplished in the same manner, using appropriate chemistry, coupling at the N- or C-termini or via side chains. In one embodiment, the coupling is conducted in such a manner that it does not block the activity of either entity.

[1544] In some embodiments a polypeptide as provided herein may be synthesised by solid-phase synthesis. In some embodiments, the synthesis of a peptide ligand as provided herein may comprise solid-phase synthesis of a polypeptide as described herein. In some embodiments the solid-phase synthesis comprises Fmoc solid-phase peptide synthesis (e.g. as described in more detail herein). In some embodiments the synthesized polypeptide is cyclised with a molecular scaffold as described herein. In some embodiments the cyclised scaffold is purified e.g. by lyophilisation.

[1545] In some embodiments, a peptide ligand as described herein may be synthesized as follows. Linear peptides may be synthesized using standard Fmoc SPPS chemistry, e.g. using a Syro II automated parallel peptide synthesizer by MultiSynTech, a Initiator+ AlstraTM automated microwave peptide synthetizer by Biotage or a PurePep Chorus automated peptide synthesizer by Gyros Protein Technologies. Following TFA-based cleavage from the resin,peptides may be precipitated with Et2O, resolubilized in CH3CN / H2O 1 / 1 (v / v) acidified with 0.1% TFA and lyophilized. Crude peptides may be dissolved with CH3CN / H2O 1 / 1 (v / v) and cyclized with 1.2 equiv of TATA scaffold using 60 mM NH4HCO3as a base. Following reaction completion, (judged by UPLC-MS), modified peptides may be lyophilized prior to purification by RP HPLC-MS. Pure fractions containing TATA-cyclised peptides may be pooled, lyophilized and kept at -20 °C for storage.

[1546] Pharmaceutical Compositions

[1547] According to a further aspect of the invention, there is provided a pharmaceutical composition comprising a peptide ligand or multimeric binding complex as defined herein in combination with one or more pharmaceutically acceptable excipients.

[1548] Generally, the present peptide ligands and complexes will be utilised in purified form together with pharmacologically appropriate excipients or carriers. Typically, these excipients or carriers include aqueous or alcoholic / aqueous solutions, emulsions or suspensions, including saline and / or buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride and lactated Ringer's. Suitable physiologically-acceptable adjuvants, if necessary to keep a polypeptide complex in suspension, may be chosen from thickeners such as carboxymethylcellulose, polyvinylpyrrolidone, gelatin and alginates.

[1549] Intravenous vehicles include fluid and nutrient replenishers and electrolyte replenishers, such as those based on Ringer's dextrose. Preservatives and other additives, such as antimicrobials, antioxidants, chelating agents and inert gases, may also be present (Mack (1982) Remington's Pharmaceutical Sciences, 16th Edition).

[1550] The peptide ligands and complexes of the present invention may be used as separately administered compositions or in conjunction with other agents. These can include antibodies, antibody fragments and various immunotherapeutic drugs, such as cyclosporine, methotrexate, adriamycin or cisplatinum and immunotoxins. Further examples of other agents which may be administered separately or in conjunction with the peptide ligands of the invention include cytokines, lymphokines, other hematopoietic factors, thrombolytic and antithrombotic factors. Pharmaceutical compositions can include "cocktails" of various cytotoxic or other agents in conjunction with the protein ligands of the present invention, or even combinations of selected polypeptides according to the present invention having different specificities, such as polypeptides selected using different target ligands, whether or not they are pooled prior to administration.The route of administration of pharmaceutical compositions according to the invention may be any of those commonly known to those of ordinary skill in the art. For therapy, the peptide ligands of the invention can be administered to any patient in accordance with standard techniques. The administration can be by any appropriate mode, including parenterally, intravenously, intramuscularly, intraperitoneally, transdermally, via the pulmonary route, or also, appropriately, by direct infusion with a catheter. Preferably, the pharmaceutical compositions according to the invention will be administered intravenously. The dosage and frequency of administration will depend on the age, sex and condition of the patient, concurrent administration of other drugs, counterindications and other parameters to be taken into account by the clinician.

[1551] The peptide ligands and complexes of this invention can be lyophilised for storage and reconstituted in a suitable carrier prior to use. This technique has been shown to be effective and art-known lyophilisation and reconstitution techniques can be employed. It will be appreciated by those skilled in the art that lyophilisation and reconstitution can lead to varying degrees of activity loss and that levels may have to be adjusted upward to compensate.

[1552] The compositions containing the present peptide ligands and complexes or a cocktail thereof can be administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, an adequate amount to accomplish at least partial inhibition, suppression, modulation, killing, or some other measurable parameter, of a population of selected cells is defined as a "therapeutically-effective dose". Amounts needed to achieve this dosage will depend upon the severity of the disease, but generally range from 0.005 to 5.0 mg of selected peptide ligand per kilogram of body weight, with doses of 0.05 to 2.0 mg / kg / dose being more commonly used. For prophylactic applications, compositions containing the present peptide ligands or cocktails thereof may also be administered in similar or slightly lower dosages.

[1553] A composition containing a peptide ligand or complex according to the present invention may be utilised in prophylactic and therapeutic settings to aid in the alteration, inactivation, killing or removal of a select target cell population in a mammal. In addition, the peptide ligands described herein may be used extracorporeally or in vitro selectively to kill, deplete or otherwise effectively remove a target cell population from a heterogeneous collection of cells. Blood from a mammal may be combined extracorporeally with the selected peptide ligands whereby the undesired cells are killed or otherwise removed from the blood for return to the mammal in accordance with standard techniques.Therapeutic Uses

[1554] The bicyclic peptides of the invention have specific utility as GFRAL binding agents. According to a further aspect of the invention, there is provided a peptide ligand or a complex comprising a peptide ligand, or pharmaceutical composition as defined herein for use in preventing, suppressing or treating a disease or disorder mediated by GFRAL.

[1555] Also provided is the use of a peptide ligand, complex or composition as described herein in the manufacture of a medicament for preventing, suppressing or treating a disease or disorder mediated by GFRAL. Also provided is a method of preventing, suppressing or treating a disease or disorder mediated by GFRAL, comprising administering to a subject in need thereof an effective amount of a peptide ligand, complex or composition as described herein.

[1556] GFRAL is also known as “GDNF family receptor receptor alpha like” and is a protein which in humans in encoded by the GFRAL gene. The X-ray determined crystal structure of GDF15 in complex with the GFRaL extracellular domain (ECD) is available under PDB accession code 5VZ4 (https: / / doi.org / 10.2210 / pdb5VZ4 / pdb). Structural data indicates that the GDF15-GFRaL interactions are mostly mediated by C- and N-terminal p-hairpins of the GDF15 finger domains and the domain 2 of GFRaL. The p-hairpin of GDF15 consists of two antiparallel 5-amino acid residue p-strands linked by a loop of 6 amino acids. Owing to the p-hairpin secondary structure, the side chains of the non-hydrogen bonding (NHB) residues are oriented on the same side of the p-hairpin plane, pointing towards GFRaL and forming mainly hydrophobic interactions with the receptor. Without in any way being bound by theory, the disclosed peptide ligands are believed to share the same binding interface to GFRaL as the endogenous GDF15 ligand.

[1557] GFRAL has recently been linked with a number of disorders, notably obesity and other cardiometabolic disorders, following the discovery that GFRAL is the receptor for GDF15 (growth differentiation factor 15) (Mullican et al (2017), Yang et al (2017), Emmerson et al (2017)). GDF15 binds to and activates GFRAL-expressing neurons in AP (area postrema) and NTS (nucleus tractus solitarius) of the hindbrain (Hsu et al (2017)), which are important areas for appetite regulation and GDF15 lowers body weight in preclinical models, including nonhuman primates. GDF15 / GFRAL biology is suggested to have therapeutic applications in obesity and cardiometabolic diseases (Wang et al (2021)). GDF15 is associated with weight loss in cancer cachexia in clinical settings (Ahmed et al (2021)). GDF15 is also involved in hyperemesis gravidarum (Fejzo et al (2018)), supporting the hypothesis that GDF15 triggers anorexia and subsequent weight loss in clinical settings. In addition, antibody-mediatedinhibition of GDF15 / GFRAL has been investigated for its anti-tumor activity in mice (Suriben et al (2020)).

[1558] References herein to the term "prevention" involves administration of the protective composition prior to the induction of the disease. " Suppression" refers to administration of the composition after an inductive event, but prior to the clinical appearance of the disease. " Treatment" involves administration of the protective composition after disease symptoms become manifest.

[1559] Accordingly, provided herein is a peptide ligand, complex or composition as defined herein (e.g. a complex, or a conjugate comprising a plurality of peptide ligands as defined herein, such as two peptide ligands as defined herein), for use in preventing, suppressing, or treating a disease or disorder mediated by GFRAL. Also provided is a method of preventing, suppressing, or treating a disease or disorder mediated by GFRAL, the method comprising administering to a subject in need thereof an effective amount of a peptide ligand, complex or composition as defined herein (e.g. a complex, or a conjugate comprising a plurality of peptide ligands as defined herein, such as two peptide ligands as defined herein). Also provided is the use of a peptide ligand, complex or composition as defined herein (e.g. a complex, or a conjugate comprising a plurality of peptide ligands as defined herein, such as two peptide ligands as defined herein), in the manufacture of a medicament for preventing, suppressing, or treating a disease or disorder mediated by GFRAL. In some embodiments the disease or disorder mediated by GFRAL is a cardiometabolic disorder. In some embodiments the disease or disorder mediated by GFRAL is cancer. In some embodiments the disease or disorder mediated by GFRAL is selected from obesity, cachexia (optionally tumor- and / or chemotherapy-induced cachexia), and type 2 diabetes.

[1560] Also provided is a peptide ligand, complex or composition as defined herein (e.g. a complex, or a conjugate comprising a plurality of peptide ligands as defined herein, such as two peptide ligands as defined herein), for use in appetite control in a subject in need thereof. Also provided is a method of appetite suppression, the method comprising administering to a subject in need thereof an effective amount of a peptide ligand, complex or composition as defined herein (e.g. a complex, or a conjugate comprising a plurality of peptide ligands as defined herein, such as two peptide ligands as defined herein). Also provided is the use of a peptide ligand, complex or composition as defined herein (e.g. a complex, or a conjugate comprising a plurality of peptide ligands as defined herein, such as two peptide ligands as defined herein), in the manufacture of an agent for appetite suppression. In some embodiments the appetite suppression is a therapeutic method. In some embodiments theappetite suppression is a non-therapeutic method (e.g. a cosmetic method of controlling body weight).

[1561] Animal model systems which can be used to screen the effectiveness of the peptide ligands in protecting against or treating the disease are available. The use of animal model systems is facilitated by the present invention, which allows the development of polypeptide ligands which can cross react with human and animal targets, to allow the use of animal models.

[1562] The invention is further described below with reference to the following examples.

[1563] EXAMPLES

[1564] Materials and Methods

[1565] Preparation of Bicyclic Peptide Ligands (General Method)

[1566] Peptide synthesis was based on Fmoc SPPS chemistry, using a Syro II synthesiser by MultiSynTech or a Biotage® Initiator AlstraTM automated microwave peptide synthetizer. Standard Fmoc-amino acids were employed, with the following side-chain protecting groups: Arg(Pbf); Asn(Trt); Asp(OtBu); Cys(Trt); Glu(OtBu); Gln(Trt); His(Trt); Lys(Boc); Ser(tBu); Thr(tBu); Trp(Boc); and Tyr(tBu). The following dipeptide pseudoprolines were also used: Fmoc-L-Asn(Trt)-L-Thr[PSI(Me, Me)Pro]-OH, Fmoc-L-Leu-L-Cys[PSI(Dmp, H)pro]-OH. All amino acids, unless noted otherwise, were used in the L- configurations. Non-natural amino acids were incorporated into peptide sequence using the general methods described below.

[1567] Preparation of Multimeric Bicyclic Peptide Ligands (General Methods)

[1568] Method 1: General methods linear peptide synthesis, cleavage condition and cyclisation with TATA linker

[1569] Method 1a

[1570] Linear peptide synthesis using a parallel synthesizer Syro II: The coupling reagent was HATU, diisopropylethylamine (DI PEA) was employed as a base, the capping step was performed using 5:6:89 v / v / v acetic anhydride / 2,6-lutidine / NMP and deprotection was achieved with 20 to 40% piperidine in DMF. Syntheses were performed using 0.51 mmol / g PS Fmoc-MBHA Rink amide AM resin, Fmoc-amino acids were utilised at a four-fold excess, coupling reagent at a 3.8-fold excess and base was at a two-fold excess with respect to the amino acids. Amino acids were dissolved at 0.5 M in DMF, HATU at 0.48 M in DMF, and DIPEA at 2 M in N-methylpyrrolidone (NMP). All amino acids were coupled twice, coupling times were 40 minutes at rt. Capping times were 5 min at rt and deprotection times 1 x3 minutes with 40% piperidinein DMF followed by 1 x 10 minutes with 20% piperidine in DMF. A final capping step was performed when N-terminus acetylation or a specific capping group, linker handle or fluorophore labelling desired. After synthesis, the resin was washed with the following solvents: DCM, MeOH, DCM, methanol and Et2O before being dried under vacuum.

[1571] Method 1b

[1572] Synthesis of C-terminal modified bicycle peptides: Fmoc-NHCH2CH2S CTC Resin (0.506 g, 0.15 mmol) was swelled in DMF (10 mL) for 1 h and the mixture was filtered. 20% Piperidine in DMF (15 mL) was added to the resin to remove Fmoc. The suspension was kept at room temperature for 0.5 h while a stream of nitrogen was bubbled through it. The mixture was filtered, the resin was washed with DMF (6*15 mL). A solution of Fmoc-homoArg(pbf)-OH (0.2 g, 0.3 mmol) in DMF (3 mL) was added into the resin. NMM and HATU were then added into the resin and the reaction was carried out under a nitrogen atmosphere. Kaiser ninhydrin test was used to indicate reaction completion. After the reaction completed, the suspension was filtered and the resin was washed with DMF (3*15 mL). The remaining amino acids of the peptide sequences were coupled by following general coupling condition followed by capping step. After synthesis, the resin was washed with the following solvents: DCM, MeOH, DCM, methanol and Et2O before being dried under vacuum.

[1573] Method 1c

[1574] Synthesis of non-terminal modified peptides: A solution of Na-Boc-protected amino acid NHS ester (e.g. L-tryptophan hydroxysuccinimide ester (Boc-L-Trp-OSu, 1.08 eq., 37 mM) or N-Boc protected linker (e.g. 6-(Boc-amino)hexanoic acid N-succinimidyl ester or DBCO-OSu, 1.08 eq., 37 mM) in DMF was added portion wise during 30 min to a solution of the TATA-modified peptide (1 eq, 17 mM) in DMF and DIPEA (20 eq.) and the reaction mixture was stirred at room temperature for 1-12 h. The reaction was monitored by UPLC-MS and upon completion. Water was added and the reaction mixture freeze dried. The crude material was taken to the next step without further purifications.

[1575] A cleavage solution of TFA / H2O (9 / 1) was added to the crude Boc-protected material and the reaction mixture (5 mM) was agitated at room temperature for 1–2 h. The reaction mixture was precipitated in cold Et2O, the precipitated product was centrifugated and the supernatant discarded. The solid material was washed two times by addition of cold Et2O and centrifugation. The resulting solid material was suspended in MeCH / H2O (50 / 50) and freeze dried. The crude deprotected product was taken to the next step without further purifications.

[1576] Method 1dLinear peptide synthesis scale-up with Alstra: The coupling reagents were DIC / Oxyma pure, and deprotection was achieved with 20% piperidine in DMF. Syntheses were performed using 0.54 mmol / g ChemMatrix Fmoc-Rink amide resin, Fmoc-amino acids were utilised at a fourfold excess. Amino acids were dissolved at 0.2 M in DMF, DIC at 2 M in DMF, and Oxyma pure at 0.5 M in DMF. Coupling times were 10 minutes at 75 °C for all amino acids except Fmoc-Cys(Trt)-OH and Fmoc-L-Leu-L-Cys[PSI(Dmp, H)pro]-OH which were coupled for 20 minutes at 40 °C and Fmoc-Arg(Pbf)-OH which were coupled for 20 minutes at rt followed by 5 minutes at 75 °C. For the first half of the peptides single couplings and deprotection times of 1 x 3 minutes followed by 1 x 10 minutes were used, while for the second half double couplings and deprotection times of 2 x 5 minutes followed by 1 x 10 minutes were employed. After synthesis, the resin was washed with MeOH and DCM before being dried under vacuum.

[1577] General conditions for peptide cleavage from solid phase: Cleavage of side-chain protecting groups and from the support was effected using 95:2.5:2.5:2.5 v / v / v / v TFA / H2O / iPr3SiH / 3,6-dioxa-1,8-octanedithiol (DODT) for 2-3 hours. Following cleavage, the spent resin was removed by filtration, and the filtrate was added to diethylether that had been cooled at 4 °C. Peptide pellet was centrifuged, the etheric supernatant discarded, and the peptide pellet washed with cold ether two more times. Peptides were then resolubilized in CH3CN-water 1:1 v / v acidified with 0.1% TFA and lyophilised. A small sample was removed for analysis of purity of the crude product by ultra-high performance liquid chromatography tandem mass spectrometry (UPLC-MS).

[1578] General conditions for the synthesis of bicycle peptide with TATA linker: Following lyophilisation, peptides were modified with 1,3,5-triacryloyl-1,3,5-triazinane (TATA). For this, the crude linear peptide was diluted with CH3CN-water 1:1 v / v to a concentration of 0.75 mM., TATA (1.2 eq) dissolved in minimum amount of CH3CN was added, and the reaction was initiated by adding a solution of 60mM NH4HCO3in H2O to afford a final peptide concentration of 0.5 mM. The reaction was allowed to proceed for 60 min at rt, and lyophilised once the reaction had completed (judged by UPLC-MS). Following lyophilisation, the modified peptide was purified by Preparative RP high performance liquid chromatography tandem mass spectrometer (HPLC-MS) using the following columns: Waters Atlantis T3 OBD column, 100 Å, 5 µm, 150 x 19 mm; Waters XSelect CSH C18 OBD column, 130 Å, 5 µm, 150 x 19 mm or Waters XSelect CSH Fluoro-Phenyl OBD column, 130 Å, 5 µm, 150 x 19 mm. The mobile phases were: A = H2O + 0.15% TFA and B = CH3CN with a flow of 30 ml / min at rt. Pure fractions containing the correct TATA-modified peptide material (as identified by UPLC-MS) were pooled, lyophilised and kept at -20 °C for storage.Method 2: Synthesis of homodimers and heterodimers

[1579] Method 2a

[1580] Synthesis of homodimers with NHS-activated linkers: A solution of the Bis-PEGx-NHS ester (1.05 eq., 14 mM) in DMF was added portion wise during 30 min to a solution of the TATA-modified peptide (2 eq, 14 mM) in DMF and DIPEA (20 eq) and the reaction mixture was stirred at room temperature for 1-12 h. The reaction was monitored by UPLC-MS and upon completion the mixture was purified by reversed phase HPLC (gradient MeCN in H2O / TFA 100 / 0.15) to give the target dimer.

[1581] Method 2b

[1582] Synthesis of heterodimer with NHS-activated linkers: A solution of the Bis-PEGx-NHS ester (1.05 eq., 14 mM) in DMF was added portion wise during 30 min to a solution of the a first monomerof a TATA-bicycle peptide (2 eq, 14 mM) in DMF and DIPEA (20 eq) and the reaction mixture was stirred at room temperature, After 2 h, a second monomer of TATA-bicycle peptide added to the reaction mixture and continued stirring for one more hour. The reaction was monitored by UPLC-MS and upon completion the mixture was purified by reversed phase HPLC (gradient MeCN in H2O / TFA 100 / 0.15) to give the target heterodimer.

[1583] Method 2c

[1584] Synthesis of bicycle-(Ahx)2 Seb dimers with activated Boc-Ahx-OSu linker: A solution of 6-(Boc-amino)hexanoic acid N-succinimidyl ester (Boc-6-Ahx-OSu, 1.05 eq., 0.06 M) portion wise during 30 min to a solution of the TATA-modified peptide (1 eq., 23 mM) in DMF DIPEA (20 eq.). The reaction mixture was stirred at room temperature for 2-4 h. The reaction was monitored by UPLC-MS and upon completion water was added and the reaction mixture freeze dried. The crude product was taken to the next step without further purifications.

[1585] A cleavage solution of TFA / H2O (9 / 1) was added to the crude Boc-protected material and the reaction mixture (9 mM) was agitated at room temperature for 2 h. The reaction mixture was precipitated in cold Et2O, the precipitated product was centrifugated and the supernatant discarded. The solid material was washed two times by addition of cold Et2O and centrifugation. The resulting solid material was suspended in MeCH / H2O (50 / 50) and freeze dried. The crude deprotected product, bicycle-Ahx, was taken to the next step without further purifications (step 1). Step 1 further repeated to give the bicycle-(Ahx)2 peptide (step 2).

[1586] A solution of the sebacic acid bis(N-succinimidyl) ester (1.04 eq., 22 mM) in DMF was added portion wise during 30 min to a solution of the bicycle-(Ahx)2 peptide (from step 1; 2 eq, 16mM) or bicycle-(Ahx)2 peptide (from step 2; 2 eq, 16 mM) in DMF and DIPEA (20 eq) and the reaction mixture was stirred at room temperature for 2 - 12 h. The reaction was monitored by UPLC-MS and upon completion the mixture was purified by reversed phase HPLC (gradient MeCN in H2O / TFA 100 / 0.15) to give the target dimer.

[1587] Method 2d

[1588] Synthesis of homodimers with strain-promoted azide-alkyne cycloaddition (SPAAC): A solution of N3-functionalised linker (1 eq, 2.49 µmol) prepared in 50 % aqeous CH3CN (2 mL) and added slowly to a DBCO-functionalised monomer (method 1C; 2 eq, 5.03 µmol). The reaction mixture stirred overnight and the monitored by UPLC-MS to confirm the conversion of starting material. The reaction directly submitted for the purification by reverse-phase HPLC (gradient MeCN in H2O / TFA 100 / 0.15) to afford a homodimer as a white solid.

[1589] Exemplified monomers and multimers of the invention were synthesized according to the above mentioned method and the Mass Spectrometry results are shown in Table 3:

[1590] Table 3: Synthesis and Characterising Data for Selected Monomers and Multimers of the Invention

[1591] BCY m / z Ion General

[1592] Number Method

[1593] BCY8969 2040.3 [M+H] 1a

[1594] BCY8970 1016.4671 [M+2H] 1a

[1595] BCY8971 893.3859 [M+2H] 1a

[1596] BCY8973 1838.1 [M+H] 1a

[1597] BCY8974 2152.4 [M+H] 1a

[1598] BCY8976 1787.2 [M+H] 1a

[1599] BCY8977 2081.4 [M+H] 1a

[1600] BCY8978 1993.3 [M+H] 1a

[1601] BCY8979 1852.1 [M+H] 1a

[1602] BCY8980 1936.3 [M+H] 1a

[1603] BCY8981 2042.3 [M+H] 1a

[1604] BCY8982 1076.9493 [M+2H] 1a

[1605] BCY8983 2334.7 [M+H] 1a

[1606] BCY8984 1000.447 [M+2H] 1a

[1607] BCY8985 1015.4755 [M+2H] 1a

[1608]

[1609] BCY8986 1922.3 [M+H] 1a BCY8988 2121.5 [M+H] 1a BCY8989 962.4089 [M+2H] 1a BCY8991 1717.1 [M+H] 1a BCY8992 1002.9667 [M+2H] 1a BCY9189 960.9341 [M+2H] 1a BCY9190 885.4063 [M+2H] 1a BCY9191 1011.4344 [M+2H] 1a BCY9192 938.4205 [M+2H] 1a BCY9193 2017.4 [M+H] 1a BCY9194 2003.4 [M+H] 1a BCY9195 944.383 [M+2H] 1a BCY9196 1026.9274 [M+2H] 1a BCY9197 1002.4143 [M+2H] 1a BCY9198 977.9244 [M+2H] 1a BCY9199 1057.9729 [M+2H] 1a BCY9200 1038.4329 [M+2H] 1a BCY9201 1133.9736 [M+2H] 1a BCY9204 1097 [M+2H] 1a BCY9205 1125.9792 [M+2H] 1a BCY9206 987.9197 [M+2H] 1a BCY9209 1136.5166 [M+2H] 1a BCY9210 1127.5023 [M+2H] 1a BCY9211 910.912 [M+2H] 1a BCY9212 941.9247 [M+2H] 1a BCY9213 897.4053 [M+2H] 1a BCY9792 1021.9606 [M+2H] 1a; 1e BCY9793 1029.9493 [M+2H] 1a BCY9794 971.4518 [M+2H] 1a BCY9795 975.9335 [M+2H] 1a; 1e BCY9796 986.949 [M+2H] 1a BCY9797 961.9369 [M+2H] 1a BCY9798 931.9415 [M+2H] 1a BCY10087 948.9578 [M+2H] 1a BCY10088 1016.4286 [M+2H] 1a

[1610]

[1611] BCY10089 1036.9552 [M+2H] 1a BCY10090 1036.4487 [M+2H] 1a BCY10091 1008.9395 [M+2H] 1a BCY10092 1001.4242 [M+2H] 1a BCY10094 976.9172 [M+2H] 1a BCY10096 1084.9515 [M+2H] 1a BCY10097 1023.9072 [M+2H] 1a BCY10098 998.8992 [M+2H] 1a BCY10099 1053.916 [M+2H] 1a BCY10100 992.4024 [M+2H] 1a BCY10101 1007.9203 [M+2H] 1a BCY10102 1050.4362 [M+2H] 1a BCY10103 1013.4167 [M+H] 1a BCY10104 1998.4 [M+2H] 1a BCY10105 1012.9174 [M+2H] 1a BCY10107 965.4271 [M+2H] 1a BCY10108 943.4151 [M+2H] 1a BCY10109 921.4243 [M+2H] 1a BCY10111 1029.9358 [M+2H] 1a BCY10112 1072.4291 [M+2H] 1a BCY10113 1073.4592 [M+2H] 1a BCY10114 1013.9415 [M+2H] 1a BCY10115 1036.4127 [M+2H] 1a BCY10116 953.4346 [M+2H] 1a BCY10118 971.959 [M+2H] 1a BCY10120 987.4183 [M+2H] 1a BCY10205 2075.4 [M+H] 1a BCY10206 2163.4 [M+H] 1a BCY10207 2070.3 [M+H] 1a BCY10208 1017.4535 [M+2H] 1a BCY10209 2001.3 [M+H] 1a BCY10210 1039.4683 [M+2H] 1a BCY10212 1033.4767 [M+2H] 1a BCY10214 1972.2 [M+H] 1a BCY10215 930.4303 [M+2H] 1a

[1612]

