Bispecific immunobinders directed against tnf and il-17

Abstract

Engineered multivalent and multispecific binding proteins, methods of making, and specifically to their uses in the prevention, diagnosis, and/or treatment of disease are provided.

1 . A binding protein capable of binding TNF, the binding protein comprising a polypeptide chain, wherein the polypeptide chain comprises VD1-(X1)n-VD2-C-(X2)n, wherein;
 VD1 is a first heavy chain variable domain;   VD2 is a second heavy chain-variable domain;   C is a heavy chain constant domain;   X1 is a linker with the proviso that it is not CH1;   X2 is an Fc region;   (X1)n, wherein n is 0 or 1;   (X2)n, wherein n is 0 or 1; and   wherein   (a) VD1 or VD2 comprises three CDRs from SEQ ID NO: 541, 551, 561, 571, 581, 591, 601, 606, 611, 616, 621, 626, 631, 636, 643, 653, 661, 671, 681, 691, 701, 711, 721, 731, 741, 753, 763, 771, 776, 781, 786, 791, 796, 801, 805, 807, 809, or any one of 36-41, 48-72, or 88-97;   (b) VD1 and VD2 independently comprise three CDRs from SEQ ID NO: 541, 551, 561, 571, 581, 591, 601, 606, 611, 616, 621, 626, 631, 636, 643, 653, 661, 671, 681, 691, 701, 711, 721, 731, 741, 753, 763, 771, 776, 781, 786, 791, 796, 801, 805, 807, or 809, or any one of 36-41, 48-72, or 88-97;   (c) VD1 comprises three CDRs from SEQ ID NO: 541, 551, 561, 571, 581, 591, 601, 606, 611, 616, 621, 626, 631, 636, 643, 653, 661, 671, 681, 691, 701, 711, 721, 731, 741, 753, 763, 771, 776, 781, 786, 791, 796, 801, 805, 807, or 809, or any one of 36-41, 48-72, or 88-97, and VD2 comprises three CDRs from SEQ ID NO: 30, 32, 34, 108, 109, 110, 111, 112, 113, 114, 115, 121-317, 527-534, 543, 553, 563, 573, 583, 593, 603, 608, 613, 618, 623, 628, 633, 638, 641, 651, 663, 673, 683, 693, 703, 713, 723, 733, 743, 751, 761, 773, 778, 783, 788, 793, 798, 803 or 811; or   (d) VD2 comprises three CDRs from SEQ ID NO: 541, 551, 561, 571, 581, 591, 601, 606, 611, 616, 621, 626, 631, 636, 643, 653, 661, 671, 681, 691, 701, 711, 721, 731, 741, 753, 763, 771, 776, 781, 786, 791, 796, 801, 805, 807, or 809, or any one of 36-41, 48-72, or 88-97, and VD1 comprises three CDRs from SEQ ID NO: 30, 32, 34, 108, 109, 110, 111, 112, 113, 114, 115, 121-317, 527-534, 543, 553, 563, 573, 583, 593, 603, 608, 613, 618, 623, 628, 633, 638, 641, 651, 663, 673, 683, 693, 703, 713, 723, 733, 743, 751, 761, 773, 778, 783, 788, 793, 798, 803 or 811.   
     
     
         2 . (canceled) 
     
