US2009081233A1PendingUtilityA1

Ligands that have binding specificity for VEGF and/or EGFR and methods of use therefor

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Assignee: DOMANTIS LTDPriority: Aug 24, 2004Filed: Jul 9, 2008Published: Mar 26, 2009
Est. expiryAug 24, 2024(expired)· nominal 20-yr term from priority
Inventors:Olga IgnatovichSteve HolmesRoland BeckmannRudolf M.T. De WildtArmin Sepp
A61P 37/02A61P 37/06A61P 3/10A61P 37/08A61P 31/04A61P 29/00A61P 25/00A61P 31/12A61P 35/00C07K 16/241A61K 47/6845C07K 2317/622C07K 2317/76C07K 2319/00A61P 21/04A61P 19/02A61P 15/08C07K 16/18C07K 2317/569A61P 17/06C07K 16/2863C07K 2317/55A61P 11/06A61K 2039/505C07K 16/40C07K 2317/31C07K 16/22A61P 1/04A61K 47/6879C07K 16/28A61K 39/395
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Claims

Abstract

Disclosed are ligands that have binding specificity for vascular endothelial growth factor (VEGF), for epidermal growth factor receptor (EGFR), or for VEGF and EGFR. Also disclosed are methods of using these ligands. In particular, the use of these ligands for cancer therapy is described.

Claims

exact text as granted — not AI-modified
1 . A ligand that has binding specificity for vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR), comprising at least one immunoglobulin single variable domain with binding specificity for VEGF and at least one immunoglobulin single variable domain with binding specificity for EGFR, wherein each said immunoglobulin single variable domain with binding specificity for VEGF competes for binding to VEGF with an anti-VEGF domain antibody (dAb) selected from the group consisting of TAR15-6 (SEQ ID NO: 117), TAR15-8 (SEQ ID NO: 119), TAR15-26 (SEQ ID NO: 123), TAR15-6-500 (SEQ ID NO:127), TAR15-6-501 (SEQ ID NO:128), TAR15-6-502 (SEQ ID NO:129), TAR15-6-503 (SEQ ID NO:130), TAR15-6-504 (SEQ ID NO: 131), TAR15-6-505 (SEQ ID NO:132), TAR15-6-506 (SEQ ID NO: 133), TAR15-6-507 (SEQ ID NO:134), TAR15-6-508 (SEQ ID NO:135), TAR15-6-509 (SEQ ID NO: 136), TAR15-6-510 (SEQ ID NO: 137), TAR15-8-500 (SEQ ID NO: 138), TAR15-8-501 (SEQ ID NO: 139), TAR15-8-502 (SEQ ID NO: 140), TAR15-8-503 (SEQ ID NO: 141), TAR15-8-505 (SEQ ID NO: 142), TAR15-8-506 (SEQ ID NO:143), TAR15-8-507 (SEQ ID NO:144), TAR15-8-508 (SEQ ID NO:145), TAR15-8-509 (SEQ ID NO:146), TAR15-8-510 (SEQ ID NO:147), TAR15-8-511 (SEQ ID NO:148), TAR15-26-500 (SEQ ID NO: 149), TAR15-26-501 (SEQ ID NO: 150), TAR15-26-502 (SEQ ID NO: 151), TAR15-26-503 (SEQ ID NO: 152), TAR15-26-504 (SEQ ID NO: 153), TAR15-26-505 (SEQ ID NO: 154), TAR15-26-506 (SEQ ID NO: 155), TAR15-26-507 (SEQ ID NO: 156), TAR15-26-508 (SEQ ID NO: 157), TAR15-26-509 (SEQ ID NO: 158), TAR15-26-510 (SEQ ID NO: 159), TAR15-26-511 (SEQ ID NO: 160), TAR15-26-512 (SEQ ID NO: 161), TAR15-26-513 (SEQ ID NO: 162), TAR15-26-514 (SEQ ID NO: 163), TAR15-26-515 (SEQ ID NO: 164), TAR15-26-516 (SEQ ID NO: 165), TAR15-26-517 (SEQ ID NO: 166), TAR15-26-518 (SEQ ID NO:167), TAR15-26-519 (SEQ ID NO:168), TAR15-26-520 (SEQ ID NO:169), TAR15-26-521 (SEQ ID NO:170), TAR15-26-522 (SEQ ID NO:171), TAR15-26-523 (SEQ ID NO: 172), TAR15-26-524 (SEQ ID NO: 173), TAR15-26-525 (SEQ ID NO:174), TAR15-26-526 (SEQ ID NO:175), TAR15-26-527 (SEQ ID NO: 176), TAR15-26-528 (SEQ ID NO: 177), TAR15-26-529 (SEQ ID NO: 178), TAR15-26-530 (SEQ ID NO: 179), TAR15-26-531 (SEQ ID NO: 180), TAR15-26-532 (SEQ ID NO: 181), TAR15-26-533 (SEQ ID NO: 182), TAR15-26-534 (SEQ ID NO: 183), TAR15-26-535 (SEQ ID NO: 184), TAR15-26-536 (SEQ ID NO:185), TAR15-26-537 (SEQ ID NO:186), TAR15-26-538 (SEQ ID NO:187), TAR15-26-539 (SEQ ID NO: 188), TAR15-26-540 (SEQ ID NO: 189), TAR15-26-541 (SEQ ID NO:190), TAR15-26-542 (SEQ ID NO:191), TAR15-26-543 (SEQ ID NO:192), TAR15-26-544 (SEQ ID NO:193), TAR15-26-545 (SEQ ID NO:194), TAR15-26-546 (SEQ ID NO:195), TAR15-26-547 (SEQ ID NO:196), TAR15-26-548 (SEQ ID NO:197), TAR15-26-549 (SEQ ID NO:198), TAR15-26-550 (SEQ ID NO:539), and TAR15-26-551 (SEQ ID NO:540). 
     