[1613] BCY10216 922.9253 [M+2H] 1a BCY10217 892.9238 [M+2H] 1a BCY10218 923.9324 [M+2H] 1a BCY10219 952.9359 [M+2H] 1a BCY10220 892.4143 [M+2H] 1a BCY10221 978.4593 [M+2H] 1a BCY10222 983.4348 [M+2H] 1a BCY10261 1128.5077 [M+2H] 1a BCY10262 1140.4945 [M+2H] 1a BCY10263 1100.4847 [M+2H] 1a BCY10264 1084.5006 [M+2H] 1a BCY10266 1084.9663 [M+2H] 1a BCY10267 1123.9723 [M+2H] 1a BCY10269 1081.9513 [M+2H] 1a BCY10270 1108.4651 [M+2H] 1a BCY10272 1171.4916 [M+2H] 1a BCY10273 1110.994 [M+2H] 1a BCY10274 1095.5168 [M+2H] 1a BCY10275 1113.4885 [M+2H] 1a BCY10276 1040.9667 [M+2H] 1a BCY10277 1023.9312 [M+2H] 1a BCY10278 968.4321 [M+2H] 1a BCY10279 1004.923 [M+2H] 1a BCY10280 1031.9565 [M+2H] 1a BCY10281 1039.4595 [M+2H] 1a BCY10282 991.4181 [M+2H] 1a BCY10283 984.9312 [M+2H] 1a BCY10285 995.4438 [M+2H] 1a BCY10286 917.3939 [M+2H] 1a BCY10301 1308.1 [M+2H] 1a BCY10302 1317.6261 [M+4H] 2a BCY10303 1261.9 [M+2H] 1a BCY10304 1271.5944 [M+4H] 2a BCY10317 1056.4175 [M+2H] 1a BCY10318 1055.9272 [M+2H] 1a

[1614]

[1615] BCY10319 1055.9454 [M+2H] 1a BCY10320 1107.9642 [M+2H] 1a BCY10322 1099.4536 [M+2H] 1a BCY10323 1030.9106 [M+2H] 1a BCY10325 1109.9498 [M+2H] 1a BCY10326 2087.3 [M+H] 1a BCY10328 1029.4698 [M+2H] 1a BCY10329 1979.2 [M+2H] 1a BCY10330 2024.2 [M+2H] 1a BCY10384 971.9265 [M+2H] 1a BCY10385 893.3793 [M+2H] 1a BCY10386 NV [M+2H] 1a BCY10387 925.8997 [M+2H] 1a BCY10583 1097.0347 [M+2H] 1a BCY10584 1088.9659 [M+2H] 1a BCY10585 1127.9662 [M+2H] 1a BCY10586 1096.4554 [M+2H] 1a BCY10765 1159.005 [M+2H] 1a BCY10767 1174.0129 [M+2H] 1a BCY10768 2279.6 [M+H] 1a BCY10769 1163.4998 [M+2H] 1a BCY10770 1134.9899 [M+2H] 1a BCY10771 2103.4 [M+H] 1a BCY10772 1078.0111 [M+2H] 1a BCY10773 2101.3 [M+H] 1a BCY10775 2096.4 [M+H] 1a BCY10776 1058.4474 [M+2H] 1a BCY10777 2096.3 [M+H] 1a BCY10778 1067.4991 [M+2H] 1a BCY10779 1067.5002 [M+2H] 1a BCY10869 2168.5 [M+H] 1a BCY10870 2040.3 [M+H] 1a BCY10871 2238.5 [M+H] 1a BCY11119 1217.0674 [M+2H] 1a BCY11120 2437.8 [M+H] 1a

[1616]

[1617] BCY11124 2463 [M+H] 1a BCY11129 1120.024 [M+2H] 1a BCY11130 1119.4901 [M+2H] 1a BCY11131 2315 [M+H] 1a BCY11132 2315 [M+H] 1a BCY11138 2341 [M+H] 1a BCY11139 1140.4902 [M+2H] 1a BCY11328 2192.5 [M+H] 1a BCY11331 1083.9685 [M+2H] 1a BCY11333 1014.929 [M+2H] 1a BCY11335 984.9312 [M+2H] 1a; 1e BCY11336 2008 [M+H] 1a BCY11337 1067.4792 [M+2H] 1a BCY11340 1026.4657 [M+2H] 1a BCY11341 990.4063 [M+2H] 1a BCY11342 1000.9454 [M+2H] 1a BCY11619 1095.4705 [M+2H] 1a BCY11620 2257 [M+H] 1a BCY11621 1118.4956 [M+2H] 1a BCY11624 1974.2 [M+H] 1a BCY11625 1046.4661 [M+2H] 1a BCY11626 704.3999 [M+3H] 1a BCY11628 2113 [M+H] 1a BCY11629 1095.4994 [M+2H] 1a BCY11630 1077.4581 [M+2H] 1a BCY11632 1051.6 [M+2H] 1a BCY11633 2124.1 [M+H] 1a BCY11635 2021.2 [M+H] 1a BCY11636 2087 [M+H] 1a BCY11637 1998 [M+H] 1a BCY11638 1077.9963 [M+2H] 1a BCY11639 993.9108 [M+2H] 1a BCY11640 1952 [M+H] 1a BCY11641 1027.4534 [M+2H] 1a BCY11973 1110.3 [M+2H] 1a

[1618]

[1619] BCY11974 1101.4836 [M+2H] 1a BCY11975 718.6659 [M+3H] 1a BCY11976 1053.8 [M+2H] 1a BCY11977 716.6793 [M+3H] 1a BCY11978 712.6603 [M+3H] 1a BCY12100 1143.4946 [M+2H] 1a BCY12101 771.688 [M+3H] 1a BCY12102 727.319 [M+3H] 1a BCY12103 771.0281 [M+3H] 1a BCY12104 1223.5615 [M+2H] 1a BCY12105 1114.5041 [M+2H] 1a BCY12106 604.5247 [M+4H] 1a BCY12107 1137.0158 [M+2H] 1a BCY12108 1167.0042 [M+2H] 1a BCY12109 1126.021 [M+2H] 1a BCY12110 1090.4966 [M+2H] 1a BCY12111 732.6674 [M+3H] 1a BCY12112 1099.4625 [M+2H] 1a BCY12113 743.6737 [M+3H] 1a BCY12114 1177.5141 [M+2H] 1a BCY12115 743.7 [M+3H] 1a BCY12152 1027.965 [M+2H] 1a BCY12153 943.8782 [M+2H] 1a BCY20398 1028.9674 [M+2H] 1a BCY20399 1022.4498 [M+2H] 1a BCY20400 1021.9606 [M+2H] 1a BCY20401 1021.9606 [M+2H] 1a BCY20402 1014.9499 [M+2H] 1a BCY20404 1008.4283 [M+2H] 1a BCY20405 1000.9316 [M+2H] 1a BCY20406 1000.9316 [M+2H] 1a BCY20407 999.9637 [M+2H] 1a BCY20408 983.9435 [M+2H] 1a BCY20409 979.4234 [M+2H] 1a BCY20410 975.9445 [M+2H] 1a

[1620]

[1621] BCY20411 975.9445 [M+2H] 1a BCY20413 1056.9783 [M+2H] 1a BCY20414 1035.97 [M+2H] 1a BCY20415 1058.4285 [M+2H] 1a BCY20416 957.4316 [M+2H] 1a BCY20417 978.4317 [M+2H] 1a BCY20418 872.3749 [M+2H] 1a BCY20419 950.4238 [M+2H] 1a BCY20420 950.4238 [M+2H] 1a BCY20421 935.4155 [M+2H] 1a BCY20422 930.4031 [M+2H] 1a BCY20423 929.3889 [M+2H] 1a BCY20426 921.9132 [M+2H] 1a BCY20427 921.4155 [M+2H] 1a BCY20430 1078.3 [M+2H] 1a BCY20431 1076.4647 [M+2H] 1a BCY20432 1074.9647 [M+2H] 1a BCY20433 1064 [M+2H] 1a BCY20434 1061.9624 [M+2H] 1a BCY20435 1054.4797 [M+2H] 1a BCY20436 1054.4783 [M+2H] 1a BCY20437 1045.5006 [M+2H] 1a BCY20438 1036.108 [M+2H] 1a BCY20439 1022.508 [M+2H] 1a BCY20440 1010.9565 [M+2H] 1a BCY20441 989.9454 [M+2H] 1a BCY20442 1005.9446 [M+2H] 1a BCY20443 1005.938 [M+2H] 1a BCY20444 989.9321 [M+2H] 1a BCY20445 982.9352 [M+2H] 1a BCY20446 981.4356 [M+2H] 1a BCY20447 981.4297 [M+2H] 1a BCY20448 981.4297 [M+2H] 1a BCY20449 981.4356 [M+2H] 1a BCY20450 976.4225 [M+2H] 1a

[1622]

[1623] BCY20451 975.9257 [M+2H] 1a BCY20452 965.4226 [M+2H] 1a BCY20453 965.413 [M+2H] 1a BCY20454 963.9 [M+2H] 1a BCY20456 637.5 [M+3H] 1a BCY20457 637.5 [M+3H] 1a BCY20458 632.2 [M+3H] 1a BCY20459 1885.8413 [M+H] 1a BCY20460 934.4 [M+3H] 1a BCY20461 919.4 [M+3H] 1a BCY20463 954.9 [M+3H] 1a BCY20464 984.9312 [M+2H] 1a BCY20466 1143.3 [M+2H] 1a BCY20467 1134.5171 [M+2H] 1a BCY20468 1129.4 [M+2H] 1a BCY20469 1108.2 [M+2H] 1a BCY20470 1105.7 [M+2H] 1a BCY20471 1101.0 [M+2H] 1a BCY20472 1099 [M+2H] 1a BCY20473 1087.992 [M+2H] 1a BCY20474 1079.98 [M+2H] 1a BCY20475 1077.033 [M+2H] 1a BCY20476 1065.9872 [M+2H] 1a BCY20477 1055.985 [M+2H] 1a BCY20478 704.3268 [M+2H] 1a BCY20479 1052.988 [M+2H] 1a BCY20480 1048.9772 [M+2H] 1a BCY20481 699.6485 [M+2H] 1a; 1e BCY20482 699.6543 [M+2H] 1a BCY20483 1039.4556 [M+2H] 1a BCY20484 1034.9642 [M+2H] 1a BCY20485 1034.9642 [M+2H] 1a BCY20486 1032.4482 [M+2H] 1a BCY20487 1019.9491 [M+2H] 1a BCY20488 1018.4487 [M+2H] 1a

[1624]

[1625] BCY20489 1014.4416 [M+2H] 1a BCY20490 1006.444 [M+2H] 1a BCY20491 998.9478 [M+2H] 1a BCY20492 998.9478 [M+2H] 1a BCY20493 968.4405 [M+2H] 1a BCY20494 949.4133 [M+2H] 1a BCY20495 941.9049 [M+2H] 1a BCY20496 941.9049 [M+2H] 1a BCY20497 934.9008 [M+2H] 1a BCY20498 926.8977 [M+2H] 1a BCY20499 919.89 [M+2H] 1a BCY20500 913.8735 [M+2H] 1a BCY20501 896.8847 [M+2H] 1a BCY20503 926.3986 [M+2H] 1a BCY20504 1013.9473 [M+2H] 1a BCY20505 978.4249 [M+2H] 1a BCY20506 976.4297 [M+2H] 1a BCY20507 1157.5245 [M+2H] 1a BCY20508 1143.504 [M+2H] 1a BCY20509 1143.0089 [M+2H] 1a BCY20510 1122.498 [M+2H] 1a BCY20511 1122.498 [M+2H] 1a BCY20512 1115.4785 [M+2H] 1a BCY20513 1113.5 [M+2H] 1a BCY20514 1108.481 [M+2H] 1a BCY20515 1108.6 [M+2H] 1a BCY20516 1072.9712 [M+2H] 1a BCY20517 1072.9569 [M+2H] 1a BCY20518 1072.9569 [M+2H] 1a BCY20519 1065.9657 [M+2H] 1a BCY20520 1044.4299 [M+2H] 1a BCY20521 1368.5812 [M+2H] 1a BCY20522 1334.5416 [M+2H] 1a BCY20523 1044.9 [M+2H] 1b BCY20524 1027.9 [M+2H] 1b

[1626]

[1627] BCY20525 985.4 [M+2H] 1b BCY20544 1039.098 [M+3H] 1a BCY20545 991.4935 [M+2H] 1a BCY20555 949.3796 [M+2H] 1a BCY20556 946.9 [M+2H] 1a BCY20557 924.3905 [M+2H] 1a BCY20558 922.3845 [M+2H] 1a BCY20559 921.4155 [M+2H] 1a BCY20560 914.4022 [M+2H] 1a BCY20561 1585.2694 [M+2H] 1a BCY20562 1232 [M+2H] 1a BCY20577 1322.5542 [M+2H] 1a BCY20578 1649.3151 [M+2H] 1a BCY20579 845.3679 [M+3H] 1c BCY20655 1209.0507 [M+2H] 1c BCY20656 1162.7 [M+2H] 1c BCY20657 765.7023 [M+3H] 1c BCY20658 1142.0188 [M+2H] 1c BCY20659 1105.5217 [M+2H] 1c BCY20661 1070.1 [M+2H] 1c BCY22761 1189.6 [M+4H] 2c BCY22762 1204.2 [M+4H] 2c BCY22763 1609.793 [M+3H] 2c BCY22764 985.1071 [M+5H] 2c BCY22766 1862.9 [M+4H] 2d BCY22767 1845.9 [M+4H] 2d BCY22768 1148.5138 [M+4H] 2a BCY22769 1549.7097 [M+3H] 2a BCY22770 1199.608 [M+4H] 2a BCY22771 1307.9 [M+4H] 2a BCY22772 1322.2 [M+4H] 2a BCY22773 1213.4 [M+4H] 2a BCY22774 1216.572 [M+4H] 2a BCY22775 1009.8859 [M+5H] 2a BCY22776 1220.4 [M+4H] 2a

[1628]

[1629] BCY22777 1617.6 [M+3H] 2a BCY22778 1220.5 [M+4H] 2a BCY22779 1191.0614 [M+4H] 2a BCY22780 1208.0723 [M+4H] 2a BCY22781 1149.5 [M+4H] 2a BCY22782 1192.5457 [M+4H] 2a BCY22783 1212.1 [M+4H] 2a BCY22784 1351.1198 [M+4H] 2a BCY22785 1366.2 [M+4H] 2a BCY22786 1377.9 [M+4H] 2a BCY22787 1236.5677 [M+4H] 2a BCY22788 1001.7 [M+5H] 2a BCY22789 1117.318 [M+4H] 2a BCY22790 1410.4 [M+4H] 2a BCY22791 1060.4633 [M+4H] 2a BCY22792 1125.2 [M+4H] 2a BCY22793 1082.4794 [M+4H] 2a BCY22794 1147.508 [M+4H] 2a BCY22795 1472.3176 [M+3H] 2a BCY22796 1491.005 [M+3H] 2a BCY22797 1263.7 [M+4H] 2a BCY22798 1278.3 [M+4H] 2a BCY22799 1169.4 [M+4H] 2a BCY22800 1208.5 [M+4H] 2a BCY22801 1557.7153 [M+3H] 2a BCY22802 1310.6 [M+4H] 2a BCY22803 1355.9 [M+4H] 2a BCY22804 1432.3 [M+4H] 2a BCY22805 1262.6 [M+4H] 2a BCY22806 1683.1 [M+3H] 2a BCY22807 1217.0902 [M+4H] 2a BCY22808 1239.0748 [M+4H] 2a BCY22809 1280.5975 [M+4H] 2a BCY22810 1327.6188 [M+4H] 2a BCY22811 1392.4 [M+4H] 2a

[1630]

[1631] BCY22812 1282.6165 [M+4H] 2a BCY22813 1308.5884 [M+4H] 2a BCY22814 1294.6141 [M+4H] 2b BCY22815 1280.5975 [M+4H] 2a BCY22816 1002.858 [M+5H] 2a BCY22817 1332.408 [M+4H] 2a BCY22818 1286.408 [M+4H] 2a BCY22819 1295.308 [M+4H] 2a BCY22820 1786.4548 [M+3H] 2a BCY22821 1439.1747 [M+4H] 2a BCY22822 1411.1431 [M+4H] 2a BCY22823 1294.6118 [M+4H] 2a BCY22824 1449.683 [M+4H] 2a 3

[1632] BCY22825 1345.8 [M+4H] 2a BCY22826 1345.7 [M+4H] 2a BCY22827 1315.1 [M+4H] 2a BCY22828 1310.108 [M+4H] 2a BCY22829 1336 [M+4H] 2a BCY22830 1349.6 [M+4H] 2a BCY22831 1362.5 [M+4H] 2a BCY22832 1315.098 [M+4H] 2a BCY22833 1272.608 [M+4H] 2a BCY22834 1438.8 [M+4H] 2a BCY22835 1285.1 [M+4H] 2a BCY22839 1244.32535 [M+4H] 2a BCY_A1 747.017 [M+3H] 1a BCY_A2 713.3477 [M+3H] 1a BCY_B1 1887.2476 [M+3H] 2a BCY_B2 1643.8007 [M+3H] 2a BCY_B4 1653.1464 [M+3H] 2a BCY_B5 1741.1737 [M+3H] 2a

[1633]

[1634] BIOLOGICAL DATA

[1635]

[1636] 1. GFRAL Surface Plasmon Resonance (SPR) Biological Assay

[1637] The affinities of the Bicyclic peptides binding to human GFRAL, mouse GFRAL and the related selectivity target GFRal were measured using Surface Plasmon Resonance (SPR). SPR experiments were performed on a Biacore T200, S200 or 8k instrument (Cytiva) at 20 °C using 1 Hz data collection with a running buffer consisting of 50 mM HEPES (pH 7.4), 150 mM NaCI, 0.005% (v / v) Tween-20 (polyoxyethylene(20)sorbitan monolaurate) and 1% (v / v) DMSO (dimethyl sulfoxide). Human GFRAL (residues 19-351) and mouse GFRAL (114-345) were immobilized to a streptavidin-coated surface using a C-terminally biotinylated Avi-tag. Human GFRal was immobilized directly using amine coupling. A Series S CMD500L sensor chip (Xantec GmbH) was docked into the system. The Sensor Chip surface was conditioned with 3 x 60 s injections of 50 mM NaOH / 1 M NaCI. The surface was then activated using a freshly prepared 1:1 mixture of 0.4 M of EDC (1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide) and 0.1 M of NHS (N-hydroxysuccinimide). For hGFRAL and mGFRAL, streptavidin at 1 pM in 10 mM acetate pH 5.5 was first immobilized at 10000 RU. Biotinylated human GFRAL and mouse GFRAL were then immobilized at 500-1000 RU. Reference and protein surfaces were subsequently blocked with biotin-PEG. Human GFR1a1 was immobilized using amine coupling at pH 5.5 at 500-1000 RU. Monomeric peptides were prepared in a 384-well polypropylene microplate (Greiner) in 10-point concentration-response series with a 10 pM or 100 pM top concentration in buffer and with 3-fold dilutions, and a constant DMSO concentration at 1.0% (v / v) DMSO. Monomeric peptide samples were analysed using multiplecycle injections with 60 s association time followed by 360 s dissociation time at 30 pL / min. Dimeric peptides were analysed using single-cycle kinetics. The dimeric peptides were prepared in 5 or 6 point concentration-response series with 4-fold dilutions and a top concentration of 0.25 pM or 1 pM. Affinity parameters were determined by global fitting to a 1:1 binding model using T200 / S200 / 8k software (Cytiva). Dimeric peptides were analyzed using a heterogeneous ligand model to account for a mixture for monovalent and bi-valent interactions. For the dimeric peptides only the higher affinity bi-valent interaction component is listed. The Kd-values for peptides binding to human GFRAL, mouse GFRAL and the related selectivity target GFRal are shown in Tables 4 and 5.

[1638] hGFRaL and mGFRaL were expressed and purified as follows. Codon optimized hGFRaL (Uniprot ID Q6UXV0) extracellular domain (S19-E351) and mGFRaL (Uniprot ID Q6SJE0) residues W114-S345 with the native signal peptide replaced by CD33 signal peptide and C-terminal His-Avi tag were cloned into an in-house mammalian expression vector (pMAZT). For HDX-MS, hGFRaL (residues W115-E351) with a CD33 signal peptide and C-terminal 6xHis-tag was cloned into pMAZT. The proteins were expressed by transienttransfection of Expi293F cells in Expi293 expression medium (ThermoFisher Scientific) using PEI Max transfection reagent (PolySciences Inc.). The cells were cultured for 6 days at 37 °C, 8% CO2. The media with secreted mGFRaL was incubated overnight at 4 °C with “teabags” containing Ni-Excel resin (Cytiva) and washed. The protein was eluted using 300 mM imidazole. Media containing hGFRaL was loaded onto HisTrap FF crude columns (Cytiva), but eluted with the wash fraction. The concentrated wash fraction of hGFRaL and the concentrated mGFRaL were loaded on a Superdex 200 16 / 60 column (Cytiva) and a Superdex 200 26 / 60 column (Cytiva), respectively, equilibrated in 25 mM HEPES, pH 7.5, 150 mM NaCI, 10% (v / v) glycerol. The concentrated proteins were then flash-frozen in liquid nitrogen. The proteins were biotinylated using “BirA biotin-protein ligase standard reaction kit” (Avidity). Media containing hGFRaL for HDX-MS was loaded on a 5 mL HisTrap Excel (Cytiva) column and eluted in 400 mM imidazole. The concentrated protein was loaded on a Superdex 200 26 / 60 column (Cytiva) equilibrated in 25 mM HEPES, pH 7.5, 150 mM NaCI. The concentrated protein was flash-frozen in liquid nitrogen.

[1639] Selected monomeric peptides of the invention were tested in the above mentioned SPR assay and the results are shown below in Table 4:

[1640] Table 4: GFRAL SPR Data For Selected Monomeric Peptides of the Invention

[1641] Monomeric SPR human SPR mouse SPRGFR1a1

[1642] BCY (pM) (pM) (pM)

[1643] Number

[1644] BCY8969 5.5 >100 >100

[1645] BCY8970 0.88 220 >100

[1646] BCY8971 100 >100

[1647] BCY8973 2.3 >100 >100

[1648] BCY8974 3.4 >100 >100

[1649] BCY8976 3.4 >100 >100

[1650] BCY8977 2.8 >100

[1651] BCY8978 1.5 84

[1652] BCY8979 3 >100 >100

[1653] BCY8980 9.1 >100 >100

[1654] BCY8981 11 >100 >100

[1655] BCY8982 6.9 200 >100

[1656] BCY8983 3.5 >100 >100

[1657] BCY8984 6.9 4.6

[1658]

[1659] BCY8985 20 170

[1660] BCY8986 9 >100 >100 BCY8988 3.8 >100 >100 BCY8989 3.5 60 >100 BCY8991 4.7 >100 >100 BCY8992 0.7 110 >100 BCY9189 3 >100

[1661] BCY9190 3.3 >100 >100 BCY9191 16 >100 >100 BCY9192 4.9 >100 BCY9193 1.9 >100 >100 BCY9194 6.3 >100 >100 BCY9195 6 >100

[1662] BCY9196 7.8 >100

[1663] BCY9197 8.7 190

[1664] BCY9198 18 160

[1665] BCY9199 1.7 32 >100 BCY9200 5.3 >100 >100 BCY9201 5.9 >100

[1666] BCY9204 3.4 >100

[1667] BCY9205 9.8 >100 >100 BCY9206 7.8 >100 >100 BCY9209 1.9 >100 >100 BCY9210 2.7 >79 >100 BCY9211 2.6 >100 >100 BCY9212 6.4 >100 >100 BCY9213 3.3 >100 >100 BCY9792 0.077 >100 >100 BCY9793 0.2 >100 >100 BCY9794 0.59 >100

[1668] BCY9795 0.54 120 >100 BCY9796 0.26 >100

[1669] BCY9797 0.54 >100 >100 BCY9798 0.96 >100 >100 BCY10087 1.5 >100 >100

[1670]

[1671] BCY10088 0.27 >100

[1672] BCY10089 0.095 >100 >100 BCY10090 0.27 180

[1673] BCY10091 2.3 >100 >100 BCY10092 100 >100 >100 BCY10094 0.35 >100 >100 BCY10096 2 >100 >100 BCY10097 0.74 >100

[1674] BCY10098 2.9 >100 >100 BCY10099 0.75 >100 >100 BCY10100 3.6 >100 >100 BCY10101 0.58 >100 >100 BCY10102 0.56 >100 >100 BCY10103 0.44 >100 >100 BCY10104 100 >100 >100 BCY10105 2.4 >100 >100 BCY10107 0.88 100 >100 BCY10108 0.24 45 >100 BCY10109 0.45 59 >100 BCY10111 1.1 45 >100 BCY10112 1.1 140 >100 BCY10113 1.3 35 >100 BCY10114 0.79 190 >100 BCY10115 0.38 120

[1675] BCY10116 1.4 >100 >100 BCY10118 2 >100 >100 BCY10120 4.7 >100

[1676] BCY10205 2.9 >100 >100 BCY10206 1.8 >100 >100 BCY10207 1.7 >100 >100 BCY10208 1.2 220 >100 BCY10209 100 >100 >100 BCY10210 0.52 120 >100 BCY10212 2.1 >100 >100 BCY10214 6.5 >100 >100

[1677]

[1678] BCY10215 1.8 >100 >100 BCY10216 4.1 >100

[1679] BCY10217 6.1 >100 >100 BCY10218 2.4 >100 >100 BCY10219 4.7 >100

[1680] BCY10220 3 >100 >100 BCY10221 3.3 >100 >100 BCY10222 3.8 >100 >100 BCY10261 1 >100 >100 BCY10262 2.4 >100 >100 BCY10263 0.92 >100 >100 BCY10264 0.72 >100 >100 BCY10266 9.7 >100 >100 BCY10267 1.8 >100 >100 BCY10269 1.6 190 >100 BCY10270 1.4 110 >100 BCY10272 2.4 >100 >100 BCY10273 2.4 >100 >100 BCY10274 0.42 >81 >100 BCY10275 1.8 >56 >100 BCY10276 1.1 110 >100 BCY10277 1.4 27 >100 BCY10278 1.5 38 >100 BCY10279 4.8 77

[1681] BCY10280 0.68 25 >100 BCY10281 1.2 57 >100 BCY10282 1.4 >100 >100 BCY10283 0.89 79 >100 BCY10285 4.9 >100 >100 BCY10286 1.8 >100 >100 BCY10301 0.46 >100 >5 BCY10303 0.23 >100 >5 BCY10317 4.6 69 >100 BCY10318 2.7 83 >100 BCY10319 1.3 >100 >100

[1682]

[1683] BCY10320 1.2 110 >100 BCY10322 4.6 200

[1684] BCY10323 19 >100

[1685] BCY10325 2.5 200

[1686] BCY10326 10 >100 >100 BCY10328 100 >100 >100 BCY10329 10 >100 >100 BCY10330 10 >100 >100 BCY10384 0.52 >100 >100 BCY10385 0.14 24 >100 BCY10386 0.86

[1687] BCY10387 0.3 >74 >100 BCY10583 10 >10

[1688] BCY10584 10 >10

[1689] BCY10585 5.9 >10

[1690] BCY10586 25 >10

[1691] BCY10765 2.5 >10

[1692] BCY10767 0.54 >10

[1693] BCY10768 0.31 >100 >100 BCY10769 1.4 >10

[1694] BCY10770 1.7 >100 >100 BCY10771 0.38 56 >100 BCY10772 0.94 >10

[1695] BCY10773 0.21 54 >100 BCY10775 0.68 >100 >100 BCY10776 1.9 >10

[1696] BCY10777 1 >100 >100 BCY10778 0.7 >10

[1697] BCY10779 1.6 >10

[1698] BCY10869 0.58 110 >100 BCY10870 0.28 32 >100 BCY10871 0.25 38 >100 BCY11119 1.8 >100

[1699] BCY11120 4.4 >100

[1700] BCY11124 4.1 5.7

[1701]

