WO2002002773A2 - Dual specificity antibodies and methods of making and using - Google Patents
Dual specificity antibodies and methods of making and using Download PDFInfo
- Publication number
- WO2002002773A2 WO2002002773A2 PCT/US2001/020755 US0120755W WO0202773A2 WO 2002002773 A2 WO2002002773 A2 WO 2002002773A2 US 0120755 W US0120755 W US 0120755W WO 0202773 A2 WO0202773 A2 WO 0202773A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- antibody
- antigen
- library
- binding portion
- antigen binding
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 171
- 230000009977 dual effect Effects 0.000 title claims abstract description 153
- 239000000427 antigen Substances 0.000 claims abstract description 386
- 108091007433 antigens Proteins 0.000 claims abstract description 386
- 102000036639 antigens Human genes 0.000 claims abstract description 386
- 230000027455 binding Effects 0.000 claims abstract description 133
- 238000001727 in vivo Methods 0.000 claims abstract description 46
- 230000000694 effects Effects 0.000 claims abstract description 34
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 9
- 108090000623 proteins and genes Proteins 0.000 claims description 144
- 102000004169 proteins and genes Human genes 0.000 claims description 99
- 210000004027 cell Anatomy 0.000 claims description 89
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 80
- 241001465754 Metazoa Species 0.000 claims description 58
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 45
- 238000000338 in vitro Methods 0.000 claims description 44
- 241000699666 Mus <mouse, genus> Species 0.000 claims description 39
- 210000004408 hybridoma Anatomy 0.000 claims description 29
- 210000004698 lymphocyte Anatomy 0.000 claims description 29
- 230000003053 immunization Effects 0.000 claims description 28
- 208000035475 disorder Diseases 0.000 claims description 27
- 238000012216 screening Methods 0.000 claims description 25
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 21
- 238000002649 immunization Methods 0.000 claims description 20
- 239000013598 vector Substances 0.000 claims description 18
- 241000699670 Mus sp. Species 0.000 claims description 17
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 17
- -1 IP- 10 Proteins 0.000 claims description 16
- 238000004519 manufacturing process Methods 0.000 claims description 16
- 108020003175 receptors Proteins 0.000 claims description 15
- 239000012472 biological sample Substances 0.000 claims description 14
- 210000001519 tissue Anatomy 0.000 claims description 14
- 230000009261 transgenic effect Effects 0.000 claims description 12
- 241000283973 Oryctolagus cuniculus Species 0.000 claims description 11
- 230000009824 affinity maturation Effects 0.000 claims description 11
- 102000000589 Interleukin-1 Human genes 0.000 claims description 10
- 108010002352 Interleukin-1 Proteins 0.000 claims description 10
- 230000004927 fusion Effects 0.000 claims description 10
- 241000283707 Capra Species 0.000 claims description 8
- 108010069514 Cyclic Peptides Proteins 0.000 claims description 8
- 102000001189 Cyclic Peptides Human genes 0.000 claims description 8
- 108700005091 Immunoglobulin Genes Proteins 0.000 claims description 7
- 241000700159 Rattus Species 0.000 claims description 7
- 229920001184 polypeptide Polymers 0.000 claims description 7
- 230000007503 antigenic stimulation Effects 0.000 claims description 6
- 239000002773 nucleotide Substances 0.000 claims description 6
- 125000003729 nucleotide group Chemical group 0.000 claims description 6
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 6
- 230000001580 bacterial effect Effects 0.000 claims description 5
- 201000006417 multiple sclerosis Diseases 0.000 claims description 5
- 239000002243 precursor Substances 0.000 claims description 5
- 230000003248 secreting effect Effects 0.000 claims description 5
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 claims description 5
- 210000005253 yeast cell Anatomy 0.000 claims description 5
- 108020004635 Complementary DNA Proteins 0.000 claims description 4
- 208000011231 Crohn disease Diseases 0.000 claims description 4
- 201000004681 Psoriasis Diseases 0.000 claims description 4
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 4
- 210000002798 bone marrow cell Anatomy 0.000 claims description 4
- 230000002950 deficient Effects 0.000 claims description 4
- 238000011503 in vivo imaging Methods 0.000 claims description 4
- 208000027866 inflammatory disease Diseases 0.000 claims description 4
- 231100000518 lethal Toxicity 0.000 claims description 4
- 230000001665 lethal effect Effects 0.000 claims description 4
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 claims description 4
- 230000001950 radioprotection Effects 0.000 claims description 4
- 238000011084 recovery Methods 0.000 claims description 4
- 241001515965 unidentified phage Species 0.000 claims description 4
- 208000023275 Autoimmune disease Diseases 0.000 claims description 3
- 239000000523 sample Substances 0.000 claims description 3
- 102000003777 Interleukin-1 beta Human genes 0.000 claims description 2
- 108090000193 Interleukin-1 beta Proteins 0.000 claims description 2
- 102000015696 Interleukins Human genes 0.000 claims description 2
- 108010063738 Interleukins Proteins 0.000 claims description 2
- 208000002491 severe combined immunodeficiency Diseases 0.000 claims 4
- 238000011813 knockout mouse model Methods 0.000 claims 2
- 230000001627 detrimental effect Effects 0.000 abstract description 9
- 235000018102 proteins Nutrition 0.000 description 83
- 108020004414 DNA Proteins 0.000 description 24
- 239000012634 fragment Substances 0.000 description 22
- 239000013604 expression vector Substances 0.000 description 21
- 108060003951 Immunoglobulin Proteins 0.000 description 20
- 239000003795 chemical substances by application Substances 0.000 description 20
- 102000018358 immunoglobulin Human genes 0.000 description 20
- 239000003814 drug Substances 0.000 description 19
- 201000010099 disease Diseases 0.000 description 18
- 230000014509 gene expression Effects 0.000 description 17
- 239000000203 mixture Substances 0.000 description 17
- 238000013459 approach Methods 0.000 description 15
- 150000001875 compounds Chemical class 0.000 description 15
- 210000004602 germ cell Anatomy 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 15
- 229940124597 therapeutic agent Drugs 0.000 description 15
- 235000001014 amino acid Nutrition 0.000 description 14
- 102000005962 receptors Human genes 0.000 description 14
- 102000004127 Cytokines Human genes 0.000 description 13
- 108090000695 Cytokines Proteins 0.000 description 13
- 229940024606 amino acid Drugs 0.000 description 13
- 150000001413 amino acids Chemical group 0.000 description 13
- 238000003259 recombinant expression Methods 0.000 description 13
- 230000001225 therapeutic effect Effects 0.000 description 13
- 239000003112 inhibitor Substances 0.000 description 11
- 238000005516 engineering process Methods 0.000 description 10
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 description 9
- 208000019693 Lung disease Diseases 0.000 description 9
- 206010035226 Plasma cell myeloma Diseases 0.000 description 9
- 239000003246 corticosteroid Substances 0.000 description 9
- 229960001334 corticosteroids Drugs 0.000 description 9
- 238000013461 design Methods 0.000 description 9
- 201000000050 myeloid neoplasm Diseases 0.000 description 9
- 230000001105 regulatory effect Effects 0.000 description 9
- 239000005541 ACE inhibitor Substances 0.000 description 8
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 8
- 102100040247 Tumor necrosis factor Human genes 0.000 description 8
- 239000005557 antagonist Substances 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- 239000001963 growth medium Substances 0.000 description 8
- 108010045069 keyhole-limpet hemocyanin Proteins 0.000 description 8
- 229960000485 methotrexate Drugs 0.000 description 8
- 238000002823 phage display Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 241000894007 species Species 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 7
- 102100026878 Interleukin-2 receptor subunit alpha Human genes 0.000 description 7
- 208000029523 Interstitial Lung disease Diseases 0.000 description 7
- 230000005875 antibody response Effects 0.000 description 7
- 230000001363 autoimmune Effects 0.000 description 7
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 7
- 229960002170 azathioprine Drugs 0.000 description 7
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 7
- 239000008194 pharmaceutical composition Substances 0.000 description 7
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 6
- 102000014914 Carrier Proteins Human genes 0.000 description 6
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 6
- 108010036949 Cyclosporine Proteins 0.000 description 6
- 238000002965 ELISA Methods 0.000 description 6
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 description 6
- 108010076504 Protein Sorting Signals Proteins 0.000 description 6
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 230000000890 antigenic effect Effects 0.000 description 6
- 229960001265 ciclosporin Drugs 0.000 description 6
- 230000009260 cross reactivity Effects 0.000 description 6
- 229930182912 cyclosporin Natural products 0.000 description 6
- 239000003937 drug carrier Substances 0.000 description 6
- 239000003550 marker Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 230000003472 neutralizing effect Effects 0.000 description 6
- 230000011664 signaling Effects 0.000 description 6
- 229960001940 sulfasalazine Drugs 0.000 description 6
- NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 0.000 description 6
- 108010088751 Albumins Proteins 0.000 description 5
- 102000009027 Albumins Human genes 0.000 description 5
- 108010078791 Carrier Proteins Proteins 0.000 description 5
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 5
- UETNIIAIRMUTSM-UHFFFAOYSA-N Jacareubin Natural products CC1(C)OC2=CC3Oc4c(O)c(O)ccc4C(=O)C3C(=C2C=C1)O UETNIIAIRMUTSM-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 5
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 5
- 239000003623 enhancer Substances 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 230000036541 health Effects 0.000 description 5
- 230000001900 immune effect Effects 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- 230000000670 limiting effect Effects 0.000 description 5
- 229960005205 prednisolone Drugs 0.000 description 5
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 5
- 206010003827 Autoimmune hepatitis Diseases 0.000 description 4
- 102100032937 CD40 ligand Human genes 0.000 description 4
- 102100035360 Cerebellar degeneration-related antigen 1 Human genes 0.000 description 4
- 206010010099 Combined immunodeficiency Diseases 0.000 description 4
- 241000701022 Cytomegalovirus Species 0.000 description 4
- 102100031111 Disintegrin and metalloproteinase domain-containing protein 17 Human genes 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 4
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 4
- 241001529936 Murinae Species 0.000 description 4
- 108020004511 Recombinant DNA Proteins 0.000 description 4
- 210000001744 T-lymphocyte Anatomy 0.000 description 4
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 4
- 230000001154 acute effect Effects 0.000 description 4
- 208000026935 allergic disease Diseases 0.000 description 4
- 125000000539 amino acid group Chemical group 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 108010057085 cytokine receptors Proteins 0.000 description 4
- 102000003675 cytokine receptors Human genes 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003102 growth factor Substances 0.000 description 4
- 229960001680 ibuprofen Drugs 0.000 description 4
- 230000028993 immune response Effects 0.000 description 4
- 230000002163 immunogen Effects 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 4
- 229960000681 leflunomide Drugs 0.000 description 4
- 210000004962 mammalian cell Anatomy 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 108020004999 messenger RNA Proteins 0.000 description 4
- 238000002703 mutagenesis Methods 0.000 description 4
- 231100000350 mutagenesis Toxicity 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- 230000000770 proinflammatory effect Effects 0.000 description 4
- 230000000069 prophylactic effect Effects 0.000 description 4
- 238000003127 radioimmunoassay Methods 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 238000010561 standard procedure Methods 0.000 description 4
- 238000001890 transfection Methods 0.000 description 4
- 101710117290 Aldo-keto reductase family 1 member C4 Proteins 0.000 description 3
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 3
- 208000036487 Arthropathies Diseases 0.000 description 3
- 102000017420 CD3 protein, epsilon/gamma/delta subunit Human genes 0.000 description 3
- 108050005493 CD3 protein, epsilon/gamma/delta subunit Proteins 0.000 description 3
- 101150013553 CD40 gene Proteins 0.000 description 3
- 206010008874 Chronic Fatigue Syndrome Diseases 0.000 description 3
- 229930105110 Cyclosporin A Natural products 0.000 description 3
- 102000053602 DNA Human genes 0.000 description 3
- 102100025137 Early activation antigen CD69 Human genes 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 3
- 101000934374 Homo sapiens Early activation antigen CD69 Proteins 0.000 description 3
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 description 3
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 description 3
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 3
- 101000934346 Homo sapiens T-cell surface antigen CD2 Proteins 0.000 description 3
- 101000716102 Homo sapiens T-cell surface glycoprotein CD4 Proteins 0.000 description 3
- 101000946843 Homo sapiens T-cell surface glycoprotein CD8 alpha chain Proteins 0.000 description 3
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 3
- 101000800116 Homo sapiens Thy-1 membrane glycoprotein Proteins 0.000 description 3
- 101000851376 Homo sapiens Tumor necrosis factor receptor superfamily member 8 Proteins 0.000 description 3
- 206010020751 Hypersensitivity Diseases 0.000 description 3
- 208000012659 Joint disease Diseases 0.000 description 3
- 241000829100 Macaca mulatta polyomavirus 1 Species 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 108091028043 Nucleic acid sequence Proteins 0.000 description 3
- 239000012826 P38 inhibitor Substances 0.000 description 3
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 3
- 102100025237 T-cell surface antigen CD2 Human genes 0.000 description 3
- 102100036011 T-cell surface glycoprotein CD4 Human genes 0.000 description 3
- 102100034922 T-cell surface glycoprotein CD8 alpha chain Human genes 0.000 description 3
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 3
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 3
- 108010022394 Threonine synthase Proteins 0.000 description 3
- 102100033523 Thy-1 membrane glycoprotein Human genes 0.000 description 3
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 3
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 3
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 3
- 102100036857 Tumor necrosis factor receptor superfamily member 8 Human genes 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 239000000464 adrenergic agent Substances 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- 230000007815 allergy Effects 0.000 description 3
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 210000000628 antibody-producing cell Anatomy 0.000 description 3
- 239000003146 anticoagulant agent Substances 0.000 description 3
- 229960004676 antithrombotic agent Drugs 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 229960002685 biotin Drugs 0.000 description 3
- 235000020958 biotin Nutrition 0.000 description 3
- 239000011616 biotin Substances 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 210000004899 c-terminal region Anatomy 0.000 description 3
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 description 3
- 238000010367 cloning Methods 0.000 description 3
- 239000004074 complement inhibitor Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 102000004419 dihydrofolate reductase Human genes 0.000 description 3
- 238000010494 dissociation reaction Methods 0.000 description 3
- 230000005593 dissociations Effects 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 208000006454 hepatitis Diseases 0.000 description 3
- 231100000283 hepatitis Toxicity 0.000 description 3
- 208000026278 immune system disease Diseases 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000003780 insertion Methods 0.000 description 3
- 230000037431 insertion Effects 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 229940043355 kinase inhibitor Drugs 0.000 description 3
- 229950007278 lenercept Drugs 0.000 description 3
- KBOPZPXVLCULAV-UHFFFAOYSA-N mesalamine Chemical compound NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 description 3
- 229960004963 mesalazine Drugs 0.000 description 3
- 239000003475 metalloproteinase inhibitor Substances 0.000 description 3
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 3
- 238000001823 molecular biology technique Methods 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 description 3
- 229960004866 mycophenolate mofetil Drugs 0.000 description 3
- 150000007523 nucleic acids Chemical class 0.000 description 3
- 229960004110 olsalazine Drugs 0.000 description 3
- QQBDLJCYGRGAKP-FOCLMDBBSA-N olsalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=C(C(O)=CC=2)C(O)=O)=C1 QQBDLJCYGRGAKP-FOCLMDBBSA-N 0.000 description 3
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 3
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 3
- 210000002381 plasma Anatomy 0.000 description 3
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 3
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 3
- 229960002930 sirolimus Drugs 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 210000004988 splenocyte Anatomy 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 3
- 238000013518 transcription Methods 0.000 description 3
- 230000035897 transcription Effects 0.000 description 3
- 238000013519 translation Methods 0.000 description 3
- 238000002054 transplantation Methods 0.000 description 3
- 108091007505 ADAM17 Proteins 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- 206010069754 Acquired gene mutation Diseases 0.000 description 2
- 102000009840 Angiopoietins Human genes 0.000 description 2
- 108010009906 Angiopoietins Proteins 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- 108010029697 CD40 Ligand Proteins 0.000 description 2
- 108091035707 Consensus sequence Proteins 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 101150074155 DHFR gene Proteins 0.000 description 2
- 108010072051 Glatiramer Acetate Proteins 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 102000004457 Granulocyte-Macrophage Colony-Stimulating Factor Human genes 0.000 description 2
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000690301 Homo sapiens Aldo-keto reductase family 1 member C4 Proteins 0.000 description 2
- 101000868215 Homo sapiens CD40 ligand Proteins 0.000 description 2
- 101001116548 Homo sapiens Protein CBFA2T1 Proteins 0.000 description 2
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 2
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 2
- 208000016604 Lyme disease Diseases 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 201000011152 Pemphigus Diseases 0.000 description 2
- 208000031845 Pernicious anaemia Diseases 0.000 description 2
- 241000276498 Pollachius virens Species 0.000 description 2
- 102100033237 Pro-epidermal growth factor Human genes 0.000 description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 2
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 2
- 206010040070 Septic Shock Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 108010090804 Streptavidin Proteins 0.000 description 2
- 201000009594 Systemic Scleroderma Diseases 0.000 description 2
- 206010042953 Systemic sclerosis Diseases 0.000 description 2
- 208000001106 Takayasu Arteritis Diseases 0.000 description 2
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
- 108700019146 Transgenes Proteins 0.000 description 2
- 206010046851 Uveitis Diseases 0.000 description 2
- 206010047115 Vasculitis Diseases 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 238000004166 bioassay Methods 0.000 description 2
- 239000013060 biological fluid Substances 0.000 description 2
- 239000004067 bulking agent Substances 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229960001714 calcium phosphate Drugs 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- BFPSDSIWYFKGBC-UHFFFAOYSA-N chlorotrianisene Chemical compound C1=CC(OC)=CC=C1C(Cl)=C(C=1C=CC(OC)=CC=1)C1=CC=C(OC)C=C1 BFPSDSIWYFKGBC-UHFFFAOYSA-N 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 230000000295 complement effect Effects 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 208000018631 connective tissue disease Diseases 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 229940038717 copaxone Drugs 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 229940111134 coxibs Drugs 0.000 description 2
- 239000002577 cryoprotective agent Substances 0.000 description 2
- 239000012228 culture supernatant Substances 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000002612 dispersion medium Substances 0.000 description 2
- 238000004520 electroporation Methods 0.000 description 2
- 210000003527 eukaryotic cell Anatomy 0.000 description 2
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000002949 hemolytic effect Effects 0.000 description 2
- 238000002744 homologous recombination Methods 0.000 description 2
- 230000006801 homologous recombination Effects 0.000 description 2
- 102000054751 human RUNX1T1 Human genes 0.000 description 2
- 102000057041 human TNF Human genes 0.000 description 2
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 2
- 238000003018 immunoassay Methods 0.000 description 2
- 230000016784 immunoglobulin production Effects 0.000 description 2
- 238000000099 in vitro assay Methods 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 229940102223 injectable solution Drugs 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 230000003278 mimic effect Effects 0.000 description 2
- 230000004001 molecular interaction Effects 0.000 description 2
- 208000029766 myalgic encephalomeyelitis/chronic fatigue syndrome Diseases 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 201000008482 osteoarthritis Diseases 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- 239000012857 radioactive material Substances 0.000 description 2
- 208000002574 reactive arthritis Diseases 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 210000001082 somatic cell Anatomy 0.000 description 2
- 230000000392 somatic effect Effects 0.000 description 2
- 230000037439 somatic mutation Effects 0.000 description 2
- 238000012409 standard PCR amplification Methods 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- 230000002103 transcriptional effect Effects 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 239000002447 tumor necrosis factor alpha converting enzyme inhibitor Substances 0.000 description 2
- 241000701161 unidentified adenovirus Species 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 description 1
- LOGFVTREOLYCPF-KXNHARMFSA-N (2s,3r)-2-[[(2r)-1-[(2s)-2,6-diaminohexanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxybutanoic acid Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H]1CCCN1C(=O)[C@@H](N)CCCCN LOGFVTREOLYCPF-KXNHARMFSA-N 0.000 description 1
- 230000006269 (delayed) early viral mRNA transcription Effects 0.000 description 1
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- SZXUTTGMFUSMCE-UHFFFAOYSA-N 2-(1h-imidazol-2-yl)pyridine Chemical class C1=CNC(C=2N=CC=CC=2)=N1 SZXUTTGMFUSMCE-UHFFFAOYSA-N 0.000 description 1
- NBGAYCYFNGPNPV-UHFFFAOYSA-N 2-aminooxybenzoic acid Chemical class NOC1=CC=CC=C1C(O)=O NBGAYCYFNGPNPV-UHFFFAOYSA-N 0.000 description 1
- QGHDLJAZIIFENW-UHFFFAOYSA-N 4-[1,1,1,3,3,3-hexafluoro-2-(4-hydroxy-3-prop-2-enylphenyl)propan-2-yl]-2-prop-2-enylphenol Chemical group C1=C(CC=C)C(O)=CC=C1C(C(F)(F)F)(C(F)(F)F)C1=CC=C(O)C(CC=C)=C1 QGHDLJAZIIFENW-UHFFFAOYSA-N 0.000 description 1
- TVZGACDUOSZQKY-LBPRGKRZSA-N 4-aminofolic acid Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 TVZGACDUOSZQKY-LBPRGKRZSA-N 0.000 description 1
- NUKYPUAOHBNCPY-UHFFFAOYSA-N 4-aminopyridine Chemical compound NC1=CC=NC=C1 NUKYPUAOHBNCPY-UHFFFAOYSA-N 0.000 description 1
- CJIJXIFQYOPWTF-UHFFFAOYSA-N 7-hydroxycoumarin Natural products O1C(=O)C=CC2=CC(O)=CC=C21 CJIJXIFQYOPWTF-UHFFFAOYSA-N 0.000 description 1
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical class O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 1
- 102000012440 Acetylcholinesterase Human genes 0.000 description 1
- 108010022752 Acetylcholinesterase Proteins 0.000 description 1
- 208000029483 Acquired immunodeficiency Diseases 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- 208000026872 Addison Disease Diseases 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 206010003267 Arthritis reactive Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 206010003645 Atopy Diseases 0.000 description 1
- 208000031212 Autoimmune polyendocrinopathy Diseases 0.000 description 1
- 206010050245 Autoimmune thrombocytopenia Diseases 0.000 description 1
- 108090001008 Avidin Proteins 0.000 description 1
- 102100039705 Beta-2 adrenergic receptor Human genes 0.000 description 1
- 101710152983 Beta-2 adrenergic receptor Proteins 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 102100026189 Beta-galactosidase Human genes 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 1
- 206010006895 Cachexia Diseases 0.000 description 1
- 101100228196 Caenorhabditis elegans gly-4 gene Proteins 0.000 description 1
- 241000282461 Canis lupus Species 0.000 description 1
- 108090000426 Caspase-1 Proteins 0.000 description 1
- 108010076667 Caspases Proteins 0.000 description 1
- 102000011727 Caspases Human genes 0.000 description 1
- 241001227713 Chiron Species 0.000 description 1
- 241000606161 Chlamydia Species 0.000 description 1
- 206010008609 Cholangitis sclerosing Diseases 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- 208000008818 Chronic Mucocutaneous Candidiasis Diseases 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 206010056370 Congestive cardiomyopathy Diseases 0.000 description 1
- 206010010941 Coombs positive haemolytic anaemia Diseases 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 241001136239 Cymbidium hybrid cultivar Species 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- 150000008574 D-amino acids Chemical class 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- XPDXVDYUQZHFPV-UHFFFAOYSA-N Dansyl Chloride Chemical compound C1=CC=C2C(N(C)C)=CC=CC2=C1S(Cl)(=O)=O XPDXVDYUQZHFPV-UHFFFAOYSA-N 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 201000010046 Dilated cardiomyopathy Diseases 0.000 description 1
- 208000006926 Discoid Lupus Erythematosus Diseases 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
- 108060006698 EGF receptor Proteins 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- YQYJSBFKSSDGFO-UHFFFAOYSA-N Epihygromycin Natural products OC1C(O)C(C(=O)C)OC1OC(C(=C1)O)=CC=C1C=C(C)C(=O)NC1C(O)C(O)C2OCOC2C1O YQYJSBFKSSDGFO-UHFFFAOYSA-N 0.000 description 1
- 101000759376 Escherichia phage Mu Tail sheath protein Proteins 0.000 description 1
- 108091029865 Exogenous DNA Proteins 0.000 description 1
- 108091008794 FGF receptors Proteins 0.000 description 1
- 208000007984 Female Infertility Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000007465 Giant cell arteritis Diseases 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 208000024869 Goodpasture syndrome Diseases 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 206010018634 Gouty Arthritis Diseases 0.000 description 1
- 208000009329 Graft vs Host Disease Diseases 0.000 description 1
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 1
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 1
- 208000003807 Graves Disease Diseases 0.000 description 1
- 208000015023 Graves' disease Diseases 0.000 description 1
- 208000031856 Haemosiderosis Diseases 0.000 description 1
- 208000001204 Hashimoto Disease Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 206010019755 Hepatitis chronic active Diseases 0.000 description 1
- 101000662009 Homo sapiens UDP-N-acetylglucosamine pyrophosphorylase Proteins 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- 206010020850 Hyperthyroidism Diseases 0.000 description 1
- 206010020983 Hypogammaglobulinaemia Diseases 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 208000000038 Hypoparathyroidism Diseases 0.000 description 1
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 description 1
- 239000003458 I kappa b kinase inhibitor Substances 0.000 description 1
- 102000039996 IL-1 family Human genes 0.000 description 1
- 108091069196 IL-1 family Proteins 0.000 description 1
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 1
- 208000016300 Idiopathic chronic eosinophilic pneumonia Diseases 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 102000009786 Immunoglobulin Constant Regions Human genes 0.000 description 1
- 108010009817 Immunoglobulin Constant Regions Proteins 0.000 description 1
- 206010021928 Infertility female Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 108010005716 Interferon beta-1a Proteins 0.000 description 1
- 108010005714 Interferon beta-1b Proteins 0.000 description 1
- 102000003996 Interferon-beta Human genes 0.000 description 1
- 108090000467 Interferon-beta Proteins 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 102000003815 Interleukin-11 Human genes 0.000 description 1
- 108090000177 Interleukin-11 Proteins 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 108010002586 Interleukin-7 Proteins 0.000 description 1
- 208000003456 Juvenile Arthritis Diseases 0.000 description 1
