Bicyclic peptide ligand specific for CD137
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 are high affinity binders of CD137. The invention also includes drug conjugates comprising said peptides, conjugated to one or more effector and/or functional groups, to pharmaceutical compositions comprising said peptide ligands and drug conjugates and to the use of said peptide ligands and drug conjugates in preventing, suppressing or treating a disease or disorder mediated by CD137.
1. A peptide ligand specific for CD137 comprising a polypeptide comprising at least three cysteine residues, separated by two loop sequences, and a molecular scaffold which forms covalent bonds with the cysteine residues of the polypeptide such that two polypeptide loops are formed on the molecular scaffold, which comprises an amino acid sequence selected from:
(SEQ ID NO: 41)
C i -I/L/M/V-E/D/P/S-P/E/A-G-P/Q-Y/F-C ii -Y-A-D-P-
Y/M-M/L/Y-C iii ;
(SEQ ID NO: 20)
C i -I-E-E-G-Q-Y-C ii -X 1 -X 2 -D-X 3 -Y/Q/M-X 4 -C iii ;
(SEQ ID NO: 21)
C i -D-I-G-P-P-Y-C ii -Y-R/A-D-M/P-Y-M-C iii ;
(SEQ ID NO: 22)
C i -D-E-W-G-L-F/Y-C ii -I/F-P/A-H-S/P-D-C iii ;
and
(SEQ ID NO: 19)
C i IEPGPFC ii YADPYMC iii ;
wherein X 1 -X 4 represent any amino acid residue and C i , C ii and C iii represent first, second and third cysteine residues, respectively or a pharmaceutically acceptable salt thereof.
2. The peptide ligand as defined in claim 1 , wherein the peptide ligand of C i -I-E-E-G-Q-Y-C ii -X 1 -X 2 -D-X 3 -Y/Q-XC iii (SEQ ID NO: 20) comprises an amino acid sequence selected from any one of SEQ ID NOS: 1-14:
(SEQ ID NO: 1)
C i IEEGQYC ii YRDMYMC iii ;
(SEQ ID NO: 2)
C i IEEGQYC ii YADPYMC iii ;
(SEQ ID NO: 3)
C i IEEGQYC ii YADPYYC iii ;
(SEQ ID NO: 4)
C i IEEGQYC ii YSDPYYC iii ;
(SEQ ID NO: 5)
C i IEEGQYC ii FADPYMC iii ;
(SEQ ID NO: 6)
C i IEEGQYC ii YADHQLC iii ;
(SEQ ID NO: 7)
C i IEEGQYC ii HADPYYC iii ;
(SEQ ID NO: 8)
C i IEEGQYC ii HADPYFC iii ;
(SEQ ID NO: 9)
C i IEEGQYC ii YADHYMC iii ;
(SEQ ID NO: 10)
C i IEEGQYC ii YADPYLC iii ;
(SEQ ID NO: 11)
C i IEEGQYC ii YSDPYLC iii ;
(SEQ ID NO: 12)
C i IEEGQYC ii FADPYLC iii ;
(SEQ ID NO: 13)
C i IEEGQYC ii HADPYMC iii ;
and
(SEQ ID NO: 14)
C i IEEGQYC ii HADPQMC iii ;
or an amino acid sequence selected from:
A-(SEQ ID NO: 1)-A (herein referred to as 74-01-00-N004);
A-(SEQ ID NO: 2)-A (herein referred to as 74-01-01-N001);
A-(SEQ ID NO: 3)-A (herein referred to as 74-01-02-N001);
A-(SEQ ID NO: 4)-A (herein referred to as 74-01-03-N001);
A-(SEQ ID NO: 5)-A (herein referred to as 74-01-04-N001);
A-(SEQ ID NO: 6)-A (herein referred to as 74-01-05-N001);
A-(SEQ ID NO: 7)-A (herein referred to as 74-01-06-N001);
A-(SEQ ID NO: 8)-A (herein referred to as 74-01-07-N001);
A-(SEQ ID NO: 9)-A (herein referred to as 74-01-08-N001);
A-(SEQ ID NO: 10)-A (herein referred to as 74-01-09-N001);
A-(SEQ ID NO: 10)-SVG (herein referred to as 74-01-09-T03-N002);
A-(SEQ ID NO: 11)-A (herein referred to as 74-01-10-N001);
A-(SEQ ID NO: 12)-A (herein referred to as 74-01-11-N001);
A-(SEQ ID NO: 13)-A (herein referred to as 74-01-13-N001); and
A-(SEQ ID NO: 14)-A (herein referred to as 74-01-14-N001).
3. The peptide ligand as defined in claim 1 , wherein the peptide ligand C i -D-I-G-P-P-Y-C ii -Y-R/A-D-M/P-Y-M-C iii (SEQ ID NO: 21) comprises an amino acid sequence selected from:
(SEQ ID NO: 15)
C i DIGPPYC ii YRDMYMC iii ;
and
(SEQ ID NO: 16)
C i DIGPPYC ii YADPYMC iii ;
or an amino acid sequence selected from:
A-(SEQ ID NO: 15)-A (herein referred to as 74-01-16-N001); and
A-(SEQ ID NO: 16)-A (herein referred to as 74-01-17-N001).