[1702] BCY11129 0.52 16

[1703] BCY11130 0.34 7.4 >100 BCY11131 0.42 6

[1704] BCY11132 0.38 16

[1705] BCY11138 0.97 >100

[1706] BCY11139 2.8 >100 >100 BCY11328 2.5 0.93

[1707] BCY11331 0.56 9

[1708] BCY11333 0.39 5.6

[1709] BCY11335 0.21 0.34

[1710] BCY11336 0.16 0.68

[1711] BCY11337 0.096 1.6

[1712] BCY11340 0.13 1.1 >100 BCY11341 12 8.5

[1713] BCY11342 0.15 2.1

[1714] BCY11619 7.4 3.4 >100 BCY11620 3.2 3.7 >100 BCY11621 4.2 7.7 >100 BCY11624 1.1 12 >100 BCY11625 0.29 4.7

[1715] BCY11626 0.13 2.8

[1716] BCY11628 1.3 0.56 >100 BCY11629 1.9 3.8 >100 BCY11630 0.62 2.3 >100 BCY11632 1.2 2.9

[1717] BCY11633 0.74 0.81

[1718] BCY11635 0.26 1.6 >100 BCY11636 0.062 1.3 >100 BCY11637 0.15 2.7 >100 BCY11638 0.066 0.22

[1719] BCY11639 0.21 0.56

[1720] BCY11640 0.12 0.4 >100 BCY11641 2.5 3.4

[1721] BCY11973 0.03 0.12

[1722] BCY11974 0.013 0.075

[1723]

[1724] BCY11975 0.038 0.16 BCY11976 0.12 0.71 BCY11977 0.062 0.4 BCY11978 0.024 0.33 BCY12100 0.12 0.2 BCY12101 0.06 0.15 BCY12102 0.25 1.2 BCY12103 0.076 0.21 BCY12104 0.013 0.14 BCY12105 0.17 0.5 BCY12106 0.046 0.25 BCY12107 0.33 0.58 BCY12108 0.054 0.21 BCY12109 0.038 0.16 BCY12110 0.14 0.41 BCY12111 0.11 0.22 BCY12112 0.16 0.68 BCY12113 0.16 0.66 BCY12114 0.12 0.24 BCY12115 0.026 0.079 BCY12152 0.0099 0.05 BCY12153 0.02 0.065 BCY20398 0.034 92 BCY20399 0.11 >100 BCY20400 3.2 >100 BCY20401 0.22 >100 BCY20402 0.053 98 BCY20404 0.15 >100 BCY20405 11 >100 BCY20406 6.6 >100 BCY20407 0.14 >100 BCY20408 7.9 >100 BCY20409 0.07 >100 BCY20410 6.1 >100 BCY20411 26 >100

[1725]

[1726] BCY20413 0.095

[1727] BCY20414 0.067

[1728] BCY20415 10 >100

[1729] BCY20416 0.18

[1730] BCY20417 0.18

[1731] BCY20418 0.24 23

[1732] BCY20419 0.39 50

[1733] BCY20420 0.23 29

[1734] BCY20421 0.089 11 >100 BCY20422 1.4 26

[1735] BCY20423 0.97 59

[1736] BCY20426 0.23 27 >100 BCY20427 0.27 50

[1737] BCY20430 1 >100 >100 BCY20431 5.4 >100 >100 BCY20432 1.7 73 >100 BCY20433 2.1 >100 >100 BCY20434 3 >100 >100 BCY20435 9.8 >100 >100 BCY20436 2.7 >100 >100 BCY20437 17 >100 >100 BCY20438 2.2 >100 >100 BCY20439 3.6 >100 >100 BCY20440 0.4

[1738] BCY20441 0.17

[1739] BCY20442 65 >100

[1740] BCY20443 88 >100

[1741] BCY20444 71 >100

[1742] BCY20445 3.5 >100

[1743] BCY20446 0.22 30

[1744] BCY20447 0.33 >100

[1745] BCY20448 1 >100

[1746] BCY20449 2.8 61

[1747] BCY20450 1.5 >100

[1748] BCY20451 63 >100

[1749]

[1750] BCY20452 46 >100 BCY20453 4.8 >100 BCY20454 0.3 61 BCY20456 2.8 >100 BCY20457 28 >100 BCY20458 0.09 29 BCY20459 1.5 >100 BCY20460 4.2 >100 BCY20461 0.61 >100 BCY20463 0.1 43 BCY20464 0.53 0.45 BCY20466 1.3 4.5 BCY20467 0.1 0.24 BCY20468 0.026 0.23 BCY20469 0.015 0.12 BCY20470 0.038 0.068 BCY20471 0.041 0.2 BCY20472 0.02 0.079 BCY20473 0.013 0.11 BCY20474 0.015 0.076 BCY20475 0.011 0.072 BCY20476 0.012 0.12 BCY20477 0.0047 0.03 BCY20478 2.9 4.8 BCY20479 0.013 0.078 BCY20480 0.0076 0.057 BCY20481 0.0092 0.076 BCY20482 0.021 0.031 BCY20483 0.049 0.27 BCY20484 0.019 0.12 BCY20485 0.0069 0.043 BCY20486 0.021 0.11 BCY20487 0.16 0.25 BCY20488 0.055 0.37 BCY20489 0.027 0.19

[1751]

[1752] BCY20490 0.015 0.095 BCY20491 0.074 0.16 BCY20492 0.089 0.22 BCY20493 0.018 0.066 BCY20494 0.17 0.27 BCY20495 0.016 0.044 BCY20496 50 62 BCY20497 0.039 0.084 BCY20498 8.4 9 BCY20499 0.41 0.61 BCY20500 69 56 BCY20501 53 >100 BCY20503 0.021 0.044 BCY20504 0.024 0.12 BCY20505 0.014 0.052 BCY20506 0.43 4.5 BCY20507 0.21 1.3 BCY20508 0.01 0.085 BCY20509 0.062 0.1 BCY20510 0.021 0.1 BCY20511 0.008 0.058 BCY20512 0.023 0.12 BCY20513 0.035 0.12 BCY20514 0.01 0.063 BCY20515 0.016 0.16 BCY20516 0.018 0.11 BCY20517 0.035 0.27 BCY20518 0.017 0.14 BCY20519 0.039 0.24 BCY20520 0.083 0.57 BCY20521 5.1 >100 BCY20522 69 >100 BCY20523 0.048 0.18 BCY20524 0.035 0.15 BCY20525 0.043 0.16

[1753]

[1754] BCY20544 2.5 >100

[1755] BCY20545 47 >100

[1756] BCY20555 0.14 10

[1757] BCY20556 0.12 13

[1758] BCY20557 0.15 19

[1759] BCY20558 0.29 25

[1760] BCY20559 0.18 21

[1761] BCY20560 0.14 16

[1762] BCY20561 27 75

[1763] BCY20562 5.2 >100 >100

[1764] BCY20577 2 >41

[1765] BCY20578 0.022 0.14

[1766] BCY20579 0.0077 0.074

[1767] BCY20655 0.027 0.24

[1768] BCY20656 0.03 0.14

[1769] BCY20657 0.04 0.19

[1770] BCY20658 0.014 0.094

[1771] BCY20659 0.015 0.1

[1772] BCY20661 0.014 0.07

[1773] BCY_A1 0.021 0.14

[1774] BCY_A2 0.01 0.01

[1775]

[1776] Selected homodimeric peptides of the invention were tested in the above mentioned SPR assay and the results are shown below in Table 5:

[1777] Table 5: GFRAL SPR Data For Selected Homodimeric Peptides of the Invention

[1778] Homodimeric BCY Number SPR human GFRaL

[1779] (nM)

[1780] BCY22807 0.52

[1781] BCY22812 1.2

[1782] BCY22809 110

[1783] BCY22810 160

[1784] BCY22813 380

[1785] BCY22811 3

[1786]

[1787] BCY22808 1.8 BCY22815 3.6 BCY22816 1.9 BCY22817 3.6 BCY22818 3.3 BCY22819 0.23 BCY22820 4.8 BCY22821 0.43 BCY22782 0.14 BCY22787 0.38 BCY22822 1 BCY22768 0.67 BCY22793 1.3 BCY22791 3.4 BCY22795 4.5 BCY22769 0.11 BCY22796 0.4 BCY22788 0.23 BCY22783 0.3 BCY22823 0.15 BCY22784 0.34 BCY22789 0.25 BCY22824 0.4 BCY22825 0.21 BCY22826 0.049 BCY22770 0.13 BCY22797 0.23 BCY22771 0.1 BCY22790 1.6 BCY22785 0.4 BCY22772 1.1 BCY22798 0.33 BCY22773 0.057 BCY22799 0.026 BCY22794 0.038

[1788]

[1789] BCY22792 0.048 BCY22827 0.15 BCY22828 0.12 BCY22829 0.05 BCY22830 0.019 BCY22831 0.065 BCY22832 0.062 BCY22834 0.69 BCY22800 0.36 BCY22833 0.12 BCY22774 0.82 BCY22835 0.16 BCY22802 1.1 BCY22761 0.22 BCY22805 0.23 BCY22801 0.85 BCY22775 0.17 BCY22806 0.44 BCY22803 0.2 BCY22766 0.26 BCY22767 2.9 BCY22762 0.2 BCY22776 0.01 BCY22777 0.025 BCY22778 1.8 BCY22763 0.21 BCY22764 0.48 BCY22779 0.01 BCY22780 0.01 BCY22781 0.17 BCY10302 2.5 BCY10304 3.4 BCY_B1 3.8 BCY_B2 0.016 BCY_B4 0.013

[1790]

[1791] Selected heterodimeric peptides of the invention were tested in the above mentioned SPR assay and the results are shown below in Table 6:

[1792] Table 6: GFRAL SPR Data For Selected Heterodimeric Peptides of the Invention

[1793] Heterodimeric BCY Number SPR human GFRaL

[1794] (nM)

[1795] BCY22814 2.2

[1796]

[1797] Competition binding studies

[1798] Competition SPR experiments with GDF15 were conducted with human GFRAL immobilized by repeating peptide concentration-response series in the presence of a fixed saturating amount (100 nM) of GDF15. A qualitative assessment of competition (yes / no) was then made. Results shown in Table 7.

[1799] Table 7: GFRAL SPR Competition Data For Selected Peptides

[1800] Compound Competitive with GDF15

[1801] Yes / No

[1802] BCY10108 YES

[1803] BCY9795 YES

[1804] BCY9792 YES

[1805] BCY_A1 YES

[1806] BCY20481 YES

[1807] BCY20477 YES

[1808] BCY_B1 YES

[1809] BCY22773 YES

[1810] BCY22826 YES

[1811] BCY22776 YES

[1812]

[1813] 2. SRF DATA

[1814] Selected peptide ligands and conjugates thereof were tested in a serum response factor (SRF) gene reporter cell-based assay.

[1815] HEK293S cells were stably co-transfected with hGFRaL and human RET as well as an SRF responsive luciferase reporter. In the presence of GDF15, formation of thehexameric GDF15-GFRaL-RET complex triggers a downstream signaling cascade resulting in activation of SRF and subsequent luciferase expression. Activity of the GDF15-GFRaL-RET complex can thus be quantified by direct measurement of the ensuing luciferase bioluminescence. To demonstrate antagonistic activity in this assay, the peptides must first compete with GDF15 (EC50of GDF15 is 0.5 nM) and inhibit the downstream signaling as the assay captures the full biological response of disruption of the GDF15-GFRaL-RET complex.

[1816] The SRF-RE-luc2P firefly luciferase reporter (pGL4.34) was obtained from Promega. cDNA encoding hRET and hGFRaLwith NCBI RefSeq entries; NM_020975.4 and NM_207410.2 were cloned into expression vectors plRESneo3 and plRESpuro3 (both from Clonetech), respectively. Parental HEK293S cells were obtained from ATCC. Cells were maintained in DMEM +10% fetal serum and transfected using either lipofectamine (ThermoFisher) or MaxCyte (Lonza). Stable cell lines were generated by selection with 0.25 mg / mL hygromycin + 0.7 mg / mL geneticin + 0.3 pg / mL puromycin (all from ThermoFisher) and validated by functional assessment and / or Sanger sequencing of genomic DNA. For assays, cells were seeded in DMEM + 10% fetal serum and grown to 80% confluency prior to starvation in serum free medium for 16 h. White 384-well plates were prepared with peptides in 10-point concentration responses with 3-fold dilution and 50 pM final maximal assay concentration yielding 0.5% DMSO. Cells were detached by Accutase (ThermoFisher), washed once in DMEM + 1% FBS prior to plating in serum free medium at 7500 cells and 15 pL per well. Plates were incubated at rt for 15 min prior to addition of GDF15 (Peprotech, 128-28C) at 0.5 nM final assay concentration corresponding to EC50. Plates were incubated at 37 °C, 5% CO2 for 5 h prior to cell lysis and addition of luciferase substrate using SteadyGlo (Promega, E2550) according to instructions from vendor. The luciferase reporter signal was read by Envision (PerkinElmer). Resulting data were used for calculation of concentration responses and fitted in Screener software (Genedata AG) using a a four parameter logistic fit, %Effect = A + (Emax-A) / (1 + (IC50 / x)^C) where A is no stimulation, Emax is the fitted maximum inhibition level at infinite concentration of peptide, x is the concentration of the peptide and C is the Hill slope. IC50 is defined as the concentration at which the inhibitory activity reaches 50% of its maximum level. To facilitate comparison of efficacy data, Emax was normalized to %Effect of the response stimulated by a saturating concentration of 500 nM of the RET inhibitor Stivarga (-100% control). An activity threshold was set to 30% of the maximum efficacy of Stivarga for peptides to be classified as active.

[1817] GDF15 was expressed and purified following a similar protocol as described by Bigalke et al (Sc / . Adv. 2019, 5 (7), eaau4202). Codon optimized human GDF15 (Uniprot ID Q99988) residues A197-I308 with a N-terminal 6xHis-tag and a TEV cleavage site (6HN-TEV-GDF15(197-308)) was cloned into a pET24a vector (Novagen) and expressed inEscherichia coli BL21(DE3) Star (ThermoFisher Scientific) via autoinduction at 25 °C. The resulting inclusion bodies were dissolved and incubated in refolding buffer for 3 days. Ni-Sepharose FF (Cytiva) was added to the refolded GDF15, incubated overnight at room temperature, washed and transferred to a column. The protein was eluted by imidazole (final concentration 300 mM). 3 mM GSH and 0.3 mM GSSG was added to the protein and then the 6xHis-tag was cleaved off by TEV-protease. Urea was added to a final concentration of 3 M. Precipitate was removed by centrifugation and the material was loaded on a Ni-Sepharose FF column. The cleaved dimeric GDF15 was collected by washing the resin with buffer containing 50 mM imidazole. The pH was lowered to pH 4 by adding acetic acid. The protein solution was loaded on a HiTrap SP column (Cytiva). The concentrated protein was loaded on a Superdex 75 column (Cytiva) equilibrated in 25 mM NaAcetate, 100 mM NaCI, pH 4.0 and the protein was flash-frozen in liquid nitrogen.

[1818] Upon cell treatment, a decrease in reporter signal was observed for the tested peptides and conjugates, indicating competition with GDF15 in a cell environment and inhibition of functional complex formation.

[1819] Table 8: GFRAL SRF Data For Selected Peptides and Conjugates

[1820] Compound SRF

[1821] IC50 (nM)

[1822] BCY_A1 4200

[1823] BCY_B1 3200

[1824] BCY12152 1600

[1825] BCY20481 1800

[1826] BCY22792 510

[1827] BCY22773 620

[1828] BCY22826 730

[1829] BCY22762 1400

[1830] BCY20475 >5200

[1831] BCY_B4 130

[1832] BCY20477 470

[1833] BCY22776 68

[1834] BCY22794 540

[1835] BCY22799 970

[1836] BCY22766 1500

[1837] BCY20472 2200

[1838]

[1839] BCY_A2 3700

[1840] BCY22775 990

[1841] BCY_B2 620

[1842]

[1843] 3. IN VIVO PHARMACOKINETICS IN MOUSE

[1844] The in vivo pharmacokinetic properties of four peptides from the 4x8 series were investigated in C57BL / 6 mice following an intravenous dose of 0.5 mg / kg (Figure 1).

[1845] Two male C57BL / 6 mice were given an intravenous bolus dose of test compound via the tail vein at a dose level of 0.5 mg / kg in a dose volume of 2 mL / kg. The animals had free access to food and drinking water during the experiment. At pre-defined time points, blood samples of approximately 0.02 mL were withdrawn from the dorsal metatarsal vein up to 24 h after dosing. The blood samples were transferred into plastic micro centrifuge tubes containing EDTA-K2. Collection tubes with blood samples and anticoagulant were inverted several times for proper mixing of the tube contents and then placed on wet ice prior to centrifugation 4,000 g for 5 min at 4 °C tO Obtain plasma. The plasma samples were stored in a freezer at -75 ± 15°C until analysis by LC-MS / MS.

[1846] The N-acetylated monomer BCY20481, containing only natural residues, displayed moderate clearance of 38 ml / min / kg and a half-life of only 4.6 minutes.

[1847] Mutation of Phe6 into the backbone stabilized unnatural aMePhe residue resulted in 5 times longer half-life for BCY20477, attributed to the decreased clearance, 9.6 ml / min / kg. The plasma protein binding of BCY20477 was low (54 % free in mouse plasma) resulting in an unbound clearance of 18 ml / min / kg. The glomerular filtration rate in mouse is estimated to approximately 10 ml / min / kg and it was therefore concluded that renal filtration of free drug into urine is the major elimination pathway for BCY20477 rather than metabolism.

[1848] A decreased clearance was alsO Observed for compound BCY22826, the PEG25 tandem of BCY20481, but, because of the lower volume of distribution, it only resulted in 3 times longer half-life compared to the monomer BCY20481.

[1849] Compound BCY22776, the PEG13 tandem of BCY20477, had low metabolic clearance already close to the glomerular filtration rate.

[1850] List of References

[1851] Mullican et al (2017) Nat Med. Oct; 23(10), 1150-1157.

[1852] Yang et al (2017) Nat Med. Oct; 23(10), 1158-1166.

[1853] Emmerson et al (2017) Nat Med; Oct; 23(10), 1215-1219.

[1854] Hsu et al (2017) Nature; Oct 12; 550(7675), 255-259.

[1855] Wang, et a / (2021) Nat Rev Endocrinol; 17, 592-607

[1856] Ahmed et al (2021) J Cancer; 12(4), 1125-1132.Fejzo et a / (2018) Epub Sep 14. PMID: 30258246; PMCID: PMC6138473.

[1857] Suriben et al (2020) Nat Med; Aug;26(8), 1264-1270.

[1858] The following are numbered aspects of the disclosure:

[1859] 1. A peptide ligand specific for GFRAL 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.

[1860] 2. The peptide ligand according to aspect 1, wherein said reactive groups comprise cysteine residues.

[1861] 3. The peptide ligand according to aspect 1 or aspect 2, wherein said loop sequences comprise 2, 3, 4, 5, 6, 7, 8, or 9 amino acids, such as wherein the combined number of amino acids in both loop sequences comprises between 8 and 12 amino acids.

[1862] 4. The peptide ligand according to any of aspects 1 to 3, wherein said loop sequences comprise three cysteine residues separated by two loop sequences the first of which consists of 2 amino acids and the second of which consists of 8 amino acids, such as an amino acid sequence which is:

[1863] CSNCPNWYlHLMCj (SEQ ID NO: 1);

[1864] wherein the three cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof, in particular wherein the peptide ligand comprises N- and / or C-terminal additions and is:

[1865] A-(SEQ ID NO: 1)-A (herein referred to as BCY10120).

[1866] 5. The peptide ligand according to any of aspects 1 to 3, wherein said loop sequences comprise three cysteine residues separated by two loop sequences the first of which consists of 3 amino acids and the second of which consists of 7 amino acids, such as

[1867] an amino acid sequence which is selected from:

[1868] CPKWCEHYSSFLC (SEQ ID NO: 2);

[1869] CPNWCHDIGIWSC (SEQ ID NO: 3);

[1870] CPAWCYRLIDSTC (SEQ ID NO: 4);

[1871] CPSWCGRLLGNAC (SEQ ID NO: 5);

[1872] CPDWCSDIGVWNC (SEQ ID NO: 6);

[1873] CPIWCSRLGIWDC (SEQ ID NO: 7);CPDWCSKLGIWEC (SEQ ID NO: 8);

[1874] CPNWCSVLGIWDC (SEQ ID NO: 9; herein referred to as BCY20418);

[1875] CPGWCSRLGIWAC (SEQ ID NO: 10);

[1876] CPSWCNRLLGFAC (SEQ ID NO: 11);

[1877] CPEWCGRLLGFAC (SEQ ID NO: 12);

[1878] CPAWCTRLLGTAC (SEQ ID NO: 13)

[1879] CPAWCYRLLGTAC (SEQ ID NO: 14)

[1880] CPEWCSRLLFSAC (SEQ ID NO: 15)

[1881] CPGWCARLLNSAC (SEQ ID NO: 16)

[1882] CPRWCSLLLDWAC (SEQ ID NO: 17)

[1883] CDRWCTNLLFMAC (SEQ ID NO: 18)

[1884] CPAWCSQLGIWDC (SEQ ID NO: 19)

[1885] CPEWCSRLGIWAC (SEQ ID NO: 20)

[1886] CPAWCSRLGIWDC (SEQ ID NO: 21)

[1887] CPHWCSTLGIWDC (SEQ ID NO: 22)

[1888] CPFWCSKLGIWDC (SEQ ID NO: 23)

[1889] CPGWCSRLGIWDC (SEQ ID NO: 24)

[1890] CPTWCSRLGIWNC (SEQ ID NO: 25)

[1891] CPNWCSVLAIWDC (SEQ ID NO: 26)

[1892] CPNWCSVL[dA]IWDC (SEQ ID NO: 27);

[1893] CPNWCAVLGIWDC (SEQ ID NO: 28);

[1894] CANWCSVLGIWDC (SEQ ID NO: 29);

[1895] CPNWCSALGIWDC (SEQ ID NO: 30);

[1896] CPAWCSVLGIWDC (SEQ ID NO: 31); and

[1897] CPNWCSVLGIWAC (SEQ ID NO: 32);

[1898] wherein the three cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof, in particular wherein the molecular scaffold is a derivative of TATA which has the following structure:

[1899] O O

[1900]

[1901] wherein * denotes the point of attachment of the three cysteine residues, the peptide ligand comprises N- and / or C-terminal additions and is selected from:

[1902] A-(SEQ ID NO: 2)-A (herein referred to as BCY8978);

[1903] A-(SEQ ID NO: 3)-A (herein referred to as BCY8989);

[1904] A-(SEQ ID NO: 4)-A (herein referred to as BCY9189);

[1905] A-(SEQ ID NO: 5)-A (herein referred to as BCY9190);

[1906] A-(SEQ ID NO: 6)-A (herein referred to as BCY9195);

[1907] A-(SEQ ID NO: 7)-A (herein referred to as BCY9794);

[1908] A-(SEQ ID NO: 8)-A (herein referred to as BCY10107);

[1909] A-(SEQ ID NO: 9)-A (herein referred to as BCY10108);

[1910] Ac-(SEQ ID NO: 9) (herein referred to as BCY10385);

[1911] Ac-(SEQ ID NO: 9)-K (herein referred to as BCY20416);

[1912] Ac-(SEQ ID NO: 9)-[K(Ac)] (herein referred to as BCY20417);

[1913] Ac-(SEQ ID NO: 9)-[K(dPEG(25))] (herein referred to as BCY20544);

[1914] [PA]-(SEQ ID NO: 9) (herein referred to as BCY20545);

[1915] [Ts]-(SEQ ID NO: 9) (herein referred to as BCY20555);

[1916] [PhtCOOH]-(SEQ ID NO: 9) (herein referred to as BCY20556); [PheCOOH]-(SEQ ID NO: 9) (herein referred to as BCY20557); [Succinate]-(SEQ ID NO: 9) (herein referred to as BCY20558);

[1917] [n-Hex]-(SEQ ID NO: 9) (herein referred to as BCY20559);

[1918] [Piv]-(SEQ ID NO: 9) (herein referred to as BCY20560);

[1919] A-(SEQ ID NO: 10)-A (herein referred to as BCY10109);

[1920] A-(SEQ ID NO: 11)-A (herein referred to as BCY10215);

[1921] A-(SEQ ID NO: 12)-A (herein referred to as BCY10216);

[1922] A-(SEQ ID NO: 13)-A (herein referred to as BCY10217);

[1923] A-(SEQ ID NO: 14)-A (herein referred to as BCY10218);

[1924] A-(SEQ ID NO: 15)-A (herein referred to as BCY10219);

[1925] A-(SEQ ID NO: 16)-A (herein referred to as BCY10220);

[1926] A-(SEQ ID NO: 17)-A (herein referred to as BCY10221);

[1927] A-(SEQ ID NO: 18)-A (herein referred to as BCY10222);

[1928] A-(SEQ ID NO: 19)-NTS (herein referred to as BCY10771);

[1929] A-(SEQ ID NO: 20)-GRV (herein referred to as BCY10772);

[1930] SGQ-(SEQ ID NO: 21)-A (herein referred to as BCY10773);

[1931] AKG-(SEQ ID NO: 22)-A (herein referred to as BCY10775);

[1932] YGA-(SEQ ID NO: 23)-A (herein referred to as BCY10869);

[1933] AGP-(SEQ ID NO: 24)-A (herein referred to as BCY10870);

[1934] A-(SEQ ID NO: 25)-AHTA (herein referred to as BCY10871);A-(SEQ ID NO: 26)-A (herein referred to as BCY20419);

[1935] A-(SEQ ID NO: 27)-A (herein referred to as BCY20420);

[1936] A-(SEQ ID NO: 28)-A (herein referred to as BCY20421);

[1937] A-(SEQ ID NO: 29)-A (herein referred to as BCY20422);

[1938] A-(SEQ ID NO: 30)-A (herein referred to as BCY20423);

[1939] A-(SEQ ID NO: 31)-A (herein referred to as BCY20426); and

[1940] A-(SEQ ID NO: 32)-A (herein referred to as BCY20427).