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 1
- 208000011200 Kawasaki disease Diseases 0.000 description 1
- ZCVMWBYGMWKGHF-UHFFFAOYSA-N Ketotifene Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2CC(=O)C2=C1C=CS2 ZCVMWBYGMWKGHF-UHFFFAOYSA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-Histidine Natural products OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-UHFFFAOYSA-N L-Methionine Natural products CSCCC(N)C(O)=O FFEARJCKVFRZRR-UHFFFAOYSA-N 0.000 description 1
- 150000008575 L-amino acids Chemical class 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- 125000002066 L-histidyl group Chemical group [H]N1C([H])=NC(C([H])([H])[C@](C(=O)[*])([H])N([H])[H])=C1[H] 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- 229930195722 L-methionine Natural products 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 208000012309 Linear IgA disease Diseases 0.000 description 1
- 239000000867 Lipoxygenase Inhibitor Substances 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 208000007466 Male Infertility Diseases 0.000 description 1
- 102000005741 Metalloproteases Human genes 0.000 description 1
- 108010006035 Metalloproteases Proteins 0.000 description 1
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 1
- 208000003250 Mixed connective tissue disease Diseases 0.000 description 1
- 206010028080 Mucocutaneous candidiasis Diseases 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 241000238367 Mya arenaria Species 0.000 description 1
- 206010028665 Myxoedema Diseases 0.000 description 1
- 241001045988 Neogene Species 0.000 description 1
- 206010029164 Nephrotic syndrome Diseases 0.000 description 1
- 206010029888 Obliterative bronchiolitis Diseases 0.000 description 1
- 206010033165 Ovarian failure Diseases 0.000 description 1
- 238000012408 PCR amplification Methods 0.000 description 1
- 108091008606 PDGF receptors Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 108090000526 Papain Proteins 0.000 description 1
- 208000030852 Parasitic disease Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 206010034277 Pemphigoid Diseases 0.000 description 1
- 208000027086 Pemphigus foliaceus Diseases 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 1
- 108010004729 Phycoerythrin Proteins 0.000 description 1
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 206010057244 Post viral fatigue syndrome Diseases 0.000 description 1
- 208000002500 Primary Ovarian Insufficiency Diseases 0.000 description 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 238000010240 RT-PCR analysis Methods 0.000 description 1
- 208000032056 Radiation Fibrosis Syndrome Diseases 0.000 description 1
- 206010067953 Radiation fibrosis Diseases 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 208000033464 Reiter syndrome Diseases 0.000 description 1
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 101710205657 Secreted proteinase Proteins 0.000 description 1
- 206010053879 Sepsis syndrome Diseases 0.000 description 1
- 208000006045 Spondylarthropathies Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 206010042742 Sympathetic ophthalmia Diseases 0.000 description 1
- 206010051379 Systemic Inflammatory Response Syndrome Diseases 0.000 description 1
- 102000043168 TGF-beta family Human genes 0.000 description 1
- 108091085018 TGF-beta family Proteins 0.000 description 1
- 108091005735 TGF-beta receptors Proteins 0.000 description 1
- 206010044248 Toxic shock syndrome Diseases 0.000 description 1
- 231100000650 Toxic shock syndrome Toxicity 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- 108060008683 Tumor Necrosis Factor Receptor Proteins 0.000 description 1
- 102100037921 UDP-N-acetylglucosamine pyrophosphorylase Human genes 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 206010047642 Vitiligo Diseases 0.000 description 1
- 241000607734 Yersinia <bacteria> Species 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 201000010272 acanthosis nigricans Diseases 0.000 description 1
- 229940022698 acetylcholinesterase Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
- 208000018254 acute transverse myelitis Diseases 0.000 description 1
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- 208000004631 alopecia areata Diseases 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229960003556 aminophylline Drugs 0.000 description 1
- FQPFAHBPWDRTLU-UHFFFAOYSA-N aminophylline Chemical compound NCCN.O=C1N(C)C(=O)N(C)C2=C1NC=N2.O=C1N(C)C(=O)N(C)C2=C1NC=N2 FQPFAHBPWDRTLU-UHFFFAOYSA-N 0.000 description 1
- 229960003896 aminopterin Drugs 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000009830 antibody antigen interaction Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229940009100 aurothiomalate Drugs 0.000 description 1
- XJHSMFDIQHVMCY-UHFFFAOYSA-M aurothiomalic acid Chemical compound OC(=O)CC(S[Au])C(O)=O XJHSMFDIQHVMCY-UHFFFAOYSA-M 0.000 description 1
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 description 1
- 230000006472 autoimmune response Effects 0.000 description 1
- 208000010928 autoimmune thyroid disease Diseases 0.000 description 1
- 201000004982 autoimmune uveitis Diseases 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 229940003504 avonex Drugs 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 229960004168 balsalazide Drugs 0.000 description 1
- IPOKCKJONYRRHP-FMQUCBEESA-N balsalazide Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1\N=N\C1=CC=C(O)C(C(O)=O)=C1 IPOKCKJONYRRHP-FMQUCBEESA-N 0.000 description 1
- WGNZRLMOMHJUSP-UHFFFAOYSA-N benzotriazol-1-yloxy(tripyrrolidin-1-yl)phosphanium Chemical compound C1CCCN1[P+](N1CCCC1)(N1CCCC1)ON1C2=CC=CC=C2N=N1 WGNZRLMOMHJUSP-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 108010005774 beta-Galactosidase Proteins 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- 229940021459 betaseron Drugs 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 238000000225 bioluminescence resonance energy transfer Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 201000003848 bronchiolitis obliterans Diseases 0.000 description 1
- 208000023367 bronchiolitis obliterans with obstructive pulmonary disease Diseases 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000007910 cell fusion Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 229960003115 certolizumab pegol Drugs 0.000 description 1
- 238000010382 chemical cross-linking Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 201000009323 chronic eosinophilic pneumonia Diseases 0.000 description 1
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 230000003475 colitic effect Effects 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 229940109248 cromoglycate Drugs 0.000 description 1
- IMZMKUWMOSJXDT-UHFFFAOYSA-N cromoglycic acid Chemical compound O1C(C(O)=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C(O)=O)O2 IMZMKUWMOSJXDT-UHFFFAOYSA-N 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 208000004921 cutaneous lupus erythematosus Diseases 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000000779 depleting effect Effects 0.000 description 1
- 201000001981 dermatomyositis Diseases 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 208000009190 disseminated intravascular coagulation Diseases 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 239000003602 elastase inhibitor Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- 238000001400 expression cloning Methods 0.000 description 1
- 229960004979 fampridine Drugs 0.000 description 1
- 210000003754 fetus Anatomy 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000001476 gene delivery Methods 0.000 description 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- 208000024908 graft versus host disease Diseases 0.000 description 1
- 208000007475 hemolytic anemia Diseases 0.000 description 1
- 229960002885 histidine Drugs 0.000 description 1
- 229940040731 human interleukin-12 Drugs 0.000 description 1
- 230000008348 humoral response Effects 0.000 description 1
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 description 1
- 229960004171 hydroxychloroquine Drugs 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000003960 inflammatory cascade Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229960001388 interferon-beta Drugs 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 229940074383 interleukin-11 Drugs 0.000 description 1
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- OEXHQOGQTVQTAT-JRNQLAHRSA-N ipratropium Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)[N@@+]2(C)C(C)C)C(=O)C(CO)C1=CC=CC=C1 OEXHQOGQTVQTAT-JRNQLAHRSA-N 0.000 description 1
- 229960001888 ipratropium Drugs 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000000366 juvenile effect Effects 0.000 description 1
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 description 1
- 229960004958 ketotifen Drugs 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000001638 lipofection Methods 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 230000000527 lymphocytic effect Effects 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 229960004452 methionine Drugs 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 238000000302 molecular modelling Methods 0.000 description 1
- 230000000921 morphogenic effect Effects 0.000 description 1
- 208000001725 mucocutaneous lymph node syndrome Diseases 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- ZTLGJPIZUOVDMT-UHFFFAOYSA-N n,n-dichlorotriazin-4-amine Chemical compound ClN(Cl)C1=CC=NN=N1 ZTLGJPIZUOVDMT-UHFFFAOYSA-N 0.000 description 1
- 210000004897 n-terminal region Anatomy 0.000 description 1
- RQTOOFIXOKYGAN-UHFFFAOYSA-N nedocromil Chemical compound CCN1C(C(O)=O)=CC(=O)C2=C1C(CCC)=C1OC(C(O)=O)=CC(=O)C1=C2 RQTOOFIXOKYGAN-UHFFFAOYSA-N 0.000 description 1
- 229960004398 nedocromil Drugs 0.000 description 1
- 101150091879 neo gene Proteins 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 201000004535 ovarian dysfunction Diseases 0.000 description 1
- 231100000539 ovarian failure Toxicity 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- NVOYVOBDTVTBDX-PMEUIYRNSA-N oxitropium Chemical compound CC[N+]1(C)[C@H]2C[C@@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)[C@H](CO)C1=CC=CC=C1 NVOYVOBDTVTBDX-PMEUIYRNSA-N 0.000 description 1
- 229960000797 oxitropium Drugs 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000004091 panning Methods 0.000 description 1
- 229940055729 papain Drugs 0.000 description 1
- 235000019834 papain Nutrition 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 102000007863 pattern recognition receptors Human genes 0.000 description 1
- 108010089193 pattern recognition receptors Proteins 0.000 description 1
- 201000001976 pemphigus vulgaris Diseases 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 125000001151 peptidyl group Chemical group 0.000 description 1
- 210000005105 peripheral blood lymphocyte Anatomy 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 238000012123 point-of-care testing Methods 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 230000008488 polyadenylation Effects 0.000 description 1
- 201000006292 polyarteritis nodosa Diseases 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 229920002704 polyhistidine Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 238000003752 polymerase chain reaction Methods 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 231100000683 possible toxicity Toxicity 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 229940071643 prefilled syringe Drugs 0.000 description 1
- 206010036601 premature menopause Diseases 0.000 description 1
- 208000017942 premature ovarian failure 1 Diseases 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 201000000742 primary sclerosing cholangitis Diseases 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- 230000009465 prokaryotic expression Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000001742 protein purification Methods 0.000 description 1
- 201000007801 psoriasis 2 Diseases 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 239000003379 purinergic P1 receptor agonist Substances 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000002708 random mutagenesis Methods 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000012340 reverse transcriptase PCR Methods 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229960002052 salbutamol Drugs 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 208000010157 sclerosing cholangitis Diseases 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 229940074404 sodium succinate Drugs 0.000 description 1
- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- VIDRYROWYFWGSY-UHFFFAOYSA-N sotalol hydrochloride Chemical compound Cl.CC(C)NCC(O)C1=CC=C(NS(C)(=O)=O)C=C1 VIDRYROWYFWGSY-UHFFFAOYSA-N 0.000 description 1
- 210000004989 spleen cell Anatomy 0.000 description 1
- 201000005671 spondyloarthropathy Diseases 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 210000001179 synovial fluid Anatomy 0.000 description 1
- 201000004595 synovitis Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940065721 systemic for obstructive airway disease xanthines Drugs 0.000 description 1
- 206010043207 temporal arteritis Diseases 0.000 description 1
- 229960000195 terbutaline Drugs 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 206010043778 thyroiditis Diseases 0.000 description 1
- XFYDIVBRZNQMJC-UHFFFAOYSA-N tizanidine Chemical compound ClC=1C=CC2=NSN=C2C=1NC1=NCCN1 XFYDIVBRZNQMJC-UHFFFAOYSA-N 0.000 description 1
- 229960000488 tizanidine Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 208000009174 transverse myelitis Diseases 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229940046728 tumor necrosis factor alpha inhibitor Drugs 0.000 description 1
- 239000002451 tumor necrosis factor inhibitor Substances 0.000 description 1
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 1
- 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- ORHBXUUXSCNDEV-UHFFFAOYSA-N umbelliferone Chemical compound C1=CC(=O)OC2=CC(O)=CC=C21 ORHBXUUXSCNDEV-UHFFFAOYSA-N 0.000 description 1
- HFTAFOQKODTIJY-UHFFFAOYSA-N umbelliferone Natural products Cc1cc2C=CC(=O)Oc2cc1OCC=CC(C)(C)O HFTAFOQKODTIJY-UHFFFAOYSA-N 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 230000003156 vasculitic effect Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
- C07K16/244—Interleukins [IL]
- C07K16/245—IL-1
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6845—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a cytokine, e.g. growth factors, VEGF, TNF, a lymphokine or an interferon
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/54—Interleukins [IL]
- C07K14/545—IL-1
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/46—Hybrid immunoglobulins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/46—Hybrid immunoglobulins
- C07K16/468—Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6863—Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
- G01N33/6869—Interleukin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/10—Immunoglobulins specific features characterized by their source of isolation or production
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
Definitions
- the mammalian immune system includes B lymphocytes that, in totality, express an antibody repertoire composed of hundreds of billions of different antibody specificities.
- a normal immune response to a particular antigen involves the selection from this repertoire of one or more antibodies that specifically bind the antigen, and the success of an immune response is based, at least in part, on the ability of these antibodies to specifically recognize (and ultimately eliminate) the stimulating antigen and "ignore" other molecules in the environment of the antibodies.
- Standard hybridoma technology now allows for the preparation of antibodies having a single specificity for an antigen of interest. More recently, recombinant antibody techniques, such as screening of in vitro antibody libraries, have been developed. These techniques also allow for production of antibodies with a single specificity for an antigen of interest.
- Antibodies having specificity for a single target antigen may, at least under certain circumstances, display undesired cross-reactivity or background binding to other antigens. This cross-reactivity or background binding, however, is usually unpredictable (i.e., it is not possible to predict which antigen the antibody will cross-react with).
- an anti-mouse X antibody may readily bind antigen X from human. This is because they share significant sequence and structural similarities though they are not identical. However, such species-cross-reactive antibodies do not constitute "dual specificity" antibodies, since they have specificity for the same antigen from different species.
- This invention provides methods for making antibodies having dual specificity for at least two structurally-related, yet different, antigens.
- the method generally involves providing an antigen that comprises a common structural feature of the two different but structurally related molecules; exposing an antibody repertoire to the antigen; and selecting from the repertoire an antibody that specifically binds the two different but structurally related molecules to thereby obtain the dual specificity antibody.
- a dual specificity antibody of the invention which binds members of the same family of proteins, to block the functions of more than one member of the protein family can be beneficial for alleviating disease symptoms or for interrupting the disease process itself.
- dual specificity antibodies of the invention are useful to detect structurally related antigens, to purify structurally related antigens and in diagnostic assays involving structurally related antigens.
- the antigen is designed based on a contiguous topological area of identity between the two different but structurally related molecules.
- the two different but structurally related molecules can be proteins and the antigen can be a peptide comprising an amino acid sequence of a contiguous topological area of identity between the two proteins.
- the antigen is designed based on structurally mimicking a loop of a common fold of the two different but structurally related molecules.
- the antigen can be a cyclic peptide that structurally mimics a loop of a common fold of two different but structurally related proteins.
- the antigen is designed based on splicing together alternating and/or overlapping portions of the two different but structurally related molecules to create a hybrid molecule.
- the antigen can be a hybrid peptide made by splicing together alternating and/or overlapping amino acid sequences of two different but structurally related proteins.
- the antigen can comprise one of the two different but structurally related molecules and the method involves selecting antibodies that specifically recognize both related molecules.
- the antibody repertoire can be exposed to the antigen of interest either in vivo or in vitro.
- exposure of the repertoire to the antigen involves immunizing an animal in vivo with the antigen.
- This in vivo approach can further involve preparing a panel of hybridomas from lymphocytes of the animal and selecting a hybridoma that secretes an antibody that specifically binds the two different but structurally related molecules.
- the animal that is immunized can be, for example, a mouse, a rat, a rabbit, or a goat, or a transgenic version of any of the foregoing animals, such as a mouse that is transgenic for human immunoglobulin genes such that the mouse makes human antibodies upon antigenic stimulation.
- mice with severe combined immunodeficiency that have been reconstituted with human peripheral blood mononuclear cells (hu-PBMC-SCID chimeric mice) or lymphoid cells or precursors thereof and mice that have been treated with lethal total body irradiation, followed by radioprotection with bone marrow cells of a severe combined immunodeficiency (SCID) mouse, followed by engraftment with functional human lymphocytes (the Trimera system).
- SCID severe combined immunodeficiency
- Still another type of animal that can be immunized is an animal (e.g., mouse) whose genome has been "knocked out” (e.g., by homologous recombination) for an endogenous gene(s) encoding the antigen(s) of interest, wherein upon immunization with the antigen(s) of interest the KO animal recognizes the antigen(s) as foreign.
- an animal e.g., mouse
- whose genome has been "knocked out” (e.g., by homologous recombination) for an endogenous gene(s) encoding the antigen(s) of interest, wherein upon immunization with the antigen(s) of interest the KO animal recognizes the antigen(s) as foreign.
- the antibody repertoire is exposed to the antigen in vitro by screening a recombinant antibody library with the antigen.
- the recombinant antibody library can be, for example, expressed on the surface of bacteriophage or on the surface of yeast cells or on the surface of bacterial cells.
- the recombinant antibody library is, for example, a scFv library or a Fab library.
- antibody libraries are expressed as RNA-protein fusions.
- Another approach to preparing the dual specificity antibodies involves a combination of in vivo and in vitro approaches, such as exposing the antibody repertoire to the antigen by in vivo immunization of an animal with the antigen, followed by in vitro screening of a recombinant antibody library prepared from lymphoid cells of the animal with the antigen. Still another approach involves exposing the antibody repertoire to the antigen by in vivo immunization of an animal with the antigen, followed by in vitro affinity maturation of a recombinant antibody library prepared from lymphoid cells of the animal.
- Yet another approach involves exposing the antibody repertoire to the antigen by in vivo immunization of an animal with the antigen, followed by selection of single antibody producing cells secreting an antibody of interest, recovery of heavy- and light chain variable region cDNAs from these selected cells (e.g., by PCR) and expression of the heavy- and light chain variable regions in mammalian host cells in vitro (referred to as the selected lymphocyte antibody method, or SLAM), thereby allowing for further selection and manipulation of the selection antibody gene sequences.
- monoconal antibodies can be selected by expression cloning by expressing heavy and light chain antibody genes in mammalian cells and selecting for mammalian cells secreting an antibody having the requisite binding specificity.
- Dual specificity antibodies prepared according to the methods of the invention are also provided.
- a preferred dual specificity antibody of the invention is one that specifically binds interleukin-1 and interleukin-1 ⁇ .
- Such a dual specificity antibody can be used in methods of detecting IL-l or E -l ⁇ comprising contacting IL-l ⁇ or IL-l ⁇ with the dual-specificity antibody, or antigen-binding portion thereof, such that IL-l ⁇ or IL-l ⁇ is detected.
- a neutralizing dual specificity antibody also can be used in methods of inhibiting IL-l ⁇ or IL-l ⁇ activity comprising contacting IL-l ⁇ or IL-l ⁇ with the dual- specificity antibody, or antigen-binding portion thereof, such that the activity of IL-l ⁇ or IL-l ⁇ is inhibited.
- Such dual specificity antibodies also can be used in methods of treating an interleukin-1 -related disorder comprising administering to a subject suffering from an interleukin-1 -related disorder the dual-specificity antibody, or antigen-binding portion thereof.
- the invention provides a method of making an antibody or an antigen binding portion thereof library by performing the following steps: a) obtaining a recombinant heavy chain or an antigen binding portion thereof library A from an antibody repertoire resulting from exposure to a first antigen; b) obtaining a recombinant light chain or an antigen binding portion thereof library B from an antibody repertoire resulting from exposure to the first antigen; c) obtaining a recombinant heavy chain or an antigen binding portion thereof library C from an antibody repertoire resulting from exposure to a second antigen; d) obtaining a recombinant light chain or an antigen binding portion thereof library D from an antibody repertoire resulting from exposure to the second antigen; and e) combining the recombinant heavy chain or an antigen binding portion thereof library A with the recombinant light chain or an antigen binding portion thereof library D to obtain an antibody or an antigen binding portion thereof library X and/or combining the recombinant heavy chain or an antigen binding portion thereof library C
- the immediately foregoing method of the invention can further comprise the step of combining the antibody or an antigen binding portion thereof library X with the antibody or an antigen binding portion thereof library Y to obtain an antibody or an antigen binding portion thereof library Z.
- the present invention is directed to the antibody or an antigen binding portion thereof libraries X , Y and Z.
- the method of the present invention allows for the identification of dual specific antibody or an antigen binding portion thereof by selecting from the libraries X , Y and/or Z an antibody or an antigen binding portion thereof that binds both the first and the second antigen.
- the present invention is directed to the dual specific antibody made and/or selected by any of the methods of the present invention.
- the present invention is also directed to the nucleotide sequence encoding each member of the antibody or an antigen binding portion thereof of libraries X, Y, and Z; and the dual specific antibody or an antigen binding portion thereof, a vector comprising the afore mentioned nucleotide sequences and host cell transfected with the afore mentioned vector.
- the first and second antigen is each independently selected from the group consisting of proteins, polypeptides and peptides provided that the first and second antigens are not the same.
- the proteins, polypeptides and peptides are secreted proteins or surface receptors and the secreted protein is selected from the group consisting of an IFN, a TNF, an Interleukin, IP- 10, PF4, a GRO, 9E3, EMAP- ⁇ , a CSF, an FGF, and a PDGF.
- the first antigen is IL-l ⁇ and the second antigen is IL-l ⁇ .
- This invention pertains to the design and use of antigens for generating dual specificity antibodies, ie., antibodies having specificity for at least two different but structurally related molecules, as well as the selection, preparation and use of such dual specificity antibodies.
- the structural relatedness of the antigens of the invention can be over the entire antigen (e.g., protein) or only in certain structurally-related regions.
- the invention provides a method for obtaining a dual-specificity antibody that specifically binds two different but structurally related molecules, wherein the method involves: providing an antigen that comprises a common structural feature of the two different but structurally related molecules; exposing an antibody repertoire to the antigen; and selecting from the repertoire an antibody that specifically binds the two different but structurally related molecules to thereby obtain the dual specificity antibody.
- dual specificity antibody is intended to include antibodies that specifically recognize even more than two different but related antigens, such as antibodies that recognize three, four, five or more structurally related but distinct antigens.
- different but structurally related antigens is intended to include antigens (e.g., proteins) whose overall structures are related as well as antigens (e.g., proteins) which share one or more structurally-related regions but that are otherwise unrelated.
- antigens e.g., proteins
- antigens e.g., proteins
- antigens e.g., proteins
- “different but structurally related” antigens could be, for example, two proteins that are members of the same protein family having a common overall structure or could be, for example, two proteins whose overall structure is disimilar (unrelated) but that each contain a structurally-related domain.
- a dual specificity antigen of the invention comprises a contiguous topological area of identity and/or similarity between the two different but structurally related molecules to which a dual specificity antibody is to be raised.
- the antigen comprises the largest (e.g., longest) contiguous topological area of identity and/or similarity between the two different but structurally related molecules.
- the two different but structurally related molecules are proteins and the dual specificity antigen comprises a linear peptide corresponding to the largest (e.g. , longest) contiguous topological area of identity and/or similarity between the two proteins.
- the appropriate region of identity/similarity that is chosen is preferably a receptor or ligand binding region, although other regions of identity/similarity can also be used.
- the two molecules are compared (e.g., homology modeling, structural information or aligned) and identical or similar regions are identified.
- an alignment algorithm can be used to create optimal alignment and identify the largest (e.g., longest) contiguous topological area of identity and/or similarity between the two proteins.
- a preferred, non-limiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin and Altschul (1990) Proc. Natl. Acad. Sci. USA 87:2264-68, modified as in Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90:5873-77.
- the dual specificity antigen corresponding to the region can be chemically synthesized.
- the peptide can be synthesized by standard peptide synthesis methods.
- the peptide antigen comprises L amino acids.
- the peptide antigen may be partially or entirely composed of D amino acids.
- a dual specificity antigen of the invention comprises a cyclic molecule, preferably a cyclic peptide, that structurally mimics a key loop of a common fold of the two different but structurally related molecules (e.g., proteins) to which dual specificity antibodies are to be raised.