4. The peptide ligand as defined in claim 1 , wherein the peptide ligand of C i -D-E-W-G-L-F/Y-C ii -I/F-P/A-H-S/P-D-C iii (SEQ ID NO: 22) comprises an amino acid sequence selected from:
(SEQ ID NO: 17)
C i DEWGLFC ii IPHSDC iii ;
and
(SEQ ID NO: 18)
C i DEWGLYC ii FAHPDC iii ;
or an amino acid sequence selected from:
Ac-A-(SEQ ID NO: 17)-A (herein referred to as 74-02-00-N004); and
A-(SEQ ID NO: 18)-A (herein referred to as 74-02-01-N001).
5. The peptide ligand as defined in claim 1 , wherein the peptide ligand of C i IEPGPFC ii YADPYMC iii (SEQ ID NO: 19) comprises an amino acid sequence of: A-(SEQ ID NO: 19)-NRV (herein referred to as 74-19-00-T01-N002).
6. A peptide ligand specific for CD137 comprising a polypeptide comprising at least three cysteine residues, separated by two loop sequences, and a molecular scaffold which forms covalent bonds with the cysteine residues of the polypeptide such that two polypeptide loops are formed on the molecular scaffold, which comprises an amino acid sequence selected from:
(SEQ ID NO: 23)
C i IEEGQYC ii FADPY(Nle)C iii ;
(SEQ ID NO: 24)
C i IKEGQYC ii FADPY(Nle)C iii ;
(SEQ ID NO: 25)
C i IEKGQYC ii FADPY(Nle)C iii ;
(SEQ ID NO: 26)
C i IEE(D-K)QYC ii FADPY(Nle)C iii ;
(SEQ ID NO: 27)
C i IEEGKYC ii FADPY(Nle)C iii ;
(SEQ ID NO: 28)
C i IEEGQYC ii KADPY(Nle)C iii ;
(SEQ ID NO: 29)
C i IEEGQYC ii FADKY(Nle)C iii ;
(SEQ ID NO: 30)
C i IEEGQYC ii FADPYKC iii ;
(SEQ ID NO: 40; 74-22-00)
C i LPPGQYC ii FPDLLLC iii
(SEQ ID NO: 31; BCY3814)
A-C i IEEGQYC ii FADPY(Nle)C iii -A;
(SEQ ID NO: 32; BCY7732)
Ac-A-C i IEEGQYC ii FADPY(Nle)C iii -Dap;
(SEQ ID NO: 33; BCY7733)
Ac-A-C i IKEGQYC ii FADPY(Nle)C iii -A;
(SEQ ID NO: 34; BCY7734)
Ac-A-C i IEKGQYC ii FADPY(Nle)C iii -A;
(SEQ ID NO: 35; BCY7735)
Ac-A-C i IEE(D-K)QYC ii FADPY(Nle)C iii -A;
(SEQ ID NO: 36; BCY7736)
Ac-A-C i IEEGKYC ii FADPY(Nle)C iii -A;
(SEQ ID NO: 37; BCY7737)
Ac-A-C i IEEGQYC ii KADPY(Nle)C iii -A;
(SEQ ID NO: 38; BCY7738)
Ac-A-C i IEEGQYC ii FADKY(Nle)C iii -A;
and
(SEQ ID NO: 39; BCY7739)
Ac-A-C i IEEGQYC ii FADPYKC iii -A;
or an amino acid sequence selected from:
SEQ ID
Peptide Number
NO:
Sequence
BCY633
42
[B-Ala]-Sar5-ACIEEGQYCYRDMYMCA
BCY634
43
[Ac]ACIEEGQYCYRDMYIVICA-Sar6-K(Fl)
BCY636
44
ACIEEGQYCYADPYIVICA-Sar6-K(Fl)
BCY635
45
[B-Ala]-Sar5-ACIEEGQYCYADPYWICA
BCY638
46
ACIEEGQYCYADPYYCASar6-K
BCY637
47
[B-Ala]-Sar5-ACIEEGQYCYADPYYCA