[1941] 6. The peptide ligand according to any of aspects 1 to 3, wherein said loop sequences comprise three cysteine residues separated by two loop sequences the first of which consists of 3 amino acids and the second of which consists of 8 amino acids, such as an amino acid sequence which is selected from:

[1942] CPDWCSALDINWHC (SEQ ID NO: 33);

[1943] CPNWCSQFPGVWSC (SEQ ID NO: 34);

[1944] CSPFCDFLMTQGLC (SEQ ID NO: 35);

[1945] CSVWCDFLRENHLC (SEQ ID NO: 36);

[1946] CTDSCPHWYINLMC (SEQ ID NO: 37);

[1947] CPDWCSRLDIDWGC (SEQ ID NO: 38);

[1948] CPDWCSHYPEIWDC (SEQ ID NO: 39);

[1949] CPDWCSHYSQIWKC (SEQ ID NO: 40);

[1950] CPDWCSRLPGVWDC (SEQ ID NO: 41);

[1951] CPDWCSYYADIWGC (SEQ ID NO: 42);

[1952] CETYCALNWYRELVC (SEQ ID NO: 43);

[1953] CSPFCDFLQEHDLC (SEQ ID NO: 44);

[1954] CSPFCDFLNLNGLC (SEQ ID NO: 45);

[1955] CSSFCDFLQTHDLC (SEQ ID NO: 46);

[1956] CSTFCDFLRNNHLC (SEQ ID NO: 47);

[1957] CSPFCDFLFQHQLC (SEQ ID NO: 48);

[1958] CSPFCDFLSENNLC (SEQ ID NO: 49);

[1959] CSSFCDFLRGNNLC (SEQ ID NO: 50);

[1960] CSSFCDFLRTNSLC (SEQ ID NO: 51);

[1961] CSSFCDFLRDNDLC (SEQ ID NO: 52);

[1962] CSSFCDFLRENDLC (SEQ ID NO: 53);

[1963] CSSFCDFLRDNNLC (SEQ ID NO: 54);

[1964] CSPFCTFLQQHGLC (SEQ ID NO: 55);

[1965] CSPFCMFLREHDLC (SEQ ID NO: 56); and

[1966] CSPFCEFLRHHKLC (SEQ ID NO: 57);wherein the three cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof, in particular wherein the molecular scaffold is a derivative of TATA which has the following structure:

[1967] N N

[1968]

[1969] wherein * denotes the point of attachment of the three cysteine residues, the peptide ligand comprises N- and / or C-terminal additions and is selected from:

[1970] A-(SEQ ID NO: 33)-A (herein referred to as BCY9196);

[1971] A-(SEQ ID NO: 34)-A (herein referred to as BCY9197);

[1972] A-(SEQ ID NO: 35)-A (herein referred to as BCY9198);

[1973] A-(SEQ ID NO: 36)-A (herein referred to as BCY9199);

[1974] A-(SEQ ID NO: 37)-A (herein referred to as BCY9200);

[1975] A-(SEQ ID NO: 38)-A (herein referred to as BCY10111);

[1976] A-(SEQ ID NO: 39)-A (herein referred to as BCY10112);

[1977] A-(SEQ ID NO: 40)-A (herein referred to as BCY10113);

[1978] A-(SEQ ID NO: 41)-A (herein referred to as BCY10114);

[1979] A-(SEQ ID NO: 42)-A (herein referred to as BCY10115);

[1980] A-(SEQ ID NO: 43)-A (herein referred to as BCY10261);

[1981] A-(SEQ ID NO: 44)-A (herein referred to as BCY10277);

[1982] A-(SEQ ID NO: 45)-A (herein referred to as BCY10278);

[1983] A-(SEQ ID NO: 46)-A (herein referred to as BCY10279);

[1984] A-(SEQ ID NO: 47)-A (herein referred to as BCY10280);

[1985] A-(SEQ ID NO: 48)-A (herein referred to as BCY10281);

[1986] A-(SEQ ID NO: 49)-A (herein referred to as BCY10282);

[1987] A-(SEQ ID NO: 50)-A (herein referred to as BCY10283);

[1988] [dPEG(25)]A-(SEQ ID NO: 50)-A (herein referred to as BCY20561);

[1989] A-(SEQ ID NO: 51)-PKV (herein referred to as BCY11129);

[1990] A-(SEQ ID NO: 52)-PIA (herein referred to as BCY11130);

[1991] A-(SEQ ID NO: 53)-SVS (herein referred to as BCY11131);

[1992] A-(SEQ ID NO: 54)-KKE (herein referred to as BCY11132);A-(SEQ ID NO: 55)-A (herein referred to as BCY11624);

[1993] A-(SEQ ID NO: 56)-A (herein referred to as BCY11625); and

[1994] A-(SEQ ID NO: 57)-A (herein referred to as BCY11626).

[1995] 7. The peptide ligand according to any of aspects 1 to 3, wherein said loop sequences comprise three cysteine residues separated by two loop sequences the first of which consists of 3 amino acids and the second of which consists of 9 amino acids, such as an amino acid sequence which is selected from:

[1996] CDDYCHLSWYNRLVC (SEQ ID NO: 58);

[1997] CGPYCHLTWYHDLVC (SEQ ID NO: 59);

[1998] CGSYCNLPWYTRLVC (SEQ ID NO: 60);

[1999] CASYCDLPWYQDLVC (SEQ ID NO: 61);

[2000] CDPYCDLSWYYNLVC (SEQ ID NO: 62);

[2001] CDDYCHLEWYSNLIC (SEQ ID NO: 63);

[2002] CPLYCDLPWYQSLVC (SEQ ID NO: 64);

[2003] CQQECPKWYVDLMDC (SEQ ID NO: 65);

[2004] CRDNCRPDWYIRLMC (SEQ ID NO: 66);

[2005] CSGLCFTRAEGLSYC (SEQ ID NO: 67);

[2006] CYDKCPNMAEGLSYC (SEQ ID NO: 68);

[2007] CSGLCFTRPNHMKAC (SEQ ID NO: 69);

[2008] CRGKCGELAEGLSYC (SEQ ID NO: 70); and

[2009] CTGHCRSFAEGLSYC (SEQ ID NO: 71);

[2010] wherein the three cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof, in particular wherein the molecular scaffold is a derivative of TATA which has the following structure:

[2011] O O

[2012]

[2013] wherein * denotes the point of attachment of the three cysteine residues, the peptide ligand comprises N- and / or C-terminal additions and is selected from:

[2014] A-(SEQ ID NO: 58)-A (herein referred to as BCY10262);A-(SEQ ID NO: 59)-A (herein referred to as BCY10263);

[2015] A-(SEQ ID NO: 60)-A (herein referred to as BCY10264);

[2016] A-(SEQ ID NO: 61)-A (herein referred to as BCY10266);

[2017] A-(SEQ ID NO: 62)-A (herein referred to as BCY10267);

[2018] A-(SEQ ID NO: 63)-A (herein referred to as BCY9201);

[2019] A-(SEQ ID NO: 64)-A (herein referred to as BCY9204);

[2020] A-(SEQ ID NO: 65)-A (herein referred to as BCY9205);

[2021] A-(SEQ ID NO: 66)-A (herein referred to as BCY8983);

[2022] A-(SEQ ID NO: 67)-A (herein referred to as BCY8984);

[2023] A-(SEQ ID NO: 68)-A (herein referred to as BCY10326);

[2024] A-(SEQ ID NO: 69)-A (herein referred to as BCY10328);

[2025] A-(SEQ ID NO: 70)-A (herein referred to as BCY10329); and

[2026] A-(SEQ ID NO: 71)-A (herein referred to as BCY10330).

[2027] 8. The peptide ligand according to any of aspects 1 to 3, wherein said loop sequences comprise three cysteine residues separated by two loop sequences both of which consist of 4 amino acids, such as an amino acid sequence which is:

[2028] CLRWMCELGIC (SEQ ID NO: 72);

[2029] wherein the three cysteine residues within the peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof, in particular wherein the molecular scaffold is a derivative of TATA which has the following structure:

[2030] O O

[2031]

[2032] wherein * denotes the point of attachment of the three cysteine residues, the peptide ligand comprises N- and / or C-terminal additions and is:

[2033] A-(SEQ ID NO: 72)-A (herein referred to as BCY8991).

[2034] 9. The peptide ligand according to any of aspects 1 to 3, wherein said loop sequences comprise three cysteine residues separated by two loop sequences the first of which consistsof 4 amino acids and the second of which consists of 6 amino acids, such as an amino acid sequence which is selected from:

[2035] CELDWCKRLFPEC (SEQ ID NO: 73);

[2036] CQLDWCNELFPNC (SEQ ID NO: 74);

[2037] CLPNWCGPLFPRC (SEQ ID NO: 75);

[2038] CQLSWCRELFPDC (SEQ ID NO: 76);

[2039] CGLSWCAELFPDC (SEQ ID NO: 77); and

[2040] CQLDW[dC]NELFPNC (SEQ ID NO: 78);

[2041] wherein the three cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof, in particular wherein the molecular scaffold is a derivative of TATA which has the following structure:

[2042] O O

[2043]

[2044] wherein * denotes the point of attachment of the three cysteine residues, the peptide ligand comprises N- and / or C-terminal additions and is selected from:

[2045] A-(SEQ ID NO: 73)-A (herein referred to as BCY8970);

[2046] A-(SEQ ID NO: 74)-A (herein referred to as BCY9206);

[2047] A-(SEQ ID NO: 75)- A (herein referred to as BCY10087);

[2048] A-(SEQ ID NO: 76)-A (herein referred to as BCY10285);

[2049] A-(SEQ ID NO: 77)-A (herein referred to as BCY10286); and

[2050] [-FI][NH-Peg6-CO]A-(SEQ ID NO: 78)-A (herein referred to as BCY20522).

[2051] 10. The peptide ligand according to any of aspects 1 to 3, wherein said loop sequences comprise three cysteine residues separated by two loop sequences the first of which consists of 4 amino acids and the second of which consists of 8 amino acids, such as an amino acid sequence which is selected from:

[2052] CTHEWCALLQANTGC (SEQ ID NO: 79);

[2053] CSDEWCALLHQTTYC (SEQ ID NO: 80);

[2054] CSEAWCNLLMSSHTC (SEQ ID NO: 81);

[2055] CSEAWCALLQTHTNC (SEQ ID NO: 82);CSGNWCKLLQSSTNC (SEQ ID NO: 83); CSGPWCALLRDATDC (SEQ ID NO: 84); CSSRWCALLQETTSC (SEQ ID NO: 85); CSLPWCALLQSNTHC (SEQ ID NO: 86); CSAEWCALLGSTTHC (SEQ ID NO: 87); CDDFQCSWKQLMGLC (SEQ ID NO: 88); CSAMLCGFLSEHTHC (SEQ ID NO: 89); CSGALCAFFRANTDC (SEQ ID NO: 90); CSGPLCIFFQKNTGC (SEQ ID NO: 91);

[2056] CSQMLCSFLQSHTRC (SEQ ID NO: 92); CYGPFCSKGGILQWC (SEQ ID NO: 93); CSPALCDFLMLHTGC (SEQ ID NO: 94); CGDFSCEWKMLMGLC (SEQ ID NO: 95); CDDFLCNWRELLGLC (SEQ ID NO: 96); CDDFSCSWRQLMGLC (SEQ ID NO: 97); CSGALCQFLKENTNC (SEQ ID NO: 98); CSPMLCAFLKENTHC (SEQ ID NO: 99); CSPALCEFLAVNTHC (SEQ ID NO: 100); CSDALCKFFRENTKC (SEQ ID NO: 101); CSDQLCAFFSTNTGC (SEQ ID NO: 102); CSPLLCAFFADNTGC (SEQ ID NO: 103); CSPRLCSFFQANTSC (SEQ ID NO: 104); CYGPFCSKHDRLIWC (SEQ ID NO: 105); CYGPFCSKDDKLFWC (SEQ ID NO: 106); CYGPFCSKNDKLVWC (SEQ ID NO: 107); CYGPFCSKDGKLYMC (SEQ ID NO: 108); CYGPFCSKQGKLHWC (SEQ ID NO: 109); CYGPFCSKDSHLVWC (SEQ ID NO: 110); CSQALCAFFAENTDC (SEQ ID NO: 111); CSPALCAFFRTNTDC (SEQ ID NO: 112); CSGALCAFFVQNTGC (SEQ ID NO: 113); CSGALCAFFRENTNC (SEQ ID NO: 114); CSDALCQFFKENTKC (SEQ ID NO: 115); CSDALCQFFSLNTKC (SEQ ID NO: 116); CSDALCHFFRENTKC (SEQ ID NO: 117); CSDALCKFFGINTGC (SEQ ID NO: 118); CSDALCKFFKENTGC (SEQ ID NO: 119);CSPLLCAFFRNNTGC (SEQ ID NO: 120);

[2057] CSPLLCAFFSQNTGC (SEQ ID NO: 121);

[2058] CSPLLCAFFQDNTGC (SEQ ID NO: 122);

[2059] CSPQLCSFFAQNTSC (SEQ ID NO: 123);

[2060] CSPQLCSFFKTNTSC (SEQ ID NO: 124);

[2061] CSPRLCSFFQSNTNC (SEQ ID NO: 125);

[2062] CSPRLCSFFQSNTGC (SEQ ID NO: 126);

[2063] CS[K(Bz)]ALC[Bpa]FFS[AzaTrp]NTKC (SEQ ID NO: 127); CS[K(Bz)]ALC[Bpa]FFSKNT[HArg]C (SEQ ID NO: 128); CSDKLC[K(Bz)]FFRENT[HArg]C (SEQ ID NO: 129);

[2064] CSKALC[K(Bz)]FFRENT[HArg]C (SEQ ID NO: 130);

[2065] CSDALC[K(Bz)]FFRKNT[HArg]C (SEQ ID NO: 131);

[2066] CSDKLC[HArg]FFRENT[HArg]C (SEQ ID NO: 132);

[2067] CS[Cys(Bn)]ALCKFFRENT[HArg]C (SEQ ID NO: 133);

[2068] CSDALC[K(Bz)]FFRENTKC (SEQ ID NO: 134);

[2069] CSKALC[HArg]FFRENT[HArg]C (SEQ ID NO: 135);

[2070] CSDALCYFFRKNT[HArg]C (SEQ ID NO: 136);

[2071] CSDALCK[aMePhe]FRENT[HArg]C (SEQ ID NO: 137); CSDALCKF[aMePhe]RENT[HArg]C (SEQ ID NO: 138); CSDALCHFFRKNT[HArg]C (SEQ ID NO: 139);

[2072] CSDALC[HArg]FFRENTKC (SEQ ID NO: 140);

[2073] CSDALCKFFRENT[HArg]C (SEQ ID NO: 141);

[2074] CSDALC[HArg]FFRENT[dK]C (SEQ ID NO: 142);

[2075] CSDALCKFFHENT[HArg]C (SEQ ID NO: 143);

[2076] CSDALC[Agb]FFRENTKC (SEQ ID NO: 144);

[2077] CSDALCKFFRENT[Agb]C (SEQ ID NO: 145);

[2078] CSDALCHFFSKNT[HArg]C (SEQ ID NO: 146);

[2079] CSDALCKFFSENT[HArg]C (SEQ ID NO: 147);

[2080] CSDALCKFFAENT[HArg]C (SEQ ID NO: 148);

[2081] CSAALCAFFRANTDC (SEQ ID NO: 149);

[2082] CS[dA]ALCAFFRANTDC (SEQ ID NO: 150);

[2083] CAGALCAFFRANTDC (SEQ ID NO: 151);

[2084] CSGALCAFFRANADC (SEQ ID NO: 152);

[2085] CSGAACAFFRANTDC (SEQ ID NO: 153);

[2086] CSGALCAAFRANTDC (SEQ ID NO: 154);

[2087] CYGPFCS[HArg]DD[HArg]LFWC (SEQ ID NO: 155);

[2088] CYGPFCSKDD[HArg]LFWC (SEQ ID NO: 156);CYGPFCS[HArg]DDKLFWC (SEQ ID NO: 157);

[2089] CYGPFCS[Agb]DD[Agb]LFWC (SEQ ID NO: 158);

[2090] CYGPFCSKDD[Agb]LFWC (SEQ ID NO: 159);

[2091] CYGPFCS[Agb]DDKLFWC (SEQ ID NO: 160);

[2092] CYGPFCSKDDALFWC (SEQ ID NO: 161);

[2093] CYGPFCSADDKLFWC (SEQ ID NO: 162);

[2094] CYGPFCSADDALFWC (SEQ ID NO: 163);

[2095] CSDALCYFFRKNT[HArg][Cysam] (SEQ ID NO: 164);

[2096] CSDALCKFFRENT[HArg][Cysam] (SEQ ID NO: 165);

[2097] CSDALCKFFAENT[HArg][Cysam] (SEQ ID NO: 166);

[2098] CSDALC[K(dPEG(25))]FFRENT[HArg]C (SEQ ID NO: 167); CSDALC[K(AS-triaz-DBCO-BA)]FFRENT[HArg]C (SEQ ID NO: 168);

[2099] CSDALC[K(CO-PEG5-CO)]FFRENT[HArg]C (SEQ ID NO: 169); CSDALC[K(Ahx, Ahx)]FFRENT[HArg]C (SEQ ID NO: 170);

[2100] CSDALC[Agb]FFRENT[K(Ahx, Ahx]C (SEQ ID NO: 171);

[2101] CSDALC[K(W)]FFRENT[HArg]C (SEQ ID NO: 172); and CSDALC[K(Ahx)]FFRENT[HArg]C (SEQ ID NO: 173);

[2102] wherein the cysteine and Cysam residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof, in particular wherein the molecular scaffold is a derivative of TATA which has the following structure:

[2103] O O

[2104]

[2105] * —

[2106] wherein * denotes the point of attachment of the three cysteine residues, the peptide ligand comprises N- and / or C-terminal additions and is selected from:

[2107] A-(SEQ ID NO: 79)-A (herein referred to as BCY8969);

[2108] A-(SEQ ID NO: 80)-A (herein referred to as BCY10205);

[2109] A-(SEQ ID NO: 81)-A (herein referred to as BCY10206);

[2110] A-(SEQ ID NO: 82)-A (herein referred to as BCY10207);

[2111] A-(SEQ ID NO: 83)-A (herein referred to as BCY10208);

[2112] A-(SEQ ID NO: 84)-A (herein referred to as BCY10209);A-(SEQ ID NO: 85)-A (herein referred to as BCY10210);

[2113] A-(SEQ ID NO: 86)-A (herein referred to as BCY10212);

[2114] A-(SEQ ID NO: 87)-A (herein referred to as BCY10214);

[2115] A-(SEQ ID NO: 88)-A (herein referred to as BCY11331);

[2116] A-(SEQ ID NO: 89)-A (herein referred to as BCY11333);

[2117] A-(SEQ ID NO: 90)-A (herein referred to as BCY11335);

[2118] A-(SEQ ID NO: 90)-[dA] (herein referred to as BCY20464);

[2119] Ac-(SEQ ID NO: 90)-[K(Ac)] (herein referred to as BCY20487); Ac-(SEQ ID NO: 90)-K (herein referred to as BCY20491);

[2120] Ac-(SEQ ID NO: 90)-[dK] (herein referred to as BCY20492);

[2121] A-(SEQ ID NO: 90) (herein referred to as BCY20494);

[2122] Ac-(SEQ ID NO: 90) (herein referred to as BCY20497);

[2123] A-(SEQ ID NO: 91)-A (herein referred to as BCY11336);

[2124] A-(SEQ ID NO: 92)-A (herein referred to as BCY11337);

[2125] A-(SEQ ID NO: 93)-A (herein referred to as BCY11340);

[2126] Ac-(SEQ ID NO: 93) (herein referred to as BCY20506);

[2127] A-(SEQ ID NO: 94)-A (herein referred to as BCY11342);

[2128] A-(SEQ ID NO: 95)-A (herein referred to as BCY11628);

[2129] A-(SEQ ID NO: 96)-A (herein referred to as BCY11629);

[2130] A-(SEQ ID NO: 97)-A (herein referred to as BCY11630);

[2131] A-(SEQ ID NO: 98)-A (herein referred to as BCY11635);

[2132] A-(SEQ ID NO: 99)-A (herein referred to as BCY11636);

[2133] A-(SEQ ID NO: 100)-A (herein referred to as BCY11637);

[2134] A-(SEQ ID NO: 101)-A (herein referred to as BCY11638);

[2135] Ac-(SEQ ID NO: 101) (herein referred to as BCY12152);

[2136] Ac-(SEQ ID NO: 101)-[K(N3)] (herein referred to as BCY20470);

[2137] [AzPnt]-(SEQ ID NO: 101) (herein referred to as BCY20661);

[2138] A-(SEQ ID NO: 102)-A (herein referred to as BCY11639);

[2139] Ac-(SEQ ID NO: 102) (herein referred to as BCY12153);

[2140] A-(SEQ ID NO: 103)-A (herein referred to as BCY11640);

[2141] Ac-(SEQ ID NO: 103) (herein referred to as BCY20503);

[2142] A-(SEQ ID NO: 104)-A (herein referred to as BCY11641);

[2143] A-(SEQ ID NO: 105)-A (herein referred to as BCY11973);

[2144] A-(SEQ ID NO: 106)-A (herein referred to as BCY11974);

[2145] A-(SEQ ID NO: 106)-[K(N3)] (herein referred to as BCY20509); A-(SEQ ID NO: 106)-[PG] (herein referred to as BCY20513);

[2146] [Aib]-(SEQ ID NO: 106) (herein referred to as BCY20516);[dA]-(SEQ ID NO: 106) (herein referred to as BCY20519);

[2147] A-(SEQ ID NO: 107)-A (herein referred to as BCY11975);

[2148] A-(SEQ ID NO: 108)-A (herein referred to as BCY11976);

[2149] A-(SEQ ID NO: 109)-A (herein referred to as BCY11977);

[2150] A-(SEQ ID NO: 110)-A (herein referred to as BCY11978);

[2151] SRT-(SEQ ID NO: 111)-A (herein referred to as BCY12100); RTS-(SEQ ID NO: 112)-A (herein referred to as BCY12101); A-(SEQ ID NO: 113)-AHM (herein referred to as BCY12102); A-(SEQ ID NO: 114)-LKN (herein referred to as BCY12103); A-(SEQ ID NO: 115)-A (herein referred to as BCY12104);

[2152] Ac-(SEQ ID NO: 115) (herein referred to as BCY20504);

[2153] ATG-(SEQ ID NO: 116)-A (herein referred to as BCY12105);

[2154] SPH-(SEQ ID NO: 117)-A (herein referred to as BCY12106); Ac-(SEQ ID NO: 117) (herein referred to as BCY20486);

[2155] A-(SEQ ID NO: 118)-RMS (herein referred to as BCY12107); A-(SEQ ID NO: 119)-SEM (herein referred to as BCY12108); Ac-(SEQ ID NO: 119) (herein referred to as BCY20505);

[2156] DIG-(SEQ ID NO: 120)-A (herein referred to as BCY12109); Ac-(SEQ ID NO: 120) (herein referred to as BCY20493);

[2157] A-(SEQ ID NO: 121)-A (herein referred to as BCY12110);

[2158] A-(SEQ ID NO: 122)-LGS (herein referred to as BCY12111); EGG-(SEQ ID NO: 123)-A (herein referred to as BCY12112); SVG-(SEQ ID NO: 124)-A (herein referred to as BCY12113); A-(SEQ ID NO: 125)-EPT (herein referred to as BCY12114); A-(SEQ ID NO: 126)-AST (herein referred to as BCY12115); Ac-(SEQ ID NO: 127) (herein referred to as BCY20466);

[2159] Ac-(SEQ ID NO: 128) (herein referred to as BCY20467);

[2160] Ac-(SEQ ID NO: 129) (herein referred to as BCY20468);

[2161] Ac-(SEQ ID NO: 130) (herein referred to as BCY20469);

[2162] Ac-(SEQ ID NO: 131) (herein referred to as BCY20471);

[2163] Ac-(SEQ ID NO: 132) (herein referred to as BCY20472);

[2164] Ac-(SEQ ID NO: 133) (herein referred to as BCY20473);

[2165] Ac-(SEQ ID NO: 134) (herein referred to as BCY20474);

[2166] Ac-(SEQ ID NO: 135) (herein referred to as BCY20475);

[2167] Ac-(SEQ ID NO: 136) (herein referred to as BCY20476);

[2168] Ac-(SEQ ID NO: 137) (herein referred to as BCY20477);

[2169] Ac-(SEQ ID NO: 138) (herein referred to as BCY20478);Ac-(SEQ ID NO: 139) (herein referred to as BCY20479);

[2170] Ac-(SEQ ID NO: 140) (herein referred to as BCY20480);

[2171] Ac-(SEQ ID NO: 141) (herein referred to as BCY20481);

[2172] Ac-(SEQ ID NO: 142) (herein referred to as BCY20482);

[2173] Ac-(SEQ ID NO: 143) (herein referred to as BCY20483);

[2174] Ac-(SEQ ID NO: 144) (herein referred to as BCY20484);

[2175] Ac-(SEQ ID NO: 145) (herein referred to as BCY20485);

[2176] Ac-(SEQ ID NO: 146) (herein referred to as BCY20488);

[2177] Ac-(SEQ ID NO: 147) (herein referred to as BCY20489);

[2178] Ac-(SEQ ID NO: 148) (herein referred to as BCY20490);

[2179] Ac-(SEQ ID NO: 149) (herein referred to as BCY20495);

[2180] Ac-(SEQ ID NO: 150) (herein referred to as BCY20496);

[2181] Ac-(SEQ ID NO: 151) (herein referred to as BCY20498);

[2182] Ac-(SEQ ID NO: 152) (herein referred to as BCY20499);

[2183] Ac-(SEQ ID NO: 153) (herein referred to as BCY20500);

[2184] Ac-(SEQ ID NO: 154) (herein referred to as BCY20501);

[2185] Ac-(SEQ ID NO: 155)-K (herein referred to as BCY20507); A-(SEQ ID NO: 155)-A (herein referred to as BCY20508); A-(SEQ ID NO: 156)-A (herein referred to as BCY20510); A-(SEQ ID NO: 157)-A (herein referred to as BCY20511); A-(SEQ ID NO: 158)-A (herein referred to as BCY20512); A-(SEQ ID NO: 159)-A (herein referred to as BCY20514); A-(SEQ ID NO: 160)-A (herein referred to as BCY20515); A-(SEQ ID NO: 161)-A (herein referred to as BCY20517); A-(SEQ ID NO: 162)-A (herein referred to as BCY20518); A-(SEQ ID NO: 163)-A (herein referred to as BCY20520); Ac-(SEQ ID NO: 164) (herein referred to as BCY20523);

[2186] Ac-(SEQ ID NO: 165) (herein referred to as BCY20524);

[2187] Ac-(SEQ ID NO: 166) (herein referred to as BCY20525);

[2188] Ac-(SEQ ID NO: 167) (herein referred to as BCY20578);

[2189] Ac-(SEQ ID NO: 168) (herein referred to as BCY20579);

[2190] Ac-(SEQ ID NO: 169) (herein referred to as BCY20655);

[2191] Ac-(SEQ ID NO: 170) (herein referred to as BCY20656);

[2192] Ac-(SEQ ID NO: 171) (herein referred to as BCY20657);

[2193] Ac-(SEQ ID NO: 172) (herein referred to as BCY20658); and Ac-(SEQ ID NO: 173) (herein referred to as BCY20659).11. The peptide ligand according to any of aspects 1 to 3, wherein said loop sequences comprise three cysteine residues separated by two loop sequences the first of which consists of 5 amino acids and the second of which consists of 4 amino acids, such as an amino acid sequence which is:

[2194] CYPEWYCRLLPC (SEQ ID NO: 174);

[2195] wherein the three cysteine residues within the peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof in particular wherein the molecular scaffold is a derivative of TATA which has the following structure:

[2196] O O

[2197]

[2198] wherein * denotes the point of attachment of the three cysteine residues, the peptide ligand comprises N- and / or C-terminal additions and is:

[2199] A-(SEQ ID NO: 174)-A (herein referred to as BCY8980).