- the structures of the two related molecules are compared and a loop of a common fold found in the two molecules is identified.
- Standard molecular modeling and crystollographic analysis can be used to aid in the identification of such loops and common folds.
- Identical and similar regions e.g., amino acid sequences between two proteins
- a consensus sequence can be designed for similar but not identical regions.
- a linear molecule e.g, a linear peptide
- this linear molecule can then be cyclized, by known chemical means, to create an antigen that mimics the key loop.
- a proline and a glycine can be added to the end of a linear peptide to allow for cyclization of the peptide.
- An example of the design of a dual specificity antigen based on a cyclic peptide mimicking a structural loop shared by two different but structurally related proteins is described in detail in Example 2.
- a dual specificity antigen of the invention comprises a hybrid molecule, preferably a hybrid peptide, that includes alternating and/or overlapping regions of the two different but structurally related molecules (e.g., proteins) to which dual specificity antibodies are to be raised.
- a hybrid molecule e.g., a hybrid peptide, when the two related molecules are proteins
- a hybrid molecule is prepared that preferably comprises alternating regions (e.g, amino acid sequences) from each of the two molecules, as well as an overlapping region that is common to both molecules.
- such a hybrid molecule can be described as: X-Y-Z, wherein Y represents a region of identity or strong similarity between the two related molecules (i.e, an overlapping region), X represents a region from one of the related molecules and Z represents a region from the other of the related molecules.
- Y represents a region of identity or strong similarity between the two related molecules (i.e, an overlapping region)
- X represents a region from one of the related molecules
- Z represents a region from the other of the related molecules.
- hybrid molecule is one in which a peptide has been introduced into a full-length protein (referred to as a "target" protein).
- Peptides are selected that represent functional regions of two different but structurally related proteins, for example, receptor interacting regions. Such peptides are referred to herein as functional peptides.
- a functional peptide from one of the related proteins is then introduced into the full-length protein of the other related protein or, alternatively, an unrelated protein.
- a peptide of IL-l ⁇ corresponding to a receptor interacting region of IL-l ⁇ is identified and this functional peptide of EL- l ⁇ is introduced into the full-length IL-l ⁇ protein to create a hybrid IL-l ⁇ /TL-l ⁇ molecule.
- a peptide of EL-l ⁇ corresponding to a receptor interacting region of DL-l ⁇ is identified and this functional peptide of IL-l ⁇ is introduced into the full-length IL-l ⁇ protein to create a hybrid IL- l ⁇ /TL-l ⁇ molecule.
- This introduction of the functional peptide into the related full- length protein constrains the functional peptide at both ends and maintains the fold- structure of the functional peptide.
- the functional peptide preferably is inserted
- a target area representing the common fold structures of IL-l ⁇ and IL-l ⁇ may be found over the entire length of the protein (e.g., in the N-terminal region, in the middle of the protein, in the C-terminal region).
- functional peptides representing the common IL-l /IL-l ⁇ fold structures can also be inserted into an irrelevant protein, such as albumin or some other naturally occurring protein.
- the preferred insertion site for the peptide is a region that allows the peptide to maintain the desired fold structure. Therefore, the insertion sites can be either at the N-terminus, the middle, or the C-terminus of the protein.
- any naturally occurring target protein is selected to mimic the structural constraints placed upon it by the native protein from which it is derived. While the functional peptide may simply be inserted into the target protein such that the amino acids of the functional peptide are added to the target protein, preferably the amino acids of the functional peptide replace a portion of the target protein into which it is inserted.
- a hybrid molecule is constructed for use as a dual specificity antigen for raising dual specificity antibodies to EL-l ⁇ and IL-l ⁇ wherein a functional peptide corresponding to a specific structural element of either IL-l ⁇ or IL- l ⁇ is introduced into the full length IL-l ⁇ or IL-l ⁇ in the equivalent structural position.
- the chosen hybrid molecule replaces residues 160-176 of BL-l ⁇ with residues 168-184 of IL-l ⁇
- the resulting molecule possesses the following amino acid sequence, in which the substituted IL-l ⁇ sequences (residues 168-184) are underlined: APVRSLNCTLRDSOOKSLVMSGPYELKALHLQGQDMEOOVVFSMGAYKSSKD
- This molecule can be prepared using standard molecular biology techniques (e.g., cloning, polymerase chain reaction) using the publicly available IL-l ⁇ and IL-l ⁇ cDNA sequences and recombinant protein expression techniques.
- a hybrid cDNA can be prepared, introduced into an appropriate expression vector and the polypeptide can be expressed by introducing the expression vector into an appropriate host cell.
- a dual specificity antigen of the invention is selected based on hydrophobicity plots to select peptides predicted to be highly antigenic.
- antigenic indexes of peptides can be calculated using computer software as described by Jameson and Wolf (CABIOS, 4(1), 181-186 (1988)) Regions of interest for antibody binding can be chosen to maximize the probability of antigenicity.
- a dual specificity antibody of the invention is prepared by immunization with antigen-transfected cells (i.e., dual specificity antigens of the invention can be antigen-transfected cells).
- Cell lines can be generated that stably express the two different but structurally related antigens, or a hybrid molecule thereof.
- cell lines can be generated that stably express IL-l ⁇ or BL-l ⁇ or an EL- l ⁇ TL-l ⁇ hybrid molecule (e.g., SEQ ID NO: 4).
- the molecules of interest can be secreted from the cells (in case of soluble proteins) or can be expressed on the cell surface (in case of receptors, enzymes).
- Gene delivery into the host cells to allow for expression of the antigens by the host cells can be accomplished by a number of conventional means, including but not limited to transfection, electroporation, cell fusion, lipofection, particle bombardment, microinjection, or viral infection.
- the cell lines expressing the antigens of interest can then be transplanted via one or more various routes (intraperitoneal, subcutaneous, intramuscular, and the like) into an animal of interest for antibody production.
- the cells then serve as a slow release source of the antigen of interest.
- the cells express the full length proteins.
- antigenic fragments can also be expressed.
- the proteins preferably are secreted by the cells.
- the receptors preferably are expressed on the cell surface.
- the dual specificity antigen is simply one of the two different but structurally related molecules to which dual specificity antibodies are to be raised.
- One of the two related molecules is used as the immunization agent and then the resultant antibody repertoire is screened for antibodies that bind, and more preferably neutralize, both of the two different but structurally related molecules.
- immunize is intended to broadly encompass the exposure of an antibody repertoire to the antigen, such as IL-l ⁇ or IL-l ⁇ , either in vivo or in vitro.
- this embodiment encompasses immunizing an animal with either IL-l ⁇ or EL-l ⁇ , and screening the resultant antibodies raised to select for those antibodies that bind both DL-l ⁇ and IL-l ⁇ , as well as screening a recombinant antibody library in vitro with either IL-l ⁇ or IL-l ⁇ and then selecting for recombinant antibodies that bind both IL-l ⁇ and IL-l ⁇ .
- U. Methods of Making Dual Specificity Antibodies To prepare a dual specificity antibody of the invention, an antibody repertoire
- Low affinity dual specificity antibodies can be generated by any of the in vitro and in vivo methods described herein and higher affinity dual specificity Mabs can be prepared by somatic mutagenesis methods described herein. Moreover, to optimize high affinity dual specificity MAbs, co-crystal structures of the low affinity MAbs with the desired antigens can be made. The structural information obtained can guide further affinity enhancements by altering (mutating) specific contact residues of the MAbs to enhance specific molecular interactions, as described herein. Methods for making dual specificity antibodies using in vivo approaches, in vitro approaches, or a combination of both, are described in further detail in the following subsections.
- a standard in vivo approach to preparing antibodies is by immunizing an appropriate animal subject with an antigen to thereby expose the in vivo antibody repertoire to the antigen, followed by recovery of an antibody or antibodies of interest from the animal.
- Such an approach can be adapted to the preparation of dual specificity antibodies by use of a dual specificity antigen and selection for antibodies that specifically recognize the two structurally related molecules of interest.
- Dual specificity antibodies can be prepared by immunizing a suitable subject, (e.g., rabbit, goat, mouse or other mammal, including transgenic and knockout versions of such mammals) with an immunogenic preparation of a dual specificity antigen.
- An appropriate immunogenic preparation can contain, for example, a chemically synthesized or recombinantly expressed dual specificity antigen.
- the preparation can further include an adjuvant, such as Freund's complete or incomplete adjuvant, or similar immunostimulatory compound.
- an adjuvant such as Freund's complete or incomplete adjuvant, or similar immunostimulatory compound.
- a dual specificity antigen of the invention when used to raise antibodies, in particular by in vivo immunization, can be used alone, or more preferably is used as a conjugate with a carrier protein. Such an approach for enhancing antibody responses is well known in the art.
- suitable carrier proteins to which a dual specificity antigen can be conjugated include keyhole limpet haemocyanin (KLH) and albumin.
- Antibody-producing cells can be obtained from the subject and used to prepare monoclonal antibodies by standard techniques, such as the hybridoma technique originally described by Kohler and Milstein (1975, Nature 256:495-497) (see also, Brown et al. (1981) J. Immunol 127:539-46; Brown et al. (1980) J Biol Chem 255:4980-83; Yeh et al. (1976) PNAS 76:2927-31; and Yeh et al. (1982) Int. J. Cancer 29:269-75).
- the technology for producing monoclonal antibody hybridomas is well known (see generally R. H.
- an immortal cell line (typically a myeloma) is fused to lymphocytes (typically splenocytes or lymph node cells or peripheral blood lymphocytes) from a mammal immunized with a dual specificity immunogen as described above, and the culture supernatants of the resulting hybridoma cells are screened to identify a hybridoma producing a monoclonal antibody with dual specificity for the two different but structurally related molecules of interest.
- lymphocytes typically splenocytes or lymph node cells or peripheral blood lymphocytes
- the immortal cell line e.g., a myeloma cell line
- murine hybridomas can be made by fusing lymphocytes from a mouse immunized with an immunogenic preparation of the present invention with an immortalized mouse cell line.
- Preferred immortal cell lines are mouse myeloma cell lines that are sensitive to culture medium containing hypoxanthine, aminopterin and thymidine ("HAT medium"). Any of a number of myeloma cell lines may be used as a fusion partner according to standard techniques, e.g., the P3-NSl/l-Ag4-l, P3-x63- Ag8.653 or Sp2/O-Agl4 myeloma lines. These myeloma lines are available from the American Type Culture Collection (ATCC), Rockville, Md. Typically, HAT-sensitive mouse myeloma cells are fused to mouse splenocytes using polyethylene glycol ("PEG").
- PEG polyethylene glycol
- Hybridoma cells resulting from the fusion are then selected using HAT medium, which kills unfused and unproductively fused myeloma cells (unfused splenocytes die after several days because they are not transformed).
- Hybridoma cells producing monoclonal antibodies that specifically recognize the two structurally related molecules of interest are identified by screening the hybridoma culture supernatants for such antibodies, e.g., using a standard ELISA assay, to select those antibodies that specifically can bind the two related molecules.
- various animal hosts may be used for in vivo immunization.
- a host that itself expresses an endogenous version of the antigen(s) of interest can be used or, alternatively, a host can be used that has been rendered deficient in an endogenous version of the antigen(s) of interest.
- mice rendered deficient for a particular endogenous protein via homologous recombination at the corresponding endogenous gene i.e., "knockout” mice
- a humoral response to the protein when immunized with it and thus can be used for the production of high affinity monoclonal antibodies to the protein
- non-human antibodies e.g., against a human dual specificity antigen
- various non-human mammals are suitable as hosts for antibody production, including but not limited to mice, rats, rabbits and goats (and knockout versions thereof), although mice are preferred for hybridoma production.
- a host non-human animal can be used that expresses a human antibody repertoire.
- Such non-human animals include transgenic animals (e.g., mice) carrying human immunoglobulin transgenes, hu-PBMC-SCID chimeric mice, and human/mouse radiation chimeras, each of which is discussed further below.
- the animal that is immunized with a dual specificity antigen is a non-human mammal, preferably a mouse, that is transgenic for human immunoglobulin genes such that the non-human mammal (e.g., mouse) makes human antibodies upon antigenic stimulation.
- a non-human mammal e.g., mouse
- human germline configuration heavy and light chain immunoglobulin transgenes are introduced into animals that have been engineered so that their endogenous heavy and light chain loci are inactive.
- antibodies derived from the human immunoglobulin sequences i.e., human antibodies
- human monoclonal antibodies can be made from lymphocytes of such animals by standard hybridoma technology.
- the animal that is immunized with a dual specificity antigen is a mouse with severe combined immunodeficiency (SCID) that has been reconstituted with human peripheral blood mononuclear cells or lymphoid cells or precursors thereof.
- SCID severe combined immunodeficiency
- Such mice referred to as hu-PBMC-SCDD chimeric mice, have been demonstrated to produce human immunoglobulin responses upon antigenic stimulation.
- hu-PBMC-SCDD chimeric mice have been demonstrated to produce human immunoglobulin responses upon antigenic stimulation.
- the animal that is immunized with a dual specificity antigen is a mouse that has been treated with lethal total body irradiation, followed by radioprotection with bone marrow cells of a severe combined immunodeficiency (SCID) mouse, followed by engraftment with functional human lymphocytes.
- SCID severe combined immunodeficiency
- This type of chimera referred to as the Trimera system, has been used to produce human monoclonal antibodies by immunization of the mice with an antigen of interest followed by preparation of monoclonal antibodies using standard hybridoma technology.
- Trimera system For further description of these mice and their use in antibody generation, see for example Eren, R. et al (1998) Immunology 93:154-161; Reisner, Y and Dagan, S.
- a dual specificity antibody of the invention can be identified and isolated by screening a recombinant combinatorial immunoglobulin library (e.g., an antibody phage display library) with a dual specificity antigen, to thereby isolate immunoglobulin library members that bind specifically to the two structurally related, but different, molecules of interest.
- Kits for generating and screening phage display libraries are commercially available (e.g., the Pharmacia Recombinant Phage Antibody System, Catalog No. 27- 9400-01; and the Stratagene Sur ⁇ APTM Phage Display Kit, Catalog No. 240612).
- the phage display library is a scFv library or a Fab library.
- the phage display technique for screening recombinant antibody libraries has been described extensively in the art. Examples of methods and compounds particularly amenable for use in generating and screening antibody display library can be found in, for example, McCafferty et al. International Publication No. WO 92/01047, U.S. Patent No. 5,969,108 and EP 589,877 (describing in particular display of scFv), Ladner et al. U.S. Patent No. 5,223,409, No. 5,403,484, No. 5,571,698, No.
- WO 92/09690 (describing in particular phage expression techniques); Knappik et al. International Publication No. WO 97/08320 (describing the human recombinant antibody library HuCal); Salfeld et al. International Publication No. WO 97/29131, describing the preparation of a recombinant human antibody to a human antigen (human tumor necrosis factor alpha), as well as in vitro affinity maturation of the recombinant antibody) and Salfeld et al.
- recombinant antibody libraries can be expressed on the surface of yeast cells or bacterial cells. Methods for preparing and screening libraries expressed on the surface of yeast cells are described further in PCT Publication WO 99/36569. Methods for preparing and screening libraries expressed on the surface of bacterial cells are described further in PCT Publication WO 98/49286.
- DNAs encoding the light and heavy chains of the antibody are isolated by standard molecular biology techniques, such as by PCR amplification of DNA from the display package (e.g., phage) isolated during the library screening process.
- Nucleotide sequences of antibody light and heavy chain genes from which PCR primers can be prepared are known in the art. For example, many such sequences are disclosed in Kabat, E.A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NTH Publication No. 91-3242 and in the "Vbase" human germline sequence database.
- An antibody, or antibody portion, of the invention can be prepared by recombinant expression of immunoglobulin light and heavy chain genes in a host cell.
- a host cell is transfected with one or more recombinant expression vectors carrying DNA fragments encoding the immunoglobulin light and heavy chains of the antibody such that the light and heavy chains are expressed in the host cell and, preferably, secreted into the medium in which the host cells are cultured, from which medium the antibodies can be recovered.
- Standard recombinant DNA methodologies are used obtain antibody heavy and light chain genes, incorporate these genes into recombinant expression vectors and introduce the vectors into host cells, such as those described in Sambrook, Fritsch and Maniatis (eds), Molecular Cloning; A Laboratory Manual, Second Edition, Cold Spring Harbor, N.Y., (1989), Ausubel, F.M. et al (eds.) Current Protocols in Molecular Biology, Greene Publishing Associates, (1989) and in U.S. Patent No. 4,816,397 by Boss et al.
- DNA fragments encoding the VH and VL segments of the antibody of interest can be further manipulated by standard recombinant DNA techniques, for example to convert the variable region genes to full- length antibody chain genes, to Fab fragment genes or to a scFv gene.
- a VL- or VH-encoding DNA fragment is operatively linked to another DNA fragment encoding another protein, such as an antibody constant region or a flexible linker.
- the term "operatively linked”, as used in this context, is intended to mean that the two DNA fragments are joined such that the amino acid sequences encoded by the two DNA fragments remain in-frame.
- the isolated DNA encoding the VH region can be converted to a full-length heavy chain gene by operatively linking the VH-encoding DNA to another DNA molecule encoding heavy chain constant regions (CHI, CH2 and CH3).
- CHI, CH2 and CH3 DNA molecule encoding heavy chain constant regions
- the sequences of human heavy chain constant region genes are known in the art (see e.g., Kabat, E.A., et al (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NTH Publication No. 91-3242) and DNA fragments encompassing these regions can be obtained by standard PCR amplification.
- the heavy chain constant region can be an IgGl, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD constant region, but most preferably is an IgGl or IgG4 constant region.
- the VH-encoding DNA can be operatively linked to another DNA molecule encoding only the heavy chain CHI constant region.
- the isolated DNA encoding the VL region can be converted to a full-length light chain gene (as well as a Fab light chain gene) by operatively linking the VL-encoding DNA to another DNA molecule encoding the light chain constant region, CL.
- the sequences of human light chain constant region genes are known in the art (see e.g., Kabat, E.A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NTH Publication No. 91-3242) and DNA fragments encompassing these regions can be obtained by standard PCR amplification.
- the light chain constant region can be a kappa or lambda constant region, but most preferably is a kappa constant region.
- the VH- and VL-encoding DNA fragments are operatively linked to another fragment encoding a flexible linker, e.g., encoding the amino acid sequence (Gly4 ⁇ Ser)3, such that the VH and VL sequences can be expressed as a contiguous single-chain protein, with the VL and VH regions joined by the flexible linker (see e.g., Bird et al. (1988) Science 242:423-426; Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883; McCafferty et al, Nature (1990) 348:552-554).
- a flexible linker e.g., encoding the amino acid sequence (Gly4 ⁇ Ser)3
- DNAs encoding partial or full-length light and heavy chains, obtained as described above, can be inserted into expression vectors such that the genes are operatively linked to transcriptional and translational control sequences.
- operatively linked is intended to mean that an antibody gene is ligated into a vector such that transcriptional and translational control sequences within the vector serve their intended function of regulating the transcription and translation of the antibody gene.
- the expression vector and expression control sequences are chosen to be compatible with the expression host cell used.
- the antibody light chain gene and the antibody heavy chain gene can be inserted into separate vector or, more typically, both genes are inserted into the same expression vector.
- the antibody genes are inserted into the expression vector by standard methods (e.g., ligation of complementary restriction sites on the antibody gene fragment and vector, or blunt end ligation if no restriction sites are present).
- the expression vector Prior to insertion of the light or heavy chain sequences, the expression vector may already carry antibody constant region sequences.
- one approach to converting the VH and VL sequences to full-length antibody genes is to insert them into expression vectors already encoding heavy chain constant and light chain constant regions, respectively, such that the VH segment is operatively linked to the CH segment(s) within the vector and the VL segment is operatively linked to the CL segment within the vector.
- the recombinant expression vector can encode a signal peptide that facilitates secretion of the antibody chain from a host cell.
- the antibody chain gene can be cloned into the vector such that the signal peptide is linked in-frame to the amino terminus of the antibody chain gene.
- the signal peptide can be an immunoglobulin signal peptide or a heterologous signal peptide (i.e., a signal peptide from a non-immunoglobulin protein).
- the recombinant expression vectors of the invention carry regulatory sequences that control the expression of the antibody chain genes in a host cell.
- the term "regulatory sequence” is intended to includes promoters, enhancers and other expression control elements (e.g., polyadenylation signals) that control the transcription or translation of the antibody chain genes.
- Such regulatory sequences are described, for example, in Goeddel; Gene Expression Technology: Methods in Enzyniology 185, Academic Press, San Diego, CA (1990). It will be appreciated by those skilled in the art that the design of the expression vector, including the selection of regulatory sequences may depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, etc.
- Preferred regulatory sequences for mammalian host cell expression include viral elements that direct high levels of protein expression in mammalian cells, such as promoters and/or enhancers derived from cytomegalovirus (CMV) (such as the CMV promoter/enhancer), Simian Virus 40 (SV40) (such as the SV40 promoter/enhancer), adenovirus, (e.g., the adenovirus major late promoter (AdMLP)) and polyoma.
- CMV cytomegalovirus
- SV40 Simian Virus 40
- AdMLP adenovirus major late promoter
- the recombinant expression vectors of the invention may carry additional sequences, such as sequences that regulate replication of the vector in host cells (e.g., origins of replication) and selectable marker genes.
- the selectable marker gene facilitates selection of host cells into which the vector has been introduced (see e.g., U.S. Patents Nos. 4,399,216, 4,634,665 and 5,179,017, all by Axel et al).
- the selectable marker gene confers resistance to drugs, such as G418, hygromycin or methotrexate, on a host cell into which the vector has been introduced.
- Preferred selectable marker genes include the dihydrofolate reductase (DHFR) gene (for use in dhfr host cells with methotrexate selection/amplification) and the neo gene (for G418 selection).
- DHFR dihydrofolate reductase
- the expression vector(s) encoding the heavy and light chains is transfected into a host cell by standard techniques.
- the various forms of the term "transfection" are intended to encompass a wide variety of techniques commonly used for the introduction of exogenous DNA into a prokaryotic or eukaryotic host cell, e.g., electroporation, calcium-phosphate precipitation, DEAE- dextran transfection and the like.
- Preferred mammalian host cells for expressing the recombinant antibodies of the invention include Chinese Hamster Ovary (CHO cells) (including dhfr- CHO cells, described in Urlaub and Chasin, (1980) Proc. Natl. Acad. Sci. USA 77:4216-4220, used with a DHFR selectable marker, e.g., as described in R.J. Kaufman and P. A. Sharp (1982) Mol. Biol. 159:601-621), NSO myeloma cells, COS cells and SP2 cells.
- Chinese Hamster Ovary CHO cells
- dhfr- CHO cells described in Urlaub and Chasin, (1980) Proc. Natl. Acad. Sci. USA 77:4216-4220, used with a DHFR selectable marker, e.g., as described in R.J. Kaufman and P. A. Sharp (1982) Mol. Biol. 159:601-621
- NSO myeloma cells
- the antibodies When recombinant expression vectors encoding antibody genes are introduced into mammalian host cells, the antibodies are produced by culturing the host cells for a period of time sufficient to allow for expression of the antibody in the host cells or, more preferably, secretion of the antibody into the culture medium in which the host cells are grown. Antibodies can be recovered from the culture medium using standard protein purification methods.
- Host cells can also be used to produce portions of intact antibodies, such as Fab fragments or scFv molecules. It will be understood that variations on the above procedure are within the scope of the present invention. For example, it may be desirable to transfect a host cell with DNA encoding either the light chain or the heavy chain (but not both) of an antibody of this invention. Recombinant DNA technology may also be used to remove some or all of the DNA encoding either or both of the light and heavy chains that is not necessary for binding to the antigens of interest The molecules expressed from such truncated DNA molecules are also encompassed by the antibodies of the invention.
- bifunctional antibodies may be produced in which one heavy and one light chain are an antibody of the invention and the other heavy and light chain are specific for an antigen other than the antigens of interest by crosslinking an antibody of the invention to a second antibody by standard chemical crosslinking methods.
- a recombinant expression vector encoding both the antibody heavy chain and the antibody light chain is introduced into dhfr- CHO cells by calcium phosphate-mediated transfection.
- the antibody heavy and light chain genes are each operatively linked to CMV enhancer/ AdMLP promoter regulatory elements to drive high levels of transcription of the genes.
- the recombinant expression vector also carries a DHFR gene, which allows for selection of CHO cells that have been transfected with the vector using methotrexate selection/amplification.
- the selected transformant host cells are culture to allow for expression of the antibody heavy and light chains and intact antibody is recovered from the culture medium.
- Standard molecular biology techniques are used to prepare the recombinant expression vector, transfect the host cells, select for transformants, culture the host cells and recover the antibody from the culture medium.
- the invention provides a method of synthesizing a recombinant antibody of the invention by culturing a host cell of the invention in a suitable culture medium until a recombinant antibody of the invention is synthesized. The method can further comprise isolating the recombinant antibody from the culture medium.
- a covalent fusion is created between an mRNA and the peptide or protein that it encodes by in vitro translation of synthetic mRNAs that carry puromycin, a peptidyl acceptor antibiotic, at their 3' end.