     
         2 . The ligand of  claim 1 , wherein each said immunoglobulin single variable domain with binding specificity for VEGF comprises an amino acid sequence that has at least about 85% amino acid sequence identity with the amino acid sequence of a dAb selected from the group consisting of TAR15-6 (SEQ ID NO:117), TAR15-8 (SEQ ID NO:119), TAR15-26 (SEQ ID NO:123), TAR15-6-500 (SEQ ID NO:127), TAR15-6-501 (SEQ ID NO:128), TAR15-6-502 (SEQ ID NO:129), TAR15-6-503 (SEQ ID NO:130), TAR15-6-504 (SEQ ID NO:131), TAR15-6-505 (SEQ ID NO:132), TAR15-6-506 (SEQ ID NO:133), TAR15-6-507 (SEQ ID NO:134), TAR15-6-508 (SEQ ID NO:135), TAR15-6-509 (SEQ ID NO:136), TAR15-6-510 (SEQ ID NO:137), TAR15-8-500 (SEQ ID NO:138), TAR15-8-501 (SEQ ID NO:139), TAR15-8-502 (SEQ ID NO:140), TAR15-8-503 (SEQ ID NO:141), TAR15-8-505 (SEQ ID NO:142), TAR15-8-506 (SEQ ID NO: 143), TAR15-8-507 (SEQ ID NO: 144), TAR15-8-508 (SEQ ID NO:145), TAR15-8-509 (SEQ ID NO:146), TAR15-8-510 (SEQ ID NO: 147), TAR15-8-511 (SEQ ID NO: 148), TAR15-26-500 (SEQ ID NO:149), TAR15-26-501 (SEQ ID NO:150), TAR15-26-502 (SEQ ID NO:151), TAR15-26-503 (SEQ ID NO: 152), TAR15-26-504 (SEQ ID NO: 153), TAR15-26-505 (SEQ ID NO: 154), TAR15-26-506 (SEQ ID NO: 155), TAR15-26-507 (SEQ ID NO:156), TAR15-26-508 (SEQ ID NO:157), TAR15-26-509 (SEQ ID NO: 158), TAR15-26-510 (SEQ ID NO: 159), TAR15-26-511 (SEQ ID NO: 160), TAR15-26-512 (SEQ ID NO:161), TAR15-26-513 (SEQ ID NO:162), TAR15-26-514 (SEQ ID NO: 163), TAR15-26-515 (SEQ ID NO: 164), TAR15-26-516 (SEQ ID NO: 165), TAR15-26-517 (SEQ ID NO: 166), TAR15-26-518 (SEQ ID NO: 167), TAR15-26-519 (SEQ ID NO: 168), TAR15-26-520 (SEQ ID NO: 169), TAR15-26-521 (SEQ ID NO: 170), TAR15-26-522 (SEQ ID NO: 171), TAR15-26-523 (SEQ ID NO: 172), TAR15-26-524 (SEQ ID NO: 173), TAR15-26-525 (SEQ ID NO: 174), TAR15-26-526 (SEQ ID NO: 175), TAR15-26-527 (SEQ ID NO: 176), TAR15-26-528 (SEQ ID NO: 177), TAR15-26-529 (SEQ ID NO: 178), TAR15-26-530 (SEQ ID NO: 179), TAR15-26-531 (SEQ ID NO: 180), TAR15-26-532 (SEQ ID NO:181), TAR15-26-533 (SEQ ID NO:182), TAR15-26-534 (SEQ ID NO: 183), TAR15-26-535 (SEQ ID NO: 184), TAR15-26-536 (SEQ ID NO: 185), TAR15-26-537 (SEQ ID NO: 186), TAR15-26-538 (SEQ ID NO: 187), TAR15-26-539 (SEQ ID NO:188), TAR15-26-540 (SEQ ID NO:189), TAR15-26-541 (SEQ ID NO: 190), TAR15-26-542 (SEQ ID NO: 191), TAR15-26-543 (SEQ ID NO: 192), TAR15-26-544 (SEQ ID NO: 193), TAR15-26-545 (SEQ ID NO: 194), TAR15-26-546 (SEQ ID NO: 195), TAR15-26-547 (SEQ ID NO: 196), TAR15-26-548 (SEQ ID NO:197), TAR15-26-549 (SEQ ID NO:198), TAR15-26-550 (SEQ ID NO:539), and TAR15-26-551 (SEQ ID NO:540). 
     