BCY639
48
ACIEEGQYCYSDPYYCA-Sar6-K
BCY640
49
ACIEEGQYCFADPYMCA-Sar6-K
BCY641
50
G-Sar5-ACIEEGQYCFADPYMCA
BCY7239
52
Ac-CIK(Peg12)EGQYCFADPYMC
BCY7240
53
Ac-CIEK(Peg12)GQYCFADPYMC
BCY7242
55
Ac-CIEEGK(Peg12)YCFADPYMC
BCY7244
57
Ac-CIEEGQYCK(Peg12)ADPYMC
BCY7245
58
Ac-CIEEGQYCFK(Peg12)DPYMC
BCY7247
60
Ac-CIEEGQYCFADK(Peg12)YMC
BCY7248
61
Ac-CIEEGQYCFADPK(Peg12)MC
BCY7249
62
Ac-CIEEGQYCFADPYK(Peg12)C
BCY7416
63
[Ac]IEE[dK(PEG12Fl)]QYCFADPY[Nle]C
BCY7519
64
ACIEEGQYCFADPY[Nle]CA
BCY7520
65
[Peg12]-ACIEEGQYCFADPY[Nle]CA
BCY642
66
ACIEEGQYCYADHQLCA-Sar6-K
BCY643
67
ACIEEGQYCHADPYYCA-Sar6-K
BCY644
68
ACIEEGQYCHADPYFCA-Sar6-K
BCY645
69
ACIEEGQYCYADHYMCA-Sar6-K
BCY646
70
ACIEEGQYCYADPYLCA-Sar6-K
BCY647
71
ACIEEGQYCYADPYLCSVG-Sar6-K
BCY648
72
(Fl)G-Sar5-ACIEEGQYCYADPYLCSVG
BCY649
73
ACIEEGQYCYSDPYLCA-Sar6-K
BCY650
74
ACIEEGQYCFADPYLCA-Sar6-K
BCY652
75
ACIEEGQYCHADPYIVICA-Sar6-K
BCY653
76
ACIEEGQYCHADPQMCA-Sar6-K
BCY655
77
ACDIGPPYCYRDMYIVICA-Sar6-K
BCY656
78
ADIGPPYCYADPYIVICA-Sar6-K
BCY7251
79
ACLDPGPFCFADPYIVICA-Sar6-K
BCY7253
80
ACLDEGPYCFADPYFCA-Sar6-K
BCY7255
81
ACINEGPYCFADPYIVICA-Sar6-K
BCY7257
82
ACIEQGPFCFADPYIVICA-Sar6-K
BCY7259
83
ACVEEGPFCFADPYYCA-Sar6-K
BCY7261
84
ACLDEGPFCFSDPYIVICA-Sar6-K
BCY657
85
[B-Ala]-Sar5-ACDEWGLFCIPHSDCA
BCY659
86
ACDEWGLYCFAHPDCA-Sar6-K
BCY7119
87
ACLDPGPYCYADPYIVICTFH-Sar6-K
BCY660
88
ACIEPGPFCYADPYMCNRV-Sar6-K
BCY661
89
G-Sar5-ACIEPGPFCYADPYMCNRV
BCY7120
90
ACLEPGPYCYADPYIVICTHL-Sar6-K
BCY7122
91
ACLPPGPYCFPDPYFCA-Sar6-K
BCY7151
92
[PEG3]-ACIEEGQYCFADPY[Nle]CA
BCY7152
115
[PEG3]-ACLEEGQYCFADPY[Nle]CA
BCY7153
116
[PEG3]-AC[Nle]EEGQYCFADPY[Nle]CA
BCY7154
117
[PEG3]-AC-Chg-EEGQYCFADPY[Nle]CA
BCY7155
118
[PEG3]-AC-Cha-EEGQYCFADPY[Nle]CA
BCY7156
119
[PEG3]-ACIPEGQYCFADPY[Nle]CA
BCY7157
120
[PEG3]-ACIDEGQYCFADPY[Nle]CA
BCY7158
121
[PEG3]-ACI-Aad-EGQYCFADPY[Nle]CA
BCY7159
122
[PEG3]-ACI-Api-EGQYCFADPY[Nle]CA
BCY7160
123
[PEG3]-ACIEPGQYCFADPY[Nle]CA
BCY7161
124
[PEG3]-ACIEDGQYCFADPY[Nle]CA
BCY7162
125
[PEG3]-ACIE-Aad-GQYCFADPY[Nle]CA
BCY7163
126
[PEG3]-ACIE-Api-GQYCFADPY[Nle]CA
BCY7164
127
[PEG3]-ACIEE-Sar-QYCFADPY[Nle]CA
BCY7165
128
[PEG3]-ACIEE-DLys-QYCFADPY[Nle]CA
BCY7166
129
[PEG3]-ACIEE-DPhe-QYCFADPY[Nle]CA
BCY7167
130
[PEG3]-ACIEE-DGlu-QYCFADPY[Nle]CA
BCY7168
131
[PEG3]-ACIEE-DGln-QYCFADPY[Nle]CA
BCY7169
132
[PEG3]-ACIEE-DLeu-QYCFADPY[Nle]CA
BCY7170
133
[PEG3]-ACIEE-DSer-QYCFADPY[Nle]CA
BCY7172
134
[PEG3]-ACIEE-MeDala-QYCFADPY[Nle]CA