[2200] 12. The peptide ligand according to any of aspects 1 to 3, wherein said loop sequences comprise three cysteine residues separated by two loop sequences the first of which consists of 5 amino acids and the second of which consists of 7 amino acids, such as an amino acid sequence which is selected from:

[2201] CKNPMWCAMFAKDDC (SEQ ID NO: 175);

[2202] CYDLPWCKELMLQHC (SEQ ID NO: 176);

[2203] CYPDWYCQLMKLPTC (SEQ ID NO: 177);

[2204] CMPKWYCDLMGTPMC (SEQ ID NO: 178);

[2205] CYDLAWCNELMATHC (SEQ ID NO: 179);

[2206] CYDLPWCNELMAQHC (SEQ ID NO: 180);

[2207] CYDLRWCHELMDQHC (SEQ ID NO: 181);

[2208] CYDLAWCRELGVWNC (SEQ ID NO: 182);

[2209] CPPLAWCRELMLQHC (SEQ ID NO: 183);

[2210] CYDLAWCKELMLMNC (SEQ ID NO: 184);

[2211] CSPLGWCAELMLQHC (SEQ ID NO: 185);

[2212] CKNPMWCAMFGEDSC (SEQ ID NO: 186);CKNPMWCAMFGDQSC (SEQ ID NO: 187);

[2213] CKNPMWCAMFTTQGC (SEQ ID NO: 188);

[2214] CKNPMWCAMFGYDRC (SEQ ID NO: 189);

[2215] CEGTLWCWMFAKDDC (SEQ ID NO: 190);

[2216] CGSSFWCAMFAKDDC (SEQ ID NO: 191);

[2217] CTDPFWCFMFAKDDC (SEQ ID NO: 192);

[2218] CSPLWYCALMKRKTC (SEQ ID NO: 193);

[2219] CAPWWYCNLMAQPTC (SEQ ID NO: 194);

[2220] CMPDWYCRLMDIDTC (SEQ ID NO: 195);

[2221] CAPNWYCMLMQHTTC (SEQ ID NO: 196);

[2222] CPDLAWCKELMLKNC (SEQ ID NO: 197);

[2223] CTELAWCKELMLTNC (SEQ ID NO: 198);

[2224] CLDLAWCKELMLMNC (SEQ ID NO: 199);

[2225] CTNLQLCAQYWLGWC (SEQ ID NO: 200);

[2226] CPDLQNCAQYWLGWC (SEQ ID NO: 201);

[2227] CNDLQYCAEYWLGWC (SEQ ID NO: 202);

[2228] CRELQSCAQYWLGWC (SEQ ID NO: 203);

[2229] CYDLAWCRELMLMNC (SEQ ID NO: 204);

[2230] CYDLPWCKELMLMNC (SEQ ID NO: 205);

[2231] CYDLAWCKELMLMHC (SEQ ID NO: 206);

[2232] CYDLAWCKELMLQNC (SEQ ID NO: 207);

[2233] CYDLAWCKEL[Nle]LMNC (SEQ ID NO: 208);

[2234] CYDLAWCKELML[Nle]NC (SEQ ID NO: 209);

[2235] CYDLAWCKEL[Nle]L[Nle]NC (SEQ ID NO: 210);

[2236] CPPLAWCRELMLMNC (SEQ ID NO: 211); and

[2237] CPPLAWCKELMLMNC (SEQ ID NO: 212);

[2238] wherein the cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof, in particular wherein the molecular scaffold is a derivative of TATA which has the following structure:O O

[2239]

[2240] wherein * denotes the point of attachment of the three cysteine residues, the peptide ligand comprises N- and / or C-terminal additions and is selected from:

[2241] A-(SEQ ID NO: 175)-A (herein referred to as BCY8982);

[2242] A-(SEQ ID NO: 176)-A (herein referred to as BCY9209);

[2243] A-(SEQ ID NO: 177)-A (herein referred to as BCY9210);

[2244] A-(SEQ ID NO: 178)-A (herein referred to as BCY10096);

[2245] A-(SEQ ID NO: 179)-A (herein referred to as BCY10269);

[2246] A-(SEQ ID NO: 180)-A (herein referred to as BCY10270);

[2247] A-(SEQ ID NO: 181)-A (herein referred to as BCY10272);

[2248] A-(SEQ ID NO: 182)-A (herein referred to as BCY10273);

[2249] A-(SEQ ID NO: 183)-A (herein referred to as BCY10274);

[2250] A-(SEQ ID NO: 184)-A (herein referred to as BCY10275);

[2251] Ac-(SEQ ID NO: 184) (herein referred to as BCY20433);

[2252] Ac-[NH-Peg6-CO]-(SEQ ID NO: 184) (herein referred to as BCY20562); A-(SEQ ID NO: 185)-A (herein referred to as BCY10276);

[2253] A-(SEQ ID NO: 186)-A (herein referred to as BCY10317);

[2254] A-(SEQ ID NO: 187)-A (herein referred to as BCY10318);

[2255] A-(SEQ ID NO: 188)-A (herein referred to as BCY10319);

[2256] A-(SEQ ID NO: 189)-A (herein referred to as BCY10320);

[2257] A-(SEQ ID NO: 190)-A (herein referred to as BCY10322);

[2258] A-(SEQ ID NO: 191)-A (herein referred to as BCY10323);

[2259] A-(SEQ ID NO: 192)-A (herein referred to as BCY10325);

[2260] A-(SEQ ID NO: 193)-A (herein referred to as BCY10583);

[2261] A-(SEQ ID NO: 194)-A (herein referred to as BCY10584);

[2262] A-(SEQ ID NO: 195)-A (herein referred to as BCY10585);

[2263] A-(SEQ ID NO: 196)-A (herein referred to as BCY10586);

[2264] SYP-(SEQ ID NO: 197)-A (herein referred to as BCY11119);

[2265] SSW-(SEQ ID NO: 198)-A (herein referred to as BCY11120);A-(SEQ ID NO: 199)-TQK (herein referred to as BCY11124);

[2266] A-(SEQ ID NO: 200)-A (herein referred to as BCY11328);

[2267] A-(SEQ ID NO: 201)-A (herein referred to as BCY11619);

[2268] A-(SEQ ID NO: 202)-A (herein referred to as BCY11620);

[2269] A-(SEQ ID NO: 203)-A (herein referred to as BCY11621);

[2270] Ac-(SEQ ID NO: 204) (herein referred to as BCY20430);

[2271] Ac-(SEQ ID NO: 205) (herein referred to as BCY20431);

[2272] Ac-(SEQ ID NO: 206) (herein referred to as BCY20432);

[2273] Ac-(SEQ ID NO: 207) (herein referred to as BCY20434);

[2274] Ac-(SEQ ID NO: 208) (herein referred to as BCY20435);

[2275] Ac-(SEQ ID NO: 209) (herein referred to as BCY20436);

[2276] Ac-(SEQ ID NO: 210) (herein referred to as BCY20437);

[2277] Ac-(SEQ ID NO: 211) (herein referred to as BCY20438); and

[2278] Ac-(SEQ ID NO: 212) (herein referred to as BCY20439).

[2279] 13. The peptide ligand according to any of aspects 1 to 3, wherein said loop sequences comprise three cysteine residues separated by two loop sequences the first of which consists of 6 amino acids and the second of which consists of 3 amino acids, such as an amino acid sequence which is selected from:

[2280] CSHPLEWCRTLC (SEQ ID NO: 213);

[2281] CMNPLGWCRTLC (SEQ ID NO: 214);

[2282] CDHPLEWCRSLC (SEQ ID NO: 215);

[2283] CNHPLAWCREVC (SEQ ID NO: 216);

[2284] CSHELKWCRDLC (SEQ ID NO: 217);

[2285] CSHPLGWCRELC (SEQ ID NO: 218);

[2286] CDHPLWWCREIC (SEQ ID NO: 219);

[2287] CHHPLWWCREIC (SEQ ID NO: 220);

[2288] CTHPLWWCREVC (SEQ ID NO: 221);

[2289] CGHPLRWCRELC (SEQ ID NO: 222);

[2290] CNHPLRWCREVC (SEQ ID NO: 223);

[2291] CHHPLRWCRELC (SEQ ID NO: 224);

[2292] CDHPLGWCRELC (SEQ ID NO: 225);

[2293] CQHPLSWCRELC (SEQ ID NO: 226);

[2294] CSHPLRWCREIC (SEQ ID NO: 227);

[2295] CEHPLAWCRELC (SEQ ID NO: 228);

[2296] CD[1Nal]PLWWCREIC (SEQ ID NO: 229);

[2297] CD[2Nal]PLWWCREIC (SEQ ID NO: 230);CD[4FPhe]PLWWCREIC (SEQ ID NO: 231);

[2298] CDHPLWWC[HArg]EIC (SEQ ID NO: 232);

[2299] CDHPLW[1Nal]CREIC (SEQ ID NO: 233);

[2300] CDHPL[1Nal]WCREIC (SEQ ID NO: 234);

[2301] CDHPL[2Nal]WCREIC (SEQ ID NO: 235);

[2302] CDHPLW[2Nal]CREIC (SEQ ID NO: 236);

[2303] CDHPLWWC[Cit]EIC (SEQ ID NO: 237);

[2304] CDHPLWWC[dR]EIC (SEQ ID NO: 238);

[2305] CDHPLW[4FPhe]CREIC (SEQ ID NO: 239);

[2306] CDHPL[4FPhe]WCREIC (SEQ ID NO: 240);

[2307] CDHALWWCREIC (SEQ ID NO: 241);

[2308] CDHPLWWCREAC (SEQ ID NO: 242);

[2309] CDHPAWWCREIC (SEQ ID NO: 243);

[2310] CDHPLWWCRAIC (SEQ ID NO: 244);

[2311] CDAPLWWCREIC (SEQ ID NO: 245);

[2312] CDHPLWWCAEIC (SEQ ID NO: 246);

[2313] CDHPLAWCREIC (SEQ ID NO: 247); and

[2314] CAHPLWWCREIC (SEQ ID NO: 248);

[2315] wherein the cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof, in particular wherein the molecular scaffold is a derivative of TATA which has the following structure:

[2316] N

[2317] N

[2318]

[2319] wherein * denotes the point of attachment of the three cysteine residues, the peptide ligand comprises N- and / or C-terminal additions and is selected from:

[2320] A-(SEQ ID NO: 213)-A (herein referred to as BCY8973);

[2321] A-(SEQ ID NO: 214)-A (herein referred to as BCY8976);

[2322] A-(SEQ ID NO: 215)-A (herein referred to as BCY8979);

[2323] A-(SEQ ID NO: 216)-A (herein referred to as BCY9211);

[2324] A-(SEQ ID NO: 217)-A (herein referred to as BCY9212);A-(SEQ ID NO: 218)-A (herein referred to as BCY9213);

[2325] [MeO-dPEG12]-A-(SEQ ID NO: 219)-A (herein referred to as BCY10303); Ac-(SEQ ID NO: 219) (herein referred to as BCY10387);

[2326] Ac-(SEQ ID NO: 219)-[K(Ac)] (herein referred to as BCY20440);

[2327] Ac-(SEQ ID NO: 219)-K (herein referred to as BCY20441);

[2328] [-FI][NH-Peg6-CO]A-(SEQ ID NO: 219)-A (herein referred to as BCY20577); A-(SEQ ID NO: 219)-A (herein referred to as BCY9795);

[2329] A-(SEQ ID NO: 220)-A (herein referred to as BCY9796);

[2330] A-(SEQ ID NO: 221)-A (herein referred to as BCY9797);

[2331] A-(SEQ ID NO: 222)-A (herein referred to as BCY9798);

[2332] A-(SEQ ID NO: 223)-A (herein referred to as BCY10116);

[2333] A-(SEQ ID NO: 224)-A (herein referred to as BCY10118);

[2334] A-(SEQ ID NO: 225)-DSY (herein referred to as BCY10776);

[2335] A-(SEQ ID NO: 226)-STN (herein referred to as BCY10777);

[2336] SQP-(SEQ ID NO: 227)-A (herein referred to as BCY10778);

[2337] RAQ-(SEQ ID NO: 228)-A (herein referred to as BCY10779);

[2338] A-(SEQ ID NO: 229)-A (herein referred to as BCY20442);

[2339] A-(SEQ ID NO: 230)-A (herein referred to as BCY20443);

[2340] A-(SEQ ID NO: 231)-A (herein referred to as BCY20444);

[2341] A-(SEQ ID NO: 232)-A (herein referred to as BCY20445);

[2342] A-(SEQ ID NO: 233)-A (herein referred to as BCY20446);

[2343] A-(SEQ ID NO: 234)-A (herein referred to as BCY20447);

[2344] A-(SEQ ID NO: 235)-A (herein referred to as BCY20448);

[2345] A-(SEQ ID NO: 236)-A (herein referred to as BCY20449);

[2346] A-(SEQ ID NO: 237)-A (herein referred to as BCY20450);

[2347] A-(SEQ ID NO: 238)-A (herein referred to as BCY20451);

[2348] A-(SEQ ID NO: 239)-A (herein referred to as BCY20452);

[2349] A-(SEQ ID NO: 240)-A (herein referred to as BCY20453);

[2350] A-(SEQ ID NO: 241)-A (herein referred to as BCY20454);

[2351] A-(SEQ ID NO: 242)-A (herein referred to as BCY20456);

[2352] A-(SEQ ID NO: 243)-A (herein referred to as BCY20457);

[2353] A-(SEQ ID NO: 244)-A (herein referred to as BCY20458);

[2354] A-(SEQ ID NO: 245)-A (herein referred to as BCY20459);

[2355] A-(SEQ ID NO: 246)-A (herein referred to as BCY20460);

[2356] A-(SEQ ID NO: 247)-A (herein referred to as BCY20461); and

[2357] A-(SEQ ID NO: 248)-A (herein referred to as BCY20463).14. The peptide ligand according to any of aspects 1 to 3, wherein said loop sequences comprise three cysteine residues separated by two loop sequences the first of which consists of 6 amino acids and the second of which consists of 4 amino acids, such as an amino acid sequence which is selected from:

[2358] CEENEWYCRLFGC (SEQ ID NO: 249);

[2359] CNKPAWYCSLFPC (SEQ ID NO: 250);

[2360] CNWDPRLCKYITC (SEQ ID NO: 251);

[2361] CYDLAWYCRLFPC (SEQ ID NO: 252);

[2362] CYDLKWYCDLFPC (SEQ ID NO: 253);

[2363] CYDLDWYCTLFPC (SEQ ID NO: 254);

[2364] CYDLEWYCKLFPC (SEQ ID NO: 255);

[2365] CYNLEWYCQLFPC (SEQ ID NO: 256);

[2366] CYDLEWYCALFPC (SEQ ID NO: 257);

[2367] CYDLGWYCQLFPC (SEQ ID NO: 258);

[2368] CYDLQWYCSLFPC (SEQ ID NO: 259);

[2369] CYDLDWYCRLFPC (SEQ ID NO: 260);

[2370] CYDLDWYCKLFPC (SEQ ID NO: 261);

[2371] CYDLSWYCQLFPC (SEQ ID NO: 262);

[2372] CYDLHWYCTLFPC (SEQ ID NO: 263);

[2373] CYDLAWYC[HArg]LFPC (SEQ ID NO: 264);

[2374] CYDLAWYC[Cit]LFPC (SEQ ID NO: 265);

[2375] CYDLAWYC[dR]LFPC (SEQ ID NO: 266);

[2376] CYDL[dA]WYCRLFPC (SEQ ID NO: 267);

[2377] CYDLAWYC[Agb]LFPC (SEQ ID NO: 268);

[2378] CYDLAWYCELFPC (SEQ ID NO: 269);

[2379] CYDLAWYCRAFPC (SEQ ID NO: 270);

[2380] CYDAAWYCRLFPC (SEQ ID NO: 271);

[2381] CYALAWYCRLFPC (SEQ ID NO: 272);

[2382] CYDLAWYCRLAPC (SEQ ID NO: 273);

[2383] CYDLAWYCALFPC (SEQ ID NO: 274);

[2384] CADLAWYCRLFPC (SEQ ID NO: 275);

[2385] CYDLAWACRLFPC (SEQ ID NO: 276); and

[2386] CYDLAWY[dC]RLFPC (SEQ ID NO: 277);

[2387] wherein the cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof, in particular wherein the molecular scaffold is a derivative of TATA which has the following structure:

[2388]

[2389] wherein * denotes the point of attachment of the three cysteine residues, the peptide ligand comprises N- and / or C-terminal additions and is selected from:

[2390] A-(SEQ ID NO: 249)-A (herein referred to as BCY8981);

[2391] A-(SEQ ID NO: 250)-A (herein referred to as BCY8986);

[2392] A-(SEQ ID NO: 251)-A (herein referred to as BCY8992);

[2393] A-(SEQ ID NO: 252)-A (herein referred to as BCY9792);

[2394] A-(SEQ ID NO: 252)-A[MeO-dPEG12] (herein referred to as BCY10301); Ac-(SEQ ID NO: 252) (herein referred to as BCY10384);

[2395] Ac-(SEQ ID NO: 252)-[K(Ac)] (herein referred to as BCY20413);

[2396] Ac-(SEQ ID NO: 252)-K (herein referred to as BCY20414);

[2397] A-(SEQ ID NO: 253)-A (herein referred to as BCY9793);

[2398] A-(SEQ ID NO: 254)-A (herein referred to as BCY10088);

[2399] A-(SEQ ID NO: 255)-A (herein referred to as BCY10089);

[2400] A-(SEQ ID NO: 256)-A (herein referred to as BCY10090);

[2401] A-(SEQ ID NO: 257)-A (herein referred to as BCY10091);

[2402] A-(SEQ ID NO: 258)-A (herein referred to as BCY10092);

[2403] A-(SEQ ID NO: 259)-SNR (herein referred to as BCY10765);

[2404] A-(SEQ ID NO: 260)-MVT (herein referred to as BCY10767);

[2405] HGP-(SEQ ID NO: 261)-A (herein referred to as BCY10768);

[2406] HTQ-(SEQ ID NO: 262)-A (herein referred to as BCY10769);

[2407] A-(SEQ ID NO: 263)-A (herein referred to as BCY10770);

[2408] A-(SEQ ID NO: 264)-A (herein referred to as BCY20398);

[2409] A-(SEQ ID NO: 265)-A (herein referred to as BCY20399);

[2410] A-(SEQ ID NO: 266)-A (herein referred to as BCY20400);

[2411] A-(SEQ ID NO: 267)-A (herein referred to as BCY20401);

[2412] A-(SEQ ID NO: 268)-A (herein referred to as BCY20402);

[2413] A-(SEQ ID NO: 269)-A (herein referred to as BCY20404);

[2414] A-(SEQ ID NO: 270)-A (herein referred to as BCY20405);A-(SEQ ID NO: 271)-A (herein referred to as BCY20406);

[2415] A-(SEQ ID NO: 272)-A (herein referred to as BCY20407);

[2416] A-(SEQ ID NO: 273)-A (herein referred to as BCY20408);

[2417] A-(SEQ ID NO: 274)-A (herein referred to as BCY20409);

[2418] A-(SEQ ID NO: 275)-A (herein referred to as BCY20410);

[2419] A-(SEQ ID NO: 276)-A (herein referred to as BCY20411); and [-FI][NH-Peg6-CO]A-(SEQ ID NO: 277)-A (herein referred to as BCY20521).

[2420] 15. The peptide ligand according to any of aspects 1 to 3, wherein said loop sequences comprise three cysteine residues separated by two loop sequences both of which consist of 6 amino acids, such as an amino acid sequence which is selected from:

[2421] CNGPFTVCNGRVRLC (SEQ ID NO: 278);

[2422] CRGLPAWCYSLFPDC (SEQ ID NO: 279); and

[2423] CPSSSAWCSSLFPSC (SEQ ID NO: 280);

[2424] wherein the cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof, in particular wherein the molecular scaffold is a derivative of TATA which has the following structure:

[2425] O O

[2426]

[2427] wherein * denotes the point of attachment of the three cysteine residues, the peptide ligand comprises N- and / or C-terminal additions and is selected from:

[2428] A-(SEQ ID NO: 278)-A (herein referred to as BCY8985);

[2429] A-(SEQ ID NO: 279)-A (herein referred to as BCY8988); and

[2430] A-(SEQ ID NO: 280)-A (herein referred to as BCY10094).

[2431] 16. The peptide ligand according to any of aspects 1 to 3, wherein said loop sequences comprise three cysteine residues separated by two loop sequences the first of which consists of 7 amino acids and the second of which consists of 3 amino acids, such as an amino acid sequence which is selected from:

[2432] CGNGHQLNCLFSC (SEQ ID NO: 281);CADRPRWYCDLMC (SEQ ID NO: 282);

[2433] CDPIWELLCPHGC (SEQ ID NO: 283);

[2434] CPYLNLQWCRDLC (SEQ ID NO: 284);

[2435] CSHKPQWYCNLMC (SEQ ID NO: 285);

[2436] CMYEPSWYCQLMC (SEQ ID NO: 286);

[2437] CVDMPDWYCQLMC (SEQ ID NO: 287);

[2438] CYYEPEWYCNLMC (SEQ ID NO: 288);

[2439] CIDMPDWYCTLMC (SEQ ID NO: 289);

[2440] CLYEPSWYCNLMC (SEQ ID NO: 290);

[2441] CRYEPEWYCNLMC (SEQ ID NO: 291);

[2442] CTNMPRWYCDLMC (SEQ ID NO: 292);

[2443] CVDMPDWYCKLMC (SEQ ID NO: 293);

[2444] CVDMPDWYCRLMC (SEQ ID NO: 294);

[2445] CARMPDWYCNLMC (SEQ ID NO: 295);

[2446] CVDMPDWYCELMC (SEQ ID NO: 296); and

[2447] CRYEPEWYCNL[MetO]C (SEQ ID NO: 297);

[2448] wherein the cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof, in particular wherein the molecular scaffold is a derivative of TATA which has the following structure:

[2449] O O

[2450] *N N*

[2451] N

[2452]

[2453] wherein * denotes the point of attachment of the three cysteine residues, the peptide ligand comprises N- and / or C-terminal additions and is selected from:

[2454] A-(SEQ ID NO: 281)-A (herein referred to as BCY8971);

[2455] A-(SEQ ID NO: 282)-A (herein referred to as BCY9191);

[2456] A-(SEQ ID NO: 283)-A (herein referred to as BCY9192);

[2457] A-(SEQ ID NO: 284)-A (herein referred to as BCY9193);

[2458] A-(SEQ ID NO: 285)-A (herein referred to as BCY9194);

[2459] A-(SEQ ID NO: 286)-A (herein referred to as BCY10097);

[2460] A-(SEQ ID NO: 287)-A (herein referred to as BCY10098);A-(SEQ ID NO: 288)-A (herein referred to as BCY10099);

[2461] A-(SEQ ID NO: 289)-A (herein referred to as BCY10100);

[2462] A-(SEQ ID NO: 290)-A (herein referred to as BCY10101);

[2463] A-(SEQ ID NO: 291)-A (herein referred to as BCY10102);

[2464] Ac-(SEQ ID NO: 291) (herein referred to as BCY10386);

[2465] A-(SEQ ID NO: 292)-A (herein referred to as BCY10103);

[2466] A-(SEQ ID NO: 293)-A (herein referred to as BCY10104);

[2467] A-(SEQ ID NO: 294)-A (herein referred to as BCY10105);

[2468] RPH-(SEQ ID NO: 295)-A (herein referred to as BCY11138);

[2469] A-(SEQ ID NO: 296)-PKK (herein referred to as BCY11139); and A-(SEQ ID NO: 297)-A (herein referred to as BCY20415).

[2470] 17. The peptide ligand according to any of aspects 1 to 3, wherein said loop sequences comprise three cysteine residues separated by two loop sequences the first of which consists of 7 amino acids and the second of which consists of 5 amino acids, such as an amino acid sequence which is selected from:

[2471] CGEFQFSWCMLSGLC (SEQ ID NO: 298); and

[2472] CNEFSKEWCALMGLC (SEQ ID NO: 299);

[2473] wherein the cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof, in particular wherein the molecular scaffold is a derivative of TATA which has the following structure:

[2474] O O

[2475]

[2476] wherein * denotes the point of attachment of the three cysteine residues, the peptide ligand comprises N- and / or C-terminal additions and is selected from:

[2477] A-(SEQ ID NO: 298)-A (herein referred to as BCY11632); and A-(SEQ ID NO: 299)-A (herein referred to as BCY11633).

[2478] 18. The peptide ligand according to any of aspects 1 to 3, wherein said loop sequences comprise three cysteine residues separated by two loop sequences the first of which consistsof 8 amino acids and the second of which consists of 2 amino acids, such as an amino acid sequence which is:

[2479] CRDWAWVFGCDEC (SEQ ID NO: 300);

[2480] wherein the cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof, in particular wherein the molecular scaffold is a derivative of TATA which has the following structure:

[2481] O O

[2482]

[2483] wherein * denotes the point of attachment of the three cysteine residues, the peptide ligand comprises N- and / or C-terminal additions and is:

[2484] A-(SEQ ID NO: 300)-A (herein referred to as BCY11341).

[2485] 19. The peptide ligand according to any of aspects 1 to 3, wherein said loop sequences comprise three cysteine residues separated by two loop sequences the first of which consists of 8 amino acids and the second of which consists of 4 amino acids, such as an amino acid sequence which is selected from:

[2486] CNSWQQYLDCVRGSC (SEQ ID NO: 301); and

[2487] CGSWLEYQLCIDTGC (SEQ ID NO: 302);

[2488] wherein the cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof, in particular wherein the molecular scaffold is a derivative of TATA which has the following structure:

[2489] O O

[2490]

[2491] wherein * denotes the point of attachment of the three cysteine residues, the peptide ligand comprises N- and / or C-terminal additions and is selected from:

[2492] A-(SEQ ID NO: 301)-A (herein referred to as BCY8974); and

[2493] A-(SEQ ID NO: 302)-A (herein referred to as BCY8977).

[2494] 20. The peptide ligand according to any of aspects 1 to 19, wherein the pharmaceutically acceptable salt is selected from the free acid or the sodium, potassium, calcium or ammonium salt.

[2495] 21. A multimeric binding complex which comprises at least two (such as 2, 3 or 4) of the bicyclic peptide ligand according to any of aspects 1 to 20.

[2496] 22. The multimeric binding complex according to aspect 21, which comprises two identical bicyclic peptides, such as the homodimeric binding complexes described in Table 1.

[2497] 23. The multimeric binding complex according to aspect 21, which comprises two differing bicyclic peptides, such as the heterodimeric binding complexes described in Table 2.

[2498] 24. A pharmaceutical composition which comprises the peptide ligand of any of aspects 1 to 20 or the multimeric binding complex of any of aspects 21 to 23, in combination with one or more pharmaceutically acceptable excipients.

[2499] 25. The pharmaceutical composition according to aspect 24, which additionally comprises one or more therapeutic agents.

[2500] 26. The peptide ligand according to any of aspects 1 to 20, or the multimeric binding complex of any of aspects 21 to 23, or the pharmaceutical composition of either of aspects 24 or 25, for use in suppressing or treating a disease or disorder mediated by GFRAL.

Claims

CLAIMS1. A peptide ligand specific for GFRAL 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; or a pharmaceutically acceptable salt thereof.