     
         3 . The ligand of  claim 1 , wherein said ligand inhibits binding of epidermal growth factor (EGF) and/or transforming growth factor alpha (TGFalpha) to EGFR. 
     
     
         4 . The ligand of  claim 1 , wherein said ligand inhibits the activity of EGFR. 
     
     
         5 . The ligand of  claim 1 , wherein said ligand inhibits the activity of EGFR without substantially inhibiting binding of epidermal growth factor (EGF) and/or transforming growth factor alpha (TGFalpha) to EGFR. 
     
     
         6 . The ligand of  claim 1 , wherein said ligand inhibits binding of VEGF to vascular endothelial growth factor receptor 1 (VEGFR1) and/or vascular endothelial growth factor receptor 2 (VEGFR2). 
     
     
         7 . The ligand of  claim 1 , wherein said ligand inhibits the activity of VEGF. 
     
     
         8 . The ligand of  claim 1 , wherein said ligand inhibits the activity of VEGF without substantially inhibiting binding of VEGF to vascular endothelial growth factor receptor 1 (VEGFR1) and/or vascular endothelial growth factor receptor 2 (VEGFR2). 
     
     
         9 . The ligand of  claim 1 , wherein each said immunoglobulin single variable domain that binding specificity for VEGF competes for binding to VEGF with bevacizumab. 
     
     
         10 . The ligand of  claim 1 , wherein each said immunoglobulin single variable domain that has binding specificity for EGFR competes for binding to EGFR with cetuximab. 
     
     
         11 . The ligand of  claim 1 , wherein each immunoglobulin single variable domain with binding specificity for VEGF binds VEGF with an affinity (KD) that is between about 100 nM and about 1 pM, as determined by surface plasmon resonance. 
     
     
         12 . The ligand of  claim 1 , wherein each immunoglobulin single variable domain with binding specificity for EGFR binds EGFR with an affinity (KD) that is between about 100 nM and about 1 pM, as determined by surface plasmon resonance. 
     