- a specific mRNA can be enriched from a complex mixture of mRNAs (e.g., a combinatorial library) based on the properties of the encoded peptide or protein, e.g., antibody, or portion thereof, such as binding of the antibody, or portion thereof, to the dual specificity antigen.
- Nucleic acid sequences encoding antibodies, or portions thereof, recovered from screening of such libraries can be expressed by recombinant means as described above (e.g., in mammalian host cells) and, moreover, can be subjected to further affinity maturation by either additional rounds of screening of mRNA-peptide fusions in which mutations have been introduced into the originally selected sequence(s), or by other methods for affinity maturation in vitro of recombinant antibodies, as described above.
- Dual specificity antibodies of the invention also can be prepared using a combination of in vivo and in vitro approaches, such as methods in which the dual specificity antigen is originally exposed to an antibody repertoire in vivo in a host animal to stimulate production of antibodies that bind the dual specificity antigen but wherein further antibody selection and/or maturation (i.e., improvement) is accomplished using one or more in vitro techniques.
- such a combination method involves first immunizing a non-human animal (e.g., a mouse, rat, rabbit, goat, or transgenic version thereof, or a chimeric mouse) with the dual specificity antigen to stimulate an antibody response against the antigen, following by preparation and screening of a phage display antibody library using immunoglobulin sequences from lymphocytes stimulated in vivo by exposure to the dual specificity antigen.
- a non-human animal e.g., a mouse, rat, rabbit, goat, or transgenic version thereof, or a chimeric mouse
- the first step of this combination procedure can be conducted as described in subsection DA above, while the second step of this procedure can be conducted as described in subsection JJB above.
- Preferred methodologies for hyperimmunization of non-human animals followed by in vitro screening of phage display libraries prepared from the stimulated lymphocytes include those described by BioSite Inc., see e.g., PCT Publication WO 98/47343, PCT Publication WO 91/17271, U.S. Patent No. 5,427,908 and U.S. Patent No. 5,580,717.
- a combination method involves first immunizing a non-human animal (e.g., a mouse, rat, rabbit, goat, or knockout and/or transgenic version thereof, or a chimeric mouse) with the dual specificity antigen to stimulate an antibody response against the antigen and selection of lymphocytes that are producing antibodies having the desired dual specificity (e.g., by screening hybridomas prepared from the immunized animals).
- the rearranged antibody genes from the selected clones are then isolated (by standard cloning methods, such as reverse transcriptase-polymerase chain reaction) and subjected to in vitro affinity maturation, to thereby enhance the binding properties of the selected antibody or antibodies.
- the first step of this procedure can be conducted as described in subsection DA above, while the second step of this procedure can be conducted as described in subsection DB above, in particular using in vitro affinity maturation methods such as those described in PCT Publication WO 97/29131 and PCT Publication WO 00/56772.
- recombinant antibodies are generated from single, isolated lymphocytes using a procedure referred to in the art as the selected lymphocyte antibody method (SLAM), as described in U.S. Patent No. 5,627,052, PCT Publication WO 92/02551 and Babcock, J.S. et al (1996) Proc. Natl. Acad. Sci. USA 93:7843-7848.
- SAM selected lymphocyte antibody method
- a non-human animal e.g., a mouse, rat, rabbit, goat, or transgenic version thereof, or a chimeric mouse
- first is immunized in vivo with the dual specificity antigen to stimulate an antibody response against the antigen and then single cells secreting antibodies of interest, e.g., specific for the dual specificity antigen, are selected using an antigen-specific hemolytic plaque assay (e.g., the dual specificity antigen itself, or the structurally-related molecules of interest, are coupled to sheep red blood cells using a linker, such as biotin, thereby allowing for identification of single cells that secrete antibodies with the appropriate specificity using the hemolytic plaque assay).
- an antigen-specific hemolytic plaque assay e.g., the dual specificity antigen itself, or the structurally-related molecules of interest, are coupled to sheep red blood cells using a linker, such as biotin, thereby allowing for identification of single cells that secrete antibodies with the appropriate specificity using the hemolytic plaque assay).
- variable regions can then be expressed, in the context of appropriate immunoglobulin constant regions (e.g., human constant regions), in mammalian host cells, such as COS or CHO cells.
- the host cells transfected with the amplified immunoglobulin sequences, derived from in vivo selected lymphocytes, can then undergo further analysis and selection in vitro, for example by panning the transfected cells to isolate cells expressing antibodies having the desired dual specificity.
- the amplified immunoglobulin sequences further can be manipulated in vitro, such as by in vitro affinity maturation, as described above.
- the combination method to produce a dual specific antibody involves the following steps.
- a first non-human animal is immunized with a first antigen and a second non-human animal is immunized with a second different antigen, wherein preferably the second antigen is structurally similar to the first antigen, to stimulate an antibody response in vivo.
- a recombinant heavy chain library and a recombinant light chain library are constructed from antibody genes derived from the first non-human animal and the second non-human animal, respectively, as described in section DB.
- the heavy chain library from the animal immunized with the first antigen is combined with the light chain library from the animal immunized with the second antigen to generate an antibody library X.
- the heavy chain library from the animal immunized with the second antigen is combined with the light chain library from the animal immunized with the first antigen to generate an antibody library Y.
- libraries X and Y can be combined to generate library XY.
- Dual specific antibodies that bind both first and second antigen can be identified and isolated from X, Y and or XY libraries. DI. Characteristics of Dual Specificity Antibodies
- the invention provides dual specificity antibodies, as well as antibody portions thereof, that can be prepared in accordance with the methods of the invention.
- the antibodies, or portions thereof are isolated antibodies.
- the antibodies, or portions thereof are neutralizing antibodies.
- the antibodies of the invention include monoclonal and recombinant antibodies, and portions thereof.
- the antibody, or portion thereof may comprise amino acid sequences derived entirely from a single species, such as a fully human or fully mouse antibody, or portion thereof.
- the antibody, or portion thereof can be a chimeric antibody or a CDR-grafted antibody or other form of humanized antibody.
- antibody is intended to refer to immunoglobulin molecules comprised of four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds.
- Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region.
- the heavy chain constant region is comprised of three domains, CHI, CH2 and CH3.
- Each light chain is comprised of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region.
- the light chain constant region is comprised of one domain, CL.
- VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
- CDR complementarity determining regions
- FR framework regions
- Each VH and VL is composed of three CDRs and four FRs, arranged from amino- terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
- antibody portion refers to one or more fragments of a dual specificity antibody that retain the ability to specifically bind two different but structurally related antigens. It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.
- binding fragments encompassed within the term "antigen-binding portion" of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CHI domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al, (1989) Nature 341:544-546 ), which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR).
- a Fab fragment a monovalent fragment consisting of the VL, VH, CL and CHI domains
- F(ab')2 fragment a bivalent fragment comprising two Fab fragments linked by a dis
- the two domains of the Fv fragment, VL and VH are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883) .
- Such single chain antibodies are also intended to be encompassed within the term "antigen-binding portion" of an antibody.
- Other forms of single chain antibodies, such as diabodies are also encompassed.
- Diabodies are bivalent, bispecific antibodies in which VH and VL domains are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain and creating two antigen binding sites (see e.g., Holliger, P., et al. (1993) Proc. Natl Acad. Sci. USA 90:6444-6448; Poljak, R.J., et al. (1994) Structure 2:1121-1123).
- an antibody or antigen-binding portion thereof may be part of a larger immunoadhesion molecules, formed by covalent or noncovalent association of the antibody or antibody portion with one or more other proteins or peptides.
- immunoadhesion molecules include use of the streptavidin core region to make a tetrameric scFv molecule (Kipriyanov, S.M., et al. (1995) Human Antibodies and Hybridomas 6:93-101) and use of a cysteine residue, a marker peptide and a C-terminal polyhistidine tag to make bivalent and biotinylated scFv molecules (Kipriyanov, S.M., et al. (1994) Mol.
- Antibody portions such as Fab and F(ab')2 fragments, can be prepared from whole antibodies using conventional techniques, such as papain or pepsin digestion, respectively, of whole antibodies. Moreover, antibodies, antibody portions and immunoadhesion molecules can be obtained using standard recombinant DNA techniques.
- An "isolated dual specificity antibody”, as used herein, is intended to refer to an a dual specificity antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds two different but structurally related antigens, or structurally-related regions of otherwise unrelated antigens, but that is substantially free of antibodies that specifically bind other unrelated antigens). Moreover, an isolated dual specificity antibody may be substantially free of other cellular material and/or chemicals.
- a “neutralizing antibody”, as used is intended to refer to an antibody whose binding to a particular antigen results in inhibition of the biological activity of the antigen. This inhibition of the biological activity of the antigen can be assessed by measuring one or more indicators of biological activity of the antigen using an appropriate in vitro or in vivo assay.
- a “monoclonal antibody” as used herein is intended to refer to a hybridoma- derived antibody (e.g., an antibody secreted by a hybridoma prepared by hybridoma technology, such as the standard Kohler and Milstein hybridoma methodology).
- a hybridoma-derived dual specificity antibody of the invention is still referred to as a monoclonal antibody although it has antigenic specificity for more than a single antigen.
- recombinant antibody refers to antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell, antibodies isolated from a recombinant, combinatorial antibody library, antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see e.g., Taylor, L.D., et al. (1992) Nucl. Acids Res. 20:6287-6295) or antibodies prepared, expressed, created or isolated by any other means that involves splicing of particular immunoglobulin gene sequences (such as human immunoglobulin gene sequences) to other DNA sequences.
- recombinant antibodies include chimeric, CDR-grafted and humanized antibodies.
- human antibody refers to antibodies having variable and constant regions corresponding to, or derived from, human germline immunoglobulin sequences as described by, for example, Kabat et al (See Kabat, et al (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NTH Publication No. 91-3242).
- the human antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDR3.
- Recombinant human antibodies of the invention have variable regions, and may also include constant regions, derived from human germline immunoglobulin sequences (See Kabat, E.A., et al (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NTH Publication No. 91- 3242).
- such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.
- such recombinant antibodies are the result of selective mutagenesis or backmutation or both.
- backmutation refers to a process in which some or all of the somatically mutated amino acids of a human antibody are replaced with the corresponding germline residues from a homologous germline antibody sequence.
- the heavy and light chain sequences of a human antibody of the invention are aligned separately with the germline sequences in the VBASE database to identify the sequences with the highest homology. Differences in the human antibody of the invention are returned to the germline sequence by mutating defined nucleotide positions encoding such different amino acid.
- the role of each amino acid thus identified as candidate for backmutation should be investigated for a direct or indirect role in antigen binding and any amino acid found after mutation to affect any desirable characteristic of the human antibody should not be included in the final human antibody.
- chimeric antibody refers to antibodies which comprise heavy and light chain variable region sequences from one species and constant region sequences from another species, such as antibodies having murine heavy and light chain variable regions linked to human constant regions.
- CDR-grafted antibody refers to antibodies which comprise heavy and light chain variable region sequences from one species but in which the sequences of one or more of the CDR regions of V H and/or VL are replaced with CDR sequences of another species, such as antibodies having murine heavy and light chain variable regions in which one or more of the murine CDRs (e.g., CDR3) has been replaced with human CDR sequences.
- humanized antibody refers to antibodies which comprise heavy and light chain variable region sequences from a non-human species (e.g., a mouse) but in which at least a portion of the VH and/or VL sequence has been altered to be more "human-like", i.e., more similar to human germline variable sequences.
- a non-human species e.g., a mouse
- human CDR-grafted antibody in which human CDR sequences are introduced into non-human VH and VL sequences to replace the corresponding nonhuman CDR sequences.
- One way of measuring the binding kinetics of an antibody is by surface plasmon resonance.
- surface plasmon resonance refers to an optical phenomenon that allows for the analysis of real-time biospecific interactions by detection of alterations in protein concentrations within a biosensor matrix, for example using the BIAcore system (Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, NJ).
- BIAcore Pharmaacia Biosensor AB, Uppsala, Sweden and Piscataway, NJ.
- K 0 ff is intended to refer to the off rate constant for dissociation of an antibody from the aritibody/antigen complex.
- K ⁇ is intended to refer to the dissociation constant of a particular antibody-antigen interaction.
- the dual specificity antibodies of the invention are prepared using any of the various methods for preparing antibodies described in subsection TJ above.
- the dual specificity antibodies of the invention may be directed against essentially any structurally related antigens, although preferred dual specificity antibodies of the invention are those that specifically bind TL-l ⁇ and TL-l ⁇ , which can be prepared using a dual specificity antigen such as those described in Examples 1-4.
- cytokine families such as IL-1 family members (e.g., TL-l/TL- 18), TNF family members (e.g., TNF ⁇ /TNF ⁇ ) , TL-6 family members, Interferons, TGF ⁇ family members, EGF family members, FGF family members, PDGF family members, VEGF family members, Angiopoietin family members, Bone morphogenic proteins, secreted proteinases (metallo-proteinases), and cytokine receptor families, such as TL-1 -receptor family members, TNF-receptors family members TGF ⁇ receptor family members, EGF receptor family members, FGF receptor family members, PDGF receptor family members, VEGF receptor family members and Angiopoietin receptor family members.
- caspase family members such as IL-1 family members (e.g., TL-l/TL- 18), TNF family members (e.g., TNF ⁇ /TNF ⁇ ) , TL-6 family members, Interferons, T
- the dual specificity antibodies of the invention may display equal binding activity toward the two different but structurally related antigens to which it binds or, alternatively, the dual specificity antibodies may bind more preferentially to one of the two antigens, yet still have specificity towards the two related antigens as compared to unrelated antigens.
- the binding activity of the dual specificity antibodies toward the structurally related antigens, as well as toward unrelated antigens, can be assessed using standard in vitro immunoassays, such as ELISA or BIAcore analysis.
- the ratio of K ⁇ j of antibody toward structurally unrelated antigens to the K d of antibody toward structurally related antigens should be at least 3, even more preferably the ratio should be at least 5, even more preferably the ratio should be at least 10, or even more preferably the ratio should be at least 50, 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000.
- the difference between background binding and dual specificity is one of level or degree.
- background binding is at a low level, e.g., less than 5%, more preferably less than 3% and most preferably, about 0.1-1% whereas specific cross-reactivity or dual specificity binding is at a higher level, e.g., greater than 1%, more preferably greater than 3%, even more preferably greater than 5% and even more preferably greater than 10%.
- the IC5 0 of the dual specificity antibody for the target antigens is close to the ED 50 S of the antigens in a given bioassay.
- a dual specificity antibody, or antigen-binding portion thereof, of the invention is preferably selected to have desirable binding kinetics (e.g., high affinity, low dissociation, slow off-rate, strong neutralizing activity) for one, and more preferably both, of the antigens to which it specifically binds.
- the dual specificity antibody, or portion thereof may bind one, and more preferably both, of the structurally related antigens with a k 0ff rate constant of 0.1s "1 or less, more preferably a k off rate
- a dual specificity antibody, or portion thereof may inhibit the activity of one, and more preferably both, of the structurally related antigens with an IC50 of 1 x 10 "6 M or less, even more preferably with an IC 50 of 1 x 10 " 7 M or less, even more preferably with an IC 50 of 1 x 10 "8 M or less, even more preferably with an IC 50 of 1 x 10 "9 M or less, even more preferably with an IC 50 of 1 x 10 "10 M or less, or even more preferably with an IC 50 of 1 x 10 " ⁇ M or less.
- IC 50 should be measured using a sensitive bioassay where IC 50 values should be close to the ED 5 0 value of the antigen in that assay.
- the invention also provides pharmaceutical compositions comprising a dual specificity antibody, or antigen-binding portion thereof, of the invention and a pharmaceutically acceptable carrier.
- the pharmaceutical composition of the invention can further comprise at least one additional therapeutic agent, e.g., one or more additional therapeutic agents for treating a disorder in which use of the dual specificity antibody is beneficial to amelioration of the disorder.
- the pharmaceutical composition can further include one or more additional therapeutic agents for treating disorders in which TL-1 activity is detrimental.
- the antibodies and antibody-portions of the invention can be incorporated into pharmaceutical compositions suitable for administration to a subject.
- the pharmaceutical composition comprises an antibody or antibody portion of the invention and a pharmaceutically acceptable carrier.
- pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
- pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof.
- isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.
- Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the antibody or antibody portion.
- the antibodies and antibody-portions of the invention can be incorporated into a pharmaceutical composition suitable for parenteral administration.
- the antibody or antibody-portions will be prepared as an injectable solution containing 0.1- 250 mg/ml antibody.
- the injectable solution can be composed of either a liquid or lyophilized dosage form in a flint or amber vial, ampule or pre-filled syringe.
- the buffer can be L-histidine (1-50 mM), optimally 5-lOmM, at pH 5.0 to 7.0 (optimally pH 6.0).
- Other suitable buffers include but are not limited to, sodium succinate, sodium citrate, sodium phosphate or potassium phosphate.
- Sodium chloride can be used to modify the toxicity of the solution at a concentration of 0-300 rnM (optimally 150 mM for a liquid dosage form).
- Cryoprotectants can be included for a lyophilized dosage form, principally 0-10% sucrose (optimally 0.5-1.0%).
- Other suitable cryoprotectants include trehalose and lactose.
- Bulking agents can be included for a lyophilized dosage form, principally 1-10% mannitol (optimally 2-4%).
- Stabilizers can be used in both liquid and lyophilized dosage forms, principally 1-50 mM L-Methionine (optimally 5-10 mM).
- Other suitable bulking agents include glycine, arginine, can be included as 0-0.05% polysorbate-80 (optimally 0.005-0.01%).
- Additional surfactants include but are not limited to polysorbate 20 and BRET surfactants.
- compositions of this invention may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories.
- liquid solutions e.g., injectable and infusible solutions
- dispersions or suspensions tablets, pills, powders, liposomes and suppositories.
- the preferred form depends on the intended mode of administration and therapeutic application. Typical preferred compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with other antibodies.
- the preferred mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular).
- the antibody is administered by intravenous infusion or injection.
- the antibody is administered by intramuscular or subcutaneous injection.
- compositions typically must be sterile and stable under the conditions of manufacture and storage.
- the composition can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable to high drug concentration.
- Sterile injectable solutions can be prepared by incorporating the active compound (i.e., antibody or antibody portion) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
- dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
- the preferred methods of preparation are vacuum drying and spray-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
- the proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
- Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.
- the antibodies and antibody-portions of the present invention can be administered by a variety of methods known in the art, although for many therapeutic applications, the preferred route/mode of administration is subcutaneous injection, intravenous injection or infusion. As will be appreciated by the skilled artisan, the route and/or mode of administration will vary depending upon the desired results.
- the active compound may be prepared with a carrier that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
- a carrier such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
- Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid.
- an antibody or antibody portion of the invention may be orally administered, for example, with an inert diluent or an assimilable edible carrier.
- the compound (and other ingredients, if desired) may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into the subject's diet.
- the compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
- a compound of the invention by other than parenteral administration, it may be necessary to coat the compound with, or co-administer the compound with, a material to prevent its inactivation.
- Supplementary active compounds can also be incorporated into the compositions.
- an antibody or antibody portion of the invention is coformulated with and/or coadministered with one or more additional therapeutic agents that are useful for treating disorders in which TL-1 activity is detrimental.
- an anti-TL-l ⁇ /IL-l ⁇ dual specificity antibodies, or antibody portions, of the invention may be coformulated and/or coadministered with one or more additional antibodies that bind other targets (e.g., antibodies that bind other cytokines or that bind cell surface molecules).
- one or more antibodies of the invention may be used in combination with two or more of the foregoing therapeutic agents.
- Such combination therapies may advantageously utilize lower dosages of the administered therapeutic agents, thus avoiding possible toxicities or complications associated with the various monotherapies.
- the dual specificity antibodies, or portions thereof, of the invention can be used to detect either or both of these antigens (e.g., in a biological sample, such as serum or plasma), using a conventional immunoassay, such as an enzyme linked immunosorbent assays (ELIS A), an radioimmunoassay (RIA) or tissue immunohistochemistry.
- a biological sample such as serum or plasma
- a conventional immunoassay such as an enzyme linked immunosorbent assays (ELIS A), an radioimmunoassay (RIA) or tissue immunohistochemistry.
- the invention provides a method for detecting an antigen in a biological sample comprising contacting a biological sample with a dual specificity antibody, or antibody portion, of the invention that specifically recognizes the antigen and detecting either the antibody (or antibody portion) bound to antigen or unbound antibody (or antibody portion), to thereby detect the antigen in the biological sample.
- the antibody is directly or indirectly labeled with a detectable substance to facilitate detection of the bound or unbound antibody.
- Suitable detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials and radioactive materials.
- suitable enzymes include horseradish peroxidase, alkaline phosphatase, ⁇ -galactosidase, or acetylcholinesterase;
- suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin;
- suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin;
- an example of a luminescent material includes Iuminol; and examples of suitable radioactive material include 125 1, 131 1, 35 S or 3 H.
- the antigen(s) can be assayed in biological fluids by a competition radioimmunoassay utilizing antigen standards labeled with a detectable substance and an unlabeled dual specificity antibody specific for the antigen(s).
- a competition radioimmunoassay utilizing antigen standards labeled with a detectable substance and an unlabeled dual specificity antibody specific for the antigen(s).
- the biological sample, the labeled antigen standards and the dual specificity antibody are combined and the amount of labeled antigen standard bound to the unlabeled antibody is determined.
- the amount of antigen in the biological sample is inversely proportional to the amount of labeled antigen standard bound to the unlabeled antibody.
- the dual specificity antibody specifically recognizes TL-l ⁇ and TL-l ⁇ and the foregoing detection methods are used to detect IL-l ⁇ and or TL- l ⁇ .
- the invention further provides a method of detecting TL-l ⁇ or TL-l ⁇ in a biological sample or tissue comprising contacting the biological sample or tissue suspected of containing TL- 1 ⁇ or IL- 1 ⁇ with a dual-specificity antibody, or antigen- binding portion thereof, of the invention and detecting TL- l or TL-l ⁇ in the biological sample or tissue.
- the biological sample can be, for example, an in vitro sample, such as a sample of cells, tissue or bodily fluid (e.g., blood, plasma, urine, saliva etc.).
- the tissue detected can be tissue located in vivo in a subject, e.g., tissue visualized by in vivo imaging of the tissue (e.g., using a labeled antibody)
- an antibody of the invention is used in a diagnostic assay in vitro, such as in a laboratory test to detect the antigen(s) of interest or in a point of care test to detect the antigen(s) of interest.
- a diagnostic assay in vitro such as in a laboratory test to detect the antigen(s) of interest or in a point of care test to detect the antigen(s) of interest. Examples of well-established in vitro assays utilizing antibodies include ELISAs, RIAs, Western blots and the like.
- an antibody of the invention is used in a diagnostic assay in vivo, such as an in vivo imaging test.
- the antibody can be labeled with a detectable substance capable of being detected in vivo, the labeled antibody can be administered to a subject, and the labeled antibody can be detected in vivo, thereby allowing for in vivo imaging.
- Dual specificity antibodies of the invention that specifically recognize IL-l ⁇ and IL-l ⁇ can be used in diagnostic assays to detect TL-l ⁇ and/or TL-l ⁇ for diagnostic purposes, for example in a variety of inflammatory diseases and disorders, as well as in spontaneous resorption of fetuses.
- the dual specificity anti-TL-l ⁇ /TL-l ⁇ antibodies of the invention can be used for diagnostic purposes in any of the diseases/disorders described herein with regard to the therapeutic uses of such antibodies (see below), such as disorders in which IL-1 activity is detrimental, discussed further below.
- the dual specificity antibodies and antibody portions of the invention preferably are capable of neutralizing, both in vitro and in vivo, the activity of the antigens to which they bind. Accordingly, such antibodies and antibody portions of the invention can be used to inhibit the activity of the antigens, e.g., in a cell culture containing the antigens or in human subjects or in other mammalian subjects having the antigens with which the dual specificity antibody of the invention reacts.
- the invention provides a method for inhibiting antigen activity comprising contacting the antigen with a dual specificity antibody or antibody portion of the invention such that antigen activity is inhibited.
- the dual specificity antibody binds TL-l ⁇ and IL-l ⁇ and the method is a method for inhibiting TL-l ⁇ and/or TL-l ⁇ activity by contacting TL-l ⁇ and/or TL-l ⁇ with the dual specificity antibody, or portion thereof.
- the TL-l ⁇ and/or TL-l ⁇ activity can be inhibited, for example, in vitro.
- an antibody or antibody portion of the invention can be added to the culture medium to inhibit IL-l ⁇ and/or TL-l ⁇ activity in the culture.
- TL- l ⁇ and/or TL-l ⁇ activity can be inhibited in vivo in a subject.
- the invention provides a method for inhibiting antigen activity in a subject suffering from a disorder in which that antigen activity is detrimental.
- the invention provides methods for inhibiting antigen activity in a subject suffering from such a disorder, which method comprises administering to the subject a dual specificity antibody or antibody portion of the invention such that antigen activity in the subject is inhibited.
- the antigen is a human antigen and the subject is a human subject.
- An antibody of the invention can be administered to a human subject for therapeutic purposes.
- an antibody of the invention can be administered to a non-human mammal expressing an antigen with which the antibody binds for veterinary purposes or as an animal model of human disease. Regarding the latter, such animal models may be useful for evaluating the therapeutic efficacy of antibodies of the invention (e.g. , testing of dosages and time courses of administration).