BCY7173
135
[PEG3]-ACIEE-Aib-QYCFADPY[Nle]CA
BCY7174
136
[PEG3]-ACIEEGPYCFADPY[Nle]CA
BCY7175
137
[PEG3]-ACIEEGQFCFADPY[Nle]CA
BCY7176
138
[PEG3]-ACIEEGQ-2MeF-CFADPY[Nle]CA
BCY7177
139
[PEG3]-ACIEEGQ-3MeF-CFADPY[Nle]CA
BCY7178
140
[PEG3]-ACIEEGQ-4MeF-CFADPY[Nle]CA
BCY7179
141
[PEG3]-ACIEEGQ-4FF-CFADPY[Nle]CA
BCY7180
142
[PEG3]-ACIEEGQ-3FF-CFADPY[Nle]CA
BCY7181
143
[PEG3]-ACIEEGQYC-2MeF-ADPY[Nle]CA
BCY7182
144
[PEG3]-ACIEEGQYC-3MeF-ADPY[Nle]CA
BCY7183
145
[PEG3]-ACIEEGQYC-4MeF-ADPY[Nle]CA
BCY7184
146
[PEG3]-ACIEEGQYC-PheG-ADPY[Nle]CA
BCY7185
147
[PEG3]-ACIEEGQYC-4FF-ADPY[Nle]CA
BCY7186
148
[PEG3]-ACIEEGQYCFGDPY[Nle]CA
BCY7187
149
[PEG3]-ACIEEGQYCFSDPY[Nle]CA
BCY7188
150
[PEG3]-ACIEEGQYCFPDPY[Nle]CA
BCY7189
151
[PEG3]-ACIEEGQYCFANPY[Nle]CA
BCY7190
152
[PEG3]-ACIEEGQYCFAD-Pip-Y[Nle]CA
BCY7191
153
[PEG3]-ACIEEGQYCFAD-MeAla-Y[Nle]CA
BCY7192
154
[PEG3]-ACIEEGQYCFAD-Sar-Y[Nle]CA
BCY7193
155
[PEG3]-ACIEEGQYCFAD-Aib-Y[Nle]CA
BCY7195
156
[PEG3]AC[tBuAla]EEGQYCFADPY[Nle]CA
BCY7196
157
[PEG3]AC[HLeu]EEGQYCFADPY[Nle]CA
BCY7197
158
[PEG3]ACIEEGQ[2FPhe]CFADPY[Nle]CA
BCY7198
159
[PEG3]ACIEEGQYC[2FPhe]ADPY[Nle]CA
BCY7199
160
[PEG3]ACIEEGQYCF[CF3G]DPY[Nle]CA
BCY7200
161
[PEG3]ACIEEGQYCFADP[pCoPhe][Nle]CA
BCY7201
162
[PEG3]ACIEEGQYCFADP[pCaPhe][Nle]CA
BCY7202
163
[PEG3]ACIEEGQYCFADPQ[Nle]CA
BCY7205
164
[PEG3]ACIEEGQYCFADP[2MePhe][Nle]CA
BCY7206
165
[PEG3]ACIEEGQYCFADP[3MePhe][Nle]CA
BCY7207
166
[PEG3]ACIEEGQYCFADP[4MePhe][Nle]CA
BCY7208
167
[PEG3]ACIEEGQYCFADP[Cit][Nle]CA
BCY7209
168
[PEG3]ACIEEGQYCFADP[4FPhe][Nle]CA
BCY7210
169
[PEG3]ACIEEGQYCFADPY[tBuAla]CA
BCY7211
170
[PEG3]ACIEEGQYCFADPY[HLeu]CA
BCY7212
171
[PEG3]ACIEEGQYCFADPYICA
BCY7213
172
[PEG3]ACIEEGQYCFADPY[Cha]CA
BCY7214
173
[PEG3]ACIEEGQYCFADPYFCA
BCY7215
174
[PEG3]ACIEEGQYCFADPY[2MePhe]CA
BCY7216
175
[PEG3]ACIEEGQYCFADPY[3MePhe]CA
BCY7217
176
[PEG3]ACIEEGQYCFADPY[4MePhe]CA
BCY7218
177
[PEG3]A[Pen]IEEGQYCFADPY[Nle]CA
BCY7219
178
[PEG3]ACIEEGQY[Pen]FADPY[Nle]CA
BCY7220
179
[PEG3]ACIEEGQYCFADPY[Nle][Pen]A
BCY7221
180
[PEG3]A[HCys]IEEGQYCFADPY[Nle]CA
BCY7222
181
[PEG3]ACIEEGQY[HCys]FADPY[Nle]CA
BCY7223
182
[PEG3]ACIEEGQYCFADPY[Nle][HCys]A
BCY7224
183
[PEG3]ACIEEGQYC[3FPhe]ADPY[Nle]CA
BCY7306
184
[PEG3]-ACI[TetraZ]EGQYCFADPY[Nle]CA
BCY7308
185
[PEG3]-ACIEEGQYCFA[TetraZ]PY[Nle]CA
BCY7309
186
[PEG3]-ACIEEGQYCFADP[HGln][Nle]CA
BCY7310
187
[PEG3]-AC[Ahp]EEGQYCFADPY[Nle]CA
BCY7311
188