     
         3 . A binding protein capable of binding TNF, the binding protein comprising a polypeptide chain, wherein the polypeptide chain comprises VD1-(X1)n-VD2-C-(X2)n, wherein;
 VD1 is a first light chain variable domain;   VD2 is a second light chain variable domain;   C is a light chain constant domain;   X1 is a linker with the proviso that it is not CH1;   X2 does not comprise an Fc region;   (X1)n, wherein n is 0 or 1;   (X2)n, wherein n is 0 or 1; and   wherein   (a) VD1 or VD2 comprises three CDRs from SEQ ID NO: 546, 556, 566, 576, 586, 596, 648, 658, 666, 676, 686, 696, 706, 716, 726, 736, 746, 758, 768 or any one of 42-47, 73-87, or 98-107;   (b) VD1 and VD2 independently comprise three CDRs from SEQ ID NO:546, 556, 566, 576, 586, 596, 648, 658, 666, 676, 686, 696, 706, 716, 726, 736, 746, 758, 768 or any one of 42-47, 73-87, or 98-107;   (c) VD1 comprises three CDRs from SEQ ID NO:546, 556, 566, 576, 586, 596, 648, 658, 666, 676, 686, 696, 706, 716, 726, 736, 746, 758, 768 or any one of 42-47, 73-87, or 98-107, and VD2 comprises three CDRs from SEQ ID NO: 31, 33, 35, 116, 117, 118, 119, 120, 318-526, 535-539, 548, 558, 568, 578, 588, 598, 646, 656, 668, 678, 688, 698, 708, 718, 728, 738, 748, 756, 766 or 812; or   (d) VD2 comprises three CDRs from SEQ ID NO:546, 556, 566, 576, 586, 596, 648, 658, 666, 676, 686, 696, 706, 716, 726, 736, 746, 758, 768 or any one of 42-47, 73-87, or 98-107, and VD1 comprises three CDRs from SEQ ID NO: 31, 33, 35, 116, 117, 118, 119, 120, 318-526, 535-539, 548, 558, 568, 578, 588, 598, 646, 656, 668, 678, 688, 698, 708, 718, 728, 738, 748, 756, 766 or 812.   
     
     
         4 - 5 . (canceled) 
     
