US20020015703A1 - Antagonists of tweak and of tweak receptor and their use to treat immunological disorders - Google Patents
Antagonists of tweak and of tweak receptor and their use to treat immunological disorders Download PDFInfo
- Publication number
- US20020015703A1 US20020015703A1 US09/905,810 US90581001A US2002015703A1 US 20020015703 A1 US20020015703 A1 US 20020015703A1 US 90581001 A US90581001 A US 90581001A US 2002015703 A1 US2002015703 A1 US 2002015703A1
- Authority
- US
- United States
- Prior art keywords
- tweak
- receptor
- cells
- cell
- ligand
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 208000026278 immune system disease Diseases 0.000 title claims abstract description 15
- 102000016946 TWEAK Receptor Human genes 0.000 title claims description 45
- 108010014401 TWEAK Receptor Proteins 0.000 title claims description 45
- 239000005557 antagonist Substances 0.000 title 1
- 101710097155 Tumor necrosis factor ligand superfamily member 12 Proteins 0.000 claims abstract description 111
- 102100024584 Tumor necrosis factor ligand superfamily member 12 Human genes 0.000 claims abstract description 111
- 230000000694 effects Effects 0.000 claims abstract description 20
- 239000000427 antigen Substances 0.000 claims description 49
- 108091007433 antigens Proteins 0.000 claims description 47
- 102000036639 antigens Human genes 0.000 claims description 47
- 230000027455 binding Effects 0.000 claims description 39
- 239000003446 ligand Substances 0.000 claims description 39
- 238000011161 development Methods 0.000 claims description 32
- 241000282414 Homo sapiens Species 0.000 claims description 30
- 241001465754 Metazoa Species 0.000 claims description 29
- 239000003795 chemical substances by application Substances 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 29
- 230000028993 immune response Effects 0.000 claims description 25
- 102000005962 receptors Human genes 0.000 claims description 23
- 108020003175 receptors Proteins 0.000 claims description 23
- 239000002981 blocking agent Substances 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 15
- 108060003951 Immunoglobulin Proteins 0.000 claims description 11
- 102000018358 immunoglobulin Human genes 0.000 claims description 11
- 210000004241 Th2 cell Anatomy 0.000 claims description 9
- 210000000447 Th1 cell Anatomy 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 230000000903 blocking effect Effects 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 230000004068 intracellular signaling Effects 0.000 claims description 4
- 230000021633 leukocyte mediated immunity Effects 0.000 claims description 4
- 102000000844 Cell Surface Receptors Human genes 0.000 claims description 3
- 108010001857 Cell Surface Receptors Proteins 0.000 claims description 3
- 108020001756 ligand binding domains Proteins 0.000 claims description 3
- 241000124008 Mammalia Species 0.000 claims description 2
- 238000011282 treatment Methods 0.000 abstract description 39
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 20
- 239000003814 drug Substances 0.000 abstract description 3
- 229940124597 therapeutic agent Drugs 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 99
- 208000009329 Graft vs Host Disease Diseases 0.000 description 54
- 210000003719 b-lymphocyte Anatomy 0.000 description 54
- 208000024908 graft versus host disease Diseases 0.000 description 54
- 241000699670 Mus sp. Species 0.000 description 53
- 230000001684 chronic effect Effects 0.000 description 36
- 210000000952 spleen Anatomy 0.000 description 35
- 238000011765 DBA/2 mouse Methods 0.000 description 33
- 210000001744 T-lymphocyte Anatomy 0.000 description 31
- 230000018109 developmental process Effects 0.000 description 31
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 27
- 201000010099 disease Diseases 0.000 description 26
- 241001529936 Murinae Species 0.000 description 21
- 210000004988 splenocyte Anatomy 0.000 description 20
- 102000004127 Cytokines Human genes 0.000 description 19
- 108090000695 Cytokines Proteins 0.000 description 19
- 230000001154 acute effect Effects 0.000 description 19
- 101000830598 Homo sapiens Tumor necrosis factor ligand superfamily member 12 Proteins 0.000 description 18
- 102000058177 human TNFSF12 Human genes 0.000 description 18
- 238000004519 manufacturing process Methods 0.000 description 17
- 241000699800 Cricetinae Species 0.000 description 16
- 238000001994 activation Methods 0.000 description 16
- 230000004913 activation Effects 0.000 description 15
- 238000004458 analytical method Methods 0.000 description 15
- 230000004044 response Effects 0.000 description 15
- 230000001404 mediated effect Effects 0.000 description 14
- 210000000056 organ Anatomy 0.000 description 14
- 108090000623 proteins and genes Proteins 0.000 description 13
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 13
- 230000003993 interaction Effects 0.000 description 12
- 230000003844 B-cell-activation Effects 0.000 description 11
- 230000006378 damage Effects 0.000 description 11
- 210000001280 germinal center Anatomy 0.000 description 10
- 210000000987 immune system Anatomy 0.000 description 10
- 108010029697 CD40 Ligand Proteins 0.000 description 9
- 102100032937 CD40 ligand Human genes 0.000 description 9
- 108010012236 Chemokines Proteins 0.000 description 9
- 102000019034 Chemokines Human genes 0.000 description 9
- 102100025137 Early activation antigen CD69 Human genes 0.000 description 9
- 101000934374 Homo sapiens Early activation antigen CD69 Proteins 0.000 description 9
- 239000002671 adjuvant Substances 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 9
- 230000003053 immunization Effects 0.000 description 9
- 238000002649 immunization Methods 0.000 description 9
- 210000004698 lymphocyte Anatomy 0.000 description 9
- 102000004169 proteins and genes Human genes 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 210000002540 macrophage Anatomy 0.000 description 8
- 208000023275 Autoimmune disease Diseases 0.000 description 7
- 238000002965 ELISA Methods 0.000 description 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 230000001419 dependent effect Effects 0.000 description 7
- 108020001507 fusion proteins Proteins 0.000 description 7
- 102000037865 fusion proteins Human genes 0.000 description 7
- 210000004408 hybridoma Anatomy 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- 206010001935 American trypanosomiasis Diseases 0.000 description 6
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 6
- 206010041660 Splenomegaly Diseases 0.000 description 6
- 108060008683 Tumor Necrosis Factor Receptor Proteins 0.000 description 6
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 description 6
- 230000004069 differentiation Effects 0.000 description 6
- 210000002443 helper t lymphocyte Anatomy 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 238000010172 mouse model Methods 0.000 description 6
- 230000028327 secretion Effects 0.000 description 6
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 101150013553 CD40 gene Proteins 0.000 description 5
- 241000283707 Capra Species 0.000 description 5
- 208000024699 Chagas disease Diseases 0.000 description 5
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 5
- 206010061218 Inflammation Diseases 0.000 description 5
- 206010052779 Transplant rejections Diseases 0.000 description 5
- 230000006907 apoptotic process Effects 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 230000030833 cell death Effects 0.000 description 5
- 210000002889 endothelial cell Anatomy 0.000 description 5
- 230000006698 induction Effects 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- YSGQGNQWBLYHPE-CFUSNLFHSA-N (7r,8r,9s,10r,13s,14s,17s)-17-hydroxy-7,13-dimethyl-2,6,7,8,9,10,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-one Chemical compound C1C[C@]2(C)[C@@H](O)CC[C@H]2[C@@H]2[C@H](C)CC3=CC(=O)CC[C@@H]3[C@H]21 YSGQGNQWBLYHPE-CFUSNLFHSA-N 0.000 description 4
- 208000031229 Cardiomyopathies Diseases 0.000 description 4
- 230000006044 T cell activation Effects 0.000 description 4
- 102100022203 Tumor necrosis factor receptor superfamily member 25 Human genes 0.000 description 4
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 4
- KOSRFJWDECSPRO-UHFFFAOYSA-N alpha-L-glutamyl-L-glutamic acid Natural products OC(=O)CCC(N)C(=O)NC(CCC(O)=O)C(O)=O KOSRFJWDECSPRO-UHFFFAOYSA-N 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 230000001413 cellular effect Effects 0.000 description 4
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 4
- 230000001472 cytotoxic effect Effects 0.000 description 4
- 230000003013 cytotoxicity Effects 0.000 description 4
- 231100000135 cytotoxicity Toxicity 0.000 description 4
- 239000012091 fetal bovine serum Substances 0.000 description 4
- 210000000285 follicular dendritic cell Anatomy 0.000 description 4
- 210000001035 gastrointestinal tract Anatomy 0.000 description 4
- 230000001900 immune effect Effects 0.000 description 4
- 239000003018 immunosuppressive agent Substances 0.000 description 4
- 229940125721 immunosuppressive agent Drugs 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 230000001717 pathogenic effect Effects 0.000 description 4
- 230000007170 pathology Effects 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 230000011664 signaling Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 241000701447 unidentified baculovirus Species 0.000 description 4
- YHKANGMVQWRMAP-DCAQKATOSA-N Ala-Leu-Arg Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N YHKANGMVQWRMAP-DCAQKATOSA-N 0.000 description 3
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 3
- 241000699679 Cricetulus migratorius Species 0.000 description 3
- -1 DR-3 Proteins 0.000 description 3
- 208000015023 Graves' disease Diseases 0.000 description 3
- 206010020751 Hypersensitivity Diseases 0.000 description 3
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 3
- HYIFFZAQXPUEAU-QWRGUYRKSA-N Leu-Gly-Leu Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC(C)C HYIFFZAQXPUEAU-QWRGUYRKSA-N 0.000 description 3
- 102100026894 Lymphotoxin-beta Human genes 0.000 description 3
- 108090000362 Lymphotoxin-beta Proteins 0.000 description 3
- 230000010799 Receptor Interactions Effects 0.000 description 3
- 230000024932 T cell mediated immunity Effects 0.000 description 3
- 102100036011 T-cell surface glycoprotein CD4 Human genes 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 210000001185 bone marrow Anatomy 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000036755 cellular response Effects 0.000 description 3
- 230000002950 deficient Effects 0.000 description 3
- 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 3
- 238000009472 formulation Methods 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 3
- 210000003714 granulocyte Anatomy 0.000 description 3
- 230000028996 humoral immune response Effects 0.000 description 3
- 230000000977 initiatory effect Effects 0.000 description 3
- 108010045069 keyhole-limpet hemocyanin Proteins 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 210000001165 lymph node Anatomy 0.000 description 3
- 239000003550 marker Substances 0.000 description 3
- 244000052769 pathogen Species 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 210000002345 respiratory system Anatomy 0.000 description 3
- 210000005212 secondary lymphoid organ Anatomy 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 210000004989 spleen cell Anatomy 0.000 description 3
- 230000002269 spontaneous effect Effects 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 238000013268 sustained release Methods 0.000 description 3
- 239000012730 sustained-release form Substances 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- UISQLSIBJKEJSS-GUBZILKMSA-N Arg-Arg-Ser Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CO)C(O)=O UISQLSIBJKEJSS-GUBZILKMSA-N 0.000 description 2
- 208000023328 Basedow disease Diseases 0.000 description 2
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 241000283074 Equus asinus Species 0.000 description 2
- 108010087819 Fc receptors Proteins 0.000 description 2
- 102000009109 Fc receptors Human genes 0.000 description 2
- 206010018378 Glomerulonephritis rapidly progressive Diseases 0.000 description 2
- UHPAZODVFFYEEL-QWRGUYRKSA-N Gly-Leu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)CN UHPAZODVFFYEEL-QWRGUYRKSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 2
- 101000801228 Homo sapiens Tumor necrosis factor receptor superfamily member 1A Proteins 0.000 description 2
- 101000679903 Homo sapiens Tumor necrosis factor receptor superfamily member 25 Proteins 0.000 description 2
- 108010058683 Immobilized Proteins Proteins 0.000 description 2
- IBMVEYRWAWIOTN-UHFFFAOYSA-N L-Leucyl-L-Arginyl-L-Proline Natural products CC(C)CC(N)C(=O)NC(CCCN=C(N)N)C(=O)N1CCCC1C(O)=O IBMVEYRWAWIOTN-UHFFFAOYSA-N 0.000 description 2
- 108010092694 L-Selectin Proteins 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 102000016551 L-selectin Human genes 0.000 description 2
- VGPCJSXPPOQPBK-YUMQZZPRSA-N Leu-Gly-Ser Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O VGPCJSXPPOQPBK-YUMQZZPRSA-N 0.000 description 2
- DXTOOBDIIAJZBJ-BQBZGAKWSA-N Pro-Gly-Ser Chemical compound [H]N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CO)C(O)=O DXTOOBDIIAJZBJ-BQBZGAKWSA-N 0.000 description 2
- YXHYJEPDKSYPSQ-AVGNSLFASA-N Pro-Leu-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1 YXHYJEPDKSYPSQ-AVGNSLFASA-N 0.000 description 2
- 108020004511 Recombinant DNA Proteins 0.000 description 2
- CUXJENOFJXOSOZ-BIIVOSGPSA-N Ser-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CO)N)C(=O)O CUXJENOFJXOSOZ-BIIVOSGPSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 108010090804 Streptavidin Proteins 0.000 description 2
- 230000005867 T cell response Effects 0.000 description 2
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 2
- 206010060872 Transplant failure Diseases 0.000 description 2
- 241000223109 Trypanosoma cruzi Species 0.000 description 2
- 102100033732 Tumor necrosis factor receptor superfamily member 1A Human genes 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- UGFMVXRXULGLNO-XPUUQOCRSA-N Val-Ser-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O UGFMVXRXULGLNO-XPUUQOCRSA-N 0.000 description 2
- LLJLBRRXKZTTRD-GUBZILKMSA-N Val-Val-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)O)N LLJLBRRXKZTTRD-GUBZILKMSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 230000009824 affinity maturation Effects 0.000 description 2
- 108010047495 alanylglycine Proteins 0.000 description 2
- 230000000961 alloantigen Effects 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000003466 anti-cipated effect Effects 0.000 description 2
- 230000000919 anti-host Effects 0.000 description 2
- 230000001028 anti-proliverative effect Effects 0.000 description 2
- 230000005875 antibody response Effects 0.000 description 2
- 210000000628 antibody-producing cell Anatomy 0.000 description 2
- 210000000612 antigen-presenting cell Anatomy 0.000 description 2
- 108010060035 arginylproline Proteins 0.000 description 2
- 230000001363 autoimmune Effects 0.000 description 2
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 2
- 229960002170 azathioprine Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000010322 bone marrow transplantation Methods 0.000 description 2
- 229940098773 bovine serum albumin Drugs 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 208000017760 chronic graft versus host disease Diseases 0.000 description 2
- 238000010367 cloning Methods 0.000 description 2
- 230000024203 complement activation Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 201000005637 crescentic glomerulonephritis Diseases 0.000 description 2
- 229960004397 cyclophosphamide Drugs 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 210000004443 dendritic cell Anatomy 0.000 description 2
- 238000009795 derivation Methods 0.000 description 2
- 238000006911 enzymatic reaction Methods 0.000 description 2
- 230000003325 follicular Effects 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 102000054766 genetic haplotypes Human genes 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 108010066198 glycyl-leucyl-phenylalanine Proteins 0.000 description 2