[PEG3]-ACIEEGQYCFADPY[Ahp]CA
BCY592
189
ACIEEGQYCFADPYIVICA
BCY589
190
HEHCIEEGQYCYADPYIVICA
BCY599
191
ACIEEGQYCFADPYLCA
BCY631
192
ACLPPGPYCFPDPYFCA
BCY592
189
ACIEEGQYCFADPYIVICA
BCY593
193
[Ac]CIEEGQYCFADPYMC
BCY3814
31
ACIEEGQYCFADPY(Nle)CA
BCY7527
194
[Ac]CIEEGQYCFADPY[Nle]C[Dap]
BCY7768
195
[PEG3]ACIPE[dF]QYCFADPY[Nle]CA
BCY7770
196
[PEG3]ACIPE[dF]PYCFADPY[Nle]CA
BCY7772
197
[PEG3]ACIEE[dF]PYCFADPY[Nle]CA
BCY7773
198
PEG3]ACIPEGPYCFADPY[Nle]CA
BCY7774
199
[PEG3]AC[tBuAla]PE[dF]P[4MePhe]C[4FPhe]ADPY[Nle]CA
BCY7775
200
[PEG3]AC[tBuAla]PE[dF]Q[4MePhe]C[4FPhe]ADPY[Nle]CA
BCY7776
201
[PEG3]AC[tBuAla]EE[dF]P[4MePhe]C[4FPhe]ADPY[Nle]CA
BCY7777
202
[PEG3]AC[tBuAla]EE[dF]Q[4MePhe]C[4FPhe]ADPY[Nle]CA
BCY7796
203
[PEG3]ACI[HyP]EGQYCFADPY[Nle]CA
BCY7798
204
[PEG3]ACIEE[dW]QYCFADPY[Nle]CA
BCY7799
205
[PEG3]ACIEEG[Aze]YCFADPY[Nle]CA
BCY7800
206
[PEG3]ACIEEG[Pip]YCFADPY[Nle]CA
BCY7801
207
[PEG3]ACIEEGQ[2Nal]CFADPY[Nle]CA
BCY7802
208
[PEG3]ACIEEGQ[4MeoPhe]CFADPY[Nle]CA
BCY7803
209
[PEG3]ACIEEGQYCYADPY[Nle]CA
BCY7804
210
[PEG3]ACIEEGQYCFAD[Aze]Y[Nle]CA
BCY7806
211
[PEG3]ACIEEGQYCFADPY[Hse(Me)]CA
BCY7923
212
[Ac]AC[NMeIle]EEGQYCFADPY[Nle]CA
BCY7924
213
[Ac]ACI[Aze]EGQYCFADPY[Nle]CA
BCY7925
214
[Ac]ACI[Pip]EGQYCFADPY[Nle]CA
BCY7926
215
[Ac]ACI[NMeGlu]EGQYCFADPY[Nle]CA
BCY7927
216
[Ac]ACIE[NMeGlu]GQYCFADPY[Nle]CA
BCY7928
217
[Ac]ACIEE[dD]QYCFADPY[Nle]CA
BCY7929
218
[Ac]ACIEEG[NMeAla]YCFADPY[Nle]CA
BCY7930
219
[Ac]ACIEEGQ[NMeTyr]CFADPY[Nle]CA
BCY7931
220
[Ac]ACIEEGQ[HPhe]CFADPY[Nle]CA
BCY7933
221
[Ac]ACIEEGQ[2Pal]CFADPY[Nle]CA
BCY7934
222
[Ac]ACIEEGQ[3Pal]CFADPY[Nle]CA
BCY7936
223
[Ac]ACIEEGQ[44BPA]CFADPY[Nle]CA
BCY7937
224
[Ac]ACIEEGQYC[HPhe]ADPY[Nle]CA
BCY7939
225
[Ac]ACIEEGQYC[2Pal]ADPY[Nle]CA
BCY7940
226
[Ac]ACIEEGQYC[3Pal]ADPY[Nle]CA
BCY7941
227
[Ac]ACIEEGQYC[4Pal]ADPY[Nle]CA
BCY7942
228
[Ac]ACIEEGQYC[44BPA]ADPY[Nle]CA
BCY7943
229
[Ac]ACIEEGQYC[1Nal]ADPY[Nle]CA
BCY7944
230
[Ac]ACIEEGQYC[4tBuPhe]ADPY[Nle]CA
BCY7945
231
[Ac]ACIEEGQYCF[NMeAla]DPY[Nle]CA
BCY7950
232
[Ac]ACIEEG[55DMp]YCFADPY[Nle]CA
BCY7953
233
[Ac]ACIEEGQYCFAD[HyP]Y[Nle]CA
BCY7954
234
[Ac]ACIEEG[Oic]YCFADPY[Nle]CA
BCY7955
235
[Ac]ACIEEGQYCFAD[Oic]Y[Nle]CA
BCY7956
236
[Ac]ACI[Oic]EGQYCFADPY[Nle]CA
BCY7957
237
[Ac]ACIEEGQYCFAD[Oxa]Y[Nle]CA
BCY7958
238
[Ac]ACI[Oxa]EGQYCFADPY[Nle]CA
BCY7959
239
[Ac]ACIEEG[Oxa]YCFADPY[Nle]CA
BCY7960
240
[Ac]ACIPEGPYCFADPY[Nle]CA
BCY7952
241
[Ac]ACIEEG[HyP]YCFADPY[Nle]CA