     
         6 . A binding protein capable of binding TNF, the binding protein comprising first and second polypeptide chains, wherein the first polypeptide chain comprises a first VD1-(X1)n-VD2-C-(X2)n, wherein
 VD1 is a first heavy chain variable domain;   VD2 is a second heavy chain variable domain;   C is a heavy chain constant domain;   X1 is a first linker;   X2 is an Fc region;   (X1)n, wherein n is 0 or 1;   (X2)n, wherein n is 0 or 1; and   wherein the second polypeptide chain comprises a second VD1-(X1)n-VD2-C-(X2)n, wherein   VD1 is a first light chain variable domain;   VD2 is a second light chain variable domain;   C is a light chain constant domain;   X1 is a second linker;   X2 does not comprise an Fc region;   (X1)n, wherein n is 0 or 1;   (X2)n, wherein n is 0 or 1; and   wherein the first and second X1 linker are the same or different;   wherein the first and/or second X1 linker is not CH1; and   wherein   (a) the VD1 or VD2 heavy chain variable domain comprises three CDRs from SEQ ID NO: 541, 551, 561, 571, 581, 591, 601, 606, 611, 616, 621, 626, 631, 636, 643, 653, 661, 671, 681, 691, 701, 711, 721, 731, 741, 753, 763, 771, 776, 781, 786, 791, 796, 801, 805, 807, 809, or any one of 36-41, 48-72, or 88-97, the VD1 or VD2 light chain variable domain comprises three CDRs from SEQ ID NO:546, 556, 566, 576, 586, 596, 648, 658, 666, 676, 686, 696, 706, 716, 726, 736, 746, 758, 768 or any one of 42-47, 73-87, or 98-107;   (b) the VD1 and VD2 heavy chain variable domains independently comprise three CDRs from SEQ ID NO:541, 551, 561, 571, 581, 591, 601, 606, 611, 616, 621, 626, 631, 636, 643, 653, 661, 671, 681, 691, 701, 711, 721, 731, 741, 753, 763, 771, 776, 781, 786, 791, 796, 801, 805, 807, 809, or any one of 36-41, 48-72, or 88-97, the VD1 and VD2 light chain variable domains independently comprise three CDRs from SEQ ID NO:546, 556, 566, 576, 586, 596, 648, 658, 666, 676, 686, 696, 706, 716, 726, 736, 746, 758, 768 or any one of 42-47, 73-87, or 98-107;   (c) the VD1 heavy chain variable domain comprises three CDRs from SEQ ID NO:541, 551, 561, 571, 581, 591, 601, 606, 611, 616, 621, 626, 631, 636, 643, 653, 661, 671, 681, 691, 701, 711, 721, 731, 741, 753, 763, 771, 776, 781, 786, 791, 796, 801, 805, 807, 809, or any one of 36-41, 48-72, or 88-97, and the VD2 heavy chain variable domain comprises three CDRs from SEQ ID NO:30, 32, 34, 108, 109, 110, 111, 112, 113, 114, 115, 121-317, 527-534, 543, 553, 563, 573, 583, 593, 603, 608, 613, 618, 623, 628, 633, 638, 641, 651, 663, 673, 683, 693, 703, 713, 723, 733, 743, 751, 761, 773, 778, 783, 788, 793, 798, 803 or 811; the VD1 light chain variable domain comprises three CDRs from SEQ ID NO:546, 556, 566, 576, 586, 596, 648, 658, 666, 676, 686, 696, 706, 716, 726, 736, 746, 758, 768 or any one of 42-47, 73-87, or 98-107, and the VD2 light chain variable domain comprises three CDRs from SEQ ID NO: 31, 33, 35, 116, 117, 118, 119, 120, 318-526, 535-539, 548, 558, 568, 578, 588, 598, 646, 656, 668, 678, 688, 698, 708, 718, 728, 738, 748, 756, 766, or 812; or   (d) the VD2 heavy chain variable domain comprises three CDRs from SEQ ID NO:541, 551, 561, 571, 581, 591, 601, 606, 611, 616, 621, 626, 631, 636, 643, 653, 661, 671, 681, 691, 701, 711, 721, 731, 741, 753, 763, 771, 776, 781, 786, 791, 796, 801, 805, 807, 809, or any one of 36-41, 48-72, or 88-97, and the VD1 heavy chain variable domain comprises three CDRs from SEQ ID NO:30, 32, 34, 108, 109, 110, 111, 112, 113, 114, 115, 121-317, 527-534, 543, 553, 563, 573, 583, 593, 603, 608, 613, 618, 623, 628, 633, 638, 641, 651, 663, 673, 683, 693, 703, 713, 723, 733, 743, 751, 761, 773, 778, 783, 788, 793, 798, 803 or 811; the VD2 light chain variable domain comprises three CDRs from SEQ ID NO:546, 556, 566, 576, 586, 596, 648, 658, 666, 676, 686, 696, 706, 716, 726, 736, 746, 758, 768 or any one of 42-47, 73-87, or 98-107, and the VD1 light chain variable domain comprises three CDRs from SEQ ID NO: 31, 33, 35, 116, 117, 118, 119, 120, 318-526, 535-539, 548, 558, 568, 578, 588, 598, 646, 656, 668, 678, 688, 698, 708, 718, 728, 738, 748, 756, 766 or 812.   
     
     
         7 . (canceled) 
     
     
         8 . The binding protein of  claim 1 , wherein X1 comprises any one of SEQ ID NOs 1-29. 
     
     
         9 - 18 . (canceled) 
     