- the dual specificity antibody binds TL-l ⁇ and TL-l ⁇ and the method for inhibiting antigen activity in a subject is a method for inhibiting IL-1 activity in a subject, for example a subject suffering from a disorder in which TL-1 activity is detrimental.
- a disorder in which TL-1 activity is detrimental is intended to include diseases and other disorders in which the presence of TL-1 (which encompasses both IL-l ⁇ and TL-l ⁇ ) in a subject suffering from the disorder has been shown to be or is suspected of being either responsible for the pathophysiology of the disorder or a factor that contributes to a worsening of the disorder.
- a disorder in which TL-1 activity is detrimental is a disorder in which inhibition of TL-1 activity (i.e., either or both of TL-1 ⁇ and TL-l ⁇ ) is expected to alleviate the symptoms and/or progression of the disorder.
- Such disorders may be evidenced, for example, by an increase in the concentration of TL-1 in a biological fluid of a subject suffering from the disorder (e.g., an increase in the concentration of TL-1 in serum, plasma, synovial fluid, etc. of the subject), which can be detected, for example, using an anti-TL-1 antibody as described above.
- Interleukin 1 plays a critical role in the pathology associated with a variety of diseases involving immune and inflammatory elements. These diseases include, but are not limited to, rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, Lyme arthritis, psoriatic arthritis, reactive arthritis, spondyloarthropathy, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, inflammatory bowel disease, insulin dependent diabetes mellitus, thyroiditis, asthma, allergic diseases, psoriasis, dermatitis scleroderma, graft versus host disease, organ transplant rejection, acute or chronic immune disease associated with organ transplantation, sarcoidosis, atherosclerosis, disseminated intravascular coagulation, Kawasaki's disease, Grave's disease, nephrotic syndrome, chronic fatigue syndrome, Wegener's granulomatosis, Henoch-Schoenlein purpurea, microscopic vasculitis of the kidneys
- the human antibodies, and antibody portions of the invention can be used to treat humans suffering from autoimmune diseases, in particular those associated with inflammation, including, rheumatoid spondylitis, allergy, autoimmune diabetes, autoimmune uveitis.
- autoimmune diseases in particular those associated with inflammation, including, rheumatoid spondylitis, allergy, autoimmune diabetes, autoimmune uveitis.
- the TL-l TL-l ⁇ dual specificity antibodies of the invention or antigen-binding portions thereof are used to treat rheumatoid arthritis, Crohn's disease, multiple sclerosis, insulin dependent diabetes, mellitus and psoriasis.
- An TL-l ⁇ TL- ⁇ dual specificity antibody, or antibody portion, of the invention also can be administered with one or more additional therapeutic agents useful in the treatment of autoimmune and inflammatory diseases.
- Antibodies of the invention, or antigen binding portions thereof can be used alone or in combination to treat such diseases.
- the antibodies of the invention or antigen binding portion thereof can be used alone or in combination with an additional agent, e.g., a therapeutic agent, said additional agent being selected by the skilled artisan for its intended purpose.
- the additional agent can be a therapeutic agent art-recognized as being useful to treat the disease or condition being treated by the antibody of the present invention.
- the additional agent also can be an agent which imparts a beneficial attribute to the therapeutic composition e.g., an agent which effects the viscosity of the composition.
- the combinations which are to be included within this invention are those combinations useful for their intended purpose.
- the agents set forth below are illustrative for purposes and not intended to be limited .
- the combinations which are part of this invention can be the antibodies of the present invention and at least one additional agent selected from the lists below.
- the combination can also include more than one additional agent, e.g., two or three additional agents if the combination is such that the formed composition can perform its intended function.
- Preferred combinations are non-steroidal anti-inflammatory drug(s) also referred to as NSATDS which include drugs like ibuprofen and COX-2 inhibitors.
- Other preferred combinations are corticosteroids including prednisolone; the well known side- effects of steroid use can be reduced or even eliminated by tapering the steroid dose required when treating patients in combination with the anti-TL-1 antibodies of this invention.
- Non-limiting examples of therapeutic agents for rheumatoid arthritis with which an antibody, or antibody portion, of the invention can be combined include the following: cytokine suppressive anti-inflammatory drug(s) (CSATDs); antibodies to or antagonists of other human cytokines or growth factors, for example, TNF, LT, TL-2, TL- 6, TL-7, TL-8, TL-12, TL-15, TL-16, IL-18, EMAP-TI, GM-CSF, FGF, and PDGF.
- CSATDs cytokine suppressive anti-inflammatory drug
- Antibodies of the invention, or antigen binding portions thereof, can be combined with antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80 (B7.1), CD86 (B7.2), CD90, or their ligands including CD154 (gp39 or CD40L).
- Preferred combinations of therapeutic agents may interfere at different points in the autoimmune and subsequent inflammatory cascade; preferred examples include TNF antagonists like chimeric, humanized or human TNF antibodies, D2E7, (PCT Publication No.
- WO 97/29131 CA2 (RemicadeTM), CDP 571, CDP 870, Thalidamide and soluble p55 or p75 TNF receptors, derivatives, thereof, (p75TNFRlgG (EnbrelTM) or p55TNFRlgG (Lenercept), and also TNF ⁇ converting enzyme (TACE) inhibitors; similarly TL-1 inhibitors (Interleukin-1 -converting enzyme inhibitors, TL-1RA etc.) may be effective for the same reason.
- Other preferred combinations include Interleukin 11.
- Yet another preferred combination are other key players of the autoimmune response which may act parallel to, dependent on or in concert with TL-1 function; especially preferred are TL-12 and or TL-18 antagonists including TL-12 and/or TL-18 antibodies or soluble TL-12 and/or TL-18 receptors, or TL-12 and or TL-18 binding proteins. It has been shown that TL-12 and TL-18 have overlapping but distinct functions and a combination of antagonists to both may be most effective. Yet another preferred combination are non- depleting anti-CD4 inhibitors. Yet other preferred combinations include antagonists of the co-stimulatory pathway CD80 (B7.1) or CD86 (B7.2) including antibodies, soluble receptors or antagonistic ligands.
- the antibodies of the invention, or antigen binding portions thereof, may also be combined with agents, such as methotrexate, 6-MP, azathioprine sulphasalazine, mesalazine, olsalazine chloroquinine/hydroxychloroquine, pencillamine, aurothiomalate (intramuscular and oral), azathioprine, cochicine, corticosteroids (oral, inhaled and local injection), beta-2 adrenoreceptor agonists (salbutamol, terbutaline, salmeteral), xanthines (theophylline, aminophylline), cromoglycate, nedocromil, ketotifen, ipratropium and oxitropium, cyclosporin, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSATDs, for example, ibuprofen, corticosteroids such as prednisolone,
- IRAK, NTK, IKK , p38 or MAP kinase inhibitors TL-l ⁇ converting enzyme inhibitors
- TNF ⁇ converting enzyme (TACE) inhibitors TNF ⁇ converting enzyme (TACE) inhibitors
- T-cell signalling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, azathioprine, 6-mercaptopurines, angiotensin converting enzyme inhibitors, soluble cytokine receptors and derivatives thereof (e.g.
- soluble p55 or p75 TNF receptors and the derivatives p75TNFRTgG include sTL-lRI, sTL-lRTI, sTL-6R) and antiinflammatory cytokines (e.g. TL-4, TL- 10, TL-11, TL-13 and TGF ⁇ ).
- Preferred combinations include methotrexate or leflunomide and in moderate or severe rheumatoid arthritis cases, cyclosporine.
- Non-limiting examples of therapeutic agents for inflammatory bowel disease with which an antibody, or antibody portion, of the invention can be combined include the following: budenoside; epidermal growth factor; corticosteroids; cyclosporin, sulfasalazine; aminosalicylates; 6-mercaptopurine; azathioprine; metronidazole; lipoxygenase inhibitors; mesalamine; olsalazine; balsalazide; antioxidants; thromboxane inhibitors; TL-1 receptor antagonists; anti-TL-l ⁇ monoclonal antibodies; anti-TL-6 monoclonal antibodies; growth factors; elastase inhibitors; pyridinyl-imidazole compounds; antibodies to or antagonists of other human cytokines or growth factors, for example, TNF, LT, TL-2, TL-6, TL-7, TL-8, TL-12, TL-15, TL-16, TL-18, EMAP-Ti,
- CD45, CD69, CD90 or their ligands may also be combined with agents, such as methotrexate, cyclosporin, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSATDs, for example, ibuprofen, corticosteroids such as prednisolone, phosphodiesterase inhibitors, adenosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, agents which interfere with signalling by proinflammatory cytokines such as TNF ⁇ or TL-1 (e.g.
- agents such as methotrexate, cyclosporin, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSATDs, for example, ibuprofen, corticosteroids such as prednisolone, phosphodiesterase inhibitors, adenosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, agents
- TRAK, NTK, TKK, p38 or MAP kinase inhibitors TL-l ⁇ converting enzyme inhibitors
- TNF ⁇ converting enzyme inhibitors T-cell signalling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, azathioprine, 6-mercaptopurines, angiotensin converting enzyme inhibitors, soluble cytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNF receptors, sTL-lRI, sTL-lRTI, sTL-6R) and antiinflammatory cytokines (e.g. TL-4, TL-10, TL-11, TL-13 and TGF ⁇ ).
- TL-4, TL-10, TL-11, TL-13 and TGF ⁇ antiinflammatory cytokines
- TNF antagonists for example, anti-TNF antibodies, D2E7 (PCT Publication No. WO 97/29131), CA2 (RemicadeTM), CDP 571, TNFR-Ig constructs, (p75TNFRIgG (EnbrelTM ⁇ and p55TNFRIgG (Lenercept)) inhibitors and PDE4 inhibitors.
- Antibodies, or antigen binding portions thereof, of the invention or antigen binding portions thereof can be combined with corticosteroids, for example, budenoside and dexamethasone.
- Antibodies of the invention or antigen binding portions thereof may also be combined with agents such as sulfasalazine, 5-aminosalicylic acid and olsalazine, and agents which interfere with synthesis or action of proinflammatory cytokines such as TL-1, for example, TL-l ⁇ converting enzyme inhibitors and TL-lra.
- Antibodies of the invention or antigen binding portion thereof may also be used with T cell signaling inhibitors, for example, tyrosine kinase inhibitors 6-mercaptopurines.
- Antibodies of the invention or antigen binding portions thereof can be combined with TL-11.
- Non-limiting examples of therapeutic agents for multiple sclerosis with which an antibody, or antibody portion, of the invention can be combined include the following: corticosteroids; prednisolone; methylprednisolone; azathioprine; cyclophosphamide; cyclosporine; methotrexate; 4-aminopyridine; tizanidine; interferon- ⁇ la (Avonex; Biogen); interferon- ⁇ lb (Betaseron; Chiron/Berlex); Copolymer 1 (Cop-1; Copaxone; Teva Pharmaceutical Industries, Inc.); hyperbaric oxygen; intravenous immunoglobulin; clabribine; antibodies to or antagonists of other human cytokines or growth factors, for example, TNF, LT, IL-2, TL-6, IL-7, TL-8, TL-12, TL-15, TL-16, TL-18, EMAP-TI, GM- CSF, FGF, and PDGF.
- Antibodies of the invention, or antigen binding portions thereof, can be combined with antibodies to cell surface molecules such as CD2, CD3, CD4, .
- the antibodies of the invention, or antigen binding portions thereof, may also be combined with agents, such as methotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSATDs, for example, ibuprofen, COX-2 inhibitors, corticosteroids such as prednisolone, phosphodiesterase inhibitors, adensosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, agents which interfere with signalling by proinflammatory cytokines such as TNF ⁇ or TL-1 (e.g.
- agents such as methotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSATDs, for example, ibuprofen, COX-2 inhibitors, corticosteroids such as prednisolone, phosphodiesterase inhibitors, adensosine agonists, antithrombotic agents,
- IL-1 ⁇ converting enzyme inhibitors TACE inhibitors
- T-cell signalling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, azathioprine, 6-mercaptopurines, angiotensin converting enzyme inhibitors, soluble cytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNF receptors, sTL-lRI, sTL-lRD, sTL-6R) and antiinflammatory cytokines (e.g. TL- 4, TL-10, TL-13 and TGF ⁇ ).
- soluble cytokine receptors e.g. soluble p55 or p75 TNF receptors, sTL-lRI, sTL-lRD, sTL-6R
- antiinflammatory cytokines e.g. TL- 4, TL-10, TL-13 and TGF ⁇ .
- therapeutic agents for multiple sclerosis in which the antibody or antigen binding portion thereof can be combined to include interferon- ⁇ , for . example, TFN ⁇ la and TFN ⁇ lb; copaxone, corticosteroids, TL-1 inhibitors, TNF inhibitors, and antibodies to CD40 ligand and CD80.
- the pharmaceutical compositions of the invention may include a "therapeutically effective amount” or a “prophylactically effective amount” of an antibody or antibody portion of the invention.
- a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result.
- a therapeutically effective amount of the antibody or antibody portion may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the antibody or antibody portion to elicit a desired response in the individual.
- a therapeutically effective amount is also one in which any toxic or detrimental effects of the antibody or antibody portion are outweighed by the therapeutically beneficial effects.
- a “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.
- Dosage regimens may be adjusted to provide the optimum desired response (e.g., a therapeutic or prophylactic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
- Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
- An exemplary, non-limiting range for a therapeutically or prophylactically effective amount of an antibody or antibody portion of the invention is 0.1-20 mg/kg, more preferably 1-10 mg/kg. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
- the largest contiguous topological area of identity between two different but structurally related proteins, TL-l ⁇ and TL-l ⁇ was determined as a basis for designing a dual specificity antigen for raising dual specificity antibodies to TL-l ⁇ and TL-l ⁇ .
- the BLAST algorithm was used to compare the two proteins and allows one to measure the tendency of one residue to replace another in similar structural or functional regions. This analysis allowed for the identification of the largest contiguous topological area of identity between TL-l ⁇ and TL-l ⁇ and to extend this area with any reasonable stretches of similarity to create a linear peptide that serves as a dual specificity antigen.
- the peptide that best fits these criteria has an amino acid sequence as follows:
- Both the L amino acid version of the peptide and the version partially substituted with D amino acid residues are synthesized by standard chemical methods.
- the peptide is then conjugated to a carrier protein (e.g., KLH or albumin) and the conjugated peptide is used to select antibodies by in vitro or in vivo methods.
- a carrier protein e.g., KLH or albumin
- EXAMPLE 2 Design of a Dual Specificity Antigen Based on a Cyclic
- a cyclic peptide that structurally mimics a key loop of a common fold between two different but structurally related proteins, IL-l ⁇ and TL-l ⁇ was constructed for use as a dual specificity antigen for raising dual specificity antibodies to TL-l ⁇ and TL-l ⁇ .
- the chosen loop represents residues 168-184 of TL-l ⁇ and residues 160-176 of TL-l ⁇ .
- the consensus sequence is:
- the asterisk (*) indicates identical residues between TL- l ⁇ and TL-l ⁇
- c indicates consensus residues, i.e, residues similar to IL-l ⁇ and TL-l ⁇ but not actually present at this location in either protein
- b indicates there was no clear consensus residue so TL- l ⁇ sequence identity was retained.
- the linear peptide is synthesized by standard chemical synthesis methods. To cyclize this peptide, a proline and a glycine residue are * added. The cyclic peptide may be synthesized using standard coupling conditions at high dilution in N,N-dimethylformamide (lmg/ml).
- Prototypical reactions are run at room temperature using excess coupling reagent, such as benzotriazole-1-yl-oxy-tris- pyrrolidino-phosphonium hexafluoro phosphate (PyBOP; 2 eq) and sodium bicarbonate (10 eq).
- the peptide is then conjugated to a carrier protein (e.g., KLH or albumin) and the conjugated peptide is used to select antibodies by in vitro or in vivo methods.
- a carrier protein e.g., KLH or albumin
- EXAMPLE 3 Design of a Dual Specificity Antigen Based on a Hybrid Peptide
- a hybrid peptide that includes alternating or overlapping sequences of two different but structurally related proteins, IL-l ⁇ and TL-l ⁇ , was constructed for use as a dual specificity antigen for raising dual specificity antibodies to TL-l ⁇ and TL-l ⁇ .
- alternating and overlapping amino acid sequences of TL-1 ⁇ and TL-l ⁇ were identified and spliced together to generate the following peptide:
- TKGGQDITDFQILENQ (SEQ ID NO : 3 ⁇ bbbbbbbbbb aaaaaaaaaaaaaaaaaaaaaaaaaaaa
- the ITDF (SEQ TD NO: 4) motif common to both proteins was included in the hybrid peptide. Moreover, this hybrid peptide focuses on sequences from the carboxy termini of both proteins, which is known to be antigenic for neutralizing antibodies in both proteins as well.
- the hybrid peptide is synthesized by standard chemical synthesis methods. The peptide is then conjugated to a carrier protein (e.g., KLH or albumin) and the conjugated peptide is used to select antibodies by in vitro or in vivo methods.
- a carrier protein e.g., KLH or albumin
- EXAMPLE 4 Generation of Dual Specific antibodies to IL-l ⁇ and IL-l ⁇
- Peptides of SEQ TD NO; 1, 2 and 3 were conjugated with KLH and individual rabbits were immunized. Antiserum from rabbits immunized with each of the three peptides showed good antibody response against the peptide used as antigen. However, only antiserum from rabbit immunized with Peptide of SEQ TD NO: 3 was able to bind both IL-l ⁇ protein and TL-1 ⁇ protein.
- mice Five mice (BA119 - BA123) were immunized subcutaneously with peptide of SEQ TD NO: 3 conjugated with KLH plus Freund's incomplete adjuvant (FIA) once every three weeks for a total of three times, followed by two intravenous boosts with peptide of SEQ TD NO: 3 conjugated with KLH. Each mouse was bled 10 days after each immunization and antibody titer was determined by ELISA. Spleen cells from mouse BA119 and BA123 respectively were fused with myloma cell line P3X36Ag8.653 as described in section TIA, and the resulting fused cells were seeded one cell per well in several 96-well plates using limiting dilution.
- FFA Freund's incomplete adjuvant
- the hybridoma clones that grew were first assayed for IgG and IgM production by standard ELISA to identify antibody-producing clones. A total of 945 clones from mouse #BA123 fusion were isolated. Supernatants from 355 clones tested in an ELISA showed antigen binding activity to TL-l ⁇ IL-l ⁇ or both TL-1 ⁇ and TL-l ⁇ .