2. The peptide ligand according to claim 1, wherein said loop sequences each comprise 2. 3, 4, 5, 6, 7, 8, or 9 amino acids, such as wherein the combined number of amino acids in both loop sequences comprises between 8 and 12 amino acids.

3. The bicycle ligand according to claim 1 or 2, wherein the bicycle ligand has an amino acid sequenceZ-SDAL-Z-X5g-X6g-X7g-X8g-X9g-NT-X12g-Zwhereineach Z is a reactive group;X5gis any amino acid;X6gis F or a derivative thereof;X7gis F or a derivative thereof;X8gis any amino acid;X9gis E, I, K, or L; andXi2g is any amino acid.

4. The bicycle ligand according to claim 1 or 2, wherein the bicycle ligand has an amino acid sequenceZ-YGPF-Z-S-X6g-X7g-X8g-X9g-L-X11g-X12g-Zwhereineach Z is a reactive group;X6gis A, K, Agb, or HArg;X7gis any amino acid;X8gis D, G or S;X9gis any amino acid;X11gis any amino acid; andXi2g is W or M.

5. The bicycle ligand according to claim 1 or 2, wherein the bicycle ligand has an amino acid sequenceZ-XI g-X2g-X3g- W-Z-Xsg- LL-Xsg-Xgg-Xl Og" Xl 1 g-Xl 2g" Zwhereineach Z is a reactive group;X2g, X3g, X8g, X9g, X10gand X12gare each any amino acid;X1gis S or T;X5gis A, K or N; andX11gis H or T.

6. The bicycle ligand according to claim 1 or 2, wherein the bicycle ligand has an amino acid sequenceZ-SG-X3g-X4g-Z-X5g-X6g-X7g-X8g-X9g-N-Xl1g-Xl2g-Zwhereineach Z is a reactive group;X8gand X9gare each any amino acid;X3gis A or P;X4g is L or A;X5gis A, I or Q;X6gis F or A;X7gis F, L or A;X11gis T or A; andXi2g is D, N or G.

7. The peptide ligand according to any of claims 3 to 7, wherein said polypeptide comprises an amino acid sequence which is selected from:CTHEWCALLQANTGC (SEQ ID NO: 79);CSDEWCALLHQTTYC (SEQ ID NO: 80);CSEAWCNLLMSSHTC (SEQ ID NO: 81);CSEAWCALLQTHTNC (SEQ ID NO: 82);CSGNWCKLLQSSTNC (SEQ ID NO: 83);CSGPWCALLRDATDC (SEQ ID NO: 84);CSSRWCALLQETTSC (SEQ ID NO: 85);CSLPWCALLQSNTHC (SEQ ID NO: 86);CSAEWCALLGSTTHC (SEQ ID NO: 87);CDDFQCSWKQLMGLC (SEQ ID NO: 88);CSAMLCGFLSEHTHC (SEQ ID NO: 89);CSGALCAFFRANTDC (SEQ ID NO: 90); CSGPLCIFFQKNTGC (SEQ ID NO: 91);CSQMLCSFLQSHTRC (SEQ ID NO: 92); CYGPFCSKGGILQWC (SEQ ID NO: 93); CSPALCDFLMLHTGC (SEQ ID NO: 94); CGDFSCEWKMLMGLC (SEQ ID NO: 95); CDDFLCNWRELLGLC (SEQ ID NO: 96); CDDFSCSWRQLMGLC (SEQ ID NO: 97); CSGALCQFLKENTNC (SEQ ID NO: 98); CSPMLCAFLKENTHC (SEQ ID NO: 99); CSPALCEFLAVNTHC (SEQ ID NO: 100); CSDALCKFFRENTKC (SEQ ID NO: 101); CSDQLCAFFSTNTGC (SEQ ID NO: 102); CSPLLCAFFADNTGC (SEQ ID NO: 103); CSPRLCSFFQANTSC (SEQ ID NO: 104); CYGPFCSKHDRLIWC (SEQ ID NO: 105); CYGPFCSKDDKLFWC (SEQ ID NO: 106); CYGPFCSKNDKLVWC (SEQ ID NO: 107); CYGPFCSKDGKLYMC (SEQ ID NO: 108); CYGPFCSKQGKLHWC (SEQ ID NO: 109); CYGPFCSKDSHLVWC (SEQ ID NO: 110); CSQALCAFFAENTDC (SEQ ID NO: 111); CSPALCAFFRTNTDC (SEQ ID NO: 112); CSGALCAFFVQNTGC (SEQ ID NO: 113); CSGALCAFFRENTNC (SEQ ID NO: 114); CSDALCQFFKENTKC (SEQ ID NO: 115); CSDALCQFFSLNTKC (SEQ ID NO: 116); CSDALCHFFRENTKC (SEQ ID NO: 117); CSDALCKFFGINTGC (SEQ ID NO: 118); CSDALCKFFKENTGC (SEQ ID NO: 119); CSPLLCAFFRNNTGC (SEQ ID NO: 120); CSPLLCAFFSQNTGC (SEQ ID NO: 121); CSPLLCAFFQDNTGC (SEQ ID NO: 122); CSPQLCSFFAQNTSC (SEQ ID NO: 123); CSPQLCSFFKTNTSC (SEQ ID NO: 124); CSPRLCSFFQSNTNC (SEQ ID NO: 125); CSPRLCSFFQSNTGC (SEQ ID NO: 126);CS[K(Bz)]ALC[Bpa]FFS[AzaTrp]NTKC (SEQ ID NO: 127); CS[K(Bz)]ALC[Bpa]FFSKNT[HArg]C (SEQ ID NO: 128); CSDKLC[K(Bz)]FFRENT[HArg]C (SEQ ID NO: 129);CSKALC[K(Bz)]FFRENT[HArg]C (SEQ ID NO: 130);CSDALC[K(Bz)]FFRKNT[HArg]C (SEQ ID NO: 131);CSDKLC[HArg]FFRENT[HArg]C (SEQ ID NO: 132);CS[Cys(Bn)]ALCKFFRENT[HArg]C (SEQ ID NO: 133);CSDALC[K(Bz)]FFRENTKC (SEQ ID NO: 134);CSKALC[HArg]FFRENT[HArg]C (SEQ ID NO: 135);CSDALCYFFRKNT[HArg]C (SEQ ID NO: 136);CSDALCK[aMePhe]FRENT[HArg]C (SEQ ID NO: 137); CSDALCKF[aMePhe]RENT[HArg]C (SEQ ID NO: 138); CSDALCHFFRKNT[HArg]C (SEQ ID NO: 139);CSDALC[HArg]FFRENTKC (SEQ ID NO: 140);CSDALCKFFRENT[HArg]C (SEQ ID NO: 141);CSDALC[HArg]FFRENT[dK]C (SEQ ID NO: 142);CSDALCKFFHENT[HArg]C (SEQ ID NO: 143);CSDALC[Agb]FFRENTKC (SEQ ID NO: 144);CSDALCKFFRENT[Agb]C (SEQ ID NO: 145);CSDALCHFFSKNT[HArg]C (SEQ ID NO: 146);CSDALCKFFSENT[HArg]C (SEQ ID NO: 147);CSDALCKFFAENT[HArg]C (SEQ ID NO: 148);CSAALCAFFRANTDC (SEQ ID NO: 149);CS[dA]ALCAFFRANTDC (SEQ ID NO: 150);CAGALCAFFRANTDC (SEQ ID NO: 151);CSGALCAFFRANADC (SEQ ID NO: 152);CSGAACAFFRANTDC (SEQ ID NO: 153);CSGALCAAFRANTDC (SEQ ID NO: 154);CYGPFCS[HArg]DD[HArg]LFWC (SEQ ID NO: 155);CYGPFCSKDD[HArg]LFWC (SEQ ID NO: 156);CYGPFCS[HArg]DDKLFWC (SEQ ID NO: 157);CYGPFCS[Agb]DD[Agb]LFWC (SEQ ID NO: 158);CYGPFCSKDD[Agb]LFWC (SEQ ID NO: 159);CYGPFCS[Agb]DDKLFWC (SEQ ID NO: 160);CYGPFCSKDDALFWC (SEQ ID NO: 161);CYGPFCSADDKLFWC (SEQ ID NO: 162);CYGPFCSADDALFWC (SEQ ID NO: 163);CSDALCYFFRKNT[HArg][Cysam] (SEQ ID NO: 164);CSDALCKFFRENT[HArg][Cysam] (SEQ ID NO: 165);CSDALCKFFAENT[HArg][Cysam] (SEQ ID NO: 166);CSDALC[K(dPEG(25))]FFRENT[HArg]C (SEQ ID NO: 167); CSDALC[K(AS-triaz-DBCO-BA)]FFRENT[HArg]C (SEQ ID NO: 168);CSDALC[K(CO-PEG5-CO)]FFRENT[HArg]C (SEQ ID NO: 169); CSDALC[K(Ahx, Ahx)]FFRENT[HArg]C (SEQ ID NO: 170);CSDALC[Agb]FFRENT[K(Ahx, Ahx]C (SEQ ID NO: 171);CSDALC[K(W)]FFRENT[HArg]C (SEQ ID NO: 172);CSDALC[K(Ahx)]FFRENT[HArg]C (SEQ ID NO: 173);CSDALC[HArg]FFRENT[HArg]C (SEQ ID NO: 303);CSDALC[HArg]FFRKNT[HArg]C (SEQ ID NO: 304) and CSDALC[K(DBCO)]FFRENT[HArg]C (SEQ ID NO: 305);wherein the cysteine and Cysam residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof, in particular wherein the molecular scaffold is a derivative of TATA which has the following structure:NNwherein * denotes the point of attachment of the three cysteine residues, the peptide ligand comprises N- and / or C-terminal additions and is selected from:A-(SEQ ID NO: 79)-A (herein referred to as BCY8969);A-(SEQ ID NO: 80)-A (herein referred to as BCY10205);A-(SEQ ID NO: 81)-A (herein referred to as BCY10206);A-(SEQ ID NO: 82)-A (herein referred to as BCY10207);A-(SEQ ID NO: 83)-A (herein referred to as BCY10208);A-(SEQ ID NO: 84)-A (herein referred to as BCY10209);A-(SEQ ID NO: 85)-A (herein referred to as BCY10210);A-(SEQ ID NO: 86)-A (herein referred to as BCY10212);A-(SEQ ID NO: 87)-A (herein referred to as BCY10214);A-(SEQ ID NO: 88)-A (herein referred to as BCY11331);A-(SEQ ID NO: 89)-A (herein referred to as BCY11333);A-(SEQ ID NO: 90)-A (herein referred to as BCY11335);A-(SEQ ID NO: 90)-[dA] (herein referred to as BCY20464);Ac-(SEQ ID NO: 90)-[K(Ac)] (herein referred to as BCY20487); Ac-(SEQ ID NO: 90)-K (herein referred to as BCY20491);Ac-(SEQ ID NO: 90)-[dK] (herein referred to as BCY20492);A-(SEQ ID NO: 90) (herein referred to as BCY20494);Ac-(SEQ ID NO: 90) (herein referred to as BCY20497);A-(SEQ ID NO: 91)-A (herein referred to as BCY11336);A-(SEQ ID NO: 92)-A (herein referred to as BCY11337);A-(SEQ ID NO: 93)-A (herein referred to as BCY11340);Ac-(SEQ ID NO: 93) (herein referred to as BCY20506);A-(SEQ ID NO: 94)-A (herein referred to as BCY11342);A-(SEQ ID NO: 95)-A (herein referred to as BCY11628);A-(SEQ ID NO: 96)-A (herein referred to as BCY11629);A-(SEQ ID NO: 97)-A (herein referred to as BCY11630);A-(SEQ ID NO: 98)-A (herein referred to as BCY11635);A-(SEQ ID NO: 99)-A (herein referred to as BCY11636);A-(SEQ ID NO: 100)-A (herein referred to as BCY11637);A-(SEQ ID NO: 101)-A (herein referred to as BCY11638);Ac-(SEQ ID NO: 101) (herein referred to as BCY12152);Ac-(SEQ ID NO: 101)-[K(N3)] (herein referred to as BCY20470);[AzPnt]-(SEQ ID NO: 101) (herein referred to as BCY20661);A-(SEQ ID NO: 102)-A (herein referred to as BCY11639);Ac-(SEQ ID NO: 102) (herein referred to as BCY12153);A-(SEQ ID NO: 103)-A (herein referred to as BCY11640);Ac-(SEQ ID NO: 103) (herein referred to as BCY20503);A-(SEQ ID NO: 104)-A (herein referred to as BCY11641);A-(SEQ ID NO: 105)-A (herein referred to as BCY11973);A-(SEQ ID NO: 106)-A (herein referred to as BCY11974);A-(SEQ ID NO: 106)-[K(N3)] (herein referred to as BCY20509); A-(SEQ ID NO: 106)-[PG] (herein referred to as BCY20513);[Aib]-(SEQ ID NO: 106) (herein referred to as BCY20516);[dA]-(SEQ ID NO: 106) (herein referred to as BCY20519);A-(SEQ ID NO: 107)-A (herein referred to as BCY11975);A-(SEQ ID NO: 108)-A (herein referred to as BCY11976);A-(SEQ ID NO: 109)-A (herein referred to as BCY11977);A-(SEQ ID NO: 110)-A (herein referred to as BCY11978);SRT-(SEQ ID NO: 111)-A (herein referred to as BCY12100); RTS-(SEQ ID NO: 112)-A (herein referred to as BCY12101); A-(SEQ ID NO: 113)-AHM (herein referred to as BCY12102); A-(SEQ ID NO: 114)-LKN (herein referred to as BCY12103); A-(SEQ ID NO: 115)-A (herein referred to as BCY12104);Ac-(SEQ ID NO: 115) (herein referred to as BCY20504);ATG-(SEQ ID NO: 116)-A (herein referred to as BCY12105);SPH-(SEQ ID NO: 117)-A (herein referred to as BCY12106); Ac-(SEQ ID NO: 117) (herein referred to as BCY20486);A-(SEQ ID NO: 118)-RMS (herein referred to as BCY12107); A-(SEQ ID NO: 119)-SEM (herein referred to as BCY12108); Ac-(SEQ ID NO: 119) (herein referred to as BCY20505);DIG-(SEQ ID NO: 120)-A (herein referred to as BCY12109); Ac-(SEQ ID NO: 120) (herein referred to as BCY20493);A-(SEQ ID NO: 121)-A (herein referred to as BCY12110);A-(SEQ ID NO: 122)-LGS (herein referred to as BCY12111); EGG-(SEQ ID NO: 123)-A (herein referred to as BCY12112); SVG-(SEQ ID NO: 124)-A (herein referred to as BCY12113); A-(SEQ ID NO: 125)-EPT (herein referred to as BCY12114); A-(SEQ ID NO: 126)-AST (herein referred to as BCY12115); Ac-(SEQ ID NO: 127) (herein referred to as BCY20466);Ac-(SEQ ID NO: 128) (herein referred to as BCY20467);Ac-(SEQ ID NO: 129) (herein referred to as BCY20468);Ac-(SEQ ID NO: 130) (herein referred to as BCY20469);Ac-(SEQ ID NO: 131) (herein referred to as BCY20471);Ac-(SEQ ID NO: 132) (herein referred to as BCY20472);Ac-(SEQ ID NO: 133) (herein referred to as BCY20473);Ac-(SEQ ID NO: 134) (herein referred to as BCY20474);Ac-(SEQ ID NO: 135) (herein referred to as BCY20475);Ac-(SEQ ID NO: 136) (herein referred to as BCY20476);Ac-(SEQ ID NO: 137) (herein referred to as BCY20477);Ac-(SEQ ID NO: 138) (herein referred to as BCY20478);Ac-(SEQ ID NO: 139) (herein referred to as BCY20479);Ac-(SEQ ID NO: 140) (herein referred to as BCY20480);Ac-(SEQ ID NO: 141) (herein referred to as BCY20481);Ac-(SEQ ID NO: 142) (herein referred to as BCY20482);Ac-(SEQ ID NO: 143) (herein referred to as BCY20483); Ac-(SEQ ID NO: 144) (herein referred to as BCY20484); Ac-(SEQ ID NO: 145) (herein referred to as BCY20485); Ac-(SEQ ID NO: 146) (herein referred to as BCY20488); Ac-(SEQ ID NO: 147) (herein referred to as BCY20489); Ac-(SEQ ID NO: 148) (herein referred to as BCY20490); Ac-(SEQ ID NO: 149) (herein referred to as BCY20495); Ac-(SEQ ID NO: 150) (herein referred to as BCY20496); Ac-(SEQ ID NO: 151) (herein referred to as BCY20498); Ac-(SEQ ID NO: 152) (herein referred to as BCY20499); Ac-(SEQ ID NO: 153) (herein referred to as BCY20500); Ac-(SEQ ID NO: 154) (herein referred to as BCY20501); Ac-(SEQ ID NO: 155)-K (herein referred to as BCY20507); A-(SEQ ID NO: 155)-A (herein referred to as BCY20508); A-(SEQ ID NO: 156)-A (herein referred to as BCY20510); A-(SEQ ID NO: 157)-A (herein referred to as BCY20511); A-(SEQ ID NO: 158)-A (herein referred to as BCY20512); A-(SEQ ID NO: 159)-A (herein referred to as BCY20514); A-(SEQ ID NO: 160)-A (herein referred to as BCY20515); A-(SEQ ID NO: 161)-A (herein referred to as BCY20517); A-(SEQ ID NO: 162)-A (herein referred to as BCY20518); A-(SEQ ID NO: 163)-A (herein referred to as BCY20520); Ac-(SEQ ID NO: 164) (herein referred to as BCY20523); Ac-(SEQ ID NO: 165) (herein referred to as BCY20524); Ac-(SEQ ID NO: 166) (herein referred to as BCY20525); Ac-(SEQ ID NO: 167) (herein referred to as BCY20578); Ac-(SEQ ID NO: 168) (herein referred to as BCY20579); Ac-(SEQ ID NO: 169) (herein referred to as BCY20655); Ac-(SEQ ID NO: 170) (herein referred to as BCY20656); Ac-(SEQ ID NO: 171) (herein referred to as BCY20657); Ac-(SEQ ID NO: 172) (herein referred to as BCY20658); Ac-(SEQ ID NO: 173) (herein referred to as BCY20659); A-(SEQ ID NO: 303)-A (herein referred to as BCY_A1);Ac-(SEQ ID NO: 304) (herein referred to as BCY_A2); and Ac-(SEQ ID NO: 305) (herein referred to as BCY_A3).

8. The bicycle ligand according to claim 1 or 2, wherein the bicycle ligand has an amino acid sequenceZ-Xl a-X2a-Z-X3a-X4a-X5a-X6a-X7a-X8a-X9a-Xl Oa’Zwhereineach Z is a reactive group;X1aand X2aare each independently selected from S and N; andX3ato X10aare each independently selected from P, N, W, Y, I, H, L and M.

9. The peptide ligand according to claim 8, wherein said polypeptide comprises an amino acid sequence which is:CSNCPNWYIHLMCi (SEQ ID NO: 1);wherein the three cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof, in particular wherein the peptide ligand comprises N- and / or C-terminal additions and is:A-(SEQ ID NO: 1)-A (herein referred to as BCY10120).

10. The bicycle ligand according to claim 1 or 2, wherein the bicycle ligand has an amino acid sequenceZ-X1b-X2b-X3b-Z-X4b-X5b-X6b-X7b-X8b-X9b-X10b-Zwhereineach Z is a reactive group;X2b, X4b, X5b, X7b, X8b, X9b, X10bare each independently any amino acid;X1bis P, D, or A;X3bis W or A; andX6bis I, Y, L, or A.

11. The bicycle ligand according to claim 10, wherein the bicycle ligand has an amino acid sequenceZ-P-X2b-W-Z-X4b-X5b-X6b-X7b-X8b-X9b-X10b-Zwhereineach Z is a reactive group;X2b, X4b, X5b, X7b, X8b, X9b, X10bare each independently any amino acid; andX6bis I, Y, L, or A.

12. The bicycle ligand according to claim 10 or 11, wherein the bicycle ligand has an amino acid sequenceZ-P-X2b-W-Z-X4b-X5b-LGIW-X10b-Zwhereineach Z is a reactive group;X2b and X5b are each independently any amino acid;X4b is S or A; andX10b is D, E, A or N.

13. The peptide ligand according to any of claims 10 to 12, wherein said polypeptide comprises an amino acid sequence which is selected from:CPKWCEHYSSFLC (SEQ ID NO: 2);CPNWCHDIGIWSC (SEQ ID NO: 3);CPAWCYRLIDSTC (SEQ ID NO: 4);CPSWCGRLLGNAC (SEQ ID NO: 5);CPDWCSDIGVWNC (SEQ ID NO: 6);CPIWCSRLGIWDC (SEQ ID NO: 7);CPDWCSKLGIWEC (SEQ ID NO: 8);CPNWCSVLGIWDC (SEQ ID NO: 9; herein referred to as BCY20418); CPGWCSRLGIWAC (SEQ ID NO: 10)CPSWCNRLLGFAC (SEQ ID NO: 11)CPEWCGRLLGFAC (SEQ ID NO: 12)CPAWCTRLLGTAC (SEQ ID NO: 13)CPAWCYRLLGTAC (SEQ ID NO: 14)CPEWCSRLLFSAC (SEQ ID NO: 15)CPGWCARLLNSAC (SEQ ID NO: 16)CPRWCSLLLDWAC (SEQ ID NO: 17)CDRWCTNLLFMAC (SEQ ID NO: 18)CPAWCSQLGIWDC (SEQ ID NO: 19)CPEWCSRLGIWAC (SEQ ID NO: 20)CPAWCSRLGIWDC (SEQ ID NO: 21)CPHWCSTLGIWDC (SEQ ID NO: 22)CPFWCSKLGIWDC (SEQ ID NO: 23)CPGWCSRLGIWDC (SEQ ID NO: 24)CPTWCSRLGIWNC (SEQ ID NO: 25)CPNWCSVLAIWDC (SEQ ID NO: 26)CPNWCSVL[dA]IWDC (SEQ ID NO: 27);CPNWCAVLGIWDC (SEQ ID NO: 28);CANWCSVLGIWDC (SEQ ID NO: 29);CPNWCSALGIWDC (SEQ ID NO: 30);CPAWCSVLGIWDC (SEQ ID NO: 31); andCPNWCSVLGIWAC (SEQ ID NO: 32);wherein the three cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof, in particular wherein the molecular scaffold is a derivative of TATA which has the following structure:O OOwherein * denotes the point of attachment of the three cysteine residues, the peptide ligand comprises N- and / or C-terminal additions and is selected from:A-(SEQ ID NO: 2)-A (herein referred to as BCY8978);A-(SEQ ID NO: 3)-A (herein referred to as BCY8989);A-(SEQ ID NO: 4)-A (herein referred to as BCY9189);A-(SEQ ID NO: 5)-A (herein referred to as BCY9190);A-(SEQ ID NO: 6)-A (herein referred to as BCY9195);A-(SEQ ID NO: 7)-A (herein referred to as BCY9794);A-(SEQ ID NO: 8)-A (herein referred to as BCY10107);A-(SEQ ID NO: 9)-A (herein referred to as BCY10108);Ac-(SEQ ID NO: 9) (herein referred to as BCY10385);Ac-(SEQ ID NO: 9)-K (herein referred to as BCY20416);Ac-(SEQ ID NO: 9)-[K(Ac)] (herein referred to as BCY20417);Ac-(SEQ ID NO: 9)-[K(dPEG(25))] (herein referred to as BCY20544);[PA]-(SEQ ID NO: 9) (herein referred to as BCY20545);[Ts]-(SEQ ID NO: 9) (herein referred to as BCY20555);[PhtCOOH]-(SEQ ID NO: 9) (herein referred to as BCY20556); [PheCOOH]-(SEQ ID NO: 9) (herein referred to as BCY20557); [Succinate]-(SEQ ID NO: 9) (herein referred to as BCY20558);[n-Hex]-(SEQ ID NO: 9) (herein referred to as BCY20559);[Piv]-(SEQ ID NO: 9) (herein referred to as BCY20560);A-(SEQ ID NO: 10)-A (herein referred to as BCY10109);A-(SEQ ID NO: 11)-A (herein referred to as BCY10215);A-(SEQ ID NO: 12)-A (herein referred to as BCY10216);A-(SEQ ID NO: 13)-A (herein referred to as BCY10217);A-(SEQ ID NO: 14)-A (herein referred to as BCY10218);A-(SEQ ID NO: 15)-A (herein referred to as BCY10219);A-(SEQ ID NO: 16)-A (herein referred to as BCY10220);A-(SEQ ID NO: 17)-A (herein referred to as BCY10221);A-(SEQ ID NO: 18)-A (herein referred to as BCY10222);A-(SEQ ID NO: 19)-NTS (herein referred to as BCY10771);A-(SEQ ID NO: 20)-GRV (herein referred to as BCY10772);SGQ-(SEQ ID NO: 21)-A (herein referred to as BCY10773);AKG-(SEQ ID NO: 22)-A (herein referred to as BCY10775);YGA-(SEQ ID NO: 23)-A (herein referred to as BCY10869);AGP-(SEQ ID NO: 24)-A (herein referred to as BCY10870);A-(SEQ ID NO: 25)-AHTA (herein referred to as BCY10871);A-(SEQ ID NO: 26)-A (herein referred to as BCY20419);A-(SEQ ID NO: 27)-A (herein referred to as BCY20420);A-(SEQ ID NO: 28)-A (herein referred to as BCY20421);A-(SEQ ID NO: 29)-A (herein referred to as BCY20422);A-(SEQ ID NO: 30)-A (herein referred to as BCY20423);A-(SEQ ID NO: 31)-A (herein referred to as BCY20426); andA-(SEQ ID NO: 32)-A (herein referred to as BCY20427).

14. The bicycle ligand according to claim 1 or 2, wherein the bicycle ligand has an amino acid sequenceZ-X1c-X2c-X3c-Z-X4c-X5c-X6c-X7c-X8c-X9c-X10c-X11c-Zwhereineach Z is a reactive group;X5c, X7c, X8c, X9c and X11c are each independently any amino acid;X1c is P, S, or T;X2c is D, N, P, or V;X3cis W, F, or S;X4c is S, D, or P;X6c is L, F, W, or Y, andX10c is W, G, H, or L.

15. The bicycle ligand according to claim 14, wherein the bicycle ligand has an amino acid sequenceZ-PDW-Z-S-X5C-X6C-X7C-X8C-X9C-W-X11C-Zwhereineach Z is a reactive group;X5c, X7c, X8c, X9c and X11c are each independently any amino acid; andX6cis L, F or Y.

16. The bicycle ligand according to claim 14, wherein the bicycle ligand has an amino acid sequenceZ-S-X2C-F-Z-X4C-FL-X7C-X8C-X9C-X10C-L-Zwhereineach Z is a reactive group;X7c, X8c, X10c are each independently any amino acid;X2c is P, S or T;X4c is D, T, M or E; andX9c is H or N.