- 108010050848 glycylleucine Proteins 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 210000003630 histaminocyte Anatomy 0.000 description 2
- 229940072221 immunoglobulins Drugs 0.000 description 2
- 238000012606 in vitro cell culture Methods 0.000 description 2
- 239000012678 infectious agent Substances 0.000 description 2
- 230000004968 inflammatory condition Effects 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 230000002452 interceptive effect Effects 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 206010025135 lupus erythematosus Diseases 0.000 description 2
- 210000005210 lymphoid organ Anatomy 0.000 description 2
- 210000001806 memory b lymphocyte Anatomy 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 230000003990 molecular pathway Effects 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 2
- 102000013415 peroxidase activity proteins Human genes 0.000 description 2
- 108040007629 peroxidase activity proteins Proteins 0.000 description 2
- 210000001986 peyer's patch Anatomy 0.000 description 2
- 230000004983 pleiotropic effect Effects 0.000 description 2
- 201000006292 polyarteritis nodosa Diseases 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 230000003248 secreting effect Effects 0.000 description 2
- 230000035939 shock Effects 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- XMQUEQJCYRFIQS-YFKPBYRVSA-N (2s)-2-amino-5-ethoxy-5-oxopentanoic acid Chemical compound CCOC(=O)CC[C@H](N)C(O)=O XMQUEQJCYRFIQS-YFKPBYRVSA-N 0.000 description 1
- WQVFQXXBNHHPLX-ZKWXMUAHSA-N Ala-Ala-His Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](Cc1cnc[nH]1)C(O)=O WQVFQXXBNHHPLX-ZKWXMUAHSA-N 0.000 description 1
- CXRCVCURMBFFOL-FXQIFTODSA-N Ala-Ala-Pro Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O CXRCVCURMBFFOL-FXQIFTODSA-N 0.000 description 1
- YYSWCHMLFJLLBJ-ZLUOBGJFSA-N Ala-Ala-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YYSWCHMLFJLLBJ-ZLUOBGJFSA-N 0.000 description 1
- SDMAQFGBPOJFOM-GUBZILKMSA-N Ala-Arg-Arg Chemical compound NC(=N)NCCC[C@H](NC(=O)[C@@H](N)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O SDMAQFGBPOJFOM-GUBZILKMSA-N 0.000 description 1
- UCIYCBSJBQGDGM-LPEHRKFASA-N Ala-Arg-Pro Chemical compound C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1CCC[C@@H]1C(=O)O)N UCIYCBSJBQGDGM-LPEHRKFASA-N 0.000 description 1
- CXZFXHGJJPVUJE-CIUDSAMLSA-N Ala-Cys-Leu Chemical compound C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(=O)O)N CXZFXHGJJPVUJE-CIUDSAMLSA-N 0.000 description 1
- LGFCAXJBAZESCF-ACZMJKKPSA-N Ala-Gln-Ala Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O LGFCAXJBAZESCF-ACZMJKKPSA-N 0.000 description 1
- ZODMADSIQZZBSQ-FXQIFTODSA-N Ala-Gln-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O ZODMADSIQZZBSQ-FXQIFTODSA-N 0.000 description 1
- SMCGQGDVTPFXKB-XPUUQOCRSA-N Ala-Gly-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@H](C)N SMCGQGDVTPFXKB-XPUUQOCRSA-N 0.000 description 1
- LBFXVAXPDOBRKU-LKTVYLICSA-N Ala-His-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O LBFXVAXPDOBRKU-LKTVYLICSA-N 0.000 description 1
- PNALXAODQKTNLV-JBDRJPRFSA-N Ala-Ile-Ala Chemical compound C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O PNALXAODQKTNLV-JBDRJPRFSA-N 0.000 description 1
- MNZHHDPWDWQJCQ-YUMQZZPRSA-N Ala-Leu-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O MNZHHDPWDWQJCQ-YUMQZZPRSA-N 0.000 description 1
- BTRULDJUUVGRNE-DCAQKATOSA-N Ala-Pro-Lys Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(O)=O BTRULDJUUVGRNE-DCAQKATOSA-N 0.000 description 1
- GMGWOTQMUKYZIE-UBHSHLNASA-N Ala-Pro-Phe Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 GMGWOTQMUKYZIE-UBHSHLNASA-N 0.000 description 1
- OEVCHROQUIVQFZ-YTLHQDLWSA-N Ala-Thr-Ala Chemical compound C[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](C)C(O)=O OEVCHROQUIVQFZ-YTLHQDLWSA-N 0.000 description 1
- 108700028369 Alleles Proteins 0.000 description 1
- 206010027654 Allergic conditions Diseases 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 206010002199 Anaphylactic shock Diseases 0.000 description 1
- KWKQGHSSNHPGOW-BQBZGAKWSA-N Arg-Ala-Gly Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)NCC(O)=O KWKQGHSSNHPGOW-BQBZGAKWSA-N 0.000 description 1
- PEFFAAKJGBZBKL-NAKRPEOUSA-N Arg-Ala-Ile Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O PEFFAAKJGBZBKL-NAKRPEOUSA-N 0.000 description 1
- JCAISGGAOQXEHJ-ZPFDUUQYSA-N Arg-Gln-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCCN=C(N)N)N JCAISGGAOQXEHJ-ZPFDUUQYSA-N 0.000 description 1
- HPSVTWMFWCHKFN-GARJFASQSA-N Arg-Glu-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O HPSVTWMFWCHKFN-GARJFASQSA-N 0.000 description 1
- HQIZDMIGUJOSNI-IUCAKERBSA-N Arg-Gly-Arg Chemical compound N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O HQIZDMIGUJOSNI-IUCAKERBSA-N 0.000 description 1
- AUFHLLPVPSMEOG-YUMQZZPRSA-N Arg-Gly-Glu Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O AUFHLLPVPSMEOG-YUMQZZPRSA-N 0.000 description 1
- NVUIWHJLPSZZQC-CYDGBPFRSA-N Arg-Ile-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O NVUIWHJLPSZZQC-CYDGBPFRSA-N 0.000 description 1
- NIUDXSFNLBIWOB-DCAQKATOSA-N Arg-Leu-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N NIUDXSFNLBIWOB-DCAQKATOSA-N 0.000 description 1
- HGKHPCFTRQDHCU-IUCAKERBSA-N Arg-Pro-Gly Chemical compound NC(N)=NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O HGKHPCFTRQDHCU-IUCAKERBSA-N 0.000 description 1
- BWMMKQPATDUYKB-IHRRRGAJSA-N Arg-Tyr-Asn Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(O)=O)CC1=CC=C(O)C=C1 BWMMKQPATDUYKB-IHRRRGAJSA-N 0.000 description 1
- BKXPJCBEHWFSTF-ACZMJKKPSA-N Asp-Gln-Asp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O BKXPJCBEHWFSTF-ACZMJKKPSA-N 0.000 description 1
- VFUXXFVCYZPOQG-WDSKDSINSA-N Asp-Glu-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O VFUXXFVCYZPOQG-WDSKDSINSA-N 0.000 description 1
- SVABRQFIHCSNCI-FOHZUACHSA-N Asp-Gly-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O SVABRQFIHCSNCI-FOHZUACHSA-N 0.000 description 1
- UJGRZQYSNYTCAX-SRVKXCTJSA-N Asp-Leu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(O)=O UJGRZQYSNYTCAX-SRVKXCTJSA-N 0.000 description 1
- 102000019260 B-Cell Antigen Receptors Human genes 0.000 description 1
- 108010012919 B-Cell Antigen Receptors Proteins 0.000 description 1
- 102100032367 C-C motif chemokine 5 Human genes 0.000 description 1
- 102100027207 CD27 antigen Human genes 0.000 description 1
- 102100025221 CD70 antigen Human genes 0.000 description 1
- 208000000425 Chagas Cardiomyopathy Diseases 0.000 description 1
- 108010055166 Chemokine CCL5 Proteins 0.000 description 1
- 102000009410 Chemokine receptor Human genes 0.000 description 1
- 108050000299 Chemokine receptor Proteins 0.000 description 1
- VYZAMTAEIAYCRO-BJUDXGSMSA-N Chromium-51 Chemical compound [51Cr] VYZAMTAEIAYCRO-BJUDXGSMSA-N 0.000 description 1
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 102000015612 Complement 3b Receptors Human genes 0.000 description 1
- 108010024114 Complement 3b Receptors Proteins 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- SFRQEQGPRTVDPO-NRPADANISA-N Cys-Gln-Val Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O SFRQEQGPRTVDPO-NRPADANISA-N 0.000 description 1
- XLLSMEFANRROJE-GUBZILKMSA-N Cys-Leu-Glu Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](CS)N XLLSMEFANRROJE-GUBZILKMSA-N 0.000 description 1
- 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 1
- 102000053602 DNA Human genes 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 101710088341 Dermatopontin Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010014950 Eosinophilia Diseases 0.000 description 1
- 102100023688 Eotaxin Human genes 0.000 description 1
- 101710139422 Eotaxin Proteins 0.000 description 1
- 108010039471 Fas Ligand Protein Proteins 0.000 description 1
- KWUSGAIFNHQCBY-DCAQKATOSA-N Gln-Arg-Arg Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O KWUSGAIFNHQCBY-DCAQKATOSA-N 0.000 description 1
- WQWMZOIPXWSZNE-WDSKDSINSA-N Gln-Asp-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O WQWMZOIPXWSZNE-WDSKDSINSA-N 0.000 description 1
- IXFVOPOHSRKJNG-LAEOZQHASA-N Gln-Asp-Val Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O IXFVOPOHSRKJNG-LAEOZQHASA-N 0.000 description 1
- SNLOOPZHAQDMJG-CIUDSAMLSA-N Gln-Glu-Glu Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O SNLOOPZHAQDMJG-CIUDSAMLSA-N 0.000 description 1
- VOLVNCMGXWDDQY-LPEHRKFASA-N Gln-Glu-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCC(=O)N)N)C(=O)O VOLVNCMGXWDDQY-LPEHRKFASA-N 0.000 description 1
- YRWWJCDWLVXTHN-LAEOZQHASA-N Gln-Ile-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CCC(=O)N)N YRWWJCDWLVXTHN-LAEOZQHASA-N 0.000 description 1
- DUGYCMAIAKAQPB-GLLZPBPUSA-N Gln-Thr-Glu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O DUGYCMAIAKAQPB-GLLZPBPUSA-N 0.000 description 1
- QZQYITIKPAUDGN-GVXVVHGQSA-N Gln-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CCC(=O)N)N QZQYITIKPAUDGN-GVXVVHGQSA-N 0.000 description 1
- FITIQFSXXBKFFM-NRPADANISA-N Gln-Val-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O FITIQFSXXBKFFM-NRPADANISA-N 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- FHPXTPQBODWBIY-CIUDSAMLSA-N Glu-Ala-Arg Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O FHPXTPQBODWBIY-CIUDSAMLSA-N 0.000 description 1
- QPRZKNOOOBWXSU-CIUDSAMLSA-N Glu-Asp-Arg Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N QPRZKNOOOBWXSU-CIUDSAMLSA-N 0.000 description 1
- MUSGDMDGNGXULI-DCAQKATOSA-N Glu-Glu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CCC(O)=O MUSGDMDGNGXULI-DCAQKATOSA-N 0.000 description 1
- YLJHCWNDBKKOEB-IHRRRGAJSA-N Glu-Glu-Phe Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O YLJHCWNDBKKOEB-IHRRRGAJSA-N 0.000 description 1
- IQACOVZVOMVILH-FXQIFTODSA-N Glu-Glu-Ser Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O IQACOVZVOMVILH-FXQIFTODSA-N 0.000 description 1
- FGSGPLRPQCZBSQ-AVGNSLFASA-N Glu-Phe-Ser Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O FGSGPLRPQCZBSQ-AVGNSLFASA-N 0.000 description 1
- DAHLWSFUXOHMIA-FXQIFTODSA-N Glu-Ser-Gln Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O DAHLWSFUXOHMIA-FXQIFTODSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- GZUKEVBTYNNUQF-WDSKDSINSA-N Gly-Ala-Gln Chemical compound NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(O)=O GZUKEVBTYNNUQF-WDSKDSINSA-N 0.000 description 1
- KFMBRBPXHVMDFN-UWVGGRQHSA-N Gly-Arg-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CCCNC(N)=N KFMBRBPXHVMDFN-UWVGGRQHSA-N 0.000 description 1
- LHRXAHLCRMQBGJ-RYUDHWBXSA-N Gly-Glu-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)CN LHRXAHLCRMQBGJ-RYUDHWBXSA-N 0.000 description 1
- TVUWMSBGMVAHSJ-KBPBESRZSA-N Gly-Leu-Phe Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 TVUWMSBGMVAHSJ-KBPBESRZSA-N 0.000 description 1
- AFWYPMDMDYCKMD-KBPBESRZSA-N Gly-Leu-Tyr Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 AFWYPMDMDYCKMD-KBPBESRZSA-N 0.000 description 1
- VBOBNHSVQKKTOT-YUMQZZPRSA-N Gly-Lys-Ala Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O VBOBNHSVQKKTOT-YUMQZZPRSA-N 0.000 description 1
- HJARVELKOSZUEW-YUMQZZPRSA-N Gly-Pro-Gln Chemical compound [H]NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(O)=O HJARVELKOSZUEW-YUMQZZPRSA-N 0.000 description 1
- FFJQHWKSGAWSTJ-BFHQHQDPSA-N Gly-Thr-Ala Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O FFJQHWKSGAWSTJ-BFHQHQDPSA-N 0.000 description 1
- NIOPEYHPOBWLQO-KBPBESRZSA-N Gly-Trp-Glu Chemical compound NCC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCC(O)=O)C(O)=O NIOPEYHPOBWLQO-KBPBESRZSA-N 0.000 description 1
- DNVDEMWIYLVIQU-RCOVLWMOSA-N Gly-Val-Asp Chemical compound NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O DNVDEMWIYLVIQU-RCOVLWMOSA-N 0.000 description 1
- BAYQNCWLXIDLHX-ONGXEEELSA-N Gly-Val-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)CN BAYQNCWLXIDLHX-ONGXEEELSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 208000024869 Goodpasture syndrome Diseases 0.000 description 1
- 208000003807 Graves Disease Diseases 0.000 description 1
- 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- RNMNYMDTESKEAJ-KKUMJFAQSA-N His-Leu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CN=CN1 RNMNYMDTESKEAJ-KKUMJFAQSA-N 0.000 description 1
- SOYCWSKCUVDLMC-AVGNSLFASA-N His-Pro-Arg Chemical compound N[C@@H](Cc1cnc[nH]1)C(=O)N2CCC[C@H]2C(=O)N[C@@H](CCCNC(=N)N)C(=O)O SOYCWSKCUVDLMC-AVGNSLFASA-N 0.000 description 1
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 description 1
- 101000934356 Homo sapiens CD70 antigen Proteins 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- TZCGZYWNIDZZMR-NAKRPEOUSA-N Ile-Arg-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](C)C(=O)O)N TZCGZYWNIDZZMR-NAKRPEOUSA-N 0.000 description 1
- TZCGZYWNIDZZMR-UHFFFAOYSA-N Ile-Arg-Ala Natural products CCC(C)C(N)C(=O)NC(C(=O)NC(C)C(O)=O)CCCN=C(N)N TZCGZYWNIDZZMR-UHFFFAOYSA-N 0.000 description 1
- QTUSJASXLGLJSR-OSUNSFLBSA-N Ile-Arg-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N QTUSJASXLGLJSR-OSUNSFLBSA-N 0.000 description 1
- HDODQNPMSHDXJT-GHCJXIJMSA-N Ile-Asn-Ser Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O HDODQNPMSHDXJT-GHCJXIJMSA-N 0.000 description 1
- APQYGMBHIVXFML-OSUNSFLBSA-N Ile-Val-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N APQYGMBHIVXFML-OSUNSFLBSA-N 0.000 description 1
- 208000001718 Immediate Hypersensitivity Diseases 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 108090000174 Interleukin-10 Proteins 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 108010002616 Interleukin-5 Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 108090001007 Interleukin-8 Proteins 0.000 description 1
- PMGDADKJMCOXHX-UHFFFAOYSA-N L-Arginyl-L-glutamin-acetat Natural products NC(=N)NCCCC(N)C(=O)NC(CCC(N)=O)C(O)=O PMGDADKJMCOXHX-UHFFFAOYSA-N 0.000 description 1
- SITWEMZOJNKJCH-UHFFFAOYSA-N L-alanine-L-arginine Natural products CC(N)C(=O)NC(C(O)=O)CCCNC(N)=N SITWEMZOJNKJCH-UHFFFAOYSA-N 0.000 description 1
- RCFDOSNHHZGBOY-UHFFFAOYSA-N L-isoleucyl-L-alanine Natural products CCC(C)C(N)C(=O)NC(C)C(O)=O RCFDOSNHHZGBOY-UHFFFAOYSA-N 0.000 description 1
- KVRKAGGMEWNURO-CIUDSAMLSA-N Leu-Ala-Cys Chemical compound C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(C)C)N KVRKAGGMEWNURO-CIUDSAMLSA-N 0.000 description 1
- WGNOPSQMIQERPK-GARJFASQSA-N Leu-Asn-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N1CCC[C@@H]1C(=O)O)N WGNOPSQMIQERPK-GARJFASQSA-N 0.000 description 1
- QKIBIXAQKAFZGL-GUBZILKMSA-N Leu-Cys-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(O)=O QKIBIXAQKAFZGL-GUBZILKMSA-N 0.000 description 1
- KVMULWOHPPMHHE-DCAQKATOSA-N Leu-Glu-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O KVMULWOHPPMHHE-DCAQKATOSA-N 0.000 description 1
- ZRHDPZAAWLXXIR-SRVKXCTJSA-N Leu-Lys-Ala Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O ZRHDPZAAWLXXIR-SRVKXCTJSA-N 0.000 description 1
- BGZCJDGBBUUBHA-KKUMJFAQSA-N Leu-Lys-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O BGZCJDGBBUUBHA-KKUMJFAQSA-N 0.000 description 1
- KQFZKDITNUEVFJ-JYJNAYRXSA-N Leu-Phe-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)CC1=CC=CC=C1 KQFZKDITNUEVFJ-JYJNAYRXSA-N 0.000 description 1
- JLYUZRKPDKHUTC-WDSOQIARSA-N Leu-Pro-Trp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O JLYUZRKPDKHUTC-WDSOQIARSA-N 0.000 description 1
- IRMLZWSRWSGTOP-CIUDSAMLSA-N Leu-Ser-Ala Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O IRMLZWSRWSGTOP-CIUDSAMLSA-N 0.000 description 1
- ZJZNLRVCZWUONM-JXUBOQSCSA-N Leu-Thr-Ala Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O ZJZNLRVCZWUONM-JXUBOQSCSA-N 0.000 description 1
- FBNPMTNBFFAMMH-AVGNSLFASA-N Leu-Val-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N FBNPMTNBFFAMMH-AVGNSLFASA-N 0.000 description 1
- FBNPMTNBFFAMMH-UHFFFAOYSA-N Leu-Val-Arg Natural products CC(C)CC(N)C(=O)NC(C(C)C)C(=O)NC(C(O)=O)CCCN=C(N)N FBNPMTNBFFAMMH-UHFFFAOYSA-N 0.000 description 1
- XZNJZXJZBMBGGS-NHCYSSNCSA-N Leu-Val-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O XZNJZXJZBMBGGS-NHCYSSNCSA-N 0.000 description 1
- FDBTVENULFNTAL-XQQFMLRXSA-N Leu-Val-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N FDBTVENULFNTAL-XQQFMLRXSA-N 0.000 description 1
- 102000018170 Lymphotoxin beta Receptor Human genes 0.000 description 1