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Cell Biology (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Food Science & Technology (AREA)
- General Physics & Mathematics (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Biotechnology (AREA)
- Toxicology (AREA)
- Microbiology (AREA)
- Epidemiology (AREA)
- Pathology (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Dermatology (AREA)
- Transplantation (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
Abstract
Description
Claims
Priority Applications (18)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020027017916A KR100919593B1 (en) | 2000-06-29 | 2001-06-28 | Dual specificity antibodies and methods of making them and composition comprising them |
SK115-2003A SK1152003A3 (en) | 2000-06-29 | 2001-06-28 | Dual specificity antibodies and methods of making and using |
AU2001271636A AU2001271636A1 (en) | 2000-06-29 | 2001-06-28 | Dual specificity antibodies and methods of making and using |
EP01950668A EP1297142B1 (en) | 2000-06-29 | 2001-06-28 | Dual specificity antibodies and methods of making and using |
CA2411374A CA2411374C (en) | 2000-06-29 | 2001-06-28 | Dual specificity antibodies and methods of making and using |
JP2002508013A JP4955185B2 (en) | 2000-06-29 | 2001-06-28 | Bispecific antibodies and methods for making and using the same |
HU0301002A HUP0301002A3 (en) | 2000-06-29 | 2001-06-28 | Dual specificity antibodies and methods of making and using |
MXPA02012867A MXPA02012867A (en) | 2000-06-29 | 2001-06-28 | Dual specificity antibodies and methods of making and using. |
BR0112026-3A BR0112026A (en) | 2000-06-29 | 2001-06-28 | Antibodies with double specificity and methods of production and use |
NZ523080A NZ523080A (en) | 2000-06-29 | 2001-06-28 | Antibodies specific for interleukin-1 alpha and interleukin-2 beta and methods of making and using |
PL359995A PL208069B1 (en) | 2000-06-29 | 2001-06-28 | Dual specificity antibodies and methods of making and using |
IL15356701A IL153567A0 (en) | 2000-06-29 | 2001-06-28 | Dual specificity antibodies and methods of making and using |
DE60137421T DE60137421D1 (en) | 2000-06-29 | 2001-06-28 | ANTIBODIES WITH TWO SPECIFICITIES AND METHOD FOR THE PRODUCTION AND USE THEREOF |
IL153567A IL153567A (en) | 2000-06-29 | 2002-12-20 | Dual specificity antibody which binds two different but structurally related proteins and method of obtaining the same |
NO20026239A NO20026239L (en) | 2000-06-29 | 2002-12-27 | Double specificity antibodies and methods of preparation and use |
BG107483A BG66209B1 (en) | 2000-06-29 | 2003-01-21 | Methods of making of dual specificity antibodies |
HK03106152.8A HK1055316A1 (en) | 2000-06-29 | 2003-08-27 | Dual specificity antibodies and methods of making and using |
IL203955A IL203955A (en) | 2000-06-29 | 2010-02-14 | DUAL SPECIFICITY ANTIBODY THAT BINDS TWO DIFFERENT BUT STRUCTURALLY RELATED PROTEINS, SUCH AS IL-1a AND IL-1b AND METHOD OF OBTAINING THE SAME |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US21537900P | 2000-06-29 | 2000-06-29 | |
US60/215,379 | 2000-06-29 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2002002773A2 true WO2002002773A2 (en) | 2002-01-10 |
WO2002002773A3 WO2002002773A3 (en) | 2002-08-22 |
Family
ID=22802758
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2001/020755 WO2002002773A2 (en) | 2000-06-29 | 2001-06-28 | Dual specificity antibodies and methods of making and using |
Country Status (27)
Country | Link |
---|---|
US (5) | US7491516B2 (en) |
EP (4) | EP2042518A3 (en) |
JP (2) | JP4955185B2 (en) |
KR (2) | KR20080074231A (en) |
CN (3) | CN102120773B (en) |
AT (1) | ATE420958T1 (en) |
AU (1) | AU2001271636A1 (en) |
BG (1) | BG66209B1 (en) |
BR (1) | BR0112026A (en) |
CA (1) | CA2411374C (en) |
CZ (1) | CZ2003291A3 (en) |
DE (1) | DE60137421D1 (en) |
EC (1) | ECSP024409A (en) |
ES (1) | ES2319866T3 (en) |
HK (1) | HK1055316A1 (en) |
HU (1) | HUP0301002A3 (en) |
IL (3) | IL153567A0 (en) |
MX (1) | MXPA02012867A (en) |
NO (1) | NO20026239L (en) |
NZ (1) | NZ523080A (en) |
PE (1) | PE20020132A1 (en) |
PL (1) | PL208069B1 (en) |
SK (1) | SK1152003A3 (en) |
TW (2) | TW200516083A (en) |
UY (1) | UY26807A1 (en) |
WO (1) | WO2002002773A2 (en) |
ZA (1) | ZA200210109B (en) |
Cited By (131)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006038027A2 (en) | 2004-10-08 | 2006-04-13 | Domantis Limited | SINGLE DOMAIN ANTIBODIES AGAINST TNFRl AND METHODS OF USE THEREFOR |
EP1747015A2 (en) * | 2004-04-26 | 2007-01-31 | Centocor, Inc. | Solution phase biopanning method using engineered decoy proteins |
WO2008027236A3 (en) * | 2006-08-30 | 2008-12-18 | Genentech Inc | Multispecific antibodies |
US7514539B2 (en) | 2004-04-26 | 2009-04-07 | Centocor, Inc. | Epitope directed selection of antibodies to murine tissue factor |
US7566772B2 (en) | 2005-01-26 | 2009-07-28 | Amgen Fremont Inc. | Antibodies against interleukin-1β |
EP2114443A2 (en) * | 2006-12-29 | 2009-11-11 | Abbott Laboratories | Dual-specific il-1a/ il-1b antibodies |
US7696320B2 (en) | 2004-08-24 | 2010-04-13 | Domantis Limited | Ligands that have binding specificity for VEGF and/or EGFR and methods of use therefor |
US7790405B2 (en) | 2004-04-26 | 2010-09-07 | Centocor, Inc. | Solution phase biopanning method using engineered decoy proteins |
EP2262840A2 (en) * | 2008-03-03 | 2010-12-22 | Dyax Corp. | Metalloproteinase 9 and metalloproteinase 2 binding proteins |
WO2011025964A2 (en) | 2009-08-29 | 2011-03-03 | Abbott Laboratories | Therapeutic dll4 binding proteins |
WO2011036460A1 (en) | 2009-09-25 | 2011-03-31 | Ucb Pharma S.A. | Disulfide stabilised multivalent antibodies |
EP2364999A2 (en) | 2001-06-28 | 2011-09-14 | Domantis Limited | Dual-specific ligand and its use |
WO2012006500A2 (en) | 2010-07-08 | 2012-01-12 | Abbott Laboratories | Monoclonal antibodies against hepatitis c virus core protein |
US8193321B2 (en) | 2008-09-03 | 2012-06-05 | Genentech, Inc. | Multispecific antibodies |
EP2495257A2 (en) | 2005-08-19 | 2012-09-05 | Abbott Laboratories | Dual variable domain immunoglobulin and uses thereof |
WO2012121775A2 (en) | 2010-12-21 | 2012-09-13 | Abbott Laboratories | Dual variable domain immunoglobulins and uses thereof |
EP2500354A2 (en) | 2005-08-19 | 2012-09-19 | Abbott Laboratories | Dual variable domain immunoglobulin and uses thereof |
WO2012163521A1 (en) | 2011-05-27 | 2012-12-06 | Dutalys | Removal of monomeric targets |
WO2012163520A1 (en) | 2011-05-27 | 2012-12-06 | Dutalys | Dual targeting |
EP2535349A1 (en) | 2007-09-26 | 2012-12-19 | UCB Pharma S.A. | Dual specificity antibody fusions |
WO2012176779A1 (en) | 2011-06-20 | 2012-12-27 | 協和発酵キリン株式会社 | Anti-erbb3 antibody |
US20130004416A1 (en) * | 2005-08-19 | 2013-01-03 | Abbott Laboratories | Dual Variable Domain Immunoglobulin and Uses Thereof |
EP2559703A1 (en) | 2007-02-08 | 2013-02-20 | Domantis Limited | Antibody single variable domains against serum albumin |
US8409577B2 (en) | 2006-06-12 | 2013-04-02 | Emergent Product Development Seattle, Llc | Single chain multivalent binding proteins with effector function |
WO2013063095A1 (en) | 2011-10-24 | 2013-05-02 | Abbvie Inc. | Immunobinders directed against sclerostin |
WO2013063110A1 (en) | 2011-10-24 | 2013-05-02 | Abbvie Inc. | Bispecific immunobinders directed against tnf and il-17 |
US8455205B2 (en) | 2008-03-03 | 2013-06-04 | Dyax Corp. | Metalloproteinase 9 binding proteins |
WO2013090635A2 (en) | 2011-12-14 | 2013-06-20 | AbbVie Deutschland GmbH & Co. KG | Composition and method for the diagnosis and treatment of iron-related disorders |
WO2013090633A2 (en) | 2011-12-14 | 2013-06-20 | AbbVie Deutschland GmbH & Co. KG | Composition and method for the diagnosis and treatment of iron-related disorders |
US8475766B2 (en) | 2000-06-29 | 2013-07-02 | Abbvie Inc. | Dual specificity antibodies and methods of making and using |
WO2013102042A2 (en) | 2011-12-30 | 2013-07-04 | Abbvie Inc. | Dual specific binding proteins directed against il-13 and/or il-17 |
WO2013112922A1 (en) | 2012-01-27 | 2013-08-01 | AbbVie Deutschland GmbH & Co. KG | Composition and method for diagnosis and treatment of diseases associated with neurite degeneration |
US8501181B2 (en) | 2007-12-17 | 2013-08-06 | Dyax Corp. | Compositions and methods for treating osteolytic disorders comprising MMP-14 binding proteins |
US8586714B2 (en) | 2009-09-01 | 2013-11-19 | Abbvie, Inc. | Dual variable domain immunoglobulins and uses thereof |
EP2679996A1 (en) | 2007-05-31 | 2014-01-01 | AbbVie Inc. | Biomarkers predictive of the responsiveness to TNF-alfa inhibitors in autoimmune disorders |
US8623367B2 (en) | 2008-12-10 | 2014-01-07 | Novartis Ag | Antibody formulation |
WO2014011955A2 (en) | 2012-07-12 | 2014-01-16 | Abbvie, Inc. | Il-1 binding proteins |
US8716450B2 (en) | 2009-10-15 | 2014-05-06 | Abbvie Inc. | Dual variable domain immunoglobulins and uses thereof |
WO2014071074A2 (en) | 2012-11-01 | 2014-05-08 | Abbvie Inc. | Anti-vegf/dll4 dual variable domain immunoglobulins and uses thereof |
US8722855B2 (en) | 2009-10-28 | 2014-05-13 | Abbvie Inc. | Dual variable domain immunoglobulins and uses thereof |
US8735546B2 (en) | 2010-08-03 | 2014-05-27 | Abbvie Inc. | Dual variable domain immunoglobulins and uses thereof |
WO2014089209A2 (en) | 2012-12-04 | 2014-06-12 | Abbvie, Inc. | Blood-brain barrier (bbb) penetrating dual specific binding proteins |
WO2014106001A2 (en) | 2012-12-28 | 2014-07-03 | Abbvie, Inc. | Dual specific binding proteins having a receptor sequence |
WO2014106004A2 (en) | 2012-12-28 | 2014-07-03 | Abbvie, Inc. | High-throughput system and method for identifying antibodies having specific antigen binding activities |
WO2014071212A3 (en) * | 2012-11-01 | 2014-07-31 | Abbvie Inc. | Stable dual variable domain immunoglobulin protein formulations |
WO2014116846A2 (en) | 2013-01-23 | 2014-07-31 | Abbvie, Inc. | Methods and compositions for modulating an immune response |
US8822645B2 (en) | 2008-07-08 | 2014-09-02 | Abbvie Inc. | Prostaglandin E2 dual variable domain immunoglobulins and uses thereof |
EP2772269A2 (en) | 2009-03-05 | 2014-09-03 | Abbvie Inc. | IL-17 binding proteins |
WO2014144355A2 (en) | 2013-03-15 | 2014-09-18 | Abbott Laboratories | Anti-gp73 monoclonal antibodies and methods of obtaining the same |
WO2014144299A2 (en) | 2013-03-15 | 2014-09-18 | Abbvie Inc. | DUAL SPECIFIC BINDING PROTEINS DIRECTED AGAINST TNFα |
US8853366B2 (en) | 2001-01-17 | 2014-10-07 | Emergent Product Development Seattle, Llc | Binding domain-immunoglobulin fusion proteins |
US8906864B2 (en) | 2005-09-30 | 2014-12-09 | AbbVie Deutschland GmbH & Co. KG | Binding domains of proteins of the repulsive guidance molecule (RGM) protein family and functional fragments thereof, and their use |
US8921528B2 (en) | 2004-06-01 | 2014-12-30 | Domantis Limited | Bispecific fusion antibodies with enhanced serum half-life |
US8987418B2 (en) | 2013-03-15 | 2015-03-24 | Abbvie Inc. | Dual specific binding proteins directed against IL-1β and/or IL-17 |
WO2015039212A1 (en) | 2013-09-17 | 2015-03-26 | University Health Network (Uhn): Technology Development And Commercialization | Agents directed against a cis rgma/neogenin interaction or lipid rafts and use of the same in methods of treatment |
US9029508B2 (en) | 2008-04-29 | 2015-05-12 | Abbvie Inc. | Dual variable domain immunoglobulins and uses thereof |
US9028822B2 (en) | 2002-06-28 | 2015-05-12 | Domantis Limited | Antagonists against TNFR1 and methods of use therefor |
US9035027B2 (en) | 2008-06-03 | 2015-05-19 | Abbvie Inc. | Dual variable domain immunoglobulins and uses thereof |
US9046513B2 (en) | 2010-08-26 | 2015-06-02 | Abbvie Inc. | Dual variable domain immunoglobulins and uses thereof |
US9101609B2 (en) | 2008-04-11 | 2015-08-11 | Emergent Product Development Seattle, Llc | CD37 immunotherapeutic and combination with bifunctional chemotherapeutic thereof |
US9109026B2 (en) | 2008-06-03 | 2015-08-18 | Abbvie, Inc. | Dual variable domain immunoglobulins and uses thereof |
US9115195B2 (en) | 2010-03-02 | 2015-08-25 | Abbvie Inc. | Therapeutic DLL4 binding proteins |
EP2915818A2 (en) | 2011-12-30 | 2015-09-09 | AbbVie Inc. | Dual variable domain immunoglobulins and uses thereof |
EP2921177A2 (en) | 2010-07-09 | 2015-09-23 | AbbVie Inc. | Dual variable domain immunoglobulins and uses thereof |
US9163082B2 (en) | 2006-12-20 | 2015-10-20 | Xoma (Us) Llc | Methods for the treatment of IL-1β related diseases |
US9175075B2 (en) | 2009-12-08 | 2015-11-03 | AbbVie Deutschland GmbH & Co. KG | Methods of treating retinal nerve fiber layer degeneration with monoclonal antibodies against a retinal guidance molecule (RGM) protein |
WO2015191783A2 (en) | 2014-06-10 | 2015-12-17 | Abbvie Inc. | Biomarkers for inflammatory disease and methods of using same |
WO2015191934A2 (en) | 2014-06-11 | 2015-12-17 | Abbvie Inc. | Blood-brain barrier (bbb) penetrating dual specific binding proteins for treating brain and neurological diseases |
EP2985294A1 (en) | 2014-08-14 | 2016-02-17 | Deutsches Krebsforschungszentrum | Recombinant antibody molecule and its use for target cell restricted T cell activation |
WO2016094881A2 (en) | 2014-12-11 | 2016-06-16 | Abbvie Inc. | Lrp-8 binding proteins |
WO2017044862A1 (en) | 2015-09-11 | 2017-03-16 | Abbvie Inc. | Methods for treating relapsing forms of multiple sclerosis |
US9605069B2 (en) | 2008-02-29 | 2017-03-28 | AbbVie Deutschland GmbH & Co. KG | Antibodies against the RGM a protein and uses thereof |
US9637557B2 (en) | 2010-04-23 | 2017-05-02 | Genentech, Inc. | Production of heteromultimeric proteins |
WO2017156500A1 (en) | 2016-03-11 | 2017-09-14 | Scholar Rock, Inc. | Tgfb1-binding immunoglobulins and use thereof |
WO2017210278A1 (en) | 2016-06-01 | 2017-12-07 | Abbvie Inc. | Anti-repulsive guidance molecule a (rgma) antagonistic antibodies for treating spinal cord injury and pain |
US9840554B2 (en) | 2015-06-15 | 2017-12-12 | Abbvie Inc. | Antibodies against platelet-derived growth factor (PDGF) |
US9856319B2 (en) | 2012-12-28 | 2018-01-02 | Abbvie Inc. | Monovalent binding proteins |
WO2018067474A1 (en) | 2016-10-03 | 2018-04-12 | Abbott Laboratories | Improved methods of assessing gfap status in patient samples |
WO2018129329A1 (en) | 2017-01-06 | 2018-07-12 | Scholar Rock, Inc. | ISOFORM-SPECIFIC, CONTEXT-PERMISSIVE TGFβ1 INHIBITORS AND USE THEREOF |
WO2018175942A1 (en) | 2017-03-23 | 2018-09-27 | Abbott Laboratories | Methods for aiding in the diagnosis and determination of the extent of traumatic brain injury in a human subject using the early biomarker ubiquitin carboxy-terminal hydrolase l1 |
WO2018191531A1 (en) | 2017-04-15 | 2018-10-18 | Abbott Laboratories | Methods for aiding in the hyperacute diagnosis and determination of traumatic brain injury in a human subject using early biomarkers |
WO2018200823A1 (en) | 2017-04-28 | 2018-11-01 | Abbott Laboratories | Methods for aiding in the hyperacute diagnosis and determination of traumatic brain injury using early biomarkers on at least two samples from the same human subject |
WO2018218169A1 (en) | 2017-05-25 | 2018-11-29 | Abbott Laboratories | Methods for aiding in the determination of whether to perform imaging on a human subject who has sustained or may have sustained an injury to the head using early biomarkers |
US10143748B2 (en) | 2005-07-25 | 2018-12-04 | Aptevo Research And Development Llc | B-cell reduction using CD37-specific and CD20-specific binding molecules |
WO2018222784A1 (en) | 2017-05-30 | 2018-12-06 | Abbott Laboratories | Methods for aiding in diagnosing and evaluating a mild traumatic brain injury in a human subject using cardiac troponin i |
WO2019010131A1 (en) | 2017-07-03 | 2019-01-10 | Abbott Laboratories | Improved methods for measuring ubiquitin carboxy-terminal hydrolase l1 levels in blood |
US10183988B2 (en) | 2013-06-07 | 2019-01-22 | Duke University | Anti-Complement factor H antibodies |
WO2019093342A1 (en) | 2017-11-08 | 2019-05-16 | 協和発酵キリン株式会社 | BISPECIFIC ANTIBODY WHICH BINDS TO CD40 AND EpCAM |
US10314909B2 (en) | 2011-10-21 | 2019-06-11 | Dyax Corp. | Combination therapy comprising an MMP-14 binding protein |
WO2019112860A1 (en) | 2017-12-09 | 2019-06-13 | Abbott Laboratories | Methods for aiding in diagnosing and evaluating a traumatic brain injury in a human subject using a combination of gfap and uch-l1 |
WO2019113525A2 (en) | 2017-12-09 | 2019-06-13 | Abbott Laboratories | Methods for aiding in the diagnosis and evaluation of a subject who has sustained an orthopedic injury and that has or may have sustained an injury to the head, such as mild traumatic brain injury (tbi), using glial fibrillary acidic protein (gfap) and/or ubiquitin carboxy-terminal hydrolase l1 (uch-l1) |
WO2019133717A1 (en) | 2017-12-29 | 2019-07-04 | Abbott Laboratories | Novel biomarkers and methods for diagnosing and evaluating traumatic brain injury |
US10407513B2 (en) | 2008-09-26 | 2019-09-10 | Ucb Biopharma Sprl | Biological products |
US10501737B2 (en) | 2013-09-30 | 2019-12-10 | Chugai Seiyaku Kabushiki Kaisha | Method for producing antigen-binding molecule using modified helper phage |
WO2020014460A1 (en) | 2018-07-11 | 2020-01-16 | Scholar Rock, Inc. | HIGH-AFFINITY, ISOFORM-SELECTIVE TGFβ1 INHIBITORS AND USE THEREOF |
WO2020014473A1 (en) | 2018-07-11 | 2020-01-16 | Scholar Rock, Inc. | TGFβ1 INHIBITORS AND USE THEREOF |
US10683348B2 (en) | 2013-12-20 | 2020-06-16 | Genentech, Inc. | Dual specific antibodies |
WO2020138487A1 (en) | 2018-12-28 | 2020-07-02 | 協和キリン株式会社 | BISPECIFIC ANTIBODY BINDING TO TfR |
EP3677278A1 (en) | 2018-07-11 | 2020-07-08 | Scholar Rock, Inc. | Isoform selective tgfbeta1 inhibitors and use thereof |
US10718762B2 (en) | 2015-10-02 | 2020-07-21 | Hoffmann-La Roche Inc. | Cellular based fret assay for the determination of simultaneous binding |
WO2020180695A1 (en) | 2019-03-01 | 2020-09-10 | Abbott Laboratories | Methods for predicting major adverse cardiovascular events in subjects with coronary artery disease |
WO2020230899A1 (en) | 2019-05-15 | 2020-11-19 | 協和キリン株式会社 | Bispecific antibody binding to cd40 and fap |
WO2020230901A1 (en) | 2019-05-15 | 2020-11-19 | 協和キリン株式会社 | Bispecific antibody capable of binding to cd40 and gpc3 |
US10865238B1 (en) | 2017-05-05 | 2020-12-15 | Duke University | Complement factor H antibodies |
WO2021142448A2 (en) | 2020-01-11 | 2021-07-15 | Scholar Rock,Inc. | Tgf-beta inhibitors and use thereof |
WO2021142427A1 (en) | 2020-01-11 | 2021-07-15 | Scholar Rock, Inc. | TGFβ INHIBITORS AND USE THEREOF |
US11130810B2 (en) | 2015-10-02 | 2021-09-28 | Hoffmann-La Roche Inc. | Bispecific antibodies specific for PD1 and TIM3 |
WO2021211331A1 (en) | 2020-04-13 | 2021-10-21 | Abbott Point Of Care Inc. | METHODS, COMPLEXES AND KITS FOR DETECTING OR DETERMINING AN AMOUNT OF A ß-CORONAVIRUS ANTIBODY IN A SAMPLE |
US11219645B2 (en) | 2015-11-18 | 2022-01-11 | Duke University | Tumor infiltrating lymphocytes for treatment of cancer |
WO2022031804A1 (en) | 2020-08-04 | 2022-02-10 | Abbott Laboratories | Improved methods and kits for detecting sars-cov-2 protein in a sample |
US11285207B2 (en) | 2017-04-05 | 2022-03-29 | Hoffmann-La Roche Inc. | Bispecific antibodies specifically binding to PD1 and LAG3 |
US11352426B2 (en) | 2015-09-21 | 2022-06-07 | Aptevo Research And Development Llc | CD3 binding polypeptides |
WO2022119841A1 (en) | 2020-12-01 | 2022-06-09 | Abbott Laboratories | Use of one or more biomarkers to determine traumatic brain injury (tbi) in a subject having received a head computerized tomography scan that is negative for a tbi |
WO2022147147A1 (en) | 2020-12-30 | 2022-07-07 | Abbott Laboratories | Methods for determining sars-cov-2 antigen and anti-sars-cov-2 antibody in a sample |
US11413331B2 (en) | 2017-04-03 | 2022-08-16 | Hoffmann-La Roche Inc. | Immunoconjugates |
WO2022204581A2 (en) | 2021-03-26 | 2022-09-29 | Scholar Rock, Inc. | Tgf-beta inhibitors and use thereof |
WO2022245920A1 (en) | 2021-05-18 | 2022-11-24 | Abbott Laboratories | Methods of evaluating brain injury in a pediatric subject |
WO2022256723A2 (en) | 2021-06-03 | 2022-12-08 | Scholar Rock, Inc. | Tgf-beta inhibitors and therapeutic use thereof |
WO2022266034A1 (en) | 2021-06-14 | 2022-12-22 | Abbott Laboratories | Methods of diagnosing or aiding in diagnosis of brain injury caused by acoustic energy, electromagnetic energy, an over pressurization wave, and/or blast wind |
EP4116427A1 (en) | 2012-05-17 | 2023-01-11 | Kymab Limited | In vivo guided selection & antibodies |
WO2023288277A1 (en) | 2021-07-14 | 2023-01-19 | Scholar Rock, Inc. | Ltbp complex-specific inhibitors of tgfb1 and uses thereof |
WO2023034777A1 (en) | 2021-08-31 | 2023-03-09 | Abbott Laboratories | Methods and systems of diagnosing brain injury |
WO2023056268A1 (en) | 2021-09-30 | 2023-04-06 | Abbott Laboratories | Methods and systems of diagnosing brain injury |
WO2023102384A1 (en) | 2021-11-30 | 2023-06-08 | Abbott Laboratories | Use of one or more biomarkers to determine traumatic brain injury (tbi) in a subject having received a head computerized tomography scan that is negative for a tbi |
WO2023114978A1 (en) | 2021-12-17 | 2023-06-22 | Abbott Laboratories | Systems and methods for determining uch-l1, gfap, and other biomarkers in blood samples |
WO2023129942A1 (en) | 2021-12-28 | 2023-07-06 | Abbott Laboratories | Use of biomarkers to determine sub-acute traumatic brain injury (tbi) in a subject having received a head computerized tomography (ct) scan that is negative for a tbi or no head ct scan |
WO2023150652A1 (en) | 2022-02-04 | 2023-08-10 | Abbott Laboratories | Lateral flow methods, assays, and devices for detecting the presence or measuring the amount of ubiquitin carboxy-terminal hydrolase l1 and/or glial fibrillary acidic protein in a sample |
WO2024006876A1 (en) | 2022-06-29 | 2024-01-04 | Abbott Laboratories | Magnetic point-of-care systems and assays for determining gfap in biological samples |
US11932673B2 (en) | 2017-07-12 | 2024-03-19 | Maxion Therapeutics Limited | Sodium channel inhibitors |
WO2024059708A1 (en) | 2022-09-15 | 2024-03-21 | Abbott Laboratories | Biomarkers and methods for differentiating between mild and supermild traumatic brain injury |
US12030926B2 (en) | 2014-05-06 | 2024-07-09 | Genentech, Inc. | Production of heteromultimeric proteins using mammalian cells |
Families Citing this family (42)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002510974A (en) * | 1997-06-27 | 2002-04-09 | ヒューマン ジノーム サイエンシーズ,インコーポレイテッド | Human NK-3-related prostate specific gene-1 |
DE60237282D1 (en) * | 2001-06-28 | 2010-09-23 | Domantis Ltd | DOUBLE-SPECIFIC LIGAND AND ITS USE |
US20070104710A1 (en) * | 2002-06-28 | 2007-05-10 | Domants Limited | Ligand that has binding specificity for IL-4 and/or IL-13 |
DK1523496T3 (en) | 2002-07-18 | 2011-10-17 | Merus B V | Recombinant preparation of mixture of antibodies |
USRE47770E1 (en) | 2002-07-18 | 2019-12-17 | Merus N.V. | Recombinant production of mixtures of antibodies |