     
         13 . The ligand of  claim 12 , wherein each immunoglobulin single variable domain with binding specificity for EGFR binds EGFR with an affinity (KD) that is between about 10 nM and about 100 pM, as determined by surface plasmon resonance. 
     
     
         14 . The ligand of  claim 1 , wherein said ligand binds VEGF with an affinity (KD) that is between about 100 nM and about 1 pM, as determined by surface plasmon resonance. 
     
     
         15 . The ligand of  claim 1 , wherein said ligand binds EGFR with an affinity (KD) that is between about 100 nM and about 1 pM, as determined by surface plasmon resonance. 
     
     
         16 . The ligand of  claim 15 , wherein said ligand binds EGFR with an affinity (KD) that is between about 10 nM and about 100 pM, as determined by surface plasmon resonance. 
     
     
         17 . The ligand of  claim 1 , wherein said ligand comprises an immunoglobulin single variable domain with binding specificity for VEGF that is a V HH  and/or an immunoglobulin single variable domain with binding specificity for EGFR that is a V HH . 
     
     
         18 . The ligand of  claim 1 , comprising an immunoglobulin single variable domain with binding specificity for VEGF and an immunoglobulin single variable domain with binding specificity for EGFR that are independently selected from the group consisting of a human V H  and a human V L . 
     
     
         19 . The ligand of  claim 1 , wherein said ligand is an IgG-like format comprising two immunoglobulin single variable domains with binding specificity for VEGF, and two immunoglobulin single variable domains with binding specificity for EGFR. 
     
     
         20 . The ligand of  claim 1 , wherein said ligand comprises an antibody Fc region. 
     
     
         21 . A ligand that has binding specificity for vascular endothelial growth factor (VEGF), comprising at least one immunoglobulin single variable domain with binding specificity for VEGF, wherein each said immunoglobulin single variable domain with binding specificity for VEGF competes for binding to VEGF with an anti-VEGF domain antibody (dAb) selected from the group consisting of TAR15-6 (SEQ ID NO: 117), TAR15-8 (SEQ ID NO: 119), TAR15-26 (SEQ ID NO:123), TAR15-6-500 (SEQ ID NO:127), TAR15-6-501 (SEQ ID NO: 128), TAR15-6-502 (SEQ ID NO: 129), TAR15-6-503 (SEQ ID NO:130), TAR15-6-504 (SEQ ID NO:131), TAR15-6-505 (SEQ ID NO:132), TAR15-6-506 (SEQ ID NO: 133), TAR15-6-507 (SEQ ID NO: 134), TAR15-6-508 (SEQ ID NO: 135), TAR15-6-509 (SEQ ID NO: 136), TAR15-6-510 (SEQ ID NO:137), TAR15-8-500 (SEQ ID NO:138), TAR15-8-501 (SEQ ID NO: 139), TAR15-8-502 (SEQ ID NO: 140), TAR15-8-503 (SEQ ID NO: 141), TAR15-8-505 (SEQ ID NO: 142), TAR15-8-506 (SEQ ID NO: 143), TAR15-8-507 (SEQ ID NO: 144), TAR15-8-508 (SEQ ID NO: 145), TAR15-8-509 (SEQ ID NO:146), TAR15-8-510 (SEQ ID NO:147), TAR15-8-511 (SEQ ID NO: 148), TAR15-26-500 (SEQ ID NO: 149), TAR15-26-501 (SEQ ID NO: 150), TAR15-26-502 (SEQ ID NO:151), TAR15-26-503 (SEQ ID NO:152), TAR15-26-504 (SEQ ID NO: 153), TAR15-26-505 (SEQ ID NO: 154), TAR15-26-506 (SEQ ID NO: 155), TAR15-26-507 (SEQ ID NO: 156), TAR15-26-508 (SEQ ID NO: 157), TAR15-26-509 (SEQ ID NO: 158), TAR15-26-510 (SEQ ID NO: 159), TAR15-26-511 (SEQ ID NO:160), TAR15-26-512 (SEQ ID NO:161), TAR15-26-513 (SEQ ID NO: 162), TAR15-26-514 (SEQ ID NO: 163), TAR15-26-515 (SEQ ID NO:164), TAR15-26-516 (SEQ ID NO:165), TAR15-26-517 (SEQ ID NO: 166), TAR15-26-518 (SEQ ID NO: 167), TAR15-26-519 (SEQ ID NO: 168), TAR15-26-520 (SEQ ID NO: 169), TAR15-26-521 (SEQ ID NO: 170), TAR15-26-522 (SEQ ID NO:171), TAR15-26-523 (SEQ ID NO:172), TAR15-26-524 (SEQ ID NO: 173), TAR15-26-525 (SEQ ID NO: 174), TAR15-26-526 (SEQ ID NO: 175), TAR15-26-527 (SEQ ID NO: 176), TAR15-26-528 (SEQ ID NO: 177), TAR15-26-529 (SEQ ID NO: 178), TAR15-26-530 (SEQ ID NO: 179), TAR15-26-531 (SEQ ID NO: 180), TAR15-26-532 (SEQ ID NO: 181), TAR15-26-533 (SEQ ID NO: 182), TAR15-26-534 (SEQ ID NO: 183), TAR15-26-535 (SEQ ID NO: 184), TAR15-26-536 (SEQ ID NO: 185), TAR15-26-537 (SEQ ID NO: 186), TAR15-26-538 (SEQ ID NO: 187), TAR15-26-539 (SEQ ID NO: 188), TAR15-26-540 (SEQ ID NO:189), TAR15-26-541 (SEQ ID NO:190), TAR15-26-542 (SEQ ID NO:191), TAR15-26-543 (SEQ ID NO:192), TAR15-26-544 (SEQ ID NO: 193), TAR15-26-545 (SEQ ID NO: 194), TAR15-26-546 (SEQ ID NO: 195), TAR15-26-547 (SEQ ID NO: 196), TAR15-26-548 (SEQ ID NO: 197), TAR15-26-549 (SEQ ID NO: 198), TAR15-26-550 (SEQ ID NO:539), and TAR15-26-551 (SEQ ID NO:540). 
     