     
         19 . A binding protein capable of binding TNF and IL-17, the binding protein comprising four polypeptide chains, wherein two polypeptide chains comprise VD1-(X1)n-VD2-C-(X2)n, wherein
 VD1 is a first heavy chain variable domain;   VD2 is a second heavy chain variable domain;   C is a heavy chain constant domain;   X1 is a first linker;   X2 is an Fc region; and   wherein two polypeptide chains comprise VD1-(X1)n-VD2-C-(X2)n, wherein   VD1 is a first light chain variable domain;   VD2 is a second light chain variable domain;   C is a light chain constant domain;   X1 is a second linker;   X2 does not comprise an Fc region;   (X1)n, wherein n is 0 or 1; and   (X2)n, wherein n is 0 or 1;   wherein the first and second X1 linker are the same or different;   wherein the first and/or second X1 linker is not CH1; and   wherein   (a) the VD1 or VD2 heavy chain variable domain comprises three CDRs from SEQ ID NO: 541, 551, 561, 571, 581, 591, 601, 606, 611, 616, 621, 626, 631, 636, 643, 653, 661, 671, 681, 691, 701, 711, 721, 731, 741, 753, 763, 771, 776, 781, 786, 791, 796, 801, 805, 807, 809, or any one of 36-41, 48-72, or 88-97, the VD1 or VD2 light chain variable domain comprises three CDRs from SEQ ID NO: 546, 556, 566, 576, 586, 596, 648, 658, 666, 676, 686, 696, 706, 716, 726, 736, 746, 758, 768 or any one of 42-47, 73-87, or 98-107;   (b) the VD1 and VD2 heavy chain variable domains independently comprise three CDRs from SEQ ID NO: 541, 551, 561, 571, 581, 591, 601, 606, 611, 616, 621, 626, 631, 636, 643, 653, 661, 671, 681, 691, 701, 711, 721, 731, 741, 753, 763, 771, 776, 781, 786, 791, 796, 801, 805, 807, 809, or any one of 36-41, 48-72, or 88-97, the VD1 and VD2 light chain variable domains independently comprise three CDRs from SEQ ID NO: 546, 556, 566, 576, 586, 596, 648, 658, 666, 676, 686, 696, 706, 716, 726, 736, 746, 758, 768 or any one of 42-47, 73-87, or 98-107;   (c) the VD1 heavy chain variable domain comprises three CDRs from SEQ ID NO: 541, 551, 561, 571, 581, 591, 601, 606, 611, 616, 621, 626, 631, 636, 643, 653, 661, 671, 681, 691, 701, 711, 721, 731, 741, 753, 763, 771, 776, 781, 786, 791, 796, 801, 805, 807, 809, or any one of 36-41, 48-72, or 88-97, and the VD2 heavy chain variable domain comprises three CDRs from SEQ ID NO:30, 32, 34, 108, 109, 110, 111, 112, 113, 114, 115, 121-317, 527-534, 543, 553, 563, 573, 583, 593, 603, 608, 613, 618, 623, 628, 633, 638, 641, 651, 663, 673, 683, 693, 703, 713, 723, 733, 743, 751, 761, 773, 778, 783, 788, 793, 798, 803 or 811; the VD1 light chain variable domain comprises three CDRs from SEQ ID NO: 546, 556, 566, 576, 586, 596, 648, 658, 666, 676, 686, 696, 706, 716, 726, 736, 746, 758, 768 or any one of 42-47, 73-87, or 98-107, and the VD2 light chain variable domain comprises three CDRs from SEQ ID NO: 31, 33, 35, 116, 117, 118, 119, 120, 318-526, 535-539, 548, 558, 568, 578, 588, 598, 646, 656, 668, 678, 688, 698, 708, 718, 728, 738, 748, 756, 766, or 812; or   (d) the VD2 heavy chain variable domain comprises three CDRs from SEQ ID NO: 541, 551, 561, 571, 581, 591, 601, 606, 611, 616, 621, 626, 631, 636, 643, 653, 661, 671, 681, 691, 701, 711, 721, 731, 741, 753, 763, 771, 776, 781, 786, 791, 796, 801, 805, 807, 809, or any one of 36-41, 48-72, or 88-97, and the VD1 heavy chain variable domain comprises three CDRs from SEQ ID NO:30, 32, 34, 108, 109, 110, 111, 112, 113, 114, 115, 121-317, 527-534, 543, 553, 563, 573, 583, 593, 603, 608, 613, 618, 623, 628, 633, 638, 641, 651, 663, 673, 683, 693, 703, 713, 723, 733, 743, 751, 761, 773, 778, 783, 788, 793, 798, 803 or 811; the VD2 light chain variable domain comprises three CDRs from SEQ ID NO: 546, 556, 566, 576, 586, 596, 648, 658, 666, 676, 686, 696, 706, 716, 726, 736, 746, 758, 768 or any one of 42-47, 73-87, or 98-107, and the VD1 light chain variable domain comprises three CDRs from SEQ ID NO: 31, 33, 35, 116, 117, 118, 119, 120, 318-526, 535-539, 548, 558, 568, 578, 588, 598, 646, 656, 668, 678, 688, 698, 708, 718, 728, 738, 748, 756, 766 or 812.   
     