US20050271660A1 (en) * | 2002-09-06 | 2005-12-08 | Alexion Pharmaceuticals, Inc. | Nebulization of monoclonal antibodies for treating pulmonary diseases |
US20110223168A1 (en) * | 2002-12-27 | 2011-09-15 | Greg Winter | Ligand that has binding specificity for il-4 and/or il-13 |
GB0230201D0 (en) * | 2002-12-27 | 2003-02-05 | Domantis Ltd | Retargeting |
ES2408582T3 (en) | 2003-05-30 | 2013-06-21 | Merus B.V. | Fab library for the preparation of a mixture of antibodies |
US20100069614A1 (en) | 2008-06-27 | 2010-03-18 | Merus B.V. | Antibody producing non-human mammals |
WO2005068622A2 (en) | 2004-01-20 | 2005-07-28 | Merus B.V. | Mixtures of binding proteins |
EP2990053A1 (en) * | 2004-01-20 | 2016-03-02 | KaloBios Pharmaceuticals, Inc. | Antibody specificity transfer using minimal essential binding determinants |
TWI439284B (en) | 2004-04-09 | 2014-06-01 | Abbvie Biotechnology Ltd | Multiple-variable dose regimen for treating tnfα-related disorders |
KR100675791B1 (en) * | 2005-02-04 | 2007-02-02 | 제주대학교 산학협력단 | Automatic feeding system for the fish breeding in landscape |
EP1879921B1 (en) | 2005-05-12 | 2011-04-27 | Crucell Holland B.V. | Host cell specific binding molecules capable of neutralizing viruses and uses thereof |
US20090130652A1 (en) * | 2005-06-23 | 2009-05-21 | Crucell Holland B.V. | Optimization of West Nile Virus Antibodies |
EP1940880A2 (en) * | 2005-10-14 | 2008-07-09 | Novo Nordisk A/S | Treating diabetes using inhibitors of il-1 |
AU2007238677B2 (en) * | 2006-04-14 | 2011-03-10 | Novartis Ag | Use of IL-I antibodies for treating ophthalmic disorders |
WO2007141274A2 (en) * | 2006-06-06 | 2007-12-13 | Crucell Holland B.V. | Human binding molecules having killing activity against staphylococci and uses thereof |
WO2008016680A1 (en) * | 2006-08-02 | 2008-02-07 | California Institute Of Technology | Methods and systems for detecting and/or sorting targets |
US20100260668A1 (en) * | 2008-04-29 | 2010-10-14 | Abbott Laboratories | Dual Variable Domain Immunoglobulins and Uses Thereof |
JP2012502058A (en) * | 2008-09-05 | 2012-01-26 | ゾーマ テクノロジー リミテッド | Methods for improving beta cell function |
US8242074B2 (en) * | 2008-09-12 | 2012-08-14 | Xbiotech, Inc. | Modulation of the amount or function of pathogenic CD14+CD16+ monocytes |
CA2749966A1 (en) * | 2009-01-29 | 2010-08-05 | Abbott Laboratories | Il-1 binding proteins |
PE20120591A1 (en) * | 2009-04-02 | 2012-05-23 | Roche Glycart Ag | MULTI-SPECIFIC ANTIBODIES INCLUDING FULL-LENGTH ANTIBODIES AND SINGLE-CHAIN FAB FRAGMENTS |
CN101957365B (en) * | 2009-07-21 | 2013-08-07 | 卫生部北京医院 | Kit for detecting cyclic citrullinated peptide (CCP) and immunoglobulin G (IgG) resistant bispecific antibody |
TW201109438A (en) * | 2009-07-29 | 2011-03-16 | Abbott Lab | Dual variable domain immunoglobulins and uses thereof |
RU2012119788A (en) * | 2009-10-15 | 2013-11-20 | Эбботт Лэборетриз | BINDING IL-1 PROTEINS |
EP2523974A4 (en) * | 2010-01-12 | 2013-11-06 | Oncomed Pharm Inc | Wnt-binding agents and uses thereof |
EP2571532B1 (en) | 2010-05-14 | 2017-05-03 | Abbvie Inc. | Il-1 binding proteins |
EP2603525A1 (en) * | 2010-08-13 | 2013-06-19 | F.Hoffmann-La Roche Ag | Antibodies to il-1beta and il-18, for treatment of disease |
SG192694A1 (en) * | 2011-02-08 | 2013-09-30 | Abbvie Inc | Treatment of osteoarthritis and pain |
PE20141941A1 (en) * | 2011-11-21 | 2014-12-28 | Abbvie Inc | PROTEINS THAT MAY BIND IL-1 |
RU2482181C1 (en) * | 2011-12-07 | 2013-05-20 | Учреждение Российской академии медицинских наук Российский онкологический научный центр имени Н.Н. Блохина РАМН | D11 human multiple myeloma cell line used for monoclonal antibody technology |
KR101963230B1 (en) | 2011-12-26 | 2019-03-29 | 삼성전자주식회사 | Protein complex comprising multi-specific monoclonal antibodies |
EP3594232A1 (en) | 2012-04-20 | 2020-01-15 | Merus N.V. | Methods and means for the production of ig-like molecules |
KR101911438B1 (en) | 2012-10-31 | 2018-10-24 | 삼성전자주식회사 | Bispecific antigen binding protein complex and preparation methods of bispecific antibodies |
CN103308697B (en) * | 2013-06-09 | 2014-11-26 | 卫生部北京医院 | Kit used for detecting natural bispecific antibody resistant to HCV (hepatitis C virus) coded non-structural proteins NS3 and NS5 |
US9879081B2 (en) | 2013-06-25 | 2018-01-30 | Samsung Electronics Co., Ltd. | Protein complex, bispecific antibody including the protein complex, and method of preparation thereof |
JP6655302B2 (en) * | 2015-05-29 | 2020-02-26 | デンカ生研株式会社 | Method for detecting subject, immunoassay instrument and monoclonal antibody therefor |
CN111793131A (en) * | 2020-05-11 | 2020-10-20 | 廊坊天光生物技术有限公司 | Antibody pair for detecting content of PF4 in serum and application thereof |
WO2023019019A2 (en) * | 2021-08-13 | 2023-02-16 | Abwiz Bio, Inc. | Humanization, affinity maturation, and optimization methods for proteins and antibodies |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998020159A1 (en) * | 1996-11-07 | 1998-05-14 | Ramot University Authority For Applied Research & Industrial Development Ltd. | Representations of bimolecular interactions |
US5756095A (en) * | 1992-05-22 | 1998-05-26 | The Research And Development Institute, Inc. | Antibodies with specificity for a common epitope on E-selectin and L-selectin |
Family Cites Families (49)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US126603A (en) | 1872-05-07 | Improvement in machines for sawing staves | ||
US4399216A (en) | 1980-02-25 | 1983-08-16 | The Trustees Of Columbia University | Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials |
US4634665A (en) | 1980-02-25 | 1987-01-06 | The Trustees Of Columbia University In The City Of New York | Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials |
US5179017A (en) | 1980-02-25 | 1993-01-12 | The Trustees Of Columbia University In The City Of New York | Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials |
US4510245A (en) | 1982-11-18 | 1985-04-09 | Chiron Corporation | Adenovirus promoter system |
GB8308235D0 (en) | 1983-03-25 | 1983-05-05 | Celltech Ltd | Polypeptides |
US5168062A (en) | 1985-01-30 | 1992-12-01 | University Of Iowa Research Foundation | Transfer vectors and microorganisms containing human cytomegalovirus immediate-early promoter-regulatory DNA sequence |
FR2577377B1 (en) * | 1985-02-21 | 1989-06-16 | Albaret Sa | METHOD FOR AVOIDING THE SKATING OF A TRACTOR EQUIPPED WITH A HYDRAULIC LIFTING WITH A TOOL BURIED IN THE GROUND, AND TRACTOR EQUIPMENT FOR IMPLEMENTING THIS METHOD |
US4772685A (en) * | 1985-10-02 | 1988-09-20 | Merck & Co., Inc. | Immunogenic peptides of human interleukin-1 and the corresponding anti-peptide antibodies |
US4968615A (en) | 1985-12-18 | 1990-11-06 | Ciba-Geigy Corporation | Deoxyribonucleic acid segment from a virus |
US5223409A (en) | 1988-09-02 | 1993-06-29 | Protein Engineering Corp. | Directed evolution of novel binding proteins |
EP1997891A1 (en) | 1988-09-02 | 2008-12-03 | Dyax Corporation | Generation and selection of recombinant varied binding proteins |
ATE102631T1 (en) | 1988-11-11 | 1994-03-15 | Medical Res Council | CLONING OF IMMUNOGLOBULIN SEQUENCES FROM THE VARIABLE DOMAINS. |
WO1991010741A1 (en) | 1990-01-12 | 1991-07-25 | Cell Genesys, Inc. | Generation of xenogeneic antibodies |
WO1996033735A1 (en) | 1995-04-27 | 1996-10-31 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
US5427908A (en) | 1990-05-01 | 1995-06-27 | Affymax Technologies N.V. | Recombinant library screening methods |
DK0585287T3 (en) | 1990-07-10 | 2000-04-17 | Cambridge Antibody Tech | Process for producing specific binding pair elements |
GB9015198D0 (en) | 1990-07-10 | 1990-08-29 | Brien Caroline J O | Binding substance |
CA2090126C (en) | 1990-08-02 | 2002-10-22 | John W. Schrader | Methods for the production of proteins with a desired function |
US5545806A (en) | 1990-08-29 | 1996-08-13 | Genpharm International, Inc. | Ransgenic non-human animals for producing heterologous antibodies |
US5625126A (en) | 1990-08-29 | 1997-04-29 | Genpharm International, Inc. | Transgenic non-human animals for producing heterologous antibodies |
US6255458B1 (en) | 1990-08-29 | 2001-07-03 | Genpharm International | High affinity human antibodies and human antibodies against digoxin |
US5877397A (en) | 1990-08-29 | 1999-03-02 | Genpharm International Inc. | Transgenic non-human animals capable of producing heterologous antibodies of various isotypes |
EP0546073B1 (en) | 1990-08-29 | 1997-09-10 | GenPharm International, Inc. | production and use of transgenic non-human animals capable of producing heterologous antibodies |
US5770429A (en) | 1990-08-29 | 1998-06-23 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
US5633425A (en) | 1990-08-29 | 1997-05-27 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
US5661016A (en) | 1990-08-29 | 1997-08-26 | Genpharm International Inc. | Transgenic non-human animals capable of producing heterologous antibodies of various isotypes |
US5814318A (en) | 1990-08-29 | 1998-09-29 | Genpharm International Inc. | Transgenic non-human animals for producing heterologous antibodies |
CA2405246A1 (en) | 1990-12-03 | 1992-06-11 | Genentech, Inc. | Enrichment method for variant proteins with alterred binding properties |
DE69233782D1 (en) | 1991-12-02 | 2010-05-20 | Medical Res Council | Preparation of Autoantibodies on Phage Surfaces Starting from Antibody Segment Libraries |
US5622701A (en) * | 1994-06-14 | 1997-04-22 | Protein Design Labs, Inc. | Cross-reacting monoclonal antibodies specific for E- and P-selectin |
EP0766564A4 (en) * | 1994-06-24 | 1998-09-23 | Immunex Corp | Controlled release polypeptide compositions and methods of treating inflammatory bowel disease |
WO1996034096A1 (en) | 1995-04-28 | 1996-10-31 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
PT859841E (en) | 1995-08-18 | 2002-11-29 | Morphosys Ag | PROTEIN LIBRARIES / (POLY) PEPTIDES |
SI9720020B (en) | 1996-02-09 | 2001-12-31 | Basf Ag | Human antibodies that bind human TNF alpha |
US6300065B1 (en) | 1996-05-31 | 2001-10-09 | Board Of Trustees Of The University Of Illinois | Yeast cell surface display of proteins and uses thereof |
JP4215172B2 (en) | 1996-12-03 | 2009-01-28 | アムジェン フレモント インク. | Transgenic mammal having human Ig locus comprising a plurality of V {lower H} and V {lower κ} regions, and antibodies produced therefrom |
EP0971946B1 (en) | 1997-01-21 | 2006-07-05 | The General Hospital Corporation | Selection of proteins using rna-protein fusions |
JP2002514919A (en) | 1997-04-04 | 2002-05-21 | バイオサイト ダイアグノスティックス,インコーポレイテッド | Multivalent and polyclonal libraries |
WO1998049286A2 (en) | 1997-05-01 | 1998-11-05 | Board Of Regents, The University Of Texas System | Directed evolution of enzymes and antibodies |
US20020029391A1 (en) | 1998-04-15 | 2002-03-07 | Claude Geoffrey Davis | Epitope-driven human antibody production and gene expression profiling |
US6680380B1 (en) | 1998-09-18 | 2004-01-20 | Schering Corporation | Nucleic acids encoding mammalian interleukin-1ζ, related reagents and methods |
CZ303725B6 (en) | 1999-03-25 | 2013-04-03 | Abbott Gmbh & Co. Kg | Human antibodies binding to human IL-12, and processes for preparing thereof |
GB0001448D0 (en) | 2000-01-21 | 2000-03-08 | Novartis Ag | Organic compounds |
KR20080074231A (en) | 2000-06-29 | 2008-08-12 | 아보트 러보러터리즈 | Dual specificity antibodies and methods of making and using |
DE60237282D1 (en) | 2001-06-28 | 2010-09-23 | Domantis Ltd | DOUBLE-SPECIFIC LIGAND AND ITS USE |
ES2263984T3 (en) | 2002-06-28 | 2006-12-16 | Domantis Limited | DOUBLE-SPECIFIC LINKS WITH AN INCREASED SERIOUS MIDDLE LIFE. |
WO2007063308A2 (en) | 2005-12-01 | 2007-06-07 | Domantis Limited | Noncompetitive domain antibody formats that bind interleukin 1 receptor type 1 |
US8324350B2 (en) | 2006-12-29 | 2012-12-04 | Abbott Laboratories | Dual-specific IL-1α/IL-1β antibodies |
-
2001
- 2001-06-28 KR KR1020087018593A patent/KR20080074231A/en not_active Application Discontinuation
- 2001-06-28 EP EP09150437A patent/EP2042518A3/en not_active Withdrawn
- 2001-06-28 AU AU2001271636A patent/AU2001271636A1/en not_active Abandoned
- 2001-06-28 PE PE2001000641A patent/PE20020132A1/en not_active Application Discontinuation
- 2001-06-28 SK SK115-2003A patent/SK1152003A3/en not_active Application Discontinuation
- 2001-06-28 NZ NZ523080A patent/NZ523080A/en not_active IP Right Cessation
- 2001-06-28 KR KR1020027017916A patent/KR100919593B1/en not_active IP Right Cessation
- 2001-06-28 DE DE60137421T patent/DE60137421D1/en not_active Expired - Lifetime
- 2001-06-28 ES ES01950668T patent/ES2319866T3/en not_active Expired - Lifetime
- 2001-06-28 EP EP10182393A patent/EP2386575A3/en not_active Withdrawn
- 2001-06-28 CA CA2411374A patent/CA2411374C/en not_active Expired - Fee Related
- 2001-06-28 CZ CZ2003291A patent/CZ2003291A3/en unknown
- 2001-06-28 US US09/894,550 patent/US7491516B2/en not_active Expired - Fee Related
- 2001-06-28 HU HU0301002A patent/HUP0301002A3/en unknown
- 2001-06-28 EP EP15154039.0A patent/EP2899210A3/en not_active Withdrawn
- 2001-06-28 IL IL15356701A patent/IL153567A0/en unknown
- 2001-06-28 CN CN2010105838125A patent/CN102120773B/en not_active Expired - Fee Related
- 2001-06-28 CN CNA2009101351381A patent/CN101525384A/en active Pending
- 2001-06-28 JP JP2002508013A patent/JP4955185B2/en not_active Expired - Fee Related
- 2001-06-28 BR BR0112026-3A patent/BR0112026A/en not_active IP Right Cessation
- 2001-06-28 PL PL359995A patent/PL208069B1/en not_active IP Right Cessation
- 2001-06-28 AT AT01950668T patent/ATE420958T1/en not_active IP Right Cessation
- 2001-06-28 CN CN01814818A patent/CN1451043A/en active Pending
- 2001-06-28 WO PCT/US2001/020755 patent/WO2002002773A2/en active Application Filing
- 2001-06-28 MX MXPA02012867A patent/MXPA02012867A/en active IP Right Grant
- 2001-06-28 EP EP01950668A patent/EP1297142B1/en not_active Expired - Lifetime
- 2001-06-28 UY UY26807A patent/UY26807A1/en not_active Application Discontinuation
- 2001-06-29 TW TW094102248A patent/TW200516083A/en unknown
- 2001-06-29 TW TW090115948A patent/TWI307716B/en not_active IP Right Cessation
-
2002
- 2002-12-12 ZA ZA200210109A patent/ZA200210109B/en unknown
- 2002-12-20 IL IL153567A patent/IL153567A/en not_active IP Right Cessation
- 2002-12-27 NO NO20026239A patent/NO20026239L/en not_active Application Discontinuation
- 2002-12-27 EC EC2002004409A patent/ECSP024409A/en unknown
-
2003
- 2003-01-21 BG BG107483A patent/BG66209B1/en unknown
- 2003-08-27 HK HK03106152.8A patent/HK1055316A1/en unknown
-
2008
- 2008-12-11 US US12/316,340 patent/US8475766B2/en not_active Expired - Lifetime
-
2010
- 2010-02-14 IL IL203955A patent/IL203955A/en not_active IP Right Cessation
-
2011
- 2011-08-31 JP JP2011188635A patent/JP2012031178A/en active Pending
-
2013
- 2013-05-23 US US13/900,841 patent/US20140155579A1/en not_active Abandoned
-
2014
- 2014-08-26 US US14/469,122 patent/US20140378666A1/en not_active Abandoned
-
2015
- 2015-03-05 US US14/639,985 patent/US20150175694A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5756095A (en) * | 1992-05-22 | 1998-05-26 | The Research And Development Institute, Inc. | Antibodies with specificity for a common epitope on E-selectin and L-selectin |
WO1998020159A1 (en) * | 1996-11-07 | 1998-05-14 | Ramot University Authority For Applied Research & Industrial Development Ltd. | Representations of bimolecular interactions |
Non-Patent Citations (2)
Title |
---|
LUGER T A ET AL: "MONOCLONAL ANTI-INTERLEUKIN 1 IS DIRECTED AGAINST A COMMON SITE OF HUMAN INTERLEUKIN 1-ALPHA AND INTERLEUKIN 1-BETA" IMMUNOBIOLOGY, vol. 172, no. 3-5, 1986, pages 346-356, XP008004584 ISSN: 0171-2985 * |
See also references of EP1297142A2 * |
Cited By (209)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8475766B2 (en) | 2000-06-29 | 2013-07-02 | Abbvie Inc. | Dual specificity antibodies and methods of making and using |
US8853366B2 (en) | 2001-01-17 | 2014-10-07 | Emergent Product Development Seattle, Llc | Binding domain-immunoglobulin fusion proteins |
EP2364999A2 (en) | 2001-06-28 | 2011-09-14 | Domantis Limited | Dual-specific ligand and its use |
US9028822B2 (en) | 2002-06-28 | 2015-05-12 | Domantis Limited | Antagonists against TNFR1 and methods of use therefor |
EP1747015A2 (en) * | 2004-04-26 | 2007-01-31 | Centocor, Inc. | Solution phase biopanning method using engineered decoy proteins |
US7514539B2 (en) | 2004-04-26 | 2009-04-07 | Centocor, Inc. | Epitope directed selection of antibodies to murine tissue factor |
EP1747015A4 (en) * | 2004-04-26 | 2009-11-18 | Centocor Ortho Biotech Inc | Solution phase biopanning method using engineered decoy proteins |
US7790405B2 (en) | 2004-04-26 | 2010-09-07 | Centocor, Inc. | Solution phase biopanning method using engineered decoy proteins |
US8921528B2 (en) | 2004-06-01 | 2014-12-30 | Domantis Limited | Bispecific fusion antibodies with enhanced serum half-life |
US7696320B2 (en) | 2004-08-24 | 2010-04-13 | Domantis Limited | Ligands that have binding specificity for VEGF and/or EGFR and methods of use therefor |
WO2006038027A2 (en) | 2004-10-08 | 2006-04-13 | Domantis Limited | SINGLE DOMAIN ANTIBODIES AGAINST TNFRl AND METHODS OF USE THEREFOR |
EP2371390A2 (en) | 2004-10-08 | 2011-10-05 | Domantis Limited | Antagonists and methods of use therefor |
US7566772B2 (en) | 2005-01-26 | 2009-07-28 | Amgen Fremont Inc. | Antibodies against interleukin-1β |
US7964193B2 (en) | 2005-01-26 | 2011-06-21 | Amgen Fremont Inc. | Antibodies against interleukin-1 β |
US10307481B2 (en) | 2005-07-25 | 2019-06-04 | Aptevo Research And Development Llc | CD37 immunotherapeutics and uses thereof |
US10143748B2 (en) | 2005-07-25 | 2018-12-04 | Aptevo Research And Development Llc | B-cell reduction using CD37-specific and CD20-specific binding molecules |
EP2520588A1 (en) | 2005-08-19 | 2012-11-07 | Abbott Laboratories | Dual variable domain immunoglobulin and uses thereof |
EP2500352A1 (en) | 2005-08-19 | 2012-09-19 | Abbott Laboratories | Dual variable domain immunoglobulin and uses thereof |
US20130004416A1 (en) * | 2005-08-19 | 2013-01-03 | Abbott Laboratories | Dual Variable Domain Immunoglobulin and Uses Thereof |
EP2500355A2 (en) | 2005-08-19 | 2012-09-19 | Abbott Laboratories | Dual variable domain immunoglobulin and uses thereof |
EP2495257A2 (en) | 2005-08-19 | 2012-09-05 | Abbott Laboratories | Dual variable domain immunoglobulin and uses thereof |
EP2500359A2 (en) | 2005-08-19 | 2012-09-19 | Abbott Laboratories | Dual variable domain immunoglobulin and uses thereof |
EP2500354A2 (en) | 2005-08-19 | 2012-09-19 | Abbott Laboratories | Dual variable domain immunoglobulin and uses thereof |
EP2500357A2 (en) | 2005-08-19 | 2012-09-19 | Abbott Laboratories | Dual variable domain immunoglobulin and uses thereof |
EP2500356A2 (en) | 2005-08-19 | 2012-09-19 | Abbott Laboratories | Dual variable domain immunoglobulin and uses thereof |
EP2500358A2 (en) | 2005-08-19 | 2012-09-19 | Abbott Laboratories | Dual variable domain immunoglobulin and uses thereof |
EP2500353A2 (en) | 2005-08-19 | 2012-09-19 | Abbott Laboratories | Dual variable domain immunoglobulin and uses thereof |
US8906864B2 (en) | 2005-09-30 | 2014-12-09 | AbbVie Deutschland GmbH & Co. KG | Binding domains of proteins of the repulsive guidance molecule (RGM) protein family and functional fragments thereof, and their use |
US8409577B2 (en) | 2006-06-12 | 2013-04-02 | Emergent Product Development Seattle, Llc | Single chain multivalent binding proteins with effector function |
EP2471816A1 (en) * | 2006-08-30 | 2012-07-04 | Genentech, Inc. | Multispecific antibodies |
US11008401B2 (en) | 2006-08-30 | 2021-05-18 | Genentech, Inc. | Multispecific antibodies |
US11851501B2 (en) | 2006-08-30 | 2023-12-26 | Genentech, Inc. | Multispecific antibodies |
WO2008027236A3 (en) * | 2006-08-30 | 2008-12-18 | Genentech Inc | Multispecific antibodies |
US10118970B2 (en) | 2006-08-30 | 2018-11-06 | Genentech, Inc. | Multispecific antibodies |
US9163082B2 (en) | 2006-12-20 | 2015-10-20 | Xoma (Us) Llc | Methods for the treatment of IL-1β related diseases |
EP2114443A4 (en) * | 2006-12-29 | 2011-08-10 | Abbott Lab | Dual-specific il-1a/ il-1b antibodies |
US8324350B2 (en) | 2006-12-29 | 2012-12-04 | Abbott Laboratories | Dual-specific IL-1α/IL-1β antibodies |
EP2114443A2 (en) * | 2006-12-29 | 2009-11-11 | Abbott Laboratories | Dual-specific il-1a/ il-1b antibodies |
EP2559703A1 (en) | 2007-02-08 | 2013-02-20 | Domantis Limited | Antibody single variable domains against serum albumin |
EP2559704A1 (en) | 2007-02-08 | 2013-02-20 | Domantis Limited | Antibody single variable domains against serum albumin |
EP2559702A1 (en) | 2007-02-08 | 2013-02-20 | Domantis Limited | Antibody single variable domains against serum albumin |
EP2679995A1 (en) | 2007-05-31 | 2014-01-01 | AbbVie Inc. | Biomarkers predictive of the responsiveness to TNF-alfa inhibitors in autoimmune disorders |
EP2679996A1 (en) | 2007-05-31 | 2014-01-01 | AbbVie Inc. | Biomarkers predictive of the responsiveness to TNF-alfa inhibitors in autoimmune disorders |
EP2535349A1 (en) | 2007-09-26 | 2012-12-19 | UCB Pharma S.A. | Dual specificity antibody fusions |
EP2535351A2 (en) | 2007-09-26 | 2012-12-19 | UCB Pharma S.A. | Dual specificity antibody fusions |
US8629246B2 (en) | 2007-09-26 | 2014-01-14 | Ucb Pharma S.A. | Dual specificity antibody fusions |
US9828438B2 (en) | 2007-09-26 | 2017-11-28 | Ucb Pharma S.A. | Dual specificity antibody fusions |
US9309327B2 (en) | 2007-09-26 | 2016-04-12 | Ucb Pharma S.A. | Dual specificity antibody fusions |
US10100130B2 (en) | 2007-09-26 | 2018-10-16 | Ucb Biopharma Sprl | Dual specificity antibody fusions |
US11427650B2 (en) | 2007-09-26 | 2022-08-30 | UCB Biopharma SRL | Dual specificity antibody fusions |
EP2535350A1 (en) | 2007-09-26 | 2012-12-19 | UCB Pharma S.A. | Dual specificity antibody fusions |
US8501181B2 (en) | 2007-12-17 | 2013-08-06 | Dyax Corp. | Compositions and methods for treating osteolytic disorders comprising MMP-14 binding proteins |
US9605069B2 (en) | 2008-02-29 | 2017-03-28 | AbbVie Deutschland GmbH & Co. KG | Antibodies against the RGM a protein and uses thereof |
EP2262840A2 (en) * | 2008-03-03 | 2010-12-22 | Dyax Corp. | Metalloproteinase 9 and metalloproteinase 2 binding proteins |
US8455205B2 (en) | 2008-03-03 | 2013-06-04 | Dyax Corp. | Metalloproteinase 9 binding proteins |
EP2262840A4 (en) * | 2008-03-03 | 2012-08-08 | Dyax Corp | Metalloproteinase 9 and metalloproteinase 2 binding proteins |
US9101609B2 (en) | 2008-04-11 | 2015-08-11 | Emergent Product Development Seattle, Llc | CD37 immunotherapeutic and combination with bifunctional chemotherapeutic thereof |
US9029508B2 (en) | 2008-04-29 | 2015-05-12 | Abbvie Inc. | Dual variable domain immunoglobulins and uses thereof |
EP2899209A1 (en) | 2008-04-29 | 2015-07-29 | Abbvie Inc. | Dual Variable Domain Immunoglobulins and uses thereof |
US9035027B2 (en) | 2008-06-03 | 2015-05-19 | Abbvie Inc. | Dual variable domain immunoglobulins and uses thereof |