BCY7961
242
[Ac]ACIPE[dA]PYCFADPY[Nle]CA
BCY7965
243
[Ac]AC[tBuAla]PE[dA]PYCFADPY[Nle]CA
BCY8217
244
ACIEEGQYCF[dA]DPY[Nle]CA
BCY8656
245
[Ac]AC[tBuAla]EEGQYCFADPY[Nle]CA
BCY8657
246
[Ac]AC[Chg]EEGQYCFADPY[Nle]CA
BCY8658
247
[Ac]AC[AC5C]EEGQYCFADPY[Nle]CA
BCY8659
248
[Ac]ACIPEGQYCFADPY[Nle]CA
BCY8660
249
[Ac]ACIQEGQYCFADPY[Nle]CA
BCY8661
250
[Ac]ACIEPGQYCFADPY[Nle]CA
BCY8662
251
[Ac]ACIEQGQYCFADPY[Nle]CA
BCY8663
252
[Ac]ACIEE[df]QYCFADPY[Nle]CA
BCY8664
253
[Ac]ACIEE[dA]QYCFADPY[Nle]CA
BCY8665
254
[Ac]ACIEE[AC5C]QYCFADPY[Nle]CA
BCY8667
255
[Ac]ACIEEGAYCFADPY[Nle]CA
BCY8668
256
[Ac]ACIEEG[Aib]YCFADPY[Nle]CA
BCY8669
257
[Ac]ACIEEG[AC5C]YCFADPY[Nle]CA
BCY8670
258
[Ac]ACIEEGQ[4MePhe]CFADPY[Nle]CA
BCY8671
259
[Ac]ACIEEGQ[1Nal]CFADPY[Nle]CA
BCY8673
260
[Ac]ACIEEGQYC[2Nal]ADPY[Nle]CA
BCY8674
261
[Ac]ACIEEGQYC[NO2Phe]ADPY[Nle]CA
BCY8675
262
[Ac]ACIEEGQYC[4BrPhe]ADPY[Nle]CA
BCY8676
263
[Ac]ACIEEGQYCF[Abu]DPY[Nle]CA
BCY8677
264
[Ac]ACIEEGQYCFADPY[Ahp]CA
BCY9273
265
[Ac]ACIEEGQYCFADPYMCA
wherein C i , C ii and C iii represent first, second and third cysteine residues, respectively, Ac represents an N-terminal acetyl group and Dap represents diaminopropionic acid or a pharmaceutically acceptable salt thereof.
7. A peptide ligand specific for CD137 comprising a polypeptide comprising at least three cysteine residues, separated by two loop sequences, and a molecular scaffold which forms covalent bonds with the cysteine residues of the polypeptide such that two polypeptide loops are formed on the molecular scaffold, wherein the peptide ligand comprises an amino acid sequence which is:
(SEQ ID NO: 266)
C i -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -C ii -X 11 -X 12 -D-X 13 -X 14 -X 15 -C iii ;
wherein C i , C ii and C iii represent first, second and third cysteine residues, respectively;
X 5 represents lie, tBuAla or Chg;
X 6 represents Glu, Pro, Asp, Lys, Aad, HyP or Oxa;
X 7 represents Glu, Lys or Aad;
X 8 represents Gly, D-Lys, D-Ala, L-Ala, D-Phe, D-Glu, D-Gln, D-Leu, D-Ser or D-Trp;
X 9 represents Gin, Lys, Ala, Pro, 5,5-dmP, Oic, Oxa, HyP, Aib or Ac5c;
X 10 represents Tyr, Phe, 3MePhe, 4MePhe, 4FPhe, 2Nal, 4MeOPhe or 4,4-BPA;
X 11 represents Phe, Lys, 4MePhe, 2FPhe, 4FPhe, 4Pal, 4,4-BPA, 4tBuPhe, NO2Phe or 4BrPhe;
X 12 represents Ala or Lys;
X 13 represents Pro or Lys;
X 14 represents Tyr or Lys; and
X 15 represents Met, Lys, Nle, HLeu or Ahp.