     
         20 - 26 . (canceled) 
     
     
         27 . An isolated nucleic acid encoding a binding protein amino acid sequence of  claim 1 . 
     
     
         28 . A vector comprising an isolated nucleic acid of  claim 27 . 
     
     
         29 . (canceled) 
     
     
         30 . A host cell comprising a vector of  claim 28 . 
     
     
         31 - 33 . (canceled) 
     
     
         34 . A method of producing a binding protein capable of binding TNF, the method comprising the step of culturing a host cell described in  claim 30  in culture medium under conditions sufficient to produce the binding protein. 
     
     
         35 . (canceled) 
     
     
         36 . A pharmaceutical composition comprising the binding protein of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         37 - 38 . (canceled) 
     
     
         39 . A method of treating a subject mammal for a disease or a disorder by administering to the mammal an effective amount of the pharmaceutical composition of  claim 36  such that treatment is achieved. 
     
     
         40 - 72 . (canceled) 
     
     
         73 . An isolated nucleic acid encoding a binding protein comprising the amino acid sequence of  claim 3 . 
     
     
         74 . A vector comprising the isolated nucleic acid of  claim 73 . 
     
     
         75 . A host cell comprising the vector of  claim 74 . 
     
     
         76 . A method for producing a protein capable of binding TNF, the method comprising the step of culturing the host cell of  claim 75  in a culture medium under conditions sufficient to produce the binding protein. 
     
     
         77 . A pharmaceutical composition comprising the binding protein of  claim 3 , and a pharmaceutically acceptable carrier. 
     
     
         78 . A method for treating a mammal for a disease or disorder comprising administering to the mammal an effective amount of the pharmaceutical composition of  claim 77 . 
     
     
         79 - 88 . (canceled) 
     
     
         89 . An isolated nucleic acid encoding a binding protein comprising the amino acid sequence of  claim 6 . 
     
     
         90 . A vector comprising the isolated nucleic acid of  claim 89 . 
     
     
         91 . A host cell comprising the vector of  claim 90 . 
     
     
         92 . A method for producing a protein capable of binding TNF, the method comprising the step of culturing the host cell of  claim 91  in a culture medium under conditions sufficient to produce the binding protein. 
     
     
         93 . A pharmaceutical composition comprising the binding protein of  claim 6 , and a pharmaceutically acceptable carrier. 
     
     
         94 . A method for treating a mammal for a disease or disorder comprising administering to the mammal an effective amount of the pharmaceutical composition of  claim 93 . 
     
     
         95 . An isolated nucleic acid encoding a binding protein comprising the amino acid sequence of  claim 19 . 
     
     
         96 . A vector comprising the isolated nucleic acid of  claim 95 . 
     
     
         97 . A host cell comprising the vector of  claim 96 . 
     
     
         98 . A method for producing a protein capable of binding TNF and IL-17, the method comprising the step of culturing the host cell of  claim 97  in a culture medium under conditions sufficient to produce the binding protein. 
     
     
         99 . A pharmaceutical composition comprising the binding protein of  claim 19 , and a pharmaceutically acceptable carrier. 
     
     
         100 . A method for treating a mammal for a disease or disorder comprising administering the mammal an effective amount of the pharmaceutical composition of  claim 99 . 
     
     
         101 . The binding protein of  claim 19 , wherein X1 comprises any of SEQ ID NOs 1-29.