- 108010091221 Lymphotoxin beta Receptor Proteins 0.000 description 1
- IRNSXVOWSXSULE-DCAQKATOSA-N Lys-Ala-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN IRNSXVOWSXSULE-DCAQKATOSA-N 0.000 description 1
- GQZMPWBZQALKJO-UWVGGRQHSA-N Lys-Gly-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O GQZMPWBZQALKJO-UWVGGRQHSA-N 0.000 description 1
- KYNNSEJZFVCDIV-ZPFDUUQYSA-N Lys-Ile-Asn Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(O)=O KYNNSEJZFVCDIV-ZPFDUUQYSA-N 0.000 description 1
- MUXNCRWTWBMNHX-SRVKXCTJSA-N Lys-Leu-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O MUXNCRWTWBMNHX-SRVKXCTJSA-N 0.000 description 1
- TVHCDSBMFQYPNA-RHYQMDGZSA-N Lys-Thr-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O TVHCDSBMFQYPNA-RHYQMDGZSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 108010061593 Member 14 Tumor Necrosis Factor Receptors Proteins 0.000 description 1
- 108010060408 Member 25 Tumor Necrosis Factor Receptors Proteins 0.000 description 1
- 102000008166 Member 25 Tumor Necrosis Factor Receptors Human genes 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- YRAWWKUTNBILNT-FXQIFTODSA-N Met-Ala-Ala Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O YRAWWKUTNBILNT-FXQIFTODSA-N 0.000 description 1
- 101710151805 Mitochondrial intermediate peptidase 1 Proteins 0.000 description 1
- 101100247594 Mus musculus Rc3h2 gene Proteins 0.000 description 1
- 101100369998 Mus musculus Tnfsf12 gene Proteins 0.000 description 1
- YBAFDPFAUTYYRW-UHFFFAOYSA-N N-L-alpha-glutamyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CCC(O)=O YBAFDPFAUTYYRW-UHFFFAOYSA-N 0.000 description 1
- KZNQNBZMBZJQJO-UHFFFAOYSA-N N-glycyl-L-proline Natural products NCC(=O)N1CCCC1C(O)=O KZNQNBZMBZJQJO-UHFFFAOYSA-N 0.000 description 1
- AJHCSUXXECOXOY-UHFFFAOYSA-N N-glycyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)CN)C(O)=O)=CNC2=C1 AJHCSUXXECOXOY-UHFFFAOYSA-N 0.000 description 1
- 108010002311 N-glycylglutamic acid Proteins 0.000 description 1
- 102000003945 NF-kappa B Human genes 0.000 description 1
- 108010057466 NF-kappa B Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108010042215 OX40 Ligand Proteins 0.000 description 1
- 206010053159 Organ failure Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- DDYIRGBOZVKRFR-AVGNSLFASA-N Phe-Asp-Glu Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N DDYIRGBOZVKRFR-AVGNSLFASA-N 0.000 description 1
- KBVJZCVLQWCJQN-KKUMJFAQSA-N Phe-Leu-Asn Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O KBVJZCVLQWCJQN-KKUMJFAQSA-N 0.000 description 1
- CMHTUJQZQXFNTQ-OEAJRASXSA-N Phe-Leu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC1=CC=CC=C1)N)O CMHTUJQZQXFNTQ-OEAJRASXSA-N 0.000 description 1
- MSSXKZBDKZAHCX-UNQGMJICSA-N Phe-Thr-Val Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O MSSXKZBDKZAHCX-UNQGMJICSA-N 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- AJLVKXCNXIJHDV-CIUDSAMLSA-N Pro-Ala-Gln Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(O)=O AJLVKXCNXIJHDV-CIUDSAMLSA-N 0.000 description 1
- CGBYDGAJHSOGFQ-LPEHRKFASA-N Pro-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@@H]2CCCN2 CGBYDGAJHSOGFQ-LPEHRKFASA-N 0.000 description 1
- LNLNHXIQPGKRJQ-SRVKXCTJSA-N Pro-Arg-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H]1CCCN1 LNLNHXIQPGKRJQ-SRVKXCTJSA-N 0.000 description 1
- HJSCRFZVGXAGNG-SRVKXCTJSA-N Pro-Gln-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1 HJSCRFZVGXAGNG-SRVKXCTJSA-N 0.000 description 1
- XZONQWUEBAFQPO-HJGDQZAQSA-N Pro-Gln-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O XZONQWUEBAFQPO-HJGDQZAQSA-N 0.000 description 1
- NXEYSLRNNPWCRN-SRVKXCTJSA-N Pro-Glu-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O NXEYSLRNNPWCRN-SRVKXCTJSA-N 0.000 description 1
- JMVQDLDPDBXAAX-YUMQZZPRSA-N Pro-Gly-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 JMVQDLDPDBXAAX-YUMQZZPRSA-N 0.000 description 1
- FNGOXVQBBCMFKV-CIUDSAMLSA-N Pro-Ser-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(O)=O FNGOXVQBBCMFKV-CIUDSAMLSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- BRKHVZNDAOMAHX-BIIVOSGPSA-N Ser-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CO)N BRKHVZNDAOMAHX-BIIVOSGPSA-N 0.000 description 1
- JPIDMRXXNMIVKY-VZFHVOOUSA-N Ser-Ala-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JPIDMRXXNMIVKY-VZFHVOOUSA-N 0.000 description 1
- QYSFWUIXDFJUDW-DCAQKATOSA-N Ser-Leu-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O QYSFWUIXDFJUDW-DCAQKATOSA-N 0.000 description 1
- XNCUYZKGQOCOQH-YUMQZZPRSA-N Ser-Leu-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O XNCUYZKGQOCOQH-YUMQZZPRSA-N 0.000 description 1
- YUJLIIRMIAGMCQ-CIUDSAMLSA-N Ser-Leu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YUJLIIRMIAGMCQ-CIUDSAMLSA-N 0.000 description 1
- XQJCEKXQUJQNNK-ZLUOBGJFSA-N Ser-Ser-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O XQJCEKXQUJQNNK-ZLUOBGJFSA-N 0.000 description 1
- 208000018359 Systemic autoimmune disease Diseases 0.000 description 1
- 108091008874 T cell receptors Proteins 0.000 description 1
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 1
- NCXVJIQMWSGRHY-KXNHARMFSA-N Thr-Leu-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N)O NCXVJIQMWSGRHY-KXNHARMFSA-N 0.000 description 1
- XVHAUVJXBFGUPC-RPTUDFQQSA-N Thr-Tyr-Phe Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O XVHAUVJXBFGUPC-RPTUDFQQSA-N 0.000 description 1
- MNYNCKZAEIAONY-XGEHTFHBSA-N Thr-Val-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O MNYNCKZAEIAONY-XGEHTFHBSA-N 0.000 description 1
- OFNPHOGOJLNVLL-KCTSRDHCSA-N Trp-Ala-His Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CC2=CNC3=CC=CC=C32)N OFNPHOGOJLNVLL-KCTSRDHCSA-N 0.000 description 1
- PEYSVKMXSLPQRU-FJHTZYQYSA-N Trp-Ala-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N)O PEYSVKMXSLPQRU-FJHTZYQYSA-N 0.000 description 1
- CZWIHKFGHICAJX-BPUTZDHNSA-N Trp-Glu-Glu Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O)=CNC2=C1 CZWIHKFGHICAJX-BPUTZDHNSA-N 0.000 description 1
- 102100026890 Tumor necrosis factor ligand superfamily member 4 Human genes 0.000 description 1
- 102100031988 Tumor necrosis factor ligand superfamily member 6 Human genes 0.000 description 1
- 102100028785 Tumor necrosis factor receptor superfamily member 14 Human genes 0.000 description 1
- 102100022153 Tumor necrosis factor receptor superfamily member 4 Human genes 0.000 description 1
- 101710165473 Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 description 1
- 206010045240 Type I hypersensitivity Diseases 0.000 description 1
- 206010053614 Type III immune complex mediated reaction Diseases 0.000 description 1
- BARBHMSSVWPKPZ-IHRRRGAJSA-N Tyr-Asp-Arg Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O BARBHMSSVWPKPZ-IHRRRGAJSA-N 0.000 description 1
- QOIKZODVIPOPDD-AVGNSLFASA-N Tyr-Cys-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(O)=O QOIKZODVIPOPDD-AVGNSLFASA-N 0.000 description 1
- UNUZEBFXGWVAOP-DZKIICNBSA-N Tyr-Glu-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O UNUZEBFXGWVAOP-DZKIICNBSA-N 0.000 description 1
- OLYXUGBVBGSZDN-ACRUOGEOSA-N Tyr-Leu-Tyr Chemical compound C([C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 OLYXUGBVBGSZDN-ACRUOGEOSA-N 0.000 description 1
- OKDNSNWJEXAMSU-IRXDYDNUSA-N Tyr-Phe-Gly Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC(O)=O)C1=CC=C(O)C=C1 OKDNSNWJEXAMSU-IRXDYDNUSA-N 0.000 description 1
- HZDQUVQEVVYDDA-ACRUOGEOSA-N Tyr-Tyr-Leu Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 HZDQUVQEVVYDDA-ACRUOGEOSA-N 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- YFOCMOVJBQDBCE-NRPADANISA-N Val-Ala-Glu Chemical compound C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N YFOCMOVJBQDBCE-NRPADANISA-N 0.000 description 1
- CVUDMNSZAIZFAE-TUAOUCFPSA-N Val-Arg-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1CCC[C@@H]1C(=O)O)N CVUDMNSZAIZFAE-TUAOUCFPSA-N 0.000 description 1
- CVUDMNSZAIZFAE-UHFFFAOYSA-N Val-Arg-Pro Natural products NC(N)=NCCCC(NC(=O)C(N)C(C)C)C(=O)N1CCCC1C(O)=O CVUDMNSZAIZFAE-UHFFFAOYSA-N 0.000 description 1
- QHDXUYOYTPWCSK-RCOVLWMOSA-N Val-Asp-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)NCC(=O)O)N QHDXUYOYTPWCSK-RCOVLWMOSA-N 0.000 description 1
- ZTKGDWOUYRRAOQ-ULQDDVLXSA-N Val-His-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CC2=CC=CC=C2)C(=O)O)N ZTKGDWOUYRRAOQ-ULQDDVLXSA-N 0.000 description 1
- YTUABZMPYKCWCQ-XQQFMLRXSA-N Val-His-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N2CCC[C@@H]2C(=O)O)N YTUABZMPYKCWCQ-XQQFMLRXSA-N 0.000 description 1
- BTWMICVCQLKKNR-DCAQKATOSA-N Val-Leu-Ser Chemical compound CC(C)[C@H]([NH3+])C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C([O-])=O BTWMICVCQLKKNR-DCAQKATOSA-N 0.000 description 1
- QIVPZSWBBHRNBA-JYJNAYRXSA-N Val-Pro-Phe Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(O)=O QIVPZSWBBHRNBA-JYJNAYRXSA-N 0.000 description 1
- JXWGBRRVTRAZQA-ULQDDVLXSA-N Val-Tyr-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](C(C)C)N JXWGBRRVTRAZQA-ULQDDVLXSA-N 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 108010008685 alanyl-glutamyl-aspartic acid Proteins 0.000 description 1
- 108010044940 alanylglutamine Proteins 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 230000009285 allergic inflammation Effects 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 230000003460 anti-nuclear Effects 0.000 description 1
- 208000037908 antibody-mediated disorder Diseases 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 108010008355 arginyl-glutamine Proteins 0.000 description 1
- 108010084758 arginyl-tyrosyl-aspartic acid Proteins 0.000 description 1
- 108010068380 arginylarginine Proteins 0.000 description 1
- 108010062796 arginyllysine Proteins 0.000 description 1
- 108010093581 aspartyl-proline Proteins 0.000 description 1
- 108010047857 aspartylglycine Proteins 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 208000010216 atopic IgE responsiveness Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 description 1
- 230000006472 autoimmune response Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 210000002469 basement membrane Anatomy 0.000 description 1
- 210000003651 basophil Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 229920001222 biopolymer Polymers 0.000 description 1
- 210000003969 blast cell Anatomy 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- 210000004556 brain Anatomy 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
- 230000003683 cardiac damage Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000005859 cell recognition Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000008614 cellular interaction Effects 0.000 description 1
- 208000019065 cervical carcinoma Diseases 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000002975 chemoattractant Substances 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 208000037893 chronic inflammatory disorder Diseases 0.000 description 1
- 229960002303 citric acid monohydrate Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 108091008034 costimulatory receptors Proteins 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 238000011461 current therapy Methods 0.000 description 1
- 230000016396 cytokine production Effects 0.000 description 1
- 230000007402 cytotoxic response Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 108010054813 diprotin B Proteins 0.000 description 1
- 230000009266 disease activity Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 210000003979 eosinophil Anatomy 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000012537 formulation buffer Substances 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 1
- 108010010147 glycylglutamine Proteins 0.000 description 1
- 108010015792 glycyllysine Proteins 0.000 description 1
- 108010084389 glycyltryptophan Proteins 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 208000006750 hematuria Diseases 0.000 description 1
- 208000007475 hemolytic anemia Diseases 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 230000002962 histologic effect Effects 0.000 description 1
- 230000008348 humoral response Effects 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 239000000819 hypertonic solution Substances 0.000 description 1
- 229940021223 hypertonic solution Drugs 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000009851 immunogenic response Effects 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 230000007233 immunological mechanism Effects 0.000 description 1
- 230000004957 immunoregulator effect Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 108010034529 leucyl-lysine Proteins 0.000 description 1
- 238000000670 ligand binding assay Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 238000012153 long-term therapy Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 108010025153 lysyl-alanyl-alanine Proteins 0.000 description 1
- 108010064235 lysylglycine Proteins 0.000 description 1
- 230000002101 lytic effect Effects 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 238000000302 molecular modelling Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 230000004660 morphological change Effects 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- AEMBWNDIEFEPTH-UHFFFAOYSA-N n-tert-butyl-n-ethylnitrous amide Chemical compound CCN(N=O)C(C)(C)C AEMBWNDIEFEPTH-UHFFFAOYSA-N 0.000 description 1
- 230000007837 negative regulation of B cell activation Effects 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 238000012261 overproduction Methods 0.000 description 1
- 210000002741 palatine tonsil Anatomy 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 210000001539 phagocyte Anatomy 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 108010051242 phenylalanylserine Proteins 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920002338 polyhydroxyethylmethacrylate Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 210000005211 primary lymphoid organ Anatomy 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 108010025826 prolyl-leucyl-arginine Proteins 0.000 description 1
- 108010077112 prolyl-proline Proteins 0.000 description 1
- 108010031719 prolyl-serine Proteins 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 201000001474 proteinuria Diseases 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 238000002864 sequence alignment Methods 0.000 description 1
- 108010026333 seryl-proline Proteins 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000011476 stem cell transplantation Methods 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000009959 type I hypersensitivity Effects 0.000 description 1
- 208000025883 type III hypersensitivity disease Diseases 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 210000000264 venule Anatomy 0.000 description 1
Images
Classifications
-
- 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
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70575—NGF/TNF-superfamily, e.g. CD70, CD95L, CD153, CD154
-
- 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
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
-
- 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
-
- 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
-
- 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
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- 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
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2875—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154
-
- 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
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
-
- 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
- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
Definitions
- the present invention relates to compositions and methods comprising reagents which bind to the novel protein TWEAK, and the use of TWEAK binding reagents to block the development of immunologic disorders.
- TWEAK binding reagents include monoclonal antibodies, as used herein to block the development of chronic Graft-Versus-Host Disease, soluble TWEAK-receptor-Ig fusion proteins, or other molecules which modify the binding of TWEAK to its' receptor(s).
- Other embodiments of the invention include reagents which bind to TWEAK receptor(s) to modify their activity, or modify the intracellular signaling of TWEAK receptor(s).