     
         22 . The ligand of  claim 21 , wherein each said immunoglobulin single variable domain with binding specificity for VEGF comprises an amino acid sequence that has at least about 85% amino acid sequence identity with the amino acid sequence of a dAb selected from the group consisting of TAR15-6 (SEQ ID NO: 117), TAR15-8 (SEQ ID NO: 119), TAR15-26 (SEQ ID NO: 123), TAR15-6-500 (SEQ ID NO: 127), TAR15-6-501 (SEQ ID NO: 128), TAR15-6-502 (SEQ ID NO: 129), TAR15-6-503 (SEQ ID NO:130), TAR15-6-504 (SEQ ID NO: 131), TAR15-6-505 (SEQ ID NO: 132), TAR15-6-506 (SEQ ID NO: 133), TAR15-6-507 (SEQ ID NO: 134), TAR15-6-508 (SEQ ID NO: 135), TAR15-6-509 (SEQ ID NO:136), TAR15-6-510 (SEQ ID NO:137), TAR15-8-500 (SEQ ID NO:138), TAR15-8-501 (SEQ ID NO:139), TAR15-8-502 (SEQ ID NO: 140), TAR15-8-503 (SEQ ID NO: 141), TAR15-8-505 (SEQ ID NO: 142), TAR15-8-506 (SEQ ID NO: 143), TAR15-8-507 (SEQ ID NO: 144), TAR15-8-508 (SEQ ID NO: 145), TAR15-8-509 (SEQ ID NO: 146), TAR15-8-510 (SEQ ID NO:147), TAR15-8-511 (SEQ ID NO:148), TAR15-26-500 (SEQ ID NO:149), TAR15-26-501 (SEQ ID NO:150), TAR15-26-502 (SEQ ID NO:151), TAR15-26-503 (SEQ ID NO: 152), TAR15-26-504 (SEQ ID NO: 153), TAR15-26-505 (SEQ ID NO: 154), TAR15-26-506 (SEQ ID NO: 155), TAR15-26-507 (SEQ ID NO:156), TAR15-26-508 (SEQ ID NO:157), TAR15-26-509 (SEQ ID NO:158), TAR15-26-510 (SEQ ID NO:159), TAR15-26-511 (SEQ ID NO:160), TAR15-26-512 (SEQ ID NO: 161), TAR15-26-513 (SEQ ID NO: 162), TAR15-26-514 (SEQ ID NO: 163), TAR15-26-515 (SEQ ID NO: 164), TAR15-26-516 (SEQ ID NO:165), TAR15-26-517 (SEQ ID NO:166), TAR15-26-518 (SEQ ID NO: 167), TAR15-26-519 (SEQ ID NO: 168), TAR15-26-520 (SEQ ID NO: 169), TAR15-26-521 (SEQ ID NO:170), TAR15-26-522 (SEQ ID NO:171), TAR15-26-523 (SEQ ID NO:172), TAR15-26-524 (SEQ ID NO:173), TAR15-26-525 (SEQ ID NO: 174), TAR15-26-526 (SEQ ID NO: 175), TAR15-26-527 (SEQ ID NO: 176), TAR15-26-528 (SEQ ID NO: 177), TAR15-26-529 (SEQ ID NO: 178), TAR15-26-530 (SEQ ID NO:179), TAR15-26-531 (SEQ ID NO:180), TAR15-26-532 (SEQ ID NO: 181), TAR15-26-533 (SEQ ID NO: 182), TAR15-26-534 (SEQ ID NO: 183), TAR15-26-535 (SEQ ID NO: 184), TAR15-26-536 (SEQ ID NO: 185), TAR15-26-537 (SEQ ID NO: 186), TAR15-26-538 (SEQ ID NO: 187), TAR15-26-539 (SEQ ID NO: 188), TAR15-26-540 (SEQ ID NO: 189), TAR15-26-541 (SEQ ID NO:190), TAR15-26-542 (SEQ ID NO:191), TAR15-26-543 (SEQ ID NO: 192), TAR15-26-544 (SEQ ID NO: 193), TAR15-26-545 (SEQ ID NO:194), TAR15-26-546 (SEQ ID NO:195), TAR15-26-547 (SEQ ID NO:196), TAR15-26-548 (SEQ ID NO:197), TAR15-26-549 (SEQ ID NO:198), TAR15-26-550 (SEQ ID NO:539), and TAR15-26-551 (SEQ ID NO:540). 
     