17. The peptide ligand according to any of claims 14 to 16, wherein said polypeptide comprises an amino acid sequence which is selected from:CPDWCSALDINWHC (SEQ ID NO: 33);CPNWCSQFPGVWSC (SEQ ID NO: 34);CSPFCDFLMTQGLC (SEQ ID NO: 35);CSVWCDFLRENHLC (SEQ ID NO: 36);CTDSCPHWYINLMC (SEQ ID NO: 37);CPDWCSRLDIDWGC (SEQ ID NO: 38);CPDWCSHYPEIWDC (SEQ ID NO: 39);CPDWCSHYSQIWKC (SEQ ID NO: 40);CPDWCSRLPGVWDC (SEQ ID NO: 41);CPDWCSYYADIWGC (SEQ ID NO: 42);CETYCALNWYRELVC (SEQ ID NO: 43);CSPFCDFLQEHDLC (SEQ ID NO: 44);CSPFCDFLNLNGLC (SEQ ID NO: 45);CSSFCDFLQTHDLC (SEQ ID NO: 46);CSTFCDFLRNNHLC (SEQ ID NO: 47);CSPFCDFLFQHQLC (SEQ ID NO: 48);CSPFCDFLSENNLC (SEQ ID NO: 49);CSSFCDFLRGNNLC (SEQ ID NO: 50);CSSFCDFLRTNSLC (SEQ ID NO: 51);CSSFCDFLRDNDLC (SEQ ID NO: 52);CSSFCDFLRENDLC (SEQ ID NO: 53);CSSFCDFLRDNNLC (SEQ ID NO: 54);CSPFCTFLQQHGLC (SEQ ID NO: 55);CSPFCMFLREHDLC (SEQ ID NO: 56); andCSPFCEFLRHHKLC (SEQ ID NO: 57);wherein the three cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof, in particular wherein the molecular scaffold is a derivative of TATA which has the following structure:Nwherein * denotes the point of attachment of the three cysteine residues, the peptide ligand comprises N- and / or C-terminal additions and is selected from:A-(SEQ ID NO: 33)-A (herein referred to as BCY9196);A-(SEQ ID NO: 34)-A (herein referred to as BCY9197);A-(SEQ ID NO: 35)-A (herein referred to as BCY9198);A-(SEQ ID NO: 36)-A (herein referred to as BCY9199);A-(SEQ ID NO: 37)-A (herein referred to as BCY9200);A-(SEQ ID NO: 38)-A (herein referred to as BCY10111);A-(SEQ ID NO: 39)-A (herein referred to as BCY10112);A-(SEQ ID NO: 40)-A (herein referred to as BCY10113);A-(SEQ ID NO: 41)-A (herein referred to as BCY10114);A-(SEQ ID NO: 42)-A (herein referred to as BCY10115);A-(SEQ ID NO: 43)-A (herein referred to as BCY10261);A-(SEQ ID NO: 44)-A (herein referred to as BCY10277);A-(SEQ ID NO: 45)-A (herein referred to as BCY10278);A-(SEQ ID NO: 46)-A (herein referred to as BCY10279);A-(SEQ ID NO: 47)-A (herein referred to as BCY10280);A-(SEQ ID NO: 48)-A (herein referred to as BCY10281);A-(SEQ ID NO: 49)-A (herein referred to as BCY10282);A-(SEQ ID NO: 50)-A (herein referred to as BCY10283);[dPEG(25)]A-(SEQ ID NO: 50)-A (herein referred to as BCY20561);A-(SEQ ID NO: 51)-PKV (herein referred to as BCY11129);A-(SEQ ID NO: 52)-PIA (herein referred to as BCY11130);A-(SEQ ID NO: 53)-SVS (herein referred to as BCY11131);A-(SEQ ID NO: 54)-KKE (herein referred to as BCY11132);A-(SEQ ID NO: 55)-A (herein referred to as BCY11624);A-(SEQ ID NO: 56)-A (herein referred to as BCY11625); andA-(SEQ ID NO: 57)-A (herein referred to as BCY11626).

18. The bicycle ligand according to claim 1 or 2, wherein the bicycle ligand has an amino acid sequenceZ-X1d-X2d-X3d-Z-X4d-X5d-X6d-X7d-X8d-X9d-X10d-X11d-X12d-Zwhereineach Z is a reactive group;X1d, X2d, X3d, X4d, X5d, X6d, X9d, X10d, and X12d are each independently any amino acid; X7dis W, A, Y, or P;X8d is Y, E, or N; andX11d is L, S, M, or K.

19. The bicycle ligand according to claim 18, wherein the bicycle ligand has an amino acid sequenceZ-X1d-X2d-X3d-Z-X4d-X5d-X6d-WY-X9d-X10d-L-X12d-Zwhereineach Z is a reactive group;X1d, X2d, X4d, X6d, X9d, and X10d are each independently any amino acid;X3d is N or Y;X5d is P or L; andX12d is M, I or V.

20. The bicycle ligand according to claim 18 or 19, wherein the bicycle ligand has an amino acid sequenceZ-X1d-X2d-Y-Z-X4d-L-X6d-WY-X9d-X10d-L-X12d-Zwhereineach Z is a reactive group;X1d, X2d, X4d, X6d, X9d, and X10d are each independently any amino acid; and X12d is I or V.

21. The peptide ligand according to any of claims 18 to 20, wherein said polypeptide comprises an amino acid sequence which is selected from:CDDYCHLSWYNRLVC (SEQ ID NO: 58);CGPYCHLTWYHDLVC (SEQ ID NO: 59);CGSYCNLPWYTRLVC (SEQ ID NO: 60);CASYCDLPWYQDLVC (SEQ ID NO: 61);CDPYCDLSWYYNLVC (SEQ ID NO: 62);CDDYCHLEWYSNLIC (SEQ ID NO: 63);CPLYCDLPWYQSLVC (SEQ ID NO: 64);CQQECPKWYVDLMDC (SEQ ID NO: 65);CRDNCRPDWYIRLMC (SEQ ID NO: 66);CSGLCFTRAEGLSYC (SEQ ID NO: 67);CYDKCPNMAEGLSYC (SEQ ID NO: 68);CSGLCFTRPNHMKAC (SEQ ID NO: 69);CRGKCGELAEGLSYC (SEQ ID NO: 70); andCTGHCRSFAEGLSYC (SEQ ID NO: 71);wherein the three cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof, in particular wherein the molecular scaffold is a derivative of TATA which has the following structure:O Owherein * denotes the point of attachment of the three cysteine residues, the peptide ligand comprises N- and / or C-terminal additions and is selected from:A-(SEQ ID NO: 58)-A (herein referred to as BCY10262);A-(SEQ ID NO: 59)-A (herein referred to as BCY10263);A-(SEQ ID NO: 60)-A (herein referred to as BCY10264);A-(SEQ ID NO: 61)-A (herein referred to as BCY10266);A-(SEQ ID NO: 62)-A (herein referred to as BCY10267);A-(SEQ ID NO: 63)-A (herein referred to as BCY9201);A-(SEQ ID NO: 64)-A (herein referred to as BCY9204);A-(SEQ ID NO: 65)-A (herein referred to as BCY9205);A-(SEQ ID NO: 66)-A (herein referred to as BCY8983);A-(SEQ ID NO: 67)-A (herein referred to as BCY8984);A-(SEQ ID NO: 68)-A (herein referred to as BCY10326);A-(SEQ ID NO: 69)-A (herein referred to as BCY10328);A-(SEQ ID NO: 70)-A (herein referred to as BCY10329); andA-(SEQ ID NO: 71)-A (herein referred to as BCY10330).

22. The bicycle ligand according to claim 1 or 2, wherein the bicycle ligand has an amino acid sequenceZ-X1e-X2e-X3e-X4e-Z-X5e-X6e-X7e-X8e-ZwhereinX1e, X2e, X3e and X4e are each independently selected from L, R, W and M; and X5e, X6e, X7e and X8e are each independently selected from E, L, G and I.

23. The peptide ligand according to claim 22, wherein said polypeptide comprises an amino acid sequence which is:CLRWMCELGIC (SEQ ID NO: 72);wherein the three cysteine residues within the peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof, in particular wherein the molecular scaffold is a derivative of TATA which has the following structure:O Owherein * denotes the point of attachment of the three cysteine residues, the peptide ligand comprises N- and / or C-terminal additions and is:A-(SEQ ID NO: 72)-A (herein referred to as BCY8991).

24. The bicycle ligand according to claim 1 or 2, wherein the bicycle ligand has an amino acid sequenceZ-X1f-X2f-X3f-W-Z-X5f-X6f-LFP-X10f-Zwhereineach Z is a reactive group;X1f, X3f, X5f and X10f are each independently any amino acids;X2f is L or P; andX6f is selected from R, E and P.

25. The peptide ligand according to claim 24, wherein said polypeptide comprises an amino acid sequence which is selected from:CELDWCKRLFPEC (SEQ ID NO: 73);CQLDWCNELFPNC (SEQ ID NO: 74);CLPNWCGPLFPRC (SEQ ID NO: 75);CQLSWCRELFPDC (SEQ ID NO: 76);CGLSWCAELFPDC (SEQ ID NO: 77); andCQLDW[dC]NELFPNC (SEQ ID NO: 78);wherein the three cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof, in particular wherein the molecular scaffold is a derivative of TATA which has the following structure:wherein * denotes the point of attachment of the three cysteine residues, the peptide ligand comprises N- and / or C-terminal additions and is selected from:A-(SEQ ID NO: 73)-A (herein referred to as BCY8970);A-(SEQ ID NO: 74)-A (herein referred to as BCY9206);A-(SEQ ID NO: 75)- A (herein referred to as BCY10087);A-(SEQ ID NO: 76)-A (herein referred to as BCY10285);A-(SEQ ID NO: 77)-A (herein referred to as BCY10286); and[-FI][NH-Peg6-CO]A-(SEQ ID NO: 78)-A (herein referred to as BCY20522).

26. The bicycle ligand according to claim 1 or 2, wherein the bicycle ligand has an amino acid sequenceZ-X1h-X2h-X3h-X4h-X5h-Z-X6h-X7h-X8h-X9h-Zwhereineach Z is a reactive group;X1h, X2h, X3h, X4h, and X5h are each independently selected from Y, P, E, W, and Y; and X6h, X7h, X8h and X9h are each independently selected from R, L and P.

27. The peptide ligand according to claim 26, wherein said polypeptide comprises an amino acid sequence which is:CYPEWYCRLLPC (SEQ ID NO: 174);wherein the three cysteine residues within the peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof in particular wherein the molecular scaffold is a derivative of TATA which has the following structure:O Owherein * denotes the point of attachment of the three cysteine residues, the peptide ligand comprises N- and / or C-terminal additions and is:A-(SEQ ID NO: 174)-A (herein referred to as BCY8980).

28. The bicycle ligand according to claim 1 or 2, wherein the bicycle ligand has an amino acid sequenceZ-X1i-X2i-L-X4i-W-Z-X6i-EL-X9i-X10i-X11i-X12i-Zwhereineach Z is a reactive group;X1i is L, P, S, or Y;X2i is D or P;X4i is A, G, P, or R;X6i is any amino acid;X9i is M, G, or Nle;Xioi is A, D, L, or V;Xm is any amino acid; andXi2i is H or N.

29. The bicycle ligand according to claim 1 or 2, wherein the bicycle ligand has an amino acid sequenceZ-KNPMW-Z-AMF-X9i-X10i-X11i-X12i-Zwhereineach Z is a reactive group;Xgi is A, G, or T;Xioi is any amino acid;Xm is D or Q: andXi2i is any amino acid.

30. The bicycle ligand according to claim 1 or 2, wherein the bicycle ligand has an amino acid sequenceZ-X1i-X2i-LQ-X5i-Z-A-X7i-YWLGW-Zwhereineach Z is a reactive group;X1i, X2i and X5i are each independently any amino acid; andX7i is E or Q.

31. The peptide ligand according to any of claims 28 to 30, wherein said polypeptide comprises an amino acid sequence which is selected from:CKNPMWCAMFAKDDC (SEQ ID NO: 175);CYDLPWCKELMLQHC (SEQ ID NO: 176);CYPDWYCQLMKLPTC (SEQ ID NO: 177);CMPKWYCDLMGTPMC (SEQ ID NO: 178);CYDLAWCNELMATHC (SEQ ID NO: 179);CYDLPWCNELMAQHC (SEQ ID NO: 180);CYDLRWCHELMDQHC (SEQ ID NO: 181);CYDLAWCRELGVWNC (SEQ ID NO: 182);CPPLAWCRELMLQHC (SEQ ID NO: 183);CYDLAWCKELMLMNC (SEQ ID NO: 184);CSPLGWCAELMLQHC (SEQ ID NO: 185);CKNPMWCAMFGEDSC (SEQ ID NO: 186);CKNPMWCAMFGDQSC (SEQ ID NO: 187);CKNPMWCAMFTTQGC (SEQ ID NO: 188);CKNPMWCAMFGYDRC (SEQ ID NO: 189);CEGTLWCWMFAKDDC (SEQ ID NO: 190);CGSSFWCAMFAKDDC (SEQ ID NO: 191);CTDPFWCFMFAKDDC (SEQ ID NO: 192);CSPLWYCALMKRKTC (SEQ ID NO: 193);CAPWWYCNLMAQPTC (SEQ ID NO: 194);CMPDWYCRLMDIDTC (SEQ ID NO: 195);CAPNWYCMLMQHTTC (SEQ ID NO: 196);CPDLAWCKELMLKNC (SEQ ID NO: 197);CTELAWCKELMLTNC (SEQ ID NO: 198);CLDLAWCKELMLMNC (SEQ ID NO: 199);CTNLQLCAQYWLGWC (SEQ ID NO: 200);CPDLQNCAQYWLGWC (SEQ ID NO: 201);CNDLQYCAEYWLGWC (SEQ ID NO: 202);CRELQSCAQYWLGWC (SEQ ID NO: 203);CYDLAWCRELMLMNC (SEQ ID NO: 204);CYDLPWCKELMLMNC (SEQ ID NO: 205);CYDLAWCKELMLMHC (SEQ ID NO: 206);CYDLAWCKELMLQNC (SEQ ID NO: 207);CYDLAWCKEL[Nle]LMNC (SEQ ID NO: 208);CYDLAWCKELML[Nle]NC (SEQ ID NO: 209);CYDLAWCKEL[Nle]L[Nle]NC (SEQ ID NO: 210);CPPLAWCRELMLMNC (SEQ ID NO: 211); andCPPLAWCKELMLMNC (SEQ ID NO: 212);wherein the cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof, in particular wherein the molecular scaffold is a derivative of TATA which has the following structure:NNwherein * denotes the point of attachment of the three cysteine residues, the peptide ligand comprises N- and / or C-terminal additions and is selected from:A-(SEQ ID NO: 175)-A (herein referred to as BCY8982);A-(SEQ ID NO: 176)-A (herein referred to as BCY9209);A-(SEQ ID NO: 177)-A (herein referred to as BCY9210);A-(SEQ ID NO: 178)-A (herein referred to as BCY10096);A-(SEQ ID NO: 179)-A (herein referred to as BCY10269);A-(SEQ ID NO: 180)-A (herein referred to as BCY10270);A-(SEQ ID NO: 181)-A (herein referred to as BCY10272);A-(SEQ ID NO: 182)-A (herein referred to as BCY10273);A-(SEQ ID NO: 183)-A (herein referred to as BCY10274);A-(SEQ ID NO: 184)-A (herein referred to as BCY10275);Ac-(SEQ ID NO: 184) (herein referred to as BCY20433);Ac-[NH-Peg6-CO]-(SEQ ID NO: 184) (herein referred to as BCY20562); A-(SEQ ID NO: 185)-A (herein referred to as BCY10276);A-(SEQ ID NO: 186)-A (herein referred to as BCY10317);A-(SEQ ID NO: 187)-A (herein referred to as BCY10318);A-(SEQ ID NO: 188)-A (herein referred to as BCY10319);A-(SEQ ID NO: 189)-A (herein referred to as BCY10320);A-(SEQ ID NO: 190)-A (herein referred to as BCY10322);A-(SEQ ID NO: 191)-A (herein referred to as BCY10323);A-(SEQ ID NO: 192)-A (herein referred to as BCY10325);A-(SEQ ID NO: 193)-A (herein referred to as BCY10583);A-(SEQ ID NO: 194)-A (herein referred to as BCY10584);A-(SEQ ID NO: 195)-A (herein referred to as BCY10585);A-(SEQ ID NO: 196)-A (herein referred to as BCY10586);SYP-(SEQ ID NO: 197)-A (herein referred to as BCY11119);SSW-(SEQ ID NO: 198)-A (herein referred to as BCY11120);A-(SEQ ID NO: 199)-TQK (herein referred to as BCY11124);A-(SEQ ID NO: 200)-A (herein referred to as BCY11328);A-(SEQ ID NO: 201)-A (herein referred to as BCY11619);A-(SEQ ID NO: 202)-A (herein referred to as BCY11620);A-(SEQ ID NO: 203)-A (herein referred to as BCY11621);Ac-(SEQ ID NO: 204) (herein referred to as BCY20430);Ac-(SEQ ID NO: 205) (herein referred to as BCY20431);Ac-(SEQ ID NO: 206) (herein referred to as BCY20432);Ac-(SEQ ID NO: 207) (herein referred to as BCY20434);Ac-(SEQ ID NO: 208) (herein referred to as BCY20435);Ac-(SEQ ID NO: 209) (herein referred to as BCY20436);Ac-(SEQ ID NO: 210) (herein referred to as BCY20437);Ac-(SEQ ID NO: 211) (herein referred to as BCY20438); andAc-(SEQ ID NO: 212) (herein referred to as BCY20439).

32. The bicycle ligand according to claim 1 or 2, wherein the bicycle ligand has an amino acid sequenceZ-X1j-X2j-X3j-X4j-X5j-X6j-Z-X7j-X8j-X9j-Zwhereineach Z is a reactive group;X1j, X2j, X5j, X6j, X7j and X8j are each independently any amino acid;X3j is A, E or P;X4j is A or L; andX9j is A, I, L or V.

33. The bicycle ligand according to claim 32, wherein the bicycle ligand has an amino acid sequenceZ-X1j-X2j-X3j-X4j-X5j-W-Z-X7j-X8j-X9j-Zwhereineach Z is a reactive group;X1j, X5j, and X8j are each independently any amino acid;X2jis A, H or N;X3j is A, E or P;X4j is A or L;X6j is W;X7j is A, E or R; andX9j is A, I, L or V.

34. The peptide ligand according to any of claims 32 to 33, wherein said polypeptide comprises an amino acid sequence which is selected from:CSHPLEWCRTLC (SEQ ID NO: 213);CMNPLGWCRTLC (SEQ ID NO: 214);CDHPLEWCRSLC (SEQ ID NO: 215);CNHPLAWCREVC (SEQ ID NO: 216);CSHELKWCRDLC (SEQ ID NO: 217);CSHPLGWCRELC (SEQ ID NO: 218);CDHPLWWCREIC (SEQ ID NO: 219);CHHPLWWCREIC (SEQ ID NO: 220);CTHPLWWCREVC (SEQ ID NO: 221);CGHPLRWCRELC (SEQ ID NO: 222);CNHPLRWCREVC (SEQ ID NO: 223);CHHPLRWCRELC (SEQ ID NO: 224);CDHPLGWCRELC (SEQ ID NO: 225);CQHPLSWCRELC (SEQ ID NO: 226);CSHPLRWCREIC (SEQ ID NO: 227);CEHPLAWCRELC (SEQ ID NO: 228);CD[1Nal]PLWWCREIC (SEQ ID NO: 229);CD[2Nal]PLWWCREIC (SEQ ID NO: 230);CD[4FPhe]PLWWCREIC (SEQ ID NO: 231);CDHPLWWC[HArg]EIC (SEQ ID NO: 232);CDHPLW[1Nal]CREIC (SEQ ID NO: 233);CDHPL[1Nal]WCREIC (SEQ ID NO: 234);CDHPL[2Nal]WCREIC (SEQ ID NO: 235);CDHPLW[2Nal]CREIC (SEQ ID NO: 236);CDHPLWWC[Cit]EIC (SEQ ID NO: 237);CDHPLWWC[dR]EIC (SEQ ID NO: 238);CDHPLW[4FPhe]CREIC (SEQ ID NO: 239);CDHPL[4FPhe]WCREIC (SEQ ID NO: 240);CDHALWWCREIC (SEQ ID NO: 241);CDHPLWWCREAC (SEQ ID NO: 242);CDHPAWWCREIC (SEQ ID NO: 243);CDHPLWWCRAIC (SEQ ID NO: 244);CDAPLWWCREIC (SEQ ID NO: 245);CDHPLWWCAEIC (SEQ ID NO: 246);CDHPLAWCREIC (SEQ ID NO: 247); andCAHPLWWCREIC (SEQ ID NO: 248);wherein the cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof, in particular wherein the molecular scaffold is a derivative of TATA which has the following structure:wherein * denotes the point of attachment of the three cysteine residues, the peptide ligand comprises N- and / or C-terminal additions and is selected from:A-(SEQ ID NO: 213)-A (herein referred to as BCY8973);A-(SEQ ID NO: 214)-A (herein referred to as BCY8976);A-(SEQ ID NO: 215)-A (herein referred to as BCY8979);A-(SEQ ID NO: 216)-A (herein referred to as BCY9211);A-(SEQ ID NO: 217)-A (herein referred to as BCY9212);A-(SEQ ID NO: 218)-A (herein referred to as BCY9213);[MeO-dPEG12]-A-(SEQ ID NO: 219)-A (herein referred to as BCY10303); Ac-(SEQ ID NO: 219) (herein referred to as BCY10387);Ac-(SEQ ID NO: 219)-[K(Ac)] (herein referred to as BCY20440);Ac-(SEQ ID NO: 219)-K (herein referred to as BCY20441);[-FI][NH-Peg6-CO]A-(SEQ ID NO: 219)-A (herein referred to as BCY20577); A-(SEQ ID NO: 219)-A (herein referred to as BCY9795);A-(SEQ ID NO: 220)-A (herein referred to as BCY9796);A-(SEQ ID NO: 221)-A (herein referred to as BCY9797);A-(SEQ ID NO: 222)-A (herein referred to as BCY9798);A-(SEQ ID NO: 223)-A (herein referred to as BCY10116);A-(SEQ ID NO: 224)-A (herein referred to as BCY10118);A-(SEQ ID NO: 225)-DSY (herein referred to as BCY10776);A-(SEQ ID NO: 226)-STN (herein referred to as BCY10777);SQP-(SEQ ID NO: 227)-A (herein referred to as BCY10778);RAQ-(SEQ ID NO: 228)-A (herein referred to as BCY10779);A-(SEQ ID NO: 229)-A (herein referred to as BCY20442);A-(SEQ ID NO: 230)-A (herein referred to as BCY20443);A-(SEQ ID NO: 231)-A (herein referred to as BCY20444);A-(SEQ ID NO: 232)-A (herein referred to as BCY20445);A-(SEQ ID NO: 233)-A (herein referred to as BCY20446);A-(SEQ ID NO: 234)-A (herein referred to as BCY20447);A-(SEQ ID NO: 235)-A (herein referred to as BCY20448);A-(SEQ ID NO: 236)-A (herein referred to as BCY20449);A-(SEQ ID NO: 237)-A (herein referred to as BCY20450);A-(SEQ ID NO: 238)-A (herein referred to as BCY20451);A-(SEQ ID NO: 239)-A (herein referred to as BCY20452);A-(SEQ ID NO: 240)-A (herein referred to as BCY20453);A-(SEQ ID NO: 241)-A (herein referred to as BCY20454);A-(SEQ ID NO: 242)-A (herein referred to as BCY20456);A-(SEQ ID NO: 243)-A (herein referred to as BCY20457);A-(SEQ ID NO: 244)-A (herein referred to as BCY20458);A-(SEQ ID NO: 245)-A (herein referred to as BCY20459);A-(SEQ ID NO: 246)-A (herein referred to as BCY20460);A-(SEQ ID NO: 247)-A (herein referred to as BCY20461); and A-(SEQ ID NO: 248)-A (herein referred to as BCY20463).

35. The bicycle ligand according to claim 1 or 2, wherein the bicycle ligand has an amino acid sequenceZ-Xl k-X2k-X3k-X4k-X5k-X6k-Z-X7k-X8k-Xgk-Xl Ok’Zwhereineach Z is a reactive group;X2k, X3k, X4k, and X7k are each independently any amino acid;X1k is A, E, Y, or N;X5k is A, R, or W;X6k is A, Y, or L;X8k is A, Y, or L;X9k is A, F, or I; andX10k is G, P, or T.

36. The bicycle ligand according to claim 35, wherein the bicycle ligand has an amino acid sequenceZ-Y-X2k-X3k-X4k-X5k-X6k-Z-X7k-X8k-X9k-P-Zwhereineach Z is a reactive group;X4k and X7k are each independently any amino acid;X2k is A, D, or N;Xsk is A or L;Xsk is A or W;Xek is A or Y;Xsk is A or L; andXgk is A or F.

37. The bicycle ligand according to claim 35 or 36, wherein the bicycle ligand has an amino acid sequenceZ-YDL-X4k-WY-Z-X7k-LFP-Zwhereineach Z is a reactive group; andX4k and X7k are each independently any amino acid.