- Immunological disorders are manifested as a wide variety of diseases and pathologies, including autoimmune diseases, acute and chronic inflammatory disorders, organ transplant rejection, Graft-Versus-Host Disease (GVHD), lymphoid cell malignancies, septic and other forms of shock, loss of immune responsiveness as seen in HIV and SCIDS, and failure of the immune response to tumor growth.
- autoimmune diseases acute and chronic inflammatory disorders
- organ transplant rejection organ transplant rejection
- GVHD Graft-Versus-Host Disease
- lymphoid cell malignancies septic and other forms of shock
- loss of immune responsiveness as seen in HIV and SCIDS
- failure of the immune response to tumor growth failure of the immune response to tumor growth.
- GVHD bone marrow transplant
- host ie. patient
- Acute inflammatory disorders such as hyper-allergic conditions and shock are the result of uncontrolled immune response to the triggering antigens.
- T cell dependent immune responses require T cell recognition of antigen.
- GVHD results from a complex interplay between donor T cells and host immune system cells.
- the initiating event is the recognition by donor T cells of non-self, ie. host, antigens. These are referred to as alloantigens.
- Alloantigen recognition by these donor cells results in the production of immunoregulatory and inflammatory cytokines and chemokines, which advance and exacerbate the donor anti-host immune response.
- This disease can develop in either an acute or chronic form, depending on the regulation of complex cytokine networks which control the type of immune response which develops.
- Immune responses can be characterized as Th0, Th1, or Th2 depending on 1) the nature of the cytokines and chemokines produced by activated T cells during the response, and 2) the nature of the cytokines and chemokines produced by accessory and other cells during the response.
- Examples of non-T cells important during immune responses are B cells, dendritic cells, monocytes and macrophages, follicular dendritic cells, and endothelial cells. Together the cytokines produced influence a variety of cell types to differentiate, and the chemokines produced influence cell trafficking and localization. Th0 responses are characteristic of the short term stimulation of previously unstimulated (naive) T cells.
- Th0 T cells produce moderate amounts of a number of cytokines, notably I1-2 and TNF. Repetitively or chronically stimulated Th0 cells can differentiate into either Th1 or Th2 T cells, depending on a number of factors. Such factors include, but are not limited to, accessory cell cytokine production, the strength of T cell receptor engagement, and the nature of secondary signals received, eg. via the CD28 costimulatory receptor.
- cytokine I1-12 produced primarily by activated macrophages, supports differentiation to Th1 T cells, while exposure to I1-4 and I1-10 supports differentiation to Th2 T cells.
- Th1 T cells produce cytokines such as I1-2 and IFN-y which are associated with inflammatory responses, T cell cytotoxicity, and macrophage activation. Th1 T cells respond to chemokines which attract cells into sites of tissue inflammation, such as Mip-1alpha, MIP-1 beta, RANTES, IP-10, and MIG. Since cytotoxic T cells and activated macrophages act to eliminate damaged or infected cells, the Th1 response is responsible for controlling the immune response to intracellular pathogens. Importantly, production of Th1 chemoattractant chemokines such as IP-10 and MIG by macrophages and endothelial cells is closely regulated by IFN-y, which is the prototypic chemokine produced by Th1 T cells. Thus feedback loops may develop between activated T cells and their environment, which augment the development of a particular type of response at a particular time and location
- Th2 T cells produce cytokines such as I1-4, I1-5, I1-6, and I1-10 which support the development of humoral immune responses, including those which require the production of IgE, IgA, and IgG. These Ig responses are driven by the T cell mediated activation of B cells which “switch” their Ig phenotype from surface bound IgM and IgD to secreted Ig. Secreted Igs normally function to control infection from pathogens in circulation (IgG), at mucosal surfaces, such as the gut and oral cavity (IgA) and in the respiratory tract (IgE).
- IgG pathogens in circulation
- IgA the gut and oral cavity
- IgE in the respiratory tract
- Th2 T cells also support the activation of eosinophils and Mast cells which can mediate acute responses to pathogens, for example in the respiratory tract. Th2 T cells respond to chemokines such as eotaxin and MDC, whose production is closely regulated by I1-4, the prototypic cytokine produced by NK1.1 and activated T cells.
- chemokines such as eotaxin and MDC, whose production is closely regulated by I1-4, the prototypic cytokine produced by NK1.1 and activated T cells.
- B cells must receive an antigen signal through the B cell antigen receptor (membrane Ig).
- B cells must receive specific contact dependent and contact independent signals from activated T cells.
- One required contact dependent signal is delivered via the binding of CD40L on T cells to CD40 on B cells.
- One required contact-independent signal is delivered by I1-4 secreted by activated T cells and by NK1.1 cells binding to the I1-4 receptor on B cells. These signals appear to take place within the T cell areas of secondary lymphoid organs, such as the spleen.
- the spleen, lymph nodes, tonsils, Peyer's patches and other secondary and tertiary lymphoid organs have distinct microanatomical areas within which T and B cells typically reside. All lymphocytes migrate out of the blood or the lymph into the T cell area of these organs first, by crossing endothelial cell layers such as the High Endothelial Venules in lymph nodes and Peyer's patches and the marginal sinus endothelial cell layer in the spleen. Then, the B cells move into B cell areas known as B cell follicles. B cells which have traversed the T cell area but have not become activated will leave the follicle after a few days. Activated B cell undergo a process of differentiation.
- Some activated B cells known as plasmacytes, secrete large amounts of antigen specific, low affinity IgM or IgG antibody. These B cells typically appear early after the induction of the immune response, and move into the red pulp of the spleen and other anatomical locations, where they persist, secreting antibody, for several days.
- Other activated B cells differentiate within a region of the follicle known as the secondary follicle, or germinal center. Germinal centers form around networks of specialized antigen retaining cells known as Follicular Dendritic Cells (FDC), which are thought to display antigen to drive or refine the germinal center reaction.
- FDC Follicular Dendritic Cells
- B cells within the germinal center have “switched” their Ig phenotype, and undergo “affinity maturation”, with the result that they display a high affinity for their antigen target.
- the antigen target is a foreign antigen, although in diseases such as chronic GVHD and autoimmune disorders the Igs recognize self-antigens.
- B cells leave the follicles, migrate back through the T cells areas, and leave the organ via efferent circulation into the bloodstream.
- B cells that have fully differentiated to express high affinity Ig are known as blast cells, and they leave B cell follicles to take up residence in various other environments, including the red-pulp areas of the spleen, the bone marrow, the liver, or mucosal cell layers lining the respiratory tract and gut. Some of these fully differentiated B cells are known as memory cells, and can persist for long periods of time, ready to respond to the same antigen if it is encountered again.
- B cells migrate from location to location within the lymphoid organs they require specific signals to guide them, and specific signals which ensure their survival. For example, multiple signals are required to maintain B cell follicular organization in the spleen. These include interaction of the BCA ligand with the chemokine receptor BLR-1, interaction of TNF with TNF-R55, and interaction of LTbeta with LT ⁇ -R (reviewed in Chaplin and Fu, Current Opin. Immunol. 10: 298-297 (1998)). Mice which are deficient in any of these molecular pathways lose B cell follicular integrity in the spleen. Furthermore, all of these gene-deficient mice have also lost the ability to undergo germinal center reactions in the spleen.
- mice deficient in CD40L maintain B cell follicles, but germinal centers do not form.
- B cells within the germinal center environment require signals through CD40 to maintain survival and to downregulate IgM and switch to Ig expression.
- B cells move not only within the follicle and germinal center, but also leave the follicle after activation, and move to other sites within the body.
- Memory B cells can be found in the bone marrow, and B cells which express IgA specifically traffic to cell layers in the gut and other mucosal sites.
- Other signals presumably guide activated T cells to specific sites within and between lymphoid compartments.
- cytotoxic T cell can migrate to the site of infection or other antigen challenge to find and lyse their targets.
- the identities of all the signals which guide T and B cells between different microanatomic locations are not yet known. However it appears that multiple pathways orchestrate the T and B cell responses to antigen, both in secondary lymphoid organs, and at the sites of infection or inflammation.
- GVHD is a well studied example of an antigen driven immune response. GVHD is an often fatal consequence of bone marrow transplantation (BMT) in human patients. The disease can occur in an acute or in a chronic form. Acute and chronic forms of GVHD are prototypic examples of the development of antigen specific Th1 and Th2 responses, respectively. The acute form of the disease occurs within the first 2 months following BMT, and is characterized by donor cytotoxic T cell-mediated damage to skin, gut, liver, and other organs.
- the chronic form of the disease is manifested much later (over 100 days post-BMT) and is characterized by hyperproduction of immunoglobulin (Ig), including autoantibodies, and damage to the skin, kidney, and other organs caused by Ig-deposition.
- Ig immunoglobulin
- the development of acute GVHD is predictive of the subsequent development of chronic GVHD.
- the same patient can develop both diseases, in sequence.
- Approximately 50% of all BMT patients develop either acute or chronic GVHD.
- Nearly 90% of acute GVHD patients go on to develop chronic GVHD. No current therapies for chronic GVHD are successful in the majority of patients.
- GVHD can be modeled in the mouse using parental into F 1 cell transplantation regimens.
- splenocytes from the DBA2 strain of mice are injected iv into (DBA2 ⁇ C57B1/6) F1 mice, which are referred to as B6D2F1.
- the injected splenocytes constitute the graft, and the DBA2 mouse is the donor of that graft.
- the F1 mouse which receives the graft is the host.
- Donor T cells present in the graft recognize half of the MHC markers (haplotypes) on host cells as foreign, because they are derived from the other, C57B1/6 parent. This induces a donor T cell response against the host resulting in GVHD.
- reagents which block critical cytokines involved in Th1 T cell differentiation block the development of acute GVHD.
- Cytotoxicity can be directly cellular (eg. by phagocytosis of host cells) or by the action of secreted cytokines such as TNF which can induce apoptosis, or cell death.
- TNF secreted cytokines
- the consequence of donor anti-host cytotoxicity can be seen in a number of ways. First, host lymphocytes are rapidly destroyed, such that mice experiencing acute GVHD are profoundly immunosuppressed.
- donor lymphocytes become engrafted and expand in the host spleen, and their cytotoxic activity can be directly measured in vitro by taking advantage of cell lines which express the host antigens that can be recognized (as foreign) by the donor cells.
- cell lines expressing the appropriate antigens can be labeled with radioactive chromium51 isotope. Release of this radioactive isotope into the culture media is evidence of the death of the labeled cell.
- the disease becomes lethal as additional tissues and cell populations are destroyed, and therefore survivorship is a measurable consequence of disease.
- Chronic GVHD appears to be a Th2 T cell mediated disease (De Wit et al., J. Immunol. 150: 361-366 (1993)).
- the development of the disease is dependent on the Th2 cytokine I14, and can be blocked by treating with anti-I14 mAb.
- Such treatment blocks the expansion of host B cells, and the concomitant hyper-Ig production.
- the development of GVHD can be followed in a number of ways.
- the expansion of the donor T cell and host B cell populations can be measured by the spleen index, which is the ratio of spleen weight to body weight, normalized to control (non-diseased) mice.
- B cells in diseased mice can be measured using analyses of B cell activation markers.
- the effects of B cell activation can be seen in the levels of Ig in circulation (eg. in serum) or produced by cultures of host splenocytes harvested several weeks after disease induction. Circulating Ig in diseased animals will contain anti-self antibodies. Ultimately, diseased animals succumb to kidney and other organ failure due to accumulated Ig deposition, and therefore survivorship is a relevant measure of disease activity.
- the invention provides methods for blocking the development or treating or reducing the severity or effects of an immunological disorder in an animal including administering a pharmaceutical composition which comprises a therapeutically effective amount of a TWEAK blocking agent and a pharmaceutically acceptable carrier.
- the compound may be an antibody directed against a TWEAK ligand; an antibody directed against a TWEAK receptor; an agent that modifies the binding of the TWEAK ligand to a TWEAK receptor; an agent that modifies cell surface receptor clustering; and an agent that can interrupt intracellular signaling of a TWEAK receptor.
- the antibody is a monoclonal antibody.
- the monoclonal antibody is directed against the TWEAK surface ligand.
- the animal may be mammalian and may be a human.
- the TWEAK blocking agent may be a soluble TWEAK receptor having a ligand binding domain that can selectively bind to a surface TWEAK ligand.
- the soluble TWEAK receptor may include a human immunoglobulin IgG domain.
- the human immunoglobulin IgG domain includes regions responsible for specific antigen binding.
- the invention further includes a method for inhibiting an immune response in an animal, including administering a pharmaceutical composition which comprises an effective amount of a TWEAK blocking agent and a pharmaceutically effective carrier.
- the immune response may be Th1 or a Th2 cell-mediated immune response or both.
- the invention also includes a composition having a therapeutically effective amount of a TWEAK blocking agent and a pharmaceutically acceptable carrier.
- FIG. 1 shows a sequence alignment of soluble recombinant murine and human TWEAK proteins. Identical residues are indicated in bold face.
- FIG. 2 shows a Fluorescent Activated Cell Sorting (FACS) analysis of the binding of hamster anti-TWEAK rnAb AB.D3 to EBNA293 cells expressing murine TWEAK protein or human TWEAK protein, compared to the binding of a hamster mAb which recognizes an irrelevant protein (Keyhole Limpet Hemocyanin).
- FACS Fluorescent Activated Cell Sorting
- 2 a Analysis of anti-TWEAK mAb binding to murine TWEAK transfected EBNA293 cells (forward scatter (size) and side scatter (granularity)); 2 b ) analysis of anti-TWEAK mAb binding to human TWEAK transfected EBNA293 cells (forward scatter (size) and side scatter (granularity)); 2 c ) histogram showing PE-reactivity of anti-TWEAK mAb binding to murine TWEAK transfected EBNA293 cells: A. unstained cells, B. stained with streptavidin-PE, C. stained with control rnAb Ha4/8, biotinylated goat anti-hampster IgG, and steptavidin-PE, D.
- FIG. 3 shows a FACS analysis of the ability of mAb AB.D3 to block the binding of FLAG-tagged recombinant soluble human TWEAK to TWEAK receptor positive cells.
- 3 a HT29 cell population showing forward scatter and side scatter;
- 3 b HT29 cells incubated A. alone, or with lug Flag-tagged human TWEAK protein plus B. no mAB, C. 10 ug mAb AB.D3, D. 10 ug control hamster mAb, or E. 10 ug soluble murine TWEAK.
- FIG. 4 shows a FACS analysis of the activation state of B cells in mice undergoing chronic GVHD, treated with anti-TWEAK mAb AB.D3, anti-CD40L mAb MR1, control mnAb, or untreated.
- 4 a Derivation of the lymphocyte gate used in the analysis
- 4 b derivation of the B220+ gate used in the analysis
- 4 c -g splenocytes derived from mice with chronic GVHD, treated as labeled, and gated using R1 and R2.
- FL1 shows FITC-anti B220 staining
- FL2 shows PE-antiCD69 staining.
- R3 encompasses the B220+/CD69+ cells.
- the terms “humoral response” and “cellular response” as used herein refer to the immunological response of an animal to an antigen whereby the animal produces antibodies to an antigen or produces a cytotoxic response to the antigen, or both.
- the Th1 class of T helper cells are important for the induction of the cellular response, and the Th2 class of T helper cells are important to the efficient production of high affinity antibodies.
- T helper (Th) cells refers to a functional subclass of T cells which help to generate cytotoxic T cells and which cooperate with B cells to stimulate antibody production. Helper T cells recognize antigen in association with class II MHC molecules and provide contact dependent and contact independent (cytokine and chemokine) signals to effector cells.
- Th1 refers to a subclass of T helper cells that produce TNF, interferon-y and IL-2 (and other cytokines) and which elicit inflammatory reactions associated with a cellular, i.e. non-immunoglobulin, response to a challenge.
- Th2 refers to a subclass of T helper cells that produces IL-4, IL-5, IL-6, IL-10, and other cytokines, which are associated with an immunoglobulin (humoral) response to an immune challenge.
- the term “germinal center” as used herein refers to a secondary B cell follicle which forms after antigen immunization. The appearance of this histologic site correlates with optimal memory generation, isotype switching, somatic hypermutation and thus the affinity maturation of an antibody response.
- antibody producing cells refers to B cells which have received contact dependent and contact independent signals from Th cells, and are secreting immunoglobulins of the IgM, IgG, IgA, or IgE subclasses.
- Fc domain of an antibody refers to a part of the molecule comprising the hinge, CH2 and CH3 domains, but lacking the antigen binding sites.
- the term is also meant to include the equivalent regions of an IgM or other antibody isotype.
- anti-TWEAK antibody refers to any antibody that specifically binds to at least one epitope of the TWEAK protein.
- anti-TWEAK receptor antibody refers to any antibody that specifically binds to at least one epitope of a TWEAK receptor.
- TWEAK receptor signaling refers to molecular reactions associated with a TWEAK receptor pathway and subsequent molecular reactions which result therefrom.