     
         23 . The ligand of  claim 21 , wherein said ligand inhibits binding of VEGF to vascular endothelial growth factor receptor 1 (VEGFR1) and/or vascular endothelial growth factor receptor 2 (VEGF2). 
     
     
         24 . The ligand of  claim 21 , wherein said ligand inhibits the activity of VEGF. 
     
     
         25 . The ligand of  claim 21 , wherein said ligand inhibits the activity of VEGF without substantially inhibiting binding of VEGF to vascular endothelial growth factor receptor 1 (VEGFR1) and/or vascular endothelial growth factor receptor 2 (VEGFR2). 
     
     
         26 . The ligand of  claim 21 , wherein each said immunoglobulin single variable domain with binding specificity for VEGF competes for binding to VEGF with bevacizumab. 
     
     
         27 . The ligand of  claim 21 , wherein each said immunoglobulin single variable domain with binding specificity for VEGF binds VEGF with an affinity (KD) that is between about 100 nM and about 1 pM, as determined by surface plasmon resonance. 
     
     
         28 . The ligand of  claim 21 , wherein said ligand binds VEGF with an affinity (KD) that is between about 100 nM and about 1 pM, as determined by surface plasmon resonance. 
     
     
         29 . The ligand of  claim 21 , wherein said ligand comprises an immunoglobulin single variable domain with binding specificity for VEGF that is a V HH . 
     
     
         30 . The ligand of  claim 21 , wherein said ligand comprises an immunoglobulin single variable domain with binding specificity for VEGF that is selected from the group consisting of a human V H  and a human V L . 
     
     
         31 . The ligand of  claim 21 , wherein said ligand is a dAb monomer. 
     
     
         32 . A composition comprising a ligand of  claim 1 , and a physiologically acceptable carrier. 
     
     
         33 . A drug delivery device comprising the composition of  claim 32 .

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