8. The peptide ligand as defined in claim 7 , wherein the peptide ligand of SEQ ID NO: 266 is selected from the C i to C iii sequences of the following peptides or the full sequences of the following peptides:
SEQ ID
Peptide Number
NO:
Sequence
BCY7239
52
Ac-CIK(Peg12)EGQYCFADPYMC
BCY7240
53
Ac-CIEK(Peg12)GQYCFADPYMC
BCY7242
55
Ac-CIEEGK(Peg12)YCFADPYMC
BCY7244
57
Ac-CIEEGQYCK(Peg12)ADPYMC
BCY7245
58
Ac-CIEEGQYCFK(Peg12)DPYMC
BCY7247
60
Ac-CIEEGQYCFADK(Peg12)YMC
BCY7248
61
Ac-CIEEGQYCFADPK(Peg12)MC
BCY7249
62
Ac-CIEEGQYCFADPYK(Peg12)C
BCY7416
63
[Ac]CIEE[dK(PEG12Fl)]QYCFADPY[Nle]C
BCY7287
97
[PEG3]-ACIEEGAYCFADPY(Nle)CA
BCY7297
106
[PEG3]-ACIEEaQYCFADPY(Nle)CA
BCY7154
117
[PEG3]-AC-Chg-EEGQYCFADPY[Nle]CA
BCY7156
119
[PEG3]-ACIPEGQYCFADPY[Nle]CA
BCY7157
120
[PEG3]-ACIDEGQYCFADPY[Nle]CA
BCY7158
121
[PEG3]-ACI-Aad-EGQYCFADPY[Nle]CA
BCY7162
125
[PEG3]-ACIE-Aad-GQYCFADPY[Nle]CA
BCY7165
128
[PEG3]-ACIEE-DLys-QYCFADPY[Nle]CA
BCY7166
129
[PEG3]-ACIEE-DPhe-QYCFADPY[Nle]CA
BCY7167
130
[PEG3]-ACIEE-DGlu-QYCFADPY[Nle]CA
BCY7168
131
[PEG3]-ACIEE-DG1n-QYCFADPY[Nle]CA
BCY7169
132
[PEG3]-ACIEE-DLeu-QYCFADPY[Nle]CA
BCY7170
133
[PEG3]-ACIEE-DSer-QYCFADPY[Nle]CA
BCY7174
136
[PEG3]-ACIEEGPYCFADPY[Nle]CA
BCY7175
137
[PEG3]-ACIEEGQFCFADPY[Nle]CA
BCY7177
139
[PEG3]-ACIEEGQ-3MeF-CFADPY[Nle]CA
BCY7178
140
[PEG3]-ACIEEGQ-4MeF-CFADPY[Nle]CA
BCY7179
141
[PEG3]-ACIEEGQ-4FF-CFADPY[Nle]CA
BCY7183
145
[PEG3]-ACIEEGQYC-4MeF-ADPY[Nle]CA
BCY7185
147
[PEG3]-ACIEEGQYC-4FF-ADPY[Nle]CA
BCY7195
156
[PEG3]AC[tBuAla]EEGQYCFADPY[Nle]CA
BCY7198
159
[PEG3]ACIEEGQYC[2FPhe]ADPY[Nle]CA
BCY7211
170
[PEG3]ACIEEGQYCFADPY[HLeu]CA
BCY7311
188
[PEG3]-ACIEEGQYCFADPY[Ahp]CA
BCY7768
195
[PEG3]ACIPE[dF]QYCFADPY[Nle]CA
BCY7770
196
[PEG3]ACIPE[dF]PYCFADPY[Nle]CA
BCY7772
197
[PEG3]ACIEE[dF]PYCFADPY[Nle]CA
BCY7773
198
PEG3]ACIPEGPYCFADPY[Nle]CA
BCY7774
199
PEG3]AC[tBuAla]PE[dF]P[4MePhe]C[4FPhe]ADPY[Nle]CA
BCY7775
200
[PEG3]AC[tBuAla]PE[dF]Q[4MePhe]C[4FPhe]ADPY[Nle]CA
BCY7776
201
[PEG3]AC[tBuAla]EE[dF]P[4MePhe]C[4FPhe]ADPY[Nle]CA
BCY7796
203
[PEG3]ACI[HyP]EGQYCFADPY[Nle]CA
BCY7798
204
[PEG3]ACIEE[dW]QYCFADPY[Nle]CA
BCY7801
207
PEG3]ACIEEGQ[2Nal]CFADPY[Nle]CA
BCY7802
208
PEG3]ACIEEGQ[4MeoPhe]CFADPY[Nle]CA
BCY7936
223
[Ac]ACIEEGQ[44BPA]CFADPY[Nle]CA
BCY7941
227
[Ac]ACIEEGQYC[4Pal]ADPY[Nle]CA
BCY7942
228
[Ac]ACIEEGQYC[44BPA]ADPY[Nle]CA
BCY7944
230
Ac]ACIEEGQYC[4tBuPhe]ADPY[Nle]CA
BCY7950
232
[Ac]ACIEEG[55DMP]YCFADPY[Nle]CA
BCY7954
234
[Ac]ACIEEG[Oic]YCFADPY[Nle]CA
BCY7958
238
[Ac]ACI[Oxa]EGQYCFADPY[Nle]CA
BCY7959
239
[Ac]ACIEEG[Oxa]YCFADPY[Nle]CA
BCY7960
240
[Ac]ACIPEGPYCFADPY[Nle]CA
BCY7952
241
[Ac]ACIEEG[HyP]YCFADPY[Nle]CA
BCY7961
242
[Ac]ACIPE[dA]PYCFADPY[Nle]CA
BCY8656
245
[Ac]AC[tBuAla]EEGQYCFADPY[Nle]CA
BCY8659
248
[Ac]ACIPEGQYCFADPY[Nle]CA
BCY8663
252
[Ac]ACIEE[df]QYCFADPY[Nle]CA
BCY8668
256
[Ac]ACIEEG[Aib]YCFADPY[Nle]CA
BCY8669
257
[Ac]ACIEEG[AC5C]YCFADPY[Nle]CA
BCY8674
261
[Ac]ACIEEGQYC[NO2Phe]ADPY[Nle]CA
BCY8675
262
[Ac]ACIEEGQYC[4BrPhe]ADPY[Nle]CA
BCY9273
265
[Ac]ACIEEGQYCFADPYWICA
BCY3814
31
ACIEEGQYCFADPY(Nle)CA
BCY7527
194
[Ac]ClEEGQYCFADPY[Nle]C[Dap]
BCY7965
243
[Ac]AC[tBuAla]PE[dA]PYCFADPY[Nle]CA.