- TWEAK or TWEAK-receptor modifying agent and “TWEAK or TWEAK-receptor modifying reagent” refers to any agent that can modify ligand binding to a TWEAK receptor, can modify cell surface TWEAK receptor clustering or TWEAK receptor signaling, or that can influence how a TWEAK receptor signal is interpreted within the cell.
- TWEAK ligand or “TWEAK protein” refers to any TWEAK monomeric, polymeric, or heteromeric complex or derivative thereof that can specifically bind to a TWEAK receptor.
- the term “subject” refers to an animal, or to one or more cells derived from an animal.
- the animal is a mammal.
- Cells may be in any form, including but not limited to cells retained in tissue, cell clusters, immortalized, transfected or transformed cells, and cells derived from an animal that has been physically or phenotypically altered.
- TWEAK is a recently discovered member of the TNF family of proteins (Chicheportiche et al., J. Biol. Chem. 51: 32401 32410 (1997)).
- TNF-R TNF-receptor
- the interaction of proteins of the TNF family with their receptors influence a wide variety of functions within the immune system.
- Well known examples include the CD40L protein, which binds to the CD40 receptor to promote the differentiation of B cells into antibody producing cells (Grewal and Flavell, Immunol. Res.
- lymphotoxin-beta ligand LT- ⁇
- LT- ⁇ lymphotoxin-beta ligand
- OX40L which binds the OX40 receptor to regulate the response of B cells to T cell signals
- Other ligand/receptor pairs within the TNF/TNF-R families which are known to play critical roles in the immune system include TNF/TNF-R55, FasL/Fas, and CD27/CD70.
- TWEAK biology is as yet only partly understood.
- Purified soluble TWEAK protein was used to induce the differentiation and/or death of some tumor cell lines, including HT29 adenocarcinoma cells (cell death via apoptosis), HeLa cervical carcinoma cells (morphological changes), and A375 melanoma cells (anti-proliferation).
- TWEAK also induced the HT29 and A375 cell lines to secrete the chemokine IL-8 and had the same effect on a fibroblast cell line, WI-38 (Chicheportiche et al., J. Biol. Chem. 51: 32401-32410 (1997)).
- TWEAK induced proliferation of a variety of normal endothelial cell lines (Lynch et al., J. Interferon Cytokine Res. 18: A-46 (1998)).
- TRAMP TRAMP
- Apo3, WSL-1, DR-3, or LARD Activation of TRAMP can induce apoptosis by engaging either the caspase-dependant cell death signaling pathway or cellular activation via NF-kB signaling pathways (Ashkenazi and Dixit, Science 281: 1305-1308 (1998)).
- TWEAK messenger RNA
- mRNA messenger RNA
- PBMCs peripheral blood mononuclear cells
- TWEAK does not appear to be expressed in the primary lymphoid organs where immune system cells develop, such as thymus, bone marrow, and fetal liver.
- immune system cells develop, such as thymus, bone marrow, and fetal liver.
- mAbs monoclonal antibodies
- anti-ligand mAbs can influence receptor signaling by influencing the binding of other ligands, when multiple ligands exist for a receptor.
- Anti-ligand mAbs may have 25 even more subtle effects in systems where multiple receptors exist for a particular ligand, eg. by modifying ligand binding to one receptor but leaving binding to another receptor unchanged.
- MAbs which recognize the receptor can also be used to modify ligand binding, or may themselves induce or modify receptor signaling.
- anti-receptor mAbs can be antagonistic or agonistic.
- Examples of mAbs used in the mouse or human systems to modify ligand/receptor interactions of TNF/TNF-R family members include mAbs specific for TNF, for CD40L, for LT- ⁇ , for Fas-L, and for TR2/HVEM, among others.
- MAbs can be used to block the initiation or development of immunologic and other diseases.
- anti-CD40L has been used in treatment of systemic lupus erythematosis (SLE), and to control organ transplant failure.
- Potent inhibitors of ligand/receptor interaction can also be created by cloning the sequences which encode the extracellular portion of receptor sequences to sequences which encode human immunoglobulin (Ig) heavy chain, then expressing the hybrid gene, using an appropriate gene promoter, in an appropriate cell line.
- Purified receptor-Ig fusion proteins can be used in vitro and in vivo to bind to available protein ligand, and thus modify the interaction of the ligand with the native, cell bound, receptor. Modification can occur by a variety of mechanisms, similar to those outlined above for anti-ligand mAbs.
- receptor-Ig fusion proteins used in the mouse or human systems to modify ligand/receptor interactions of TNF/TNF-R family members include TNF-R55-Ig, TNF-R75-Ig, LT ⁇ -R-Ig, and OX40-Ig, among others.
- Receptor-Ig fusion proteins can be used to block the initiation or development of immunologic and other diseases.
- TNF-R75-Ig has been used to treat Inflammatory Bowel Disease (IBD).
- a mAb which specifically binds to murine and human TWEAK blocks the development of a prototypical antigen-driven immunological disorder, Graft-Versus-Host Disease (GVHD).
- GVHD Graft-Versus-Host Disease
- Our invention anticipates the use of TWEAK and TWEAK receptor(s) modifying reagents to treat a variety of immunological disorders which result from the introduction of foreign antigen into patients, such as GVHD which results from bone marrow or stem cell transplantation, and organ transplant failure resulting from graft rejection.
- this invention anticipates the use of TWEAK and TWEAK receptor(s) modifying reagents to treat a variety of autoimmune disorders, such as SLE, Idiopathic Thrombocytopenia Purpura, Wegener's Granulomatosis, Polyarteritis Nodosa, Retinal Uveitis, Rapidly Progressive Crescentic Glomerulonephritis, Rheumatoid Arthritis, Multiple Sclerosis, and ulcerative colitis, among other examples.
- Other anticipated uses include treatment of acute and chronic inflammatory conditions, such as allergic inflammation, asthma, eosinophilia, Graves'disease, and Chagas'disease, among others.
- mice Six to eight week old female mice of the DBA/2 and C57BI/6 strains, and the (DBA/2 ⁇ C57B1/6)F1 cross were purchased from Jackson Laboratory (Bar Harbor, ME USA), housed under conventional barrier protection, and handled in accordance with institutional guidelines.
- Monoclonal antibodies Monoclonal antibodies which recognize human and murine TWEAK protein were generated in Armenian hamsters using soluble human TWEAK protein that had been generated in baculovirus and purified as described (Chicheportiche et al., J. Biol. Chem. 51: 32401-32410 (1997)). For the first immunization each hamster received 50 ⁇ gs TWEAK in complete Freund's adjuvant (CFA), injected ip.
- CFA complete Freund's adjuvant
- each hamster recieved 50 days 14 and 28 or 33 (day 42) ⁇ gs TWEAK in Incomplete Freund's Adjuvant (IFA), ip.
- IFA Incomplete Freund's Adjuvant
- the final immunization before fusion of the spleen cell for hybridoma formation was with 100 ⁇ gs TWEAK without adjuvant, ip.
- Hybridoma generation was performed using standard procedures (Lerner, Yale J. Biol. Med. 54: 387-402 (1981)).
- the hybridoma which produces anti-murine CD40L mAb MR1 (Noelle et al., Proc. Natl. Acad. Sci. USA 89: 6550-6554 (1992)) was purchased from ATCC (Rockville, MD. USA).
- the hybridoma which produces anti-KLH mAb Ha4/8 was obtained from Dr. Mendrick (Human Genome Sciences, Inc. Rockville, MD. USA).
- ELISA analyses of mAb activity Anti-human TWEAK mAbs were tested for their ability to bind to human and murine TWEAK in a variety of experimental formats. Several mAbs raised against human TWEAK protein also recognized the mouse TWEAK protein in an initial screening of mAB activity which was done using ELISA format assays. Murine TWEAK protein was generated in baculovirus using methods similar to those described for human TWEAK protein (Chicheportiche et al., J. Biol. Chem. 51: 32401-32410 (1997)). Purified human and murine TWEAK proteins were coated onto 96 well plates, and various hamster mAbs were tested for their ability to bind to these immobilized proteins.
- the cell solution was pelleted again, resuspended in sterile, pyrogen-free PBS, pelleted, and resuspended a second time in sterile, pyrogen-free PBS.
- Cell number was determined using a hemocytometer, and the cell density was adjusted to 2 ⁇ 10 8 /ml. This solution was then passed through a sterile 70um cell filter, and kept on ice until use.6-8 week old B6D2F1 female mice were used as recipients. Each recipient was injected with 500 ⁇ l (1 ⁇ 10 8 ) cells in the vail vein.
- Blocking chronic GVHD Mice received anti-TWEAK mAb AB.D3, anti-CD40L mAb MR1, control mAb Ha4/8, or no treatment.
- the treatment schedule was 250 ⁇ gs mAb ip 4 hours prior to graft injection, and 2, 4, and 6 days afterwards.
- the streptavidin reagent was purchased from Southern Biotechnology Corp (Birmingham, Ala. USA). Splenocytes were stained with biotinylated anti-H-2K b a haplotype marker which can distinguish the donor cells (H-2K b ⁇ ) from host cells (H-2K b +) in various combinations with directly conjugated FITC or PE labelled anti-CD4, anti-CD8, anti-B220, anti-CD69, anti I-A d , anti-L-selectin, and anti-H2D d , in PBS/0.5% Bovine serum albumin (BSA)/0.1% sodium azide (FACS buffer) containing 10 ⁇ g/ml FcBlockTM (Pharmingen) to interrupt non-specific binding to Fc receptors.
- BSA Bovine serum albumin
- FACS buffer containing 10 ⁇ g/ml FcBlockTM (Pharmingen) to interrupt non-specific binding to Fc receptors.
- the cells were incubated with the mAbs for 1 h on ice. Each sample was then resuspended in 2 ml FACS buffer to wash, then centrifuged to pellet the cell. The cells were resuspended in FACS buffer containing CyChrome labelled streptavidin, which bound to the biotinylated mAb to provide a third channel for FACS analysis, washed a final time, and analyzed using FACscan instrumentation and Cellquest software (Becton Dickenson, San Jose, Calif. USA).
- Ig secretion cells were pelleted and resuspended in DMEM containing 10% Fetal Bovine Serum (FBS)/4 mM glutamine, at a concentration of 1 ⁇ 10 7 cells/ml. One ml per well was distributed into 6 well plates. Cell supernatants were recovered after 24 hours.
- FBS Fetal Bovine Serum
- antibodies (Abs) directed against TWEAK function as TWEAK blocking agents. Abs can be raised against monomeric, dimeric, or trimeric forms of the TWEAK protein, with or without heterologous subunits, if these exist. Furthermore, Abs can be raised against soluble, mutant, altered, or chimeric forms of TWEAK proteins.
- the anti-TWEAK Abs of this invention can be polyclonal or monoclonal (mAbs) and can be modified to optimize their ability to block TWEAK binding to its receptor(s), their in vivo bioavailability, stability, or other desired traits.
- Polyclonal antibody sera directed against TWEAK are prepared using conventional techniques by injecting animals such as goats, rabbits, rats, hamsters or mice subcutaneously with human TWEAK in complete Freund's adjuvant (CFA), followed by booster intraperitoneal or subcutaneous injection in incomplete Freund's adjuvant (IFA). Polyclonal antisera containing the desired Abs directed against TWEAK are screened by conventional immunological procedures.
- CFA complete Freund's adjuvant
- IFA incomplete Freund's adjuvant
- Hamster monoclonal antibodies (mAbs) directed against human TWEAK are prepared using conventional methods by injecting armenian hamsters subcutaneously with recombinant soluble human TWEAK in CFA, followed by booster intraperitoneal or subcutaneous injection in IFA.
- a hybridoma cell line (AB.D3.7.2) which produces the hamster anti-TWEAK mAb AB.D3 was deposited on Dec. 17, 1998 with the American Type Culture Collection (ATCC) (Rockville, Md.) according to the provisions of the Budapest Treaty, and was assigned the ATCC accession number HB-12622. All restrictions on the availability to the public of the above ATCC deposit will be irrevocably removed upon the granting of a patent on this application.
- anti-TWEAK Abs can also be made using standard recombinant DNA techniques (Winter and Milstein, Nature, 349, pp. 293-99 (1991)).
- “chimeric” antibodies can be constructed in which the antigen binding domain from an animal antibody is linked to a human constant domain (e.g. Cabilly et al., U.S Ser. No 4,816,567; Morrison et al., Proc. Natl. Acad. Sci. U.S.A., 81, pp. 6851-55 (1984)).
- Chimeric Abs reduce the observed immunogenic responses elicited by animal Abs when used in human clinical treatments.
- Humanized Abs which recognize TWEAK can be synthesized.
- Humanized Abs are chimeras comprising mostly human IgG sequences into which the regions responsible for specific antigen-binding have been inserted (e.g. WO 94/04679). Animals are immunized with the desired antigen, the corresponding Abs are isolated, and the portion of the variable region sequences responsible for specific antigen binding are removed. The animal-derived antigen binding regions are then cloned into the appropriate position of human antibody genes in which the antigen binding regions have been deleted. Humanized Abs minimize the use of heterologous (inter-species) sequences in human Abs, and are less likely to elicit immune responses in the treated subject.
- anti-TWEAK Abs can also be accomplished by making chimeric or humanized Abs comprising the anti-TWEAK variable domains and human constant domains (CH 1, CH2, CH3) isolated from different classes of immunoglobulins.
- anti-TWEAK IgM Abs with increased antigen binding site valencies can be recombinantly produced by cloning the antigen binding site into vectors carrying the human IgM heavy chain constant regions (Arulanandam et al., J. Exp. Med., 177, pp. 1439-50 (1993); Lane et al., Eur. J. Immunol., 22, pp. 2573-78 (1993); Traunecker et al., Nature, 339, pp. 68-70 (1989)).
- the antigen binding affinity of a humanized Ab can be increased by mutagenesis based on molecular modeling (Queen et al., Proc. Natl. Acad. Sci. U.S.A., 86, pp. 10029-33 (1989); WO 94/04679).
- anti-TWEAK Abs for TWEAK depending on the targeted tissue type or the particular treatment schedule envisioned. For example, it may be advantageous to treat a patient with constant levels of anti-TWEAK Abs with reduced ability to modify the TWEAK pathway for semi-prophylactic treatments. Likewise, anti-TWEAK Abs with increased affinity for TWEAK may be advantageous for short-term treatments.
- mice received 1 ⁇ 10 8 splenoc isolated from DBA/2 mice, in an 0.5 ml injection given intraveneously (iv).
- the iv injected DBA/2 splenocytes constituted the allograft. 2, 4, and 6 days after the graft was given, the mice were again treated with 250 ⁇ gs anti-TWEAK mAb AB.D3, anti-KLH control mAb Ha4/8, or anti-CD40L mab MR 1.
- a control group of mice received 1 ⁇ 10 8 B6D2F1 splenocytes, which cannot induce disease in B6D2F1 recipients.
- ungrafted and untreated B6D2F1 mice were used as controls. 14 days after the graft was given the mice were sacrificed and examined for evidence of disease.
- Untreated graft-recipient mice manifest a variety of symptoms that are indicative of the development of chronic GVHD. Splenomegaly, or enlargement of the spleen, is evidence that donor T cells and host B cells have become activated, and are undergoing polyclonal expansion, with dramatic increases in cell number. The appearance of cell surface proteins such as CD69 on a subset of B cells is indicative of B cell activation. The loss of L-selectin molecules from CD4+ and CD8+ T cells is evidence of T cell activation.
- Ig molecules such as IgG classes, IgA, and IgE
- IgG classes IgA, and IgE
- B cells have become activated, and have switched their Ig class.
- the appearance of anti-self Igs in the serum or in in vitro cell culture assays shows that Igs that are being produced have inappropriate autoantigen recognition.
- survivorship can be measured as an outcome of different treatment regimens.
- mice In untreated and control mAb treated mice a small but readily visible proportion of the B200+ B cells express the activation marker CD69 (FIG. 4 and Table 3). In contrast, virtually no B200+ B cells in MR1 or AD.B3 treated mice express CD69. Lack of measurable B cell activation in the spleen of AB.D3 mice could be due to one or more of several mechanisms of action, including failure of T cell activation, failure of B cell activation, or cell death (apoptosis). Next we measured total IgG in cultures of splenocytes in mice from different treatment groups to determine if the loss of the CD69 activation marker from the B cell populations correlated with a functional readout, ie. IgG production.