US9109026B2 (en) | 2008-06-03 | 2015-08-18 | Abbvie, Inc. | Dual variable domain immunoglobulins and uses thereof |
EP3002299A1 (en) | 2008-06-03 | 2016-04-06 | AbbVie Inc. | Dual variable domain immunoglobulins and uses thereof |
US8822645B2 (en) | 2008-07-08 | 2014-09-02 | Abbvie Inc. | Prostaglandin E2 dual variable domain immunoglobulins and uses thereof |
US8193321B2 (en) | 2008-09-03 | 2012-06-05 | Genentech, Inc. | Multispecific antibodies |
US9017686B2 (en) | 2008-09-03 | 2015-04-28 | Genentech, Inc. | Multispecific antibodies |
US9522960B2 (en) | 2008-09-03 | 2016-12-20 | Genentech, Inc. | Multispecific antibodies |
US10407513B2 (en) | 2008-09-26 | 2019-09-10 | Ucb Biopharma Sprl | Biological products |
US8623367B2 (en) | 2008-12-10 | 2014-01-07 | Novartis Ag | Antibody formulation |
EP2810652A2 (en) | 2009-03-05 | 2014-12-10 | AbbVie Inc. | IL-17 binding proteins |
US9663587B2 (en) | 2009-03-05 | 2017-05-30 | Abbvie Inc. | IL-17 binding proteins |
EP2772269A2 (en) | 2009-03-05 | 2014-09-03 | Abbvie Inc. | IL-17 binding proteins |
EP3029070A1 (en) | 2009-08-29 | 2016-06-08 | AbbVie Inc. | Therapeutic dll4 binding proteins |
US8623358B2 (en) | 2009-08-29 | 2014-01-07 | Abbvie Inc. | Therapeutic DLL4 binding proteins |
US9132190B2 (en) | 2009-08-29 | 2015-09-15 | Abbvie Inc. | Therapeutic DLL4 binding proteins |
US9469688B2 (en) | 2009-08-29 | 2016-10-18 | Abbvie Inc. | Therapeutic DLL4 binding proteins |
WO2011025964A2 (en) | 2009-08-29 | 2011-03-03 | Abbott Laboratories | Therapeutic dll4 binding proteins |
US8586714B2 (en) | 2009-09-01 | 2013-11-19 | Abbvie, Inc. | Dual variable domain immunoglobulins and uses thereof |
WO2011036460A1 (en) | 2009-09-25 | 2011-03-31 | Ucb Pharma S.A. | Disulfide stabilised multivalent antibodies |
US8716450B2 (en) | 2009-10-15 | 2014-05-06 | Abbvie Inc. | Dual variable domain immunoglobulins and uses thereof |
US8722855B2 (en) | 2009-10-28 | 2014-05-13 | Abbvie Inc. | Dual variable domain immunoglobulins and uses thereof |
US9175075B2 (en) | 2009-12-08 | 2015-11-03 | AbbVie Deutschland GmbH & Co. KG | Methods of treating retinal nerve fiber layer degeneration with monoclonal antibodies against a retinal guidance molecule (RGM) protein |
US9115195B2 (en) | 2010-03-02 | 2015-08-25 | Abbvie Inc. | Therapeutic DLL4 binding proteins |
EP3680253A2 (en) | 2010-03-02 | 2020-07-15 | AbbVie Inc. | Therapeutic dll4 binding proteins |
EP3072904A1 (en) | 2010-03-02 | 2016-09-28 | Abbvie Inc. | Therapeutic dll4 binding proteins |
US9469689B2 (en) | 2010-03-02 | 2016-10-18 | Abbvie Inc. | Therapeutic DLL4 binding proteins |
US9637557B2 (en) | 2010-04-23 | 2017-05-02 | Genentech, Inc. | Production of heteromultimeric proteins |
WO2012006500A2 (en) | 2010-07-08 | 2012-01-12 | Abbott Laboratories | Monoclonal antibodies against hepatitis c virus core protein |
EP2921177A2 (en) | 2010-07-09 | 2015-09-23 | AbbVie Inc. | Dual variable domain immunoglobulins and uses thereof |
US9493560B2 (en) | 2010-08-03 | 2016-11-15 | Abbvie Inc. | Dual variable domain immunoglobulins and uses thereof |
US8735546B2 (en) | 2010-08-03 | 2014-05-27 | Abbvie Inc. | Dual variable domain immunoglobulins and uses thereof |
EP3252072A2 (en) | 2010-08-03 | 2017-12-06 | AbbVie Inc. | Dual variable domain immunoglobulins and uses thereof |
US9046513B2 (en) | 2010-08-26 | 2015-06-02 | Abbvie Inc. | Dual variable domain immunoglobulins and uses thereof |
WO2012121775A2 (en) | 2010-12-21 | 2012-09-13 | Abbott Laboratories | Dual variable domain immunoglobulins and uses thereof |
WO2012163521A1 (en) | 2011-05-27 | 2012-12-06 | Dutalys | Removal of monomeric targets |
WO2012163520A1 (en) | 2011-05-27 | 2012-12-06 | Dutalys | Dual targeting |
WO2012176779A1 (en) | 2011-06-20 | 2012-12-27 | 協和発酵キリン株式会社 | Anti-erbb3 antibody |
US10314909B2 (en) | 2011-10-21 | 2019-06-11 | Dyax Corp. | Combination therapy comprising an MMP-14 binding protein |
WO2013063095A1 (en) | 2011-10-24 | 2013-05-02 | Abbvie Inc. | Immunobinders directed against sclerostin |
WO2013063110A1 (en) | 2011-10-24 | 2013-05-02 | Abbvie Inc. | Bispecific immunobinders directed against tnf and il-17 |
US10118958B2 (en) | 2011-12-14 | 2018-11-06 | AbbVie Deutschland GmbH & Co. KG | Composition and method for the diagnosis and treatment of iron-related disorders |
US9636398B2 (en) | 2011-12-14 | 2017-05-02 | AbbVie Deutschland GmbH & Co. KG | Composition and method for the diagnosis and treatment of iron-related disorders |
WO2013090633A2 (en) | 2011-12-14 | 2013-06-20 | AbbVie Deutschland GmbH & Co. KG | Composition and method for the diagnosis and treatment of iron-related disorders |
WO2013090635A2 (en) | 2011-12-14 | 2013-06-20 | AbbVie Deutschland GmbH & Co. KG | Composition and method for the diagnosis and treatment of iron-related disorders |
EP3800200A1 (en) | 2011-12-14 | 2021-04-07 | AbbVie Deutschland GmbH & Co. KG | Composition and method for the diagnosis and treatment of iron-related disorders |
US10822403B2 (en) | 2011-12-14 | 2020-11-03 | AbbVie Deutschland GmbH & Co. KG | Composition and method for the diagnosis and treatment of iron-related disorders |
EP2915818A2 (en) | 2011-12-30 | 2015-09-09 | AbbVie Inc. | Dual variable domain immunoglobulins and uses thereof |
WO2013102042A2 (en) | 2011-12-30 | 2013-07-04 | Abbvie Inc. | Dual specific binding proteins directed against il-13 and/or il-17 |
US9120870B2 (en) | 2011-12-30 | 2015-09-01 | Abbvie Inc. | Dual specific binding proteins directed against IL-13 and IL-17 |
US10106602B2 (en) | 2012-01-27 | 2018-10-23 | AbbVie Deutschland GmbH & Co. KG | Isolated monoclonal anti-repulsive guidance molecule A antibodies and uses thereof |
EP3653647A1 (en) | 2012-01-27 | 2020-05-20 | AbbVie Deutschland GmbH & Co KG | Composition and method for diagnosis and treatment of diseases associated with neurite degeneration |
US9365643B2 (en) | 2012-01-27 | 2016-06-14 | AbbVie Deutschland GmbH & Co. KG | Antibodies that bind to repulsive guidance molecule A (RGMA) |
WO2013112922A1 (en) | 2012-01-27 | 2013-08-01 | AbbVie Deutschland GmbH & Co. KG | Composition and method for diagnosis and treatment of diseases associated with neurite degeneration |
EP3369746A1 (en) | 2012-01-27 | 2018-09-05 | AbbVie Deutschland GmbH & Co KG | Composition and method for diagnosis and treatment of diseases associated with neurite degeneration |
US9102722B2 (en) | 2012-01-27 | 2015-08-11 | AbbVie Deutschland GmbH & Co. KG | Composition and method for the diagnosis and treatment of diseases associated with neurite degeneration |
EP4116427A1 (en) | 2012-05-17 | 2023-01-11 | Kymab Limited | In vivo guided selection & antibodies |
US9670276B2 (en) | 2012-07-12 | 2017-06-06 | Abbvie Inc. | IL-1 binding proteins |
WO2014011955A2 (en) | 2012-07-12 | 2014-01-16 | Abbvie, Inc. | Il-1 binding proteins |
WO2014071074A2 (en) | 2012-11-01 | 2014-05-08 | Abbvie Inc. | Anti-vegf/dll4 dual variable domain immunoglobulins and uses thereof |
WO2014071212A3 (en) * | 2012-11-01 | 2014-07-31 | Abbvie Inc. | Stable dual variable domain immunoglobulin protein formulations |
US9045551B2 (en) | 2012-11-01 | 2015-06-02 | Abbvie Inc. | Anti-DLL4/VEGF dual variable domain immunoglobulin and uses thereof |
US9163093B2 (en) | 2012-11-01 | 2015-10-20 | Abbvie Inc. | Anti-DLL4/VEGF dual variable domain immunoglobulin and uses thereof |
US9944720B2 (en) | 2012-11-01 | 2018-04-17 | Abbvie Inc. | Anti-DLL4/VEGF dual variable domain immunoglobulin and uses thereof |
WO2014089209A2 (en) | 2012-12-04 | 2014-06-12 | Abbvie, Inc. | Blood-brain barrier (bbb) penetrating dual specific binding proteins |
WO2014106004A2 (en) | 2012-12-28 | 2014-07-03 | Abbvie, Inc. | High-throughput system and method for identifying antibodies having specific antigen binding activities |
WO2014106001A2 (en) | 2012-12-28 | 2014-07-03 | Abbvie, Inc. | Dual specific binding proteins having a receptor sequence |
US9856319B2 (en) | 2012-12-28 | 2018-01-02 | Abbvie Inc. | Monovalent binding proteins |
US20140219913A1 (en) * | 2012-12-28 | 2014-08-07 | Abbvie, Inc. | Dual Specific Binding Proteins Having a Receptor Sequence |
WO2014116846A2 (en) | 2013-01-23 | 2014-07-31 | Abbvie, Inc. | Methods and compositions for modulating an immune response |
US10308709B2 (en) | 2013-03-15 | 2019-06-04 | Abbott Laboratories | Anti-GP73 monoclonal antibodies and methods of obtaining the same |
US8987418B2 (en) | 2013-03-15 | 2015-03-24 | Abbvie Inc. | Dual specific binding proteins directed against IL-1β and/or IL-17 |
WO2014144355A2 (en) | 2013-03-15 | 2014-09-18 | Abbott Laboratories | Anti-gp73 monoclonal antibodies and methods of obtaining the same |
EP3124499A1 (en) | 2013-03-15 | 2017-02-01 | Abbott Laboratories | Anti-gp73 monoclonal antibodies and methods of obtaining the same |
WO2014144299A2 (en) | 2013-03-15 | 2014-09-18 | Abbvie Inc. | DUAL SPECIFIC BINDING PROTEINS DIRECTED AGAINST TNFα |
EP3527586A1 (en) | 2013-03-15 | 2019-08-21 | Abbott Laboratories | Anti-gp73 monoclonal antibodies and methods of obtaining the same |
US9062108B2 (en) | 2013-03-15 | 2015-06-23 | Abbvie Inc. | Dual specific binding proteins directed against IL-1 and/or IL-17 |
US9469686B2 (en) | 2013-03-15 | 2016-10-18 | Abbott Laboratories | Anti-GP73 monoclonal antibodies and methods of obtaining the same |
US11421023B2 (en) | 2013-03-15 | 2022-08-23 | Abbott Laboratories | Anti-GP73 monoclonal antibodies and methods of obtaining the same |
US11897946B2 (en) | 2013-06-07 | 2024-02-13 | Duke University | Methods of inhibiting complement factor H (CFH) comprising administering an antibody that binds CFH |
US11136380B2 (en) | 2013-06-07 | 2021-10-05 | Duke University | Anti-complement factor H antibodies |
US10183988B2 (en) | 2013-06-07 | 2019-01-22 | Duke University | Anti-Complement factor H antibodies |
EP3632467A1 (en) | 2013-06-07 | 2020-04-08 | Duke University | Inhibitors of complement factor h |
WO2015039212A1 (en) | 2013-09-17 | 2015-03-26 | University Health Network (Uhn): Technology Development And Commercialization | Agents directed against a cis rgma/neogenin interaction or lipid rafts and use of the same in methods of treatment |
US10501737B2 (en) | 2013-09-30 | 2019-12-10 | Chugai Seiyaku Kabushiki Kaisha | Method for producing antigen-binding molecule using modified helper phage |
RU2732032C2 (en) * | 2013-12-20 | 2020-09-10 | Дженентек, Инк. | Double specificity antibodies |
US10683348B2 (en) | 2013-12-20 | 2020-06-16 | Genentech, Inc. | Dual specific antibodies |
US12006360B2 (en) | 2013-12-20 | 2024-06-11 | Genentech, Inc. | Dual specific antibodies for binding interleukin 4 (IL4) and interleukin 5 (IL5) |
US12030926B2 (en) | 2014-05-06 | 2024-07-09 | Genentech, Inc. | Production of heteromultimeric proteins using mammalian cells |
WO2015191783A2 (en) | 2014-06-10 | 2015-12-17 | Abbvie Inc. | Biomarkers for inflammatory disease and methods of using same |
WO2015191934A2 (en) | 2014-06-11 | 2015-12-17 | Abbvie Inc. | Blood-brain barrier (bbb) penetrating dual specific binding proteins for treating brain and neurological diseases |
WO2016023909A1 (en) | 2014-08-14 | 2016-02-18 | Deutsches Krebsforschungszentrum, Stiftung Des Öffentlichen Rechts | Recombinant antibody molecule and its use for target cell restricted t cell activation |
EP2985294A1 (en) | 2014-08-14 | 2016-02-17 | Deutsches Krebsforschungszentrum | Recombinant antibody molecule and its use for target cell restricted T cell activation |
US10093733B2 (en) | 2014-12-11 | 2018-10-09 | Abbvie Inc. | LRP-8 binding dual variable domain immunoglobulin proteins |
WO2016094881A2 (en) | 2014-12-11 | 2016-06-16 | Abbvie Inc. | Lrp-8 binding proteins |
US9840554B2 (en) | 2015-06-15 | 2017-12-12 | Abbvie Inc. | Antibodies against platelet-derived growth factor (PDGF) |
EP4324476A2 (en) | 2015-09-11 | 2024-02-21 | AbbVie Inc. | Methods for treating relapsing forms of multiple sclerosis |
WO2017044862A1 (en) | 2015-09-11 | 2017-03-16 | Abbvie Inc. | Methods for treating relapsing forms of multiple sclerosis |
US11352426B2 (en) | 2015-09-21 | 2022-06-07 | Aptevo Research And Development Llc | CD3 binding polypeptides |
US11130810B2 (en) | 2015-10-02 | 2021-09-28 | Hoffmann-La Roche Inc. | Bispecific antibodies specific for PD1 and TIM3 |
US10718762B2 (en) | 2015-10-02 | 2020-07-21 | Hoffmann-La Roche Inc. | Cellular based fret assay for the determination of simultaneous binding |
US11219645B2 (en) | 2015-11-18 | 2022-01-11 | Duke University | Tumor infiltrating lymphocytes for treatment of cancer |
WO2017156500A1 (en) | 2016-03-11 | 2017-09-14 | Scholar Rock, Inc. | Tgfb1-binding immunoglobulins and use thereof |
EP4169942A1 (en) | 2016-03-11 | 2023-04-26 | Scholar Rock, Inc. | Tgfbeta1-binding immunoglobulins and use thereof |
WO2017210278A1 (en) | 2016-06-01 | 2017-12-07 | Abbvie Inc. | Anti-repulsive guidance molecule a (rgma) antagonistic antibodies for treating spinal cord injury and pain |
WO2018067468A1 (en) | 2016-10-03 | 2018-04-12 | Abbott Laboratories | Improved methods of assessing uch-l1 status in patient samples |
WO2018067474A1 (en) | 2016-10-03 | 2018-04-12 | Abbott Laboratories | Improved methods of assessing gfap status in patient samples |
WO2018129329A1 (en) | 2017-01-06 | 2018-07-12 | Scholar Rock, Inc. | ISOFORM-SPECIFIC, CONTEXT-PERMISSIVE TGFβ1 INHIBITORS AND USE THEREOF |
WO2018175942A1 (en) | 2017-03-23 | 2018-09-27 | Abbott Laboratories | Methods for aiding in the diagnosis and determination of the extent of traumatic brain injury in a human subject using the early biomarker ubiquitin carboxy-terminal hydrolase l1 |
US12023368B2 (en) | 2017-04-03 | 2024-07-02 | Hoffmann-La Roche Inc. | Immunoconjugates |
US11413331B2 (en) | 2017-04-03 | 2022-08-16 | Hoffmann-La Roche Inc. | Immunoconjugates |
US11285207B2 (en) | 2017-04-05 | 2022-03-29 | Hoffmann-La Roche Inc. | Bispecific antibodies specifically binding to PD1 and LAG3 |
WO2018191531A1 (en) | 2017-04-15 | 2018-10-18 | Abbott Laboratories | Methods for aiding in the hyperacute diagnosis and determination of traumatic brain injury in a human subject using early biomarkers |
WO2018200823A1 (en) | 2017-04-28 | 2018-11-01 | Abbott Laboratories | Methods for aiding in the hyperacute diagnosis and determination of traumatic brain injury using early biomarkers on at least two samples from the same human subject |
US10865238B1 (en) | 2017-05-05 | 2020-12-15 | Duke University | Complement factor H antibodies |
WO2018218169A1 (en) | 2017-05-25 | 2018-11-29 | Abbott Laboratories | Methods for aiding in the determination of whether to perform imaging on a human subject who has sustained or may have sustained an injury to the head using early biomarkers |
WO2018222783A1 (en) | 2017-05-30 | 2018-12-06 | Abbott Laboratories | Methods for aiding in diagnosing and evaluating a mild traumatic brain injury in a human subject using cardiac troponin i and early biomarkers |
WO2018222784A1 (en) | 2017-05-30 | 2018-12-06 | Abbott Laboratories | Methods for aiding in diagnosing and evaluating a mild traumatic brain injury in a human subject using cardiac troponin i |
WO2019010131A1 (en) | 2017-07-03 | 2019-01-10 | Abbott Laboratories | Improved methods for measuring ubiquitin carboxy-terminal hydrolase l1 levels in blood |
US11932673B2 (en) | 2017-07-12 | 2024-03-19 | Maxion Therapeutics Limited | Sodium channel inhibitors |
WO2019093342A1 (en) | 2017-11-08 | 2019-05-16 | 協和発酵キリン株式会社 | BISPECIFIC ANTIBODY WHICH BINDS TO CD40 AND EpCAM |
WO2019113525A2 (en) | 2017-12-09 | 2019-06-13 | Abbott Laboratories | Methods for aiding in the diagnosis and evaluation of a subject who has sustained an orthopedic injury and that has or may have sustained an injury to the head, such as mild traumatic brain injury (tbi), using glial fibrillary acidic protein (gfap) and/or ubiquitin carboxy-terminal hydrolase l1 (uch-l1) |
WO2019112860A1 (en) | 2017-12-09 | 2019-06-13 | Abbott Laboratories | Methods for aiding in diagnosing and evaluating a traumatic brain injury in a human subject using a combination of gfap and uch-l1 |
WO2019133717A1 (en) | 2017-12-29 | 2019-07-04 | Abbott Laboratories | Novel biomarkers and methods for diagnosing and evaluating traumatic brain injury |
WO2020014473A1 (en) | 2018-07-11 | 2020-01-16 | Scholar Rock, Inc. | TGFβ1 INHIBITORS AND USE THEREOF |
EP4019046A1 (en) | 2018-07-11 | 2022-06-29 | Scholar Rock, Inc. | Isoform selective tgfbeta1 inhibitors and use thereof |
EP3677278A1 (en) | 2018-07-11 | 2020-07-08 | Scholar Rock, Inc. | Isoform selective tgfbeta1 inhibitors and use thereof |
WO2020014460A1 (en) | 2018-07-11 | 2020-01-16 | Scholar Rock, Inc. | HIGH-AFFINITY, ISOFORM-SELECTIVE TGFβ1 INHIBITORS AND USE THEREOF |
WO2020138487A1 (en) | 2018-12-28 | 2020-07-02 | 協和キリン株式会社 | BISPECIFIC ANTIBODY BINDING TO TfR |
WO2020180695A1 (en) | 2019-03-01 | 2020-09-10 | Abbott Laboratories | Methods for predicting major adverse cardiovascular events in subjects with coronary artery disease |
WO2020230899A1 (en) | 2019-05-15 | 2020-11-19 | 協和キリン株式会社 | Bispecific antibody binding to cd40 and fap |
WO2020230901A1 (en) | 2019-05-15 | 2020-11-19 | 協和キリン株式会社 | Bispecific antibody capable of binding to cd40 and gpc3 |
WO2021142427A1 (en) | 2020-01-11 | 2021-07-15 | Scholar Rock, Inc. | TGFβ INHIBITORS AND USE THEREOF |
WO2021142448A2 (en) | 2020-01-11 | 2021-07-15 | Scholar Rock,Inc. | Tgf-beta inhibitors and use thereof |
WO2021211331A1 (en) | 2020-04-13 | 2021-10-21 | Abbott Point Of Care Inc. | METHODS, COMPLEXES AND KITS FOR DETECTING OR DETERMINING AN AMOUNT OF A ß-CORONAVIRUS ANTIBODY IN A SAMPLE |
WO2022031804A1 (en) | 2020-08-04 | 2022-02-10 | Abbott Laboratories | Improved methods and kits for detecting sars-cov-2 protein in a sample |
WO2022119841A1 (en) | 2020-12-01 | 2022-06-09 | Abbott Laboratories | Use of one or more biomarkers to determine traumatic brain injury (tbi) in a subject having received a head computerized tomography scan that is negative for a tbi |
WO2022147147A1 (en) | 2020-12-30 | 2022-07-07 | Abbott Laboratories | Methods for determining sars-cov-2 antigen and anti-sars-cov-2 antibody in a sample |
WO2022204581A2 (en) | 2021-03-26 | 2022-09-29 | Scholar Rock, Inc. | Tgf-beta inhibitors and use thereof |
WO2022245920A1 (en) | 2021-05-18 | 2022-11-24 | Abbott Laboratories | Methods of evaluating brain injury in a pediatric subject |
WO2022256723A2 (en) | 2021-06-03 | 2022-12-08 | Scholar Rock, Inc. | Tgf-beta inhibitors and therapeutic use thereof |
WO2022266034A1 (en) | 2021-06-14 | 2022-12-22 | Abbott Laboratories | Methods of diagnosing or aiding in diagnosis of brain injury caused by acoustic energy, electromagnetic energy, an over pressurization wave, and/or blast wind |
WO2023288277A1 (en) | 2021-07-14 | 2023-01-19 | Scholar Rock, Inc. | Ltbp complex-specific inhibitors of tgfb1 and uses thereof |
WO2023034777A1 (en) | 2021-08-31 | 2023-03-09 | Abbott Laboratories | Methods and systems of diagnosing brain injury |
WO2023056268A1 (en) | 2021-09-30 | 2023-04-06 | Abbott Laboratories | Methods and systems of diagnosing brain injury |
WO2023102384A1 (en) | 2021-11-30 | 2023-06-08 | Abbott Laboratories | Use of one or more biomarkers to determine traumatic brain injury (tbi) in a subject having received a head computerized tomography scan that is negative for a tbi |
WO2023114978A1 (en) | 2021-12-17 | 2023-06-22 | Abbott Laboratories | Systems and methods for determining uch-l1, gfap, and other biomarkers in blood samples |
WO2023129942A1 (en) | 2021-12-28 | 2023-07-06 | Abbott Laboratories | Use of biomarkers to determine sub-acute traumatic brain injury (tbi) in a subject having received a head computerized tomography (ct) scan that is negative for a tbi or no head ct scan |
WO2023150652A1 (en) | 2022-02-04 | 2023-08-10 | Abbott Laboratories | Lateral flow methods, assays, and devices for detecting the presence or measuring the amount of ubiquitin carboxy-terminal hydrolase l1 and/or glial fibrillary acidic protein in a sample |
WO2024006876A1 (en) | 2022-06-29 | 2024-01-04 | Abbott Laboratories | Magnetic point-of-care systems and assays for determining gfap in biological samples |
WO2024059708A1 (en) | 2022-09-15 | 2024-03-21 | Abbott Laboratories | Biomarkers and methods for differentiating between mild and supermild traumatic brain injury |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1297142B1 (en) | Dual specificity antibodies and methods of making and using | |
US7767207B2 (en) | Antibodies that bind IL-18 and methods of inhibiting IL-18 activity | |
AU2007202323B9 (en) | Dual specificity antibodies and methods of making and using | |
AU2013203432A1 (en) | Dual specificity antibodies and methods of making and using | |
AU2012200225A1 (en) | Dual specificity antibodies and methods of making and using |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
AK | Designated states |
Kind code of ref document: A3 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A3 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2411374 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 523080 Country of ref document: NZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2002/10109 Country of ref document: ZA Ref document number: 200210109 Country of ref document: ZA |
|
WWE | Wipo information: entry into national phase |
Ref document number: PA/a/2002/012867 Country of ref document: MX |
|
WWE | Wipo information: entry into national phase |
Ref document number: 153567 Country of ref document: IL |
|
WWE | Wipo information: entry into national phase |
Ref document number: 02115769 Country of ref document: CO |
|
ENP | Entry into the national phase |
Ref document number: 2002 508013 Country of ref document: JP Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1020027017916 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2001271636 Country of ref document: AU Ref document number: IN/PCT/2002/01900/MU Country of ref document: IN Ref document number: IN/PCT/2002/01899/MU Country of ref document: IN |
|
ENP | Entry into the national phase |
Ref document number: 10748301 Country of ref document: BG Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2001950668 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1152003 Country of ref document: SK Ref document number: PV2003-291 Country of ref document: CZ |
|
WWP | Wipo information: published in national office |
Ref document number: 1020027017916 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 018148182 Country of ref document: CN |
|
WWP | Wipo information: published in national office |
Ref document number: 2001950668 Country of ref document: EP |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWP | Wipo information: published in national office |
Ref document number: PV2003-291 Country of ref document: CZ |
|
WWP | Wipo information: published in national office |
Ref document number: 523080 Country of ref document: NZ |
|
WWG | Wipo information: grant in national office |
Ref document number: 523080 Country of ref document: NZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: 203955 Country of ref document: IL |