9. The peptide ligand as defined in claim 7 , which comprises three cysteine residues separated by two loop sequences both of which consist of 6 amino acids, and said peptide ligand comprises an amino acid sequence selected from:
(SEQ ID NO: 267)
C i -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -C ii -X 11 -A-D-P-Y-X 15 -C iii ;
wherein C i , C ii and C iii represent first, second and third cysteine residues, respectively;
X 5 represents lie or tBuAla;
X 6 represents Lys, Glu or Pro;
X 7 represents Glu or D-Lys;
X 8 represents Gly, D-Lys, D-Phe or D-Ala;
X 9 represents Gin, Lys or Pro;
X 10 represents Tyr or 4MePhe;
X 11 represents Phe or 4FPhe; and
X 15 represents Met or Nle.
10. The peptide ligand as defined in claim 9 , wherein the peptide ligand of SEQ ID NO: 267 is selected from the C i to C iii sequences of the following peptides or the full sequences of the following peptides:
Peptide Number
SEQ ID NO:
Sequence
BCY7239
52
Ac-CIK(Peg12)EGQYCFADPYMC
BCY7240
53
Ac-CIEK(Peg12)GQYCFADPYMC
BCY7242
55
Ac-CIEEGK(Peg12)YCFADPYMC
BCY7416
63
[Ac]CIEE[dK(PEG12Fl)]QYCFADPY[Nle]C
BCY7156
119
[PEG3]-ACIPEGQYCFADPY[Nle]CA
BCY7166
129
[PEG3]-ACIEE-DPhe-QYCFADPY[Nle]CA
BCY7174
136
[PEG3]-ACIEEGPYCFADPY[Nle]CA
BCY7774
199
PEG3]AC[tBuAla]PE[dF]P[4MePhe]C[4FPhe]ADPY[Nle]CA
BCY9273
265
[Ac]ACIEEGQYCFADPYMCA
BCY3814
31
ACIEEGQYCFADPY(Nle)CA
BCY7527
194
[Ac]CIEEGQYCFADPY[Nle]C[Dap]
BCY7965
243
[Ac]AC[tBuAla]PE[dA]PYCFADPY[Nle]CA.
11. The peptide ligand as defined in claim 1 , wherein the molecular scaffold is 1,1′,1″-(1,3,5-triazinane-1,3,5-triyl)triprop-2-en-1-one (TATA).
12. The peptide ligand as defined in claim 1 , wherein the pharmaceutically acceptable salt is selected from the free acid or the sodium, potassium, calcium, or ammonium salt.
13. The peptide ligand as defined in claim 1 , wherein the CD137 is human CD137.
14. A drug conjugate comprising the peptide ligand as defined in claim 1 , conjugated to one or more effector and/or functional groups.
15. A drug conjugate comprising the peptide ligand as defined in claim 1 , conjugated to one or more cytotoxic agents.
16. A pharmaceutical composition which comprises the peptide ligand of claim 1 , in combination with one or more pharmaceutically acceptable excipients.
17. The peptide ligand as defined in claim 6 , wherein the molecular scaffold is 1,1′,1″-(1,3,5-triazinane-1,3,5-triyl)triprop-2-en-1-one (TATA).
18. The peptide ligand as defined in claim 7 , wherein the molecular scaffold is 1,1′,1″-(1,3,5-triazinane-1,3,5-triyl)triprop-2-en-1-one (TATA).
19. A drug conjugate comprising the peptide ligand as defined in claim 6 , conjugated to one or more effector and/or functional groups.
20. A drug conjugate comprising the peptide ligand as defined in claim 7 , conjugated to one or more effector and/or functional groups.
21. A pharmaceutical composition which comprises the peptide ligand of claim 6 , in combination with one or more pharmaceutically acceptable excipients.
22. A pharmaceutical composition which comprises the peptide ligand of claim 7 , in combination with one or more pharmaceutically acceptable excipients.
23. The drug conjugate of claim 14 , wherein the peptide ligand is as defined in claim 2 .
24. The drug conjugate of claim 20 , wherein the peptide ligand is as defined in claim 8 .
25. The drug conjugate of claim 20 , wherein the peptide ligand is as defined in claim 10 .