- autoimmune diseases involve pathological antibody responses. Such conditions include: Myasthenia Gravis, autoimmune hemolytic anemia, Chaga's disease, Grave's disease, idiopathic thrombocytopenia purpura (ITP) Systemic Lupus Erythematosus (SLE), Wegener's Granulomatosis, Poly-arteritis Nodosa and Rapidly Progressive Crescentic Glomerulonephritis (From Benjamini, et al. Immunology. A Short Course , (Wiley-Liss, New York 3d ed. (1996))
- ITP idiopathic thrombocytopenia purpura
- SLE Systemic Lupus Erythematosus
- Wegener's Granulomatosis Poly-arteritis Nodosa
- Rapidly Progressive Crescentic Glomerulonephritis from Benjamini, et al. Immunology. A Short Course , (Wiley-Liss, New York 3d ed. (1996))
- SLE has been studied in murine models for decades. The development of SLE can be blocked using reagents such as CTLA4-Ig fusion protein and anti-CD40L, which interrupt critical steps in T and B cell activation (Grewal and Flavell, Immunol. Rev. 153: 85-106 (1996)). Recently, the therapeutic efficacy of a reagent specific for the murine CD40 ligand was evaluated in several models (Mohan, et al., J. Immunol., 154, pp. 1470-1480 (1995)).
- reagents which modify TWEAK/TWEAK receptor(s) interaction in vivo inhibit B cell activation and Ig production will be useful for treating or preventing SLE.
- IDP idiopathic thrombocytopenia purpura
- TWEAK modifying agents of this invention which inhibit antibody generation -- will be useful to treat or prevent these autoimmune diseases as well.
- the normal immune response to some pathogenic infectious agents can also elicit hypersensitivity reactions that can become excessive and present themselves as a medical problem.
- type I hypersensitivity is allergic reaction. These are mediated by IgE antibodies which bind via their Fc portion to receptors on mast cells and basophils to trigger the release of pharmacologically active agents that mediate anaphylaxis. ITP and Goodpasture's syndrome are sometimes thought to be Type II reactions which occur when IgM or IgG antibodies bind to antigen on the cell surface and activate the complement cascade. Granulocytes are then attracted to the site of activation, and damage from the release of lytic enzymes from their granules results in the destruction of cells.
- Rheumatic arthritis is thought to result from a type III hypersensitivity reaction mediated by immune complexes of antigen (in this case rheumatoid factor, an IgM autoantibody) that binds to the Fc portion of normal IgG.
- antigen in this case rheumatoid factor, an IgM autoantibody
- IgM autoantibody an antigen that binds to the Fc portion of normal IgG.
- anti-CD40L and CTLA4-Ig have been used separately and together to control organ transplant rejection in animal models (Kirk et al., Proc. Natl. Acad. Sci. USA. 94 :8789-8794 (1997)).
- Much of the immune response to transplanted organs is Th1 T cell mediated, and consists of a cytotoxic cellular immune response.
- Such cellular immune responses are responsible for cell mediated damage in a variety of other immune disorders such as autoimmune diseases such as inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, diabetes, ulcerative colitis, and Crohn's disease, as examples.
- autoimmune diseases such as inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, diabetes, ulcerative colitis, and Crohn's disease, as examples.
- our invention anticipates the use of TWEAK or TWEAK-receptor modifying reagents in the therapeutic treatment of cellular immune disorders.
- compositions of this invention will be administered at an effective dose to treat the particular clinical condition addressed. Determination of a preferred pharmaceutical formulation and a therapeutically efficient dose regiment for a given application is well within the skill of the art taking into consideration, for example, the condition and weight of the patient, the extent of desired treatment and the tolerance of the patient for the treatment.
- Doses of about 5 mg/kg of a TWEAK or TWEAK-Receptor modifying agent are expected to be suitable starting points for optimizing treatment doses.
- Determination of a therapeutically effective dose can also be assessed by performing in vitro experiments that measure the concentration of the modifying agent required to coat target cells (TWEAK or TWEAK-Receptor-positive cells depending on the modifying agent) for suitable (therapeutic) time periods.
- the FACS and ELISA receptor-ligand binding assays described herein can be used to monitor the cell coating reaction. Based on the results of such in vitro binding assays, a range of suitable modifying agent concentrations can be selected to test in animals.
- Administration of the soluble modifying agents of this invention may be accomplished using any of the conventionally accepted modes of administration of agents which exhibit immunosuppressive activity.
- compositions used in these therapies may also be in a variety of forms. These include, for example, solid, semi-solid and liquid dosage forms such as tablets, pills, powders, liquid solutions or suspensions, suppositories, and injectable and infusible solutions.
- solid, semi-solid and liquid dosage forms such as tablets, pills, powders, liquid solutions or suspensions, suppositories, and injectable and infusible solutions.
- the preferred form depends on the intended mode of administration and therapeutic application. Modes of administration may include oral, parenteral, subcutaneous, intravenous, intralesional or topical administration.
- the TWEAK and TWEAK-receptor modifying agents of this invention may, for example, be placed into sterile, isotonic formulations with or without cofactors which stimulate uptake or stability.
- the formulation is preferably liquid, or may be lyophilized powder.
- the TWEAK and TWEAK-receptor modifying agents of this invention may be diluted with a formulation buffer comprising 5.0 mg/ml citric acid monohydrate, 2.7 mg/ml trisodium citrate, 41 mg/ml mannitol, 1 mg/ml glycine and 1 mg/ml polysorbate 20.
- This solution can be lyophilized, stored under refrigeration and reconstituted prior to administration with sterile Water-For-Injection (USP).
- compositions also will preferably include conventional pharmaceutically acceptable carriers well known in the art (see for example Remington's Pharmaceutical Sciences, 16th Edition, 1980, Mac Publishing Company).
- pharmaceutically acceptable carriers may include other medicinal agents, carriers, genetic carriers, adjuvants, excipients, etc., such as human serum albumin or plasma preparations.
- the compositions are preferably in the form of a unit dose and will usually be administered one or more times a day.
- compositions of this invention may also be administered using microspheres, liposomes, other microparticulate delivery systems or sustained release formulations placed in, near, or otherwise in communication with affected tissues or the bloodstream.
- sustained release carriers include semipermeable polymer matrices in the form of shaped articles such as suppositories or microcapsules.
- Implantable or microcapsular sustained release matrices include polylactides (U.S. Pat. No. 3,773,319; EP 58,481), copolymers of L-glutamic acid and ethyl-L-glutamate (Sidman et al., Biopolymers, 22, pp.
- TWEAK and TWEAK-receptor modifying agents of this invention are capable of inhibiting immune responses, as shown by the inhibition of B cell activation and Ig production in the chronic GVHD model.
- the ability to selectively inhibit such immune mediated responses will be useful for treating immune disorders including various autoimmune diseases, organ transplant rejection, and acute and chronic inflammatory conditions.
- Treatment of such pathologic immune disorders generally employs immunomodulatory and immunosuppressive agents which have pleiotropic effects on a wide variety of cell types and immunological responses. These non-specific immunosuppressive agents are generally required in high and often cytotoxic doses that cause adverse side effects.
- three general immunosuppressive agents currently used include steroids, cyclophosphamide and azathioprine.
- Steroids are pleiotropic anti-inflammatory agents which suppress activated macrophages and inhibit the activity of antigen presenting cells in ways which reverse many pathologic T cell effects.
- Cyclophosphamide an alkylating agent, mediates cell death by inhibiting DNA replication and repair.
- Azathioprine is an anti-proliferative agent which inhibits DNA synthesis.
- These non-specific immunosuppressive agents are generally required in high doses which increase their toxicity (e.g. nephro-and hepatotoxicity) and cause adverse side effects. They are thus unsuitable for long term therapies.
- Murine TWEAK protein was generated in baculovirus using methods similar to those described for human TWEAK protein (Chicheportiche et al., J. Biol. Chem. 51: 32401-32410 (1997)). Purified human and murine TWEAK proteins were coated onto 96 well plates, and various hamster mAbs were tested for their ability to bind to these immobilized proteins. The capture of hamster mAb by the immobilized TWEAK proteins was visualized using HRP-coupled donkey anti-hamster IgG (Jackson ImmunoResearch, West Grove, Pa. USA), and an appropriate enzymatic reaction.
- FIG. 2 Four mAbs, including AB.D3, bound well to EBNA293 cells expressing murine TWEAK (FIG. 2). These 4 mAbs were also capable of preventing the binding of human TWEAK to HT29 cells which are known to express one or more TWEAK-receptors (eg., FIG. 3). Together these FACS analyses indicated that anti-TWEAK mAbs specifically recognized TWEAK proteins, and were capable of modifying the ability of TWEAK proteins to bind to one or more TWEAK receptors.
- Chronic GVHD was induced in 6-8 week old B6D2F1 female mice using DBA/2 splenocyte grafts as described in methods. Each recipient was injected with 500 ⁇ l (1 ⁇ 10 8 ) cells in the tail vein. Experimental groups recieved the DBA/2 graft (DBA/2>F1), while a set of control animals recieved a B6D2F1 graft (F1>F1). Mice received anti-TWEAK mAb AB.D3, anti-CD40L mAb MR1, control mAb Ha4/8, or no treatment. Animals were dosed with 250 ⁇ ug mAb ip 4 hours prior to graft injection, and 2, 4, and 6 days afterwards.
- mice On day 14 of the experiment the mice were sacrificed and the spleen index was calculated as the ratio of spleen weight to body weight for each animal in the control F1>F1 group, averaged to give a value of one. The average spleen index for all other groups is normalized to the control value.
- Table 2 Animals receiving the DBA/2 graft (DBA/2 >F1), and left untreated or treated with control mAb Ha4/8 showed a dramatic increase in spleen weight when compared to F1>F1 graft controls. This result is reflected in the spleen index, which showed an increase from the normalized control value of 1.0 to 2.6.
- mice with anti-CD40L mAb MR1 reduced the spleen index nearly to control levels (1.1), and treatment with anti-TWEAK mAb AB.D3 reduced splenomegaly by 35% to 1.7 (Table 2).
- Table 2 EXPERI- EXPERI- AVER- TREATMENT MENT 1 MENT 2 AGE F1 > F1 (control) 1.0 1.0 1.0 1.0 DBA/2 > F1, untreated 2.7 2.6 2.65 DBA/2 > F1, Ha4/8 treated 2.9 2.6 2.75 DBA/2 > F1, MR1 treated 1.1 1.1 1.1 DBA/2 > F1, AB.D3 treated 1.8 1.7 1.75
- mice On day 14 of the experiment the mice were sacrificed and weighed. Then, the spleen was aseptically removed and weighed. The spleen index was calculated as the ratio of spleen to body weight for each animal in the control F1>F1 group, averaged to give a value of one. The average spleen index for all other groups is normalized to the control value.
- splenocytes from each group of mice were stained on ice for 1 h with PE-coupled anti-H2k b and FITC-coupled anti-H-2D d to measure expression of MHC alleles.
- Host splenocytes are positive for both markers, but donor splenocytes are H-2k b negative. Percent values reflect events within the lymphocyte population, as determined by forward and side scatter characteristics.
- Splenocytes were stained with PE-labelled anti-B220 and FITC labelled anti-CD69 for 1 h on ice, washed with FACS buffer, then analyzed. Percentages are based events collected within the lymphocyte population, as determined by forward and side scatter characteristics.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Gastroenterology & Hepatology (AREA)
- Diabetes (AREA)
- Zoology (AREA)
- Communicable Diseases (AREA)
- Virology (AREA)
- Neurology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Toxicology (AREA)
- Cell Biology (AREA)
- Pain & Pain Management (AREA)
- Microbiology (AREA)
- Transplantation (AREA)
- Rheumatology (AREA)
- Urology & Nephrology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Pulmonology (AREA)
Abstract
The present invention relates to reagents which modify the activity of TWEAK and their use as therapeutic agents for the treatment of immunological disorders.
Description
- The present invention relates to compositions and methods comprising reagents which bind to the novel protein TWEAK, and the use of TWEAK binding reagents to block the development of immunologic disorders. TWEAK binding reagents include monoclonal antibodies, as used herein to block the development of chronic Graft-Versus-Host Disease, soluble TWEAK-receptor-Ig fusion proteins, or other molecules which modify the binding of TWEAK to its' receptor(s). Other embodiments of the invention include reagents which bind to TWEAK receptor(s) to modify their activity, or modify the intracellular signaling of TWEAK receptor(s).
- Immunological disorders are manifested as a wide variety of diseases and pathologies, including autoimmune diseases, acute and chronic inflammatory disorders, organ transplant rejection, Graft-Versus-Host Disease (GVHD), lymphoid cell malignancies, septic and other forms of shock, loss of immune responsiveness as seen in HIV and SCIDS, and failure of the immune response to tumor growth.
- Many immunological disorders are triggered by aberrant or uncontrolled responses to antigen. Autoimmune diseases are the result of the inappropriate response of the immune system to self-antigens, resulting in damage to cells and tissues. GVHD develops when donor cells from a bone marrow transplant (BMT) respond to host (ie. patient) antigens. Organ transplant rejection results when the patient's immune system responds to antigens derived from the transplanted organ. Acute inflammatory disorders such as hyper-allergic conditions and shock are the result of uncontrolled immune response to the triggering antigens.
- T cell dependent immune responses require T cell recognition of antigen. For example, GVHD results from a complex interplay between donor T cells and host immune system cells. The initiating event is the recognition by donor T cells of non-self, ie. host, antigens. These are referred to as alloantigens. Alloantigen recognition by these donor cells results in the production of immunoregulatory and inflammatory cytokines and chemokines, which advance and exacerbate the donor anti-host immune response. This disease can develop in either an acute or chronic form, depending on the regulation of complex cytokine networks which control the type of immune response which develops. Immune responses can be characterized as Th0, Th1, or Th2 depending on 1) the nature of the cytokines and chemokines produced by activated T cells during the response, and 2) the nature of the cytokines and chemokines produced by accessory and other cells during the response. Examples of non-T cells important during immune responses are B cells, dendritic cells, monocytes and macrophages, follicular dendritic cells, and endothelial cells. Together the cytokines produced influence a variety of cell types to differentiate, and the chemokines produced influence cell trafficking and localization. Th0 responses are characteristic of the short term stimulation of previously unstimulated (naive) T cells. Th0 T cells produce moderate amounts of a number of cytokines, notably I1-2 and TNF. Repetitively or chronically stimulated Th0 cells can differentiate into either Th1 or Th2 T cells, depending on a number of factors. Such factors include, but are not limited to, accessory cell cytokine production, the strength of T cell receptor engagement, and the nature of secondary signals received, eg. via the CD28 costimulatory receptor. In particular exposure of activated T cells to the cytokine I1-12, produced primarily by activated macrophages, supports differentiation to Th1 T cells, while exposure to I1-4 and I1-10 supports differentiation to Th2 T cells.
- Th1 T cells produce cytokines such as I1-2 and IFN-y which are associated with inflammatory responses, T cell cytotoxicity, and macrophage activation. Th1 T cells respond to chemokines which attract cells into sites of tissue inflammation, such as Mip-1alpha, MIP-1 beta, RANTES, IP-10, and MIG. Since cytotoxic T cells and activated macrophages act to eliminate damaged or infected cells, the Th1 response is responsible for controlling the immune response to intracellular pathogens. Importantly, production of Th1 chemoattractant chemokines such as IP-10 and MIG by macrophages and endothelial cells is closely regulated by IFN-y, which is the prototypic chemokine produced by Th1 T cells. Thus feedback loops may develop between activated T cells and their environment, which augment the development of a particular type of response at a particular time and location
- Th2 T cells produce cytokines such as I1-4, I1-5, I1-6, and I1-10 which support the development of humoral immune responses, including those which require the production of IgE, IgA, and IgG. These Ig responses are driven by the T cell mediated activation of B cells which “switch” their Ig phenotype from surface bound IgM and IgD to secreted Ig. Secreted Igs normally function to control infection from pathogens in circulation (IgG), at mucosal surfaces, such as the gut and oral cavity (IgA) and in the respiratory tract (IgE). Overproduction of Ig can cause disease, for example in SLE (IgG and IgA), allergic (Type I) hypersensitivity (IgE), and GVHD (IgG, IgA, and IgE). Th2 T cells also support the activation of eosinophils and Mast cells which can mediate acute responses to pathogens, for example in the respiratory tract. Th2 T cells respond to chemokines such as eotaxin and MDC, whose production is closely regulated by I1-4, the prototypic cytokine produced by NK1.1 and activated T cells.
- The interaction of T cells with B cells is a complex and closely regulated process. To begin the activation process, B cells must receive an antigen signal through the B cell antigen receptor (membrane Ig). Secondly, B cells must receive specific contact dependent and contact independent signals from activated T cells. One required contact dependent signal is delivered via the binding of CD40L on T cells to CD40 on B cells. One required contact-independent signal is delivered by I1-4 secreted by activated T cells and by NK1.1 cells binding to the I1-4 receptor on B cells. These signals appear to take place within the T cell areas of secondary lymphoid organs, such as the spleen. The spleen, lymph nodes, tonsils, Peyer's patches and other secondary and tertiary lymphoid organs have distinct microanatomical areas within which T and B cells typically reside. All lymphocytes migrate out of the blood or the lymph into the T cell area of these organs first, by crossing endothelial cell layers such as the High Endothelial Venules in lymph nodes and Peyer's patches and the marginal sinus endothelial cell layer in the spleen. Then, the B cells move into B cell areas known as B cell follicles. B cells which have traversed the T cell area but have not become activated will leave the follicle after a few days. Activated B cell undergo a process of differentiation. Some activated B cells, known as plasmacytes, secrete large amounts of antigen specific, low affinity IgM or IgG antibody. These B cells typically appear early after the induction of the immune response, and move into the red pulp of the spleen and other anatomical locations, where they persist, secreting antibody, for several days. Other activated B cells differentiate within a region of the follicle known as the secondary follicle, or germinal center. Germinal centers form around networks of specialized antigen retaining cells known as Follicular Dendritic Cells (FDC), which are thought to display antigen to drive or refine the germinal center reaction. B cells within the germinal center have “switched” their Ig phenotype, and undergo “affinity maturation”, with the result that they display a high affinity for their antigen target. Normally, the antigen target is a foreign antigen, although in diseases such as chronic GVHD and autoimmune disorders the Igs recognize self-antigens. Finally, B cells leave the follicles, migrate back through the T cells areas, and leave the organ via efferent circulation into the bloodstream.