38. The peptide ligand according to any of claims 35 to 37, wherein said polypeptide comprises an amino acid sequence which is selected from:CEENEWYCRLFGC (SEQ ID NO: 249);CNKPAWYCSLFPC (SEQ ID NO: 250);CNWDPRLCKYITC (SEQ ID NO: 251);CYDLAWYCRLFPC (SEQ ID NO: 252);CYDLKWYCDLFPC (SEQ ID NO: 253);CYDLDWYCTLFPC (SEQ ID NO: 254);CYDLEWYCKLFPC (SEQ ID NO: 255);CYNLEWYCQLFPC (SEQ ID NO: 256);CYDLEWYCALFPC (SEQ ID NO: 257);CYDLGWYCQLFPC (SEQ ID NO: 258);CYDLQWYCSLFPC (SEQ ID NO: 259);CYDLDWYCRLFPC (SEQ ID NO: 260);CYDLDWYCKLFPC (SEQ ID NO: 261);CYDLSWYCQLFPC (SEQ ID NO: 262);CYDLHWYCTLFPC (SEQ ID NO: 263);CYDLAWYC[HArg]LFPC (SEQ ID NO: 264);CYDLAWYC[Cit]LFPC (SEQ ID NO: 265);CYDLAWYC[dR]LFPC (SEQ ID NO: 266);CYDL[dA]WYCRLFPC (SEQ ID NO: 267);CYDLAWYC[Agb]LFPC (SEQ ID NO: 268);CYDLAWYCELFPC (SEQ ID NO: 269);CYDLAWYCRAFPC (SEQ ID NO: 270);CYDAAWYCRLFPC (SEQ ID NO: 271);CYALAWYCRLFPC (SEQ ID NO: 272);CYDLAWYCRLAPC (SEQ ID NO: 273);CYDLAWYCALFPC (SEQ ID NO: 274);CADLAWYCRLFPC (SEQ ID NO: 275);CYDLAWACRLFPC (SEQ ID NO: 276); andCYDLAWY[dC]RLFPC (SEQ ID NO: 277);wherein the cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof, in particular wherein the molecular scaffold is a derivative of TATA which has the following structure:wherein * denotes the point of attachment of the three cysteine residues, the peptide ligand comprises N- and / or C-terminal additions and is selected from:A-(SEQ ID NO: 249)-A (herein referred to as BCY8981);A-(SEQ ID NO: 250)-A (herein referred to as BCY8986);A-(SEQ ID NO: 251)-A (herein referred to as BCY8992);A-(SEQ ID NO: 252)-A (herein referred to as BCY9792);A-(SEQ ID NO: 252)-A[MeO-dPEG12] (herein referred to as BCY10301); Ac-(SEQ ID NO: 252) (herein referred to as BCY10384);Ac-(SEQ ID NO: 252)-[K(Ac)] (herein referred to as BCY20413);Ac-(SEQ ID NO: 252)-K (herein referred to as BCY20414);A-(SEQ ID NO: 253)-A (herein referred to as BCY9793);A-(SEQ ID NO: 254)-A (herein referred to as BCY10088);A-(SEQ ID NO: 255)-A (herein referred to as BCY10089);A-(SEQ ID NO: 256)-A (herein referred to as BCY10090);A-(SEQ ID NO: 257)-A (herein referred to as BCY10091);A-(SEQ ID NO: 258)-A (herein referred to as BCY10092);A-(SEQ ID NO: 259)-SNR (herein referred to as BCY10765);A-(SEQ ID NO: 260)-MVT (herein referred to as BCY10767);HGP-(SEQ ID NO: 261)-A (herein referred to as BCY10768);HTQ-(SEQ ID NO: 262)-A (herein referred to as BCY10769);A-(SEQ ID NO: 263)-A (herein referred to as BCY10770);A-(SEQ ID NO: 264)-A (herein referred to as BCY20398);A-(SEQ ID NO: 265)-A (herein referred to as BCY20399);A-(SEQ ID NO: 266)-A (herein referred to as BCY20400);A-(SEQ ID NO: 267)-A (herein referred to as BCY20401);A-(SEQ ID NO: 268)-A (herein referred to as BCY20402);A-(SEQ ID NO: 269)-A (herein referred to as BCY20404);A-(SEQ ID NO: 270)-A (herein referred to as BCY20405);A-(SEQ ID NO: 271)-A (herein referred to as BCY20406);A-(SEQ ID NO: 272)-A (herein referred to as BCY20407);A-(SEQ ID NO: 273)-A (herein referred to as BCY20408);A-(SEQ ID NO: 274)-A (herein referred to as BCY20409);A-(SEQ ID NO: 275)-A (herein referred to as BCY20410);A-(SEQ ID NO: 276)-A (herein referred to as BCY20411); and [-FI][NH-Peg6-CO]A-(SEQ ID NO: 277)-A (herein referred to as BCY20521).

39. The bicycle ligand according to claim 1 or 2, wherein the bicycle ligand has an amino acid sequenceZ-X1al-X2al-X3al-X4al-X5al-X6al-Z-X7al-X8al-X9al-X10al-X11l-X12l-ZwhereinX1l is selected from N, P and R;X2ai is selected from G and S;X3aiis selected from P, L and S;X4ai is selected from F, P and S;Xsai is selected from T and A;Xeai is selected from V and W;X?ai is selected from N, Y and S;Xsai is selected from G and S;Xgaiis selected from R and L;X10al is selected from V and F;X11l is selected from R and P; andX12l is selected from L, D and S.

40. The peptide ligand according to claim 39, wherein said polypeptide comprises an amino acid sequence which is selected from:CNGPFTVCNGRVRLC (SEQ ID NO: 278);CRGLPAWCYSLFPDC (SEQ ID NO: 279); andCPSSSAWCSSLFPSC (SEQ ID NO: 280);wherein the cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof, in particular wherein the molecular scaffold is a derivative of TATA which has the following structure:O O* N N *wherein * denotes the point of attachment of the three cysteine residues, the peptide ligand comprises N- and / or C-terminal additions and is selected from:A-(SEQ ID NO: 278)-A (herein referred to as BCY8985);A-(SEQ ID NO: 279)-A (herein referred to as BCY8988); andA-(SEQ ID NO: 280)-A (herein referred to as BCY10094).

41. The bicycle ligand according to claim 1 or 2, wherein the bicycle ligand has an amino acid sequenceZ-X1m-X2m-X3m-X4m-X5m-X6m-X7m-Z-X8m-X9m-X10m-Zwhereineach Z is a reactive group;X1m, X2m, X3m, X5m, X8mand X10mare each independently any amino acid;X4mis P, H, N orW;Xem is W, L or Q;Xymis Y, L, N, or W; andXgmis selected from L, D, F, and H.

42. The bicycle ligand according to claim 41, wherein the bicycle ligand has an amino acid sequenceZ-X1m-X2m-X3m-P-X5m-WY-Z-X8m-LM-Zwhereineach Z is a reactive group;X1m, X2m, X5mand X8mare each independently any amino acid; andX3mis E, K, M or R.

43. The peptide ligand according to any of claims 41 to 42, wherein said polypeptide comprises an amino acid sequence which is selected from:CGNGHQLNCLFSC (SEQ ID NO: 281);CADRPRWYCDLMC (SEQ ID NO: 282);CDPIWELLCPHGC (SEQ ID NO: 283);CPYLNLQWCRDLC (SEQ ID NO: 284);CSHKPQWYCNLMC (SEQ ID NO: 285);CMYEPSWYCQLMC (SEQ ID NO: 286);CVDMPDWYCQLMC (SEQ ID NO: 287);CYYEPEWYCNLMC (SEQ ID NO: 288);CIDMPDWYCTLMC (SEQ ID NO: 289);CLYEPSWYCNLMC (SEQ ID NO: 290);CRYEPEWYCNLMC (SEQ ID NO: 291);CTNMPRWYCDLMC (SEQ ID NO: 292);CVDMPDWYCKLMC (SEQ ID NO: 293);CVDMPDWYCRLMC (SEQ ID NO: 294);CARMPDWYCNLMC (SEQ ID NO: 295);CVDMPDWYCELMC (SEQ ID NO: 296); andCRYEPEWYCNL[MetO]C (SEQ ID NO: 297);wherein the cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof, in particular wherein the molecular scaffold is a derivative of TATA which has the following structure:O O*N N*wherein * denotes the point of attachment of the three cysteine residues, the peptide ligand comprises N- and / or C-terminal additions and is selected from:A-(SEQ ID NO: 281)-A (herein referred to as BCY8971);A-(SEQ ID NO: 282)-A (herein referred to as BCY9191);A-(SEQ ID NO: 283)-A (herein referred to as BCY9192);A-(SEQ ID NO: 284)-A (herein referred to as BCY9193);A-(SEQ ID NO: 285)-A (herein referred to as BCY9194);A-(SEQ ID NO: 286)-A (herein referred to as BCY10097);A-(SEQ ID NO: 287)-A (herein referred to as BCY10098);A-(SEQ ID NO: 288)-A (herein referred to as BCY10099);A-(SEQ ID NO: 289)-A (herein referred to as BCY10100);A-(SEQ ID NO: 290)-A (herein referred to as BCY10101);A-(SEQ ID NO: 291)-A (herein referred to as BCY10102);Ac-(SEQ ID NO: 291) (herein referred to as BCY10386);A-(SEQ ID NO: 292)-A (herein referred to as BCY10103);A-(SEQ ID NO: 293)-A (herein referred to as BCY10104);A-(SEQ ID NO: 294)-A (herein referred to as BCY10105);RPH-(SEQ ID NO: 295)-A (herein referred to as BCY11138);A-(SEQ ID NO: 296)-PKK (herein referred to as BCY11139); and A-(SEQ ID NO: 297)-A (herein referred to as BCY20415).

44. The bicycle ligand according to claim 1 or 2, wherein the bicycle ligand has an amino acid sequenceZ-X1n-X2n-X3n-X4n-X5n-X6n-X7n-Z-X8n-X9n-X10n-X11n-X12n-Zwhereineach Z is a reactive group;X1n, X4n, X5n, X6n, X8nand X10nare each independently any amino acid;X2nis E;X3nis F;X7nis W;X9nis L;X11nis G andXl2n is L.

45. The peptide ligand according to claim 44, wherein said polypeptide comprises an amino acid sequence which is selected from:CGEFQFSWCMLSGLC (SEQ ID NO: 298); andCNEFSKEWCALMGLC (SEQ ID NO: 299);wherein the cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof, in particular wherein the molecular scaffold is a derivative of TATA which has the following structure:wherein * denotes the point of attachment of the three cysteine residues, the peptide ligand comprises N- and / or C-terminal additions and is selected from:A-(SEQ ID NO: 298)-A (herein referred to as BCY11632); and A-(SEQ ID NO: 299)-A (herein referred to as BCY11633).

46. The bicycle ligand according to claim 1 or 2, wherein the bicycle ligand has an amino acid sequenceZ-X1o-X2o-X3o-X4o-X5o-X6o-X7o-X8o-Z-X9o-X10o-Zwhereineach Z is a reactive group;X1o, X2o, X3o, X4o, X5o, X6o, X7oand X8oare each independently selected from R, D, W, A, W, V, F and G; andX9oand X10oare selected from D and E.

47. The peptide ligand according to claim 46, wherein said polypeptide comprises an amino acid sequence which is:CRDWAWVFGCDEC (SEQ ID NO: 300);wherein the cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof, in particular wherein the molecular scaffold is a derivative of TATA which has the following structure:N Nwherein * denotes the point of attachment of the three cysteine residues, the peptide ligand comprises N- and / or C-terminal additions and is:A-(SEQ ID NO: 300)-A (herein referred to as BCY11341).

48. The bicycle ligand according to claim 1 or 2, wherein the bicycle ligand has an amino acid sequenceZ-X1p-X2p-X3p-X4p-X5p-X6p-X7p-X8p-Z-X9p-X10p-X11p-X12p-Zwhereineach Z is a reactive group;each of X1pto X12pare each independently any amino acid;X2p is S;X3pis W; andX6pis Y.

49. The peptide ligand according to claim 48, wherein said polypeptide comprises an amino acid sequence which is selected from:CNSWQQYLDCVRGSC (SEQ ID NO: 301); andCGSWLEYQLCIDTGC (SEQ ID NO: 302);wherein the cysteine residues within each peptide ligand represent the three reactive groups, or a pharmaceutically acceptable salt thereof, in particular wherein the molecular scaffold is a derivative of TATA which has the following structure:O Owherein * denotes the point of attachment of the three cysteine residues, the peptide ligand comprises N- and / or C-terminal additions and is selected from:A-(SEQ ID NO: 301)-A (herein referred to as BCY8974); andA-(SEQ ID NO: 302)-A (herein referred to as BCY8977).

50. The peptide ligand according to any one of the preceding claims, wherein said reactive groups are selected from cysteine, d-cysteine, cysteamine, homocysteine, βCys, penicillamine, Dap ((S)-2,3-diaminopropanoic acid) and N-methyl-Dap.

51. A peptide ligand specific for GFRAL 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 the polypeptide comprises (i) an amino acid sequence selected from any one of SEQ ID NOs: 1 to 305 or (ii) an amino acid sequence selected from any one of SEQ ID NOs: 1 to 305 wherein 1, 2, or 3 cysteine residues are substituted for a reactive group as defined in claim 50 and / or wherein 1, 2, or 3 non-cysteine residues are replaced with any alternative amino acid.

52. The peptide ligand according to any of the preceding claims, wherein the peptide ligand is in the form of the free acid or a sodium, potassium, calcium or ammonium salt.

53. A multimeric binding complex which comprises at least two (such as 2, 3 or 4) of the bicyclic peptide ligand according to any of claims 1 to 52.

54. The multimeric binding complex according to claim 53, which comprises two identical bicyclic peptides,such as a multimeric binding complex comprising:Two peptide ligands, each of which are BCY9795, attached together via an amido- Peg25-amido linker, wherein said linker is attached to each of said ligands at the N- terminus (herein referred to as BCY10304);Two peptide ligands, each of which are BCY10109, attached together via an amido- Peg25-amido linker, wherein said linker is attached to each of said ligands at the N- terminus (herein referred to as BCY22807);Two peptide ligands, each of which are BCY9796, attached together via an amido- Peg25-amido linker, wherein said linker is attached to each of said ligands at the N- terminus (herein referred to as BCY22812);Two peptide ligands, each of which are BCY10283, attached together via an amido- Peg25-amido linker, wherein said linker is attached to each of said ligands at the N- terminus (herein referred to as BCY22809);Two peptide ligands, each of which are BCY10280, attached together via an amido- Peg25-amido linker, wherein said linker is attached to each of said ligands at the N-terminus (herein referred to as BCY22810);Two peptide ligands, each of which are BCY10105, attached together via an amido-Peg25-amido linker, wherein said linker is attached to each of said ligands at the N-terminus (herein referred to as BCY22813);Two peptide ligands, each of which are BCY10274, attached together via an amido-Peg25-amido linker, wherein said linker is attached to each of said ligands at the N-terminus (herein referred to as BCY22811);Two peptide ligands, each of which are BCY10108, attached together via an amido-Peg25-amido linker, wherein said linker is attached to each of said ligands at the N-terminus (herein referred to as BCY22808);Two peptide ligands, each of which are BCY11335, attached together via an amido-Peg25-amido linker, wherein said linker is attached to each of said ligands at the N-terminus (herein referred to as BCY22815);Two peptide ligands, each of which are BCY20416, attached together via an amido-Peg25-amido linker, wherein said linker is attached to each of said ligands at the C-terminal Lys (herein referred to as BCY22816);Two peptide ligands, each of which are BCY20414, attached together via an amido-Peg25-amido linker, wherein said linker is attached to each of said ligands at the C-terminal Lys (herein referred to as BCY22817);Two peptide ligands, each of which are BCY20441, attached together via an amido-Peg25-amido linker, wherein said linker is attached to each of said ligands at the C-terminal Lys (herein referred to as BCY22818);Two peptide ligands, each of which are BCY20491, attached together via an amido-Peg25-amido linker, wherein said linker is attached to each of said ligands at the C-terminal Lys (herein referred to as BCY22819);Two peptide ligands, each of which are BCY20520, attached together via an amido-Peg25-amido linker, wherein said linker is attached to each of said ligands at the N-terminus (herein referred to as BCY22820);Two peptide ligands, each of which are BCY20508, attached together via an amido-Peg25-amido linker, wherein said linker is attached to each of said ligands at the N-terminus (herein referred to as BCY22821);Two peptide ligands, each of which are BCY11335, attached together via an amido-Peg17-amido linker, wherein said linker is attached to each of said ligands at the N-terminus (herein referred to as BCY22782);Two peptide ligands, each of which are BCY11335, attached together via an amido-Peg21 -amido linker, wherein said linker is attached to each of said ligands at the N-terminus (herein referred to as BCY22787);Two peptide ligands, each of which are BCY20512, attached together via an amido-Peg25-amido linker, wherein said linker is attached to each of said ligands at the N-terminus (herein referred to as BCY22822);Two peptide ligands, each of which are BCY11335, attached together via an amido-Peg13-amido linker, wherein said linker is attached to each of said ligands at the N-terminus (herein referred to as BCY22768);Two peptide ligands, each of which are BCY11335, attached together via an amido-Peg7-amido linker, wherein said linker is attached to each of said ligands at the N-terminus (herein referred to as BCY22793);Two peptide ligands, each of which are BCY11335, attached together via an amido-Peg5-amido linker, wherein said linker is attached to each of said ligands at the N-terminus (herein referred to as BCY22791);Two peptide ligands, each of which are BCY11335, attached together via an amido-Peg9-amido linker, wherein said linker is attached to each of said ligands at the N-terminus (herein referred to as BCY22795);Two peptide ligands, each of which are BCY20491, attached together via an amido-Peg13-amido linker, wherein said linker is attached to each of said ligands at the C-terminal Lys (herein referred to as BCY22769);Two peptide ligands, each of which are BCY20491, attached together via an amido-Peg9-amido linker, wherein said linker is attached to each of said ligands at the C-terminal Lys (herein referred to as BCY22796);Two peptide ligands, each of which are BCY20491, attached together via an amido-Peg21 -amido linker, wherein said linker is attached to each of said ligands at the C-terminal Lys (herein referred to as BCY22788);Two peptide ligands, each of which are BCY20491, attached together via an amido-Peg17-amido linker, wherein said linker is attached to each of said ligands at the C-terminal Lys (herein referred to as BCY22783);Two peptide ligands, each of which are BCY20492, attached together via an amido-Peg25-amido linker, wherein said linker is attached to each of said ligands at the C-terminal D-Lys (herein referred to as BCY22823);Two peptide ligands, each of which are BCY20508, attached together via an amido-Peg17-amido linker, wherein said linker is attached to each of said ligands at the N-terminus (herein referred to as BCY22784);Two peptide ligands, each of which are BCY20508, attached together via an amido-Peg21 -amido linker, wherein said linker is attached to each of said ligands at the N-terminus (herein referred to as BCY22789);Two peptide ligands, each of which are BCY20507, attached together via an amido-Peg25-amido linker, wherein said linker is attached to each of said ligands at the C-terminal Lys (herein referred to as BCY22824);Two peptide ligands, each of which are BCY20480, attached together via an amido-Peg25-amido linker, wherein said linker is attached to each of said ligands at Lys12 (herein referred to as BCY22825);Two peptide ligands, each of which are BCY20481, attached together via an amido-Peg25-amido linker, wherein said linker is attached to each of said ligands at Lys5 (herein referred to as BCY22826);Two peptide ligands, each of which are BCY20485, attached together via an amido-Peg13-amido linker, wherein said linker is attached to each of said ligands at Lys5 (herein referred to as BCY22770);Two peptide ligands, each of which are BCY20508, attached together via an amido-Peg9-amido linker, wherein said linker is attached to each of said ligands at the N-terminus (herein referred to as BCY22797);Two peptide ligands, each of which are BCY20508, attached together via an amido-Peg13-amido linker, wherein said linker is attached to each of said ligands at the N-terminus (herein referred to as BCY22771);Two peptide ligands, each of which are BCY20507, attached together via an amido-Peg21 -amido linker, wherein said linker is attached to each of said ligands at the C-terminal Lys (herein referred to as BCY22790);Two peptide ligands, each of which are BCY20507, attached together via an amido-Peg17-amido linker, wherein said linker is attached to each of said ligands at the C-terminal Lys (herein referred to as BCY22785);Two peptide ligands, each of which are BCY20507, attached together via an amido-Peg13-amido linker, wherein said linker is attached to each of said ligands at the C-terminal Lys (herein referred to as BCY22772);Two peptide ligands, each of which are BCY20507, attached together via an amido-Peg9-amido linker, wherein said linker is attached to each of said ligands at the C-terminal Lys (herein referred to as BCY22798);Two peptide ligands, each of which are BCY20481, attached together via an amido-Peg13-amido linker, wherein said linker is attached to each of said ligands at Lys5 (herein referred to as BCY22773);Two peptide ligands, each of which are BCY20481, attached together via an amido-Peg9-amido linker, wherein said linker is attached to each of said ligands at Lys5 (herein referred to as BCY22799);Two peptide ligands, each of which are BCY20481, attached together via an amido-Peg7-amido linker, wherein said linker is attached to each of said ligands at Lys5(herein referred to as BCY22794);Two peptide ligands, each of which are BCY20481, attached together via an amido-Peg5-amido linker, wherein said linker is attached to each of said ligands at Lys5 (herein referred to as BCY22792);Two peptide ligands, each of which are BCY20489, attached together via an amido-Peg25-amido linker, wherein said linker is attached to each of said ligands at Lys5 (herein referred to as BCY22827);Two peptide ligands, each of which are BCY20490, attached together via an amido-Peg25-amido linker, wherein said linker is attached to each of said ligands at Lys5 (herein referred to as BCY22828);Two peptide ligands, each of which are BCY20483, attached together via an amido-Peg25-amido linker, wherein said linker is attached to each of said ligands at Lys5 (herein referred to as BCY22829);Two peptide ligands, each of which are BCY20479, attached together via an amido-Peg25-amido linker, wherein said linker is attached to each of said ligands at Lys9 (herein referred to as BCY22830);Two peptide ligands, each of which are BCY20476, attached together via an amido-Peg25-amido linker, wherein said linker is attached to each of said ligands at Lys9 (herein referred to as BCY22831);Two peptide ligands, each of which are BCY20488, attached together via an amido-Peg25-amido linker, wherein said linker is attached to each of said ligands at Lys9 (herein referred to as BCY22832);Two peptide ligands, each of which are BCY20481, attached together via an amido-W-Peg25-W-amido linker, wherein said linker is attached to each of said ligands at Lys5 (herein referred to as BCY22834);Two peptide ligands, each of which are BCY20473, attached together via an amido-Peg9-amido linker, wherein said linker is attached to each of said ligands at Lys5 (herein referred to as BCY22800);Two peptide ligands, each of which are BCY20506, attached together via an amido-Peg25-amido linker, wherein said linker is attached to each of said ligands at Lys6 (herein referred to as BCY22833);Two peptide ligands, each of which are BCY20479, attached together via an amido-Peg13-amido linker, wherein said linker is attached to each of said ligands at Lys9 (herein referred to as BCY22774);Two peptide ligands, each of which are BCY20475, attached together via an amido-Peg17-amido linker, wherein said linker is attached to each of said ligands at Lys2 (herein referred to as BCY22835);Two peptide ligands, each of which are BCY20479, attached together via an amido-W-Peg13-W-amido linker, wherein said linker is attached to each of said ligands at Lys9 (herein referred to as BCY22802);Two peptide ligands, each of which are BCY20475, attached together via an amido-W-Peg17-W-amido linker, wherein said linker is attached to each of said ligands at Lys2 (herein referred to as BCY22786);Two peptide ligands, each of which are BCY20484, attached together via an amido-Ahx2-C10-Ahx2-amido linker, wherein said linker is attached to each of said ligands at Lys12 (herein referred to as BCY22761);Two peptide ligands, each of which are BCY20481, attached together via an amido-W-Peg9-W-amido linker, wherein said linker is attached to each of said ligands at Lys5 (herein referred to as BCY22805);Two peptide ligands, each of which are BCY20480, attached together via an amido-Peg9-amido linker, wherein said linker is attached to each of said ligands at Lys12 (herein referred to as BCY22801);Two peptide ligands, each of which are BCY20472, attached together via an amido-Peg13-amido linker, wherein said linker is attached to each of said ligands at Lys3 (herein referred to as BCY22775);Two peptide ligands, each of which are BCY20480, attached together via an amido-W-Peg9-W-amido linker, wherein said linker is attached to each of said ligands at Lys12 (herein referred to as BCY22806);Two peptide ligands, each of which are BCY20472, attached together via an amido-W-Peg13-W-amido linker, wherein said linker is attached to each of said ligands at Lys3 (herein referred to as BCY22803);Two peptide ligands, each of which are BCY20481, attached together via an DBCO-KAAAE5-DBCO linker, wherein said linker is attached to each of said ligands at Lys5 (herein referred to as BCY22766);Two peptide ligands, each of which are BCY20486, attached together via an DBCO-KAAAE5-DBCO linker, wherein said linker is attached to each of said ligands at Lys12 (herein referred to as BCY22767);Two peptide ligands, each of which are BCY20481, attached together via an amido-Ahx2-C10-Ahx2-amido linker, wherein said linker is attached to each of said ligands at Lys5 (herein referred to as BCY22762);Two peptide ligands, each of which are BCY20477, attached together via an amido-Peg13-amido linker, wherein said linker is attached to each of said ligands at Lys5 (herein referred to as BCY22776);Two peptide ligands, each of which are BCY20482, attached together via an amido-Peg13-amido linker, wherein said linker is attached to each of said ligands at D-Lys12 (herein referred to as BCY22777);Two peptide ligands, each of which are BCY20478, attached together via an amido-Peg13-amido linker, wherein said linker is attached to each of said ligands at Lys5 (herein referred to as BCY22778);Two peptide ligands, each of which are BCY20479, attached together via an amido-Ahx2-C10-Ahx2-amido linker, wherein said linker is attached to each of said ligands at Lys9 (herein referred to as BCY22763);Two peptide ligands, each of which are BCY20475, attached together via an amido-Ahx2-C10-Ahx2-amido linker, wherein said linker is attached to each of said ligands at Lys2 (herein referred to as BCY22764);Two peptide ligands, each of which are BCY20524, attached together via an amido-Peg13-amido linker, wherein said linker is attached to each of said ligands at Lys5 (herein referred to as BCY22779);Two peptide ligands, each of which are BCY20523, attached together via an amido-Peg13-amido linker, wherein said linker is attached to each of said ligands at Lys9 (herein referred to as BCY22780);Two peptide ligands, each of which are BCY20525, attached together via an amido-Peg13-amido linker, wherein said linker is attached to each of said ligands at Lys5 (herein referred to as BCY22781);Two peptide ligands, each of which are BCY20481, attached together via an amido-AS-tria-DBCO-BA-Peg13-AS-tria-DBCO-BA-amido linker, wherein said linker is attached to each of said ligands at Lys5 (herein referred to as BCY22804);Two peptide ligands, each of which are BCY20474, attached together via an amido-Peg13-amido linker, wherein said linker is attached to each of said ligands at Lys12 (herein referred to as BCY22839);Two peptide ligands, each of which are BCY9792, attached together via an amido-Peg25-amido linker, wherein said linker is attached to each of said ligands at the N-terminus (herein referred to as BCY10302);Two peptide ligands, each of which are BCY_A1, attached together via an amido-Peg25-amido linker, wherein said linker is attached to each of said ligands at the N-terminus (herein referred to as BCY_B1);Two peptide ligands, each of which are BCY_A2, attached together via an amido-Peg13-amido linker, wherein said linker is attached to each of said ligands at Lys9 (herein referred to as BCY_B2);Two peptide ligands, each of which are BCY20656, attached together via an amido-octanyl-amido linker, wherein said linker is attached to each of said ligands at Lys5(herein referred to as BCY_B3);Two peptide ligands, each of which are BCY20475, attached together via an amido-Peg13-amido linker, wherein said linker is attached to each of said ligands at Lys2 (herein referred to as BCY_B4);Two peptide ligands, each of which are BCY20472, attached together via an amido- Peg17-amido linker, wherein said linker is attached to each of said ligands at Lys3 (herein referred to as BCY_B5).

55. The multimeric binding complex according to claim 53, which is BCY22776 or a pharmaceutically acceptable salt thereof, wherein BCY22776 is:

56. The multimeric binding complex according to claim 53, which comprises two differing bicyclic peptides,such as a multimeric binding complex comprising:- A first peptide ligand which is BCY9795 attached via an amido-Peg25-amido linker to a second peptide ligand which is BCY9792, wherein said linker is attached to each of said ligands at the N-terminus (herein referred to as BCY22814).

57. A pharmaceutical composition which comprises the peptide ligand of any of claims 1 to 52 or the multimeric binding complex of any of claims 53 to 55, in combination with one or more pharmaceutically acceptable excipients.

58. The pharmaceutical composition according to claim 56, which additionally comprises one or more therapeutic agents.

59. The peptide ligand according to any of claims 1 to 52, or the multimeric binding complex of any of claims 53 to 55, or the pharmaceutical composition of either of claims 56 or 57, for use in suppressing or treating a disease or disorder mediated by GFRAL.

60. The peptide ligand, multimeric binding complex or pharmaceutical composition for use according to claim 59, wherein the disease or disorder mediated by GFRAL is a cardiometabolic disorder; optionally wherein the disease or disorder mediated by GFRAL is selected from obesity, cachexia (optionally tumor- and / or chemotherapy-induced cachexia), and type 2 diabetes.

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