- B cells that have fully differentiated to express high affinity Ig are known as blast cells, and they leave B cell follicles to take up residence in various other environments, including the red-pulp areas of the spleen, the bone marrow, the liver, or mucosal cell layers lining the respiratory tract and gut. Some of these fully differentiated B cells are known as memory cells, and can persist for long periods of time, ready to respond to the same antigen if it is encountered again.
- As B cells migrate from location to location within the lymphoid organs they require specific signals to guide them, and specific signals which ensure their survival. For example, multiple signals are required to maintain B cell follicular organization in the spleen. These include interaction of the BCA ligand with the chemokine receptor BLR-1, interaction of TNF with TNF-R55, and interaction of LTbeta with LTβ-R (reviewed in Chaplin and Fu,Current Opin. Immunol. 10: 298-297 (1998)). Mice which are deficient in any of these molecular pathways lose B cell follicular integrity in the spleen. Furthermore, all of these gene-deficient mice have also lost the ability to undergo germinal center reactions in the spleen. Disruption of other molecular pathways affects the germinal center reaction only. For example, mice deficient in CD40L maintain B cell follicles, but germinal centers do not form. B cells within the germinal center environment require signals through CD40 to maintain survival and to downregulate IgM and switch to Ig expression.
- B cells move not only within the follicle and germinal center, but also leave the follicle after activation, and move to other sites within the body. Memory B cells can be found in the bone marrow, and B cells which express IgA specifically traffic to cell layers in the gut and other mucosal sites. Other signals presumably guide activated T cells to specific sites within and between lymphoid compartments. For example, cytotoxic T cell can migrate to the site of infection or other antigen challenge to find and lyse their targets. The identities of all the signals which guide T and B cells between different microanatomic locations are not yet known. However it appears that multiple pathways orchestrate the T and B cell responses to antigen, both in secondary lymphoid organs, and at the sites of infection or inflammation.
- GVHD is a well studied example of an antigen driven immune response. GVHD is an often fatal consequence of bone marrow transplantation (BMT) in human patients. The disease can occur in an acute or in a chronic form. Acute and chronic forms of GVHD are prototypic examples of the development of antigen specific Th1 and Th2 responses, respectively. The acute form of the disease occurs within the first 2 months following BMT, and is characterized by donor cytotoxic T cell-mediated damage to skin, gut, liver, and other organs. The chronic form of the disease is manifested much later (over 100 days post-BMT) and is characterized by hyperproduction of immunoglobulin (Ig), including autoantibodies, and damage to the skin, kidney, and other organs caused by Ig-deposition. The development of acute GVHD is predictive of the subsequent development of chronic GVHD. Thus, the same patient can develop both diseases, in sequence. Approximately 50% of all BMT patients develop either acute or chronic GVHD. Nearly 90% of acute GVHD patients go on to develop chronic GVHD. No current therapies for chronic GVHD are successful in the majority of patients.
- GVHD can be modeled in the mouse using parental into F1 cell transplantation regimens. In the model described here, splenocytes from the DBA2 strain of mice are injected iv into (DBA2 ×C57B1/6) F1 mice, which are referred to as B6D2F1. The injected splenocytes constitute the graft, and the DBA2 mouse is the donor of that graft. The F1 mouse which receives the graft is the host. Donor T cells present in the graft recognize half of the MHC markers (haplotypes) on host cells as foreign, because they are derived from the other, C57B1/6 parent. This induces a donor T cell response against the host resulting in GVHD. When DBA/2 parental splenocytes are injected into the B6D2F1 host, chronic GVHD develops. In contrast when C57B1/6 splenocytes are injected into the B6D2F1 host, acute GVHD develops. Although it remains unclear what underlying mechanism is responsible for the distinct disease outcomes using these 2 injection protocols it is believed that the cytokines expressed by the cells contained within the DBA/2 splenocyte graft favor the development of chronic GVHD while the cytokines expressed by the cells contained within the C57B1/6 splenocyte graft favor the development of acute GVHD. Reagents which interfere with T cell interactions with antigen presenting cells (eg. dendritic cells, macrophages, B cells: APC) effectively block both acute and chronic GVHD.
- A number of lines of evidence suggest that acute GVHD is a Th1 mediated disease (Krenger and Ferrara,Immunol. Res. 15: 50-73 (1996), Williamson et al., J. Immunol. 157: 689-699 (1996)). Cytotoxic activity by CD4+ and CD8+ T cells, by natural killer (NK) cells, and by activated granulocytes such as macrophages, is a well defined consequence of Th1 mediated T cell response, and shows a characteristic dependence on the expression of I1-2 and IFN-y, which are typical Th1 cytokines. Such cytotoxicity is a defining characteristic of acute GVHD. Furthermore, reagents which block critical cytokines involved in Th1 T cell differentiation, such as mAbs to I1-2 and I1-12, block the development of acute GVHD. Cytotoxicity can be directly cellular (eg. by phagocytosis of host cells) or by the action of secreted cytokines such as TNF which can induce apoptosis, or cell death. The consequence of donor anti-host cytotoxicity can be seen in a number of ways. First, host lymphocytes are rapidly destroyed, such that mice experiencing acute GVHD are profoundly immunosuppressed. Secondly, donor lymphocytes become engrafted and expand in the host spleen, and their cytotoxic activity can be directly measured in vitro by taking advantage of cell lines which express the host antigens that can be recognized (as foreign) by the donor cells. For example, cell lines expressing the appropriate antigens can be labeled with radioactive chromium51 isotope. Release of this radioactive isotope into the culture media is evidence of the death of the labeled cell. Third, the disease becomes lethal as additional tissues and cell populations are destroyed, and therefore survivorship is a measurable consequence of disease.
- Chronic GVHD appears to be a Th2 T cell mediated disease (De Wit et al.,J. Immunol. 150: 361-366 (1993)). In the mouse model the development of the disease is dependent on the Th2 cytokine I14, and can be blocked by treating with anti-I14 mAb. Such treatment blocks the expansion of host B cells, and the concomitant hyper-Ig production. The development of GVHD can be followed in a number of ways. The expansion of the donor T cell and host B cell populations can be measured by the spleen index, which is the ratio of spleen weight to body weight, normalized to control (non-diseased) mice. The activation of B cells in diseased mice can be measured using analyses of B cell activation markers. Finally, the effects of B cell activation can be seen in the levels of Ig in circulation (eg. in serum) or produced by cultures of host splenocytes harvested several weeks after disease induction. Circulating Ig in diseased animals will contain anti-self antibodies. Ultimately, diseased animals succumb to kidney and other organ failure due to accumulated Ig deposition, and therefore survivorship is a relevant measure of disease activity.
- We now show that a monoclonal antibody specific for TWEAK effectively and specifically blocks aspects of the development of GVHD, using the mouse model of chronic GVHD. The block in development of chronic GVHD is shown as a reduction in the spleen index, the loss of activation markers on host B cells, and reduced Ig production in the anti-TWEAK treated animals.
- The invention provides methods for blocking the development or treating or reducing the severity or effects of an immunological disorder in an animal including administering a pharmaceutical composition which comprises a therapeutically effective amount of a TWEAK blocking agent and a pharmaceutically acceptable carrier. The compound may be an antibody directed against a TWEAK ligand; an antibody directed against a TWEAK receptor; an agent that modifies the binding of the TWEAK ligand to a TWEAK receptor; an agent that modifies cell surface receptor clustering; and an agent that can interrupt intracellular signaling of a TWEAK receptor. In a preferred embodiment the antibody is a monoclonal antibody. In a more preferred embodiment the monoclonal antibody is directed against the TWEAK surface ligand. The animal may be mammalian and may be a human. The TWEAK blocking agent may be a soluble TWEAK receptor having a ligand binding domain that can selectively bind to a surface TWEAK ligand. In one embodiment the soluble TWEAK receptor may include a human immunoglobulin IgG domain. In a preferred embodiment, the human immunoglobulin IgG domain includes regions responsible for specific antigen binding.
- The invention further includes a method for inhibiting an immune response in an animal, including administering a pharmaceutical composition which comprises an effective amount of a TWEAK blocking agent and a pharmaceutically effective carrier. The immune response may be Th1 or a Th2 cell-mediated immune response or both.
- The invention also includes a composition having a therapeutically effective amount of a TWEAK blocking agent and a pharmaceutically acceptable carrier.
- FIG. 1 shows a sequence alignment of soluble recombinant murine and human TWEAK proteins. Identical residues are indicated in bold face.
- FIG. 2 shows a Fluorescent Activated Cell Sorting (FACS) analysis of the binding of hamster anti-TWEAK rnAb AB.D3 to EBNA293 cells expressing murine TWEAK protein or human TWEAK protein, compared to the binding of a hamster mAb which recognizes an irrelevant protein (Keyhole Limpet Hemocyanin).2 a) Analysis of anti-TWEAK mAb binding to murine TWEAK transfected EBNA293 cells (forward scatter (size) and side scatter (granularity)); 2 b) analysis of anti-TWEAK mAb binding to human TWEAK transfected EBNA293 cells (forward scatter (size) and side scatter (granularity)); 2 c) histogram showing PE-reactivity of anti-TWEAK mAb binding to murine TWEAK transfected EBNA293 cells: A. unstained cells, B. stained with streptavidin-PE, C. stained with control rnAb Ha4/8, biotinylated goat anti-hampster IgG, and steptavidin-PE, D. stained with AB.D3, biotinylated goat anti-hamster IgG, and steptavidin-PE; 2 d) histogram showing PE-reactivity of anti-TWEAK mAb binding to human TWEAK transfected EBNA293 cells: A. unstained cells, B. stained with streptavidin-PE, C. stained with control mAb Ha4/8, biotinylated goat anti-hampster IgG, and steptavidin-PE, D. stained with AB.D3, biotinylated goat anti-hamster IgG, and steptavidin-PE.
- FIG. 3 shows a FACS analysis of the ability of mAb AB.D3 to block the binding of FLAG-tagged recombinant soluble human TWEAK to TWEAK receptor positive cells.3 a) HT29 cell population showing forward scatter and side scatter; 3 b) HT29 cells incubated A. alone, or with lug Flag-tagged human TWEAK protein plus B. no mAB, C. 10 ug mAb AB.D3, D. 10 ug control hamster mAb, or E. 10 ug soluble murine TWEAK.
- FIG. 4 shows a FACS analysis of the activation state of B cells in mice undergoing chronic GVHD, treated with anti-TWEAK mAb AB.D3, anti-CD40L mAb MR1, control mnAb, or untreated.4 a) Derivation of the lymphocyte gate used in the analysis; 4 b) derivation of the B220+ gate used in the analysis; 4 c-g) splenocytes derived from mice with chronic GVHD, treated as labeled, and gated using R1 and R2. FL1 shows FITC-anti B220 staining and FL2 shows PE-antiCD69 staining. R3 encompasses the B220+/CD69+ cells.
- Definitions
- In order that the invention herein described may be fully understood, the following detailed description is set forth.
- The terms “humoral response” and “cellular response” as used herein refer to the immunological response of an animal to an antigen whereby the animal produces antibodies to an antigen or produces a cytotoxic response to the antigen, or both. The Th1 class of T helper cells are important for the induction of the cellular response, and the Th2 class of T helper cells are important to the efficient production of high affinity antibodies.
- The term “T helper (Th) cells” as used herein, refers to a functional subclass of T cells which help to generate cytotoxic T cells and which cooperate with B cells to stimulate antibody production. Helper T cells recognize antigen in association with class II MHC molecules and provide contact dependent and contact independent (cytokine and chemokine) signals to effector cells.
- The term “Th1” refers to a subclass of T helper cells that produce TNF, interferon-y and IL-2 (and other cytokines) and which elicit inflammatory reactions associated with a cellular, i.e. non-immunoglobulin, response to a challenge.
- The term “Th2” refers to a subclass of T helper cells that produces IL-4, IL-5, IL-6, IL-10, and other cytokines, which are associated with an immunoglobulin (humoral) response to an immune challenge.
- The term “germinal center” as used herein refers to a secondary B cell follicle which forms after antigen immunization. The appearance of this histologic site correlates with optimal memory generation, isotype switching, somatic hypermutation and thus the affinity maturation of an antibody response.
- The term “antibody producing cells” refers to B cells which have received contact dependent and contact independent signals from Th cells, and are secreting immunoglobulins of the IgM, IgG, IgA, or IgE subclasses.
- The term “Fc domain” of an antibody refers to a part of the molecule comprising the hinge, CH2 and CH3 domains, but lacking the antigen binding sites. The term is also meant to include the equivalent regions of an IgM or other antibody isotype.
- The term “anti-TWEAK antibody” refers to any antibody that specifically binds to at least one epitope of the TWEAK protein.
- The term “anti-TWEAK receptor antibody” refers to any antibody that specifically binds to at least one epitope of a TWEAK receptor.
- The term “TWEAK receptor signaling” refers to molecular reactions associated with a TWEAK receptor pathway and subsequent molecular reactions which result therefrom.
- The terms “TWEAK or TWEAK-receptor modifying agent” and “TWEAK or TWEAK-receptor modifying reagent” refers to any agent that can modify ligand binding to a TWEAK receptor, can modify cell surface TWEAK receptor clustering or TWEAK receptor signaling, or that can influence how a TWEAK receptor signal is interpreted within the cell.
- The term “TWEAK ligand” or “TWEAK protein” refers to any TWEAK monomeric, polymeric, or heteromeric complex or derivative thereof that can specifically bind to a TWEAK receptor.
- The term “subject” refers to an animal, or to one or more cells derived from an animal. Preferably, the animal is a mammal. Cells may be in any form, including but not limited to cells retained in tissue, cell clusters, immortalized, transfected or transformed cells, and cells derived from an animal that has been physically or phenotypically altered.
- TWEAK ligand
- TWEAK is a recently discovered member of the TNF family of proteins (Chicheportiche et al.,J. Biol. Chem. 51: 32401 32410 (1997)). Members of the TNF family of proteins bind to receptors of the TNF-receptor (TNF-R) family of proteins. The interaction of proteins of the TNF family with their receptors influence a wide variety of functions within the immune system. Well known examples include the CD40L protein, which binds to the CD40 receptor to promote the differentiation of B cells into antibody producing cells (Grewal and Flavell, Immunol. Res. 16: 59-70 (1997)), the lymphotoxin-beta ligand (LT-β), which binds to the lymphotoxin-beta receptor to influence humoral immune responses by regulating the differentiation state of follicular dendritic cells (Mackay and Browning, Nature 395: 26-27 (1998)), and the OX40L, which binds the OX40 receptor to regulate the response of B cells to T cell signals (Flynn et al., J. Exp. Med. 188: 297-304 (1998)). Other ligand/receptor pairs within the TNF/TNF-R families which are known to play critical roles in the immune system include TNF/TNF-R55, FasL/Fas, and CD27/CD70.
- TWEAK biology is as yet only partly understood. Purified soluble TWEAK protein was used to induce the differentiation and/or death of some tumor cell lines, including HT29 adenocarcinoma cells (cell death via apoptosis), HeLa cervical carcinoma cells (morphological changes), and A375 melanoma cells (anti-proliferation). TWEAK also induced the HT29 and A375 cell lines to secrete the chemokine IL-8 and had the same effect on a fibroblast cell line, WI-38 (Chicheportiche et al.,J. Biol. Chem. 51: 32401-32410 (1997)). In addition TWEAK induced proliferation of a variety of normal endothelial cell lines (Lynch et al., J. Interferon Cytokine Res. 18: A-46 (1998)).
- A putative receptor for TWEAK has been described (Marsters et al.,Curr. Biol. 8: 525-528 (1998)) 1998). This receptor, variably known as TRAMP, Apo3, WSL-1, DR-3, or LARD is a member of the TNF-R family. Activation of TRAMP can induce apoptosis by engaging either the caspase-dependant cell death signaling pathway or cellular activation via NF-kB signaling pathways (Ashkenazi and Dixit, Science 281: 1305-1308 (1998)).
- The expression of TWEAK in mouse and human tissues is widespread, with messenger RNA (mRNA) found in heart, brain, lung, liver, among other tissues, and secondary lymphoid organs such as spleen, lymph nodes, and peripheral blood mononuclear cells (PBMCs). TWEAK does not appear to be expressed in the primary lymphoid organs where immune system cells develop, such as thymus, bone marrow, and fetal liver. Thus the roles that TWEAK may play in the immune system are likely be in immune responses, rather than in the development of the immune system.
- The interaction of protein ligands and their receptors can be modified using a number of specific tools. For example, monoclonal antibodies (mAbs) which specifically recognize the ligand can be used to prevent or modify ligand/receptor binding, by virtue of recognition of the binding site, or by physically interfering with the interaction. Alternatively, anti-ligand mAbs can influence receptor signaling by influencing the binding of other ligands, when multiple ligands exist for a receptor. Such complicated effects have been noted for mAbs to the B7 family of CD28 ligands (Lenschow et al.J. Exp. Med. 181: 1145-1155 (1995)). Anti-ligand mAbs may have 25 even more subtle effects in systems where multiple receptors exist for a particular ligand, eg. by modifying ligand binding to one receptor but leaving binding to another receptor unchanged. MAbs which recognize the receptor can also be used to modify ligand binding, or may themselves induce or modify receptor signaling. Thus anti-receptor mAbs can be antagonistic or agonistic. Examples of mAbs used in the mouse or human systems to modify ligand/receptor interactions of TNF/TNF-R family members include mAbs specific for TNF, for CD40L, for LT-β, for Fas-L, and for TR2/HVEM, among others. MAbs can be used to block the initiation or development of immunologic and other diseases. For example, anti-CD40L has been used in treatment of systemic lupus erythematosis (SLE), and to control organ transplant failure.
- Potent inhibitors of ligand/receptor interaction can also be created by cloning the sequences which encode the extracellular portion of receptor sequences to sequences which encode human immunoglobulin (Ig) heavy chain, then expressing the hybrid gene, using an appropriate gene promoter, in an appropriate cell line. Purified receptor-Ig fusion proteins can be used in vitro and in vivo to bind to available protein ligand, and thus modify the interaction of the ligand with the native, cell bound, receptor. Modification can occur by a variety of mechanisms, similar to those outlined above for anti-ligand mAbs. Examples of receptor-Ig fusion proteins used in the mouse or human systems to modify ligand/receptor interactions of TNF/TNF-R family members include TNF-R55-Ig, TNF-R75-Ig, LTβ-R-Ig, and OX40-Ig, among others. Receptor-Ig fusion proteins can be used to block the initiation or development of immunologic and other diseases. For example, TNF-R75-Ig has been used to treat Inflammatory Bowel Disease (IBD).
- Herein we demonstrate that a mAb which specifically binds to murine and human TWEAK blocks the development of a prototypical antigen-driven immunological disorder, Graft-Versus-Host Disease (GVHD). Our invention anticipates the use of TWEAK and TWEAK receptor(s) modifying reagents to treat a variety of immunological disorders which result from the introduction of foreign antigen into patients, such as GVHD which results from bone marrow or stem cell transplantation, and organ transplant failure resulting from graft rejection. Furthermore this invention anticipates the use of TWEAK and TWEAK receptor(s) modifying reagents to treat a variety of autoimmune disorders, such as SLE, Idiopathic Thrombocytopenia Purpura, Wegener's Granulomatosis, Polyarteritis Nodosa, Retinal Uveitis, Rapidly Progressive Crescentic Glomerulonephritis, Rheumatoid Arthritis, Multiple Sclerosis, and ulcerative colitis, among other examples. Other anticipated uses include treatment of acute and chronic inflammatory conditions, such as allergic inflammation, asthma, eosinophilia, Graves'disease, and Chagas'disease, among others.
- Materials and Methods
- Mice Six to eight week old female mice of the DBA/2 and C57BI/6 strains, and the (DBA/2 ×C57B1/6)F1 cross were purchased from Jackson Laboratory (Bar Harbor, ME USA), housed under conventional barrier protection, and handled in accordance with institutional guidelines.
- Monoclonal antibodies Monoclonal antibodies which recognize human and murine TWEAK protein were generated in Armenian hamsters using soluble human TWEAK protein that had been generated in baculovirus and purified as described (Chicheportiche et al.,J. Biol. Chem. 51: 32401-32410 (1997)). For the first immunization each hamster received 50 μgs TWEAK in complete Freund's adjuvant (CFA), injected ip. For the subsequent immunizations (days 14, 28, and 42 after the primary immunization) each hamster recieved 50 (days 14 and 28) or 33 (day 42) μgs TWEAK in Incomplete Freund's Adjuvant (IFA), ip. The final immunization before fusion of the spleen cell for hybridoma formation was with 100 μgs TWEAK without adjuvant, ip. Hybridoma generation was performed using standard procedures (Lerner, Yale J. Biol. Med. 54: 387-402 (1981)).
- The hybridoma which produces anti-murine CD40L mAb MR1 (Noelle et al.,Proc. Natl. Acad. Sci. USA 89: 6550-6554 (1992)) was purchased from ATCC (Rockville, MD. USA). The hybridoma which produces anti-KLH mAb Ha4/8 was obtained from Dr. Mendrick (Human Genome Sciences, Inc. Rockville, MD. USA).
- ELISA analyses of mAb activity Anti-human TWEAK mAbs were tested for their ability to bind to human and murine TWEAK in a variety of experimental formats. Several mAbs raised against human TWEAK protein also recognized the mouse TWEAK protein in an initial screening of mAB activity which was done using ELISA format assays. Murine TWEAK protein was generated in baculovirus using methods similar to those described for human TWEAK protein (Chicheportiche et al.,J. Biol. Chem. 51: 32401-32410 (1997)). Purified human and murine TWEAK proteins were coated onto 96 well plates, and various hamster mAbs were tested for their ability to bind to these immobilized proteins. The capture of hamster mAb by the immobilized TWEAK proteins was visualized using Peroxidase-coupled donkey anti-hamster IgG (Jackson ImmunoResearch, West Grove, PA. USA), and an appropriate peroxidase-dependent enzymatic reaction.
- FACS analyses of mAb activity Soluble TWEAK protein induces apoptosis in HT29 cells, indicating that these cells express a TWEAK receptor (Chicheportiche et al.,J. Biol. Chem. 51: 32401-32410 (1997)). Purified mAbs (10 μg/ml) were tested for their ability to block the binding of FLAG-tagged murine or human TWEAK to HT29 cells, as detected by a biotinylated anti-FLAG antibody, streptaviden-peroxidase, and appropriate enzymatic substrate.
- Induction of chronic GVHD 6-8 week old DBA/2 and B6D2F1 female mice were sacrificed, and the spleens were removed using sterile technique. Single cell suspensions were made by gently grinding the organs between rough glass slides, allowing gross debris to settle out, then pelleting the cleared supernatant. This cell pellet was resuspended in Gey's buffered hypertonic solution, and incubated on ice for 3′ to lyse red blood cells. 5 ml Geys was used per each spleen disrupted. The cell solution was pelleted again, resuspended in sterile, pyrogen-free PBS, pelleted, and resuspended a second time in sterile, pyrogen-free PBS. Cell number was determined using a hemocytometer, and the cell density was adjusted to 2×108/ml. This solution was then passed through a sterile 70um cell filter, and kept on ice until use.6-8 week old B6D2F1 female mice were used as recipients. Each recipient was injected with 500 μl (1×108) cells in the vail vein. Experimental groups recieved the DBA/2 graft (DBA/2 >F1), while a set of control animals recieved a B6D2F1 graft (F1>F1). Animals were assayed for the development of chronic GVHD 14 days after injection.
- Blocking chronic GVHD Mice received anti-TWEAK mAb AB.D3, anti-CD40L mAb MR1, control mAb Ha4/8, or no treatment. The treatment schedule was 250 μgs mAb ip 4 hours prior to graft injection, and 2, 4, and 6 days afterwards.
- Assays of disease development On day 14 of the experiment the mice were sacrificed and weighed. Then, the spleen was aseptically removed and weighed. The spleen index was calculated as the ratio of spleen to body weight for each animal in the control F1>F1 group, averaged to give a value of one. The average spleen index for all other groups is normalized to the control value. Splenocytes were then isolated from these spleens, as described above, then diluted to a concentration of 1×107 cells/ml in sterile PBS. For
FACS analysis 100 μμls of cell were stained for the following cell surface markers. All mAbs described were purchased from Pharmingen (San Diego, Calif. USA). The streptavidin reagent was purchased from Southern Biotechnology Corp (Birmingham, Ala. USA). Splenocytes were stained with biotinylated anti-H-2Kb a haplotype marker which can distinguish the donor cells (H-2Kb−) from host cells (H-2Kb+) in various combinations with directly conjugated FITC or PE labelled anti-CD4, anti-CD8, anti-B220, anti-CD69, anti I-Ad, anti-L-selectin, and anti-H2Dd, in PBS/0.5% Bovine serum albumin (BSA)/0.1% sodium azide (FACS buffer) containing 10 μg/ml FcBlock™ (Pharmingen) to interrupt non-specific binding to Fc receptors. The cells were incubated with the mAbs for 1 h on ice. Each sample was then resuspended in 2 ml FACS buffer to wash, then centrifuged to pellet the cell. The cells were resuspended in FACS buffer containing CyChrome labelled streptavidin, which bound to the biotinylated mAb to provide a third channel for FACS analysis, washed a final time, and analyzed using FACscan instrumentation and Cellquest software (Becton Dickenson, San Jose, Calif. USA). - For in vitro analysis of Ig secretion cells were pelleted and resuspended in DMEM containing 10% Fetal Bovine Serum (FBS)/4 mM glutamine, at a concentration of 1×107 cells/ml. One ml per well was distributed into 6 well plates. Cell supernatants were recovered after 24 hours.
- Source of Anti-TWEAK Antibodies In one embodiment of this invention, antibodies (Abs) directed against TWEAK function as TWEAK blocking agents. Abs can be raised against monomeric, dimeric, or trimeric forms of the TWEAK protein, with or without heterologous subunits, if these exist. Furthermore, Abs can be raised against soluble, mutant, altered, or chimeric forms of TWEAK proteins. The anti-TWEAK Abs of this invention can be polyclonal or monoclonal (mAbs) and can be modified to optimize their ability to block TWEAK binding to its receptor(s), theirin vivo bioavailability, stability, or other desired traits.
- Polyclonal antibody sera directed against TWEAK are prepared using conventional techniques by injecting animals such as goats, rabbits, rats, hamsters or mice subcutaneously with human TWEAK in complete Freund's adjuvant (CFA), followed by booster intraperitoneal or subcutaneous injection in incomplete Freund's adjuvant (IFA). Polyclonal antisera containing the desired Abs directed against TWEAK are screened by conventional immunological procedures.
- Hamster monoclonal antibodies (mAbs) directed against human TWEAK are prepared using conventional methods by injecting armenian hamsters subcutaneously with recombinant soluble human TWEAK in CFA, followed by booster intraperitoneal or subcutaneous injection in IFA. A hybridoma cell line (AB.D3.7.2) which produces the hamster anti-TWEAK mAb AB.D3 was deposited on Dec. 17, 1998 with the American Type Culture Collection (ATCC) (Rockville, Md.) according to the provisions of the Budapest Treaty, and was assigned the ATCC accession number HB-12622. All restrictions on the availability to the public of the above ATCC deposit will be irrevocably removed upon the granting of a patent on this application.
- Various forms of anti-TWEAK Abs can also be made using standard recombinant DNA techniques (Winter and Milstein,Nature, 349, pp. 293-99 (1991)). For example, “chimeric” antibodies can be constructed in which the antigen binding domain from an animal antibody is linked to a human constant domain (e.g. Cabilly et al., U.S Ser. No 4,816,567; Morrison et al., Proc. Natl. Acad. Sci. U.S.A., 81, pp. 6851-55 (1984)). Chimeric Abs reduce the observed immunogenic responses elicited by animal Abs when used in human clinical treatments.
- In addition, recombinant “humanized antibodies” which recognize TWEAK can be synthesized. Humanized Abs are chimeras comprising mostly human IgG sequences into which the regions responsible for specific antigen-binding have been inserted (e.g. WO 94/04679). Animals are immunized with the desired antigen, the corresponding Abs are isolated, and the portion of the variable region sequences responsible for specific antigen binding are removed. The animal-derived antigen binding regions are then cloned into the appropriate position of human antibody genes in which the antigen binding regions have been deleted. Humanized Abs minimize the use of heterologous (inter-species) sequences in human Abs, and are less likely to elicit immune responses in the treated subject.
- Construction of different classes of recombinant anti-TWEAK Abs can also be accomplished by making chimeric or humanized Abs comprising the anti-TWEAK variable domains and human constant domains (
CH 1, CH2, CH3) isolated from different classes of immunoglobulins. For example, anti-TWEAK IgM Abs with increased antigen binding site valencies can be recombinantly produced by cloning the antigen binding site into vectors carrying the human IgM heavy chain constant regions (Arulanandam et al., J. Exp. Med., 177, pp. 1439-50 (1993); Lane et al., Eur. J. Immunol., 22, pp. 2573-78 (1993); Traunecker et al., Nature, 339, pp. 68-70 (1989)). - In addition, standard recombinant DNA techniques can be used to alter the binding affinities of recombinant Abs with their antigens by altering amino acid residues in the vicinity of the antigen binding sites.
- The antigen binding affinity of a humanized Ab can be increased by mutagenesis based on molecular modeling (Queen et al.,Proc. Natl. Acad. Sci. U.S.A., 86, pp. 10029-33 (1989); WO 94/04679).
- It may be desirable to increase or to decrease the affinity of anti-TWEAK Abs for TWEAK depending on the targeted tissue type or the particular treatment schedule envisioned. For example, it may be advantageous to treat a patient with constant levels of anti-TWEAK Abs with reduced ability to modify the TWEAK pathway for semi-prophylactic treatments. Likewise, anti-TWEAK Abs with increased affinity for TWEAK may be advantageous for short-term treatments.
- The production of hamster anti-human TWEAK monoclonal antibody is illustrated in EXAMPLE 1.
- Use of Anti-TWEAK mAb to Block the Development of Chronic GVHD, an Antigen-Driven Immunological Disease. We now show the effects of a TWEAK blocking agent, mAb AB.D3, on the development of an immunological response in a mouse model of chronic graft-versus-host disease (GVHD). The ability to block chronic GVHD includes effects on B cell activation and proliferation, and on the generation of secreted IgG. Mice were treated intraperitoneally (ip) with 250ggs anti-TWEAK mAb AB.D3, anti-KLH control mAb Ha4/8, anti-CD40L mAb MR1, or were left untreated. 4 hours later mice received 1×108 splenoc isolated from DBA/2 mice, in an 0.5 ml injection given intraveneously (iv). The iv injected DBA/2 splenocytes constituted the allograft. 2, 4, and 6 days after the graft was given, the mice were again treated with 250 μgs anti-TWEAK mAb AB.D3, anti-KLH control mAb Ha4/8, or
anti-CD40L mab MR 1. A control group of mice received 1×108 B6D2F1 splenocytes, which cannot induce disease in B6D2F1 recipients. Alternatively ungrafted and untreated B6D2F1 mice were used as controls. 14 days after the graft was given the mice were sacrificed and examined for evidence of disease. - Untreated graft-recipient mice manifest a variety of symptoms that are indicative of the development of chronic GVHD. Splenomegaly, or enlargement of the spleen, is evidence that donor T cells and host B cells have become activated, and are undergoing polyclonal expansion, with dramatic increases in cell number. The appearance of cell surface proteins such as CD69 on a subset of B cells is indicative of B cell activation. The loss of L-selectin molecules from CD4+ and CD8+ T cells is evidence of T cell activation. The secretion of Ig molecules, such as IgG classes, IgA, and IgE, either into the serum, or in in vitro cell culture assays, indicates that B cells have become activated, and have switched their Ig class. In this regard the appearance of anti-self Igs in the serum or in in vitro cell culture assays shows that Igs that are being produced have inappropriate autoantigen recognition. Finally, survivorship can be measured as an outcome of different treatment regimens.
- We compared control mice to untreated allograft-recipient mice to examine the extent of splenomegaly, B cell activation, and Ig secretion during GVHD. Anti-CD40L mAb MR1 was used as a positive control in these experiments, since it has been previously shown that blocking the CD40L/CD40 interaction is an effective means of interfering with the development of chronic GVHD (Durie, et al.,J. Clin. Invest. 94: 1333-1338 (1994)). A hamster mAb, Ha4/8, raised to Keyhole Limpet Hemocyanin (KLH) served as a negative control treatment. Results from 2 experiments are shown in Table 2. In both experiments treatment with anti-TWEAK mAb AB.D3 reduced the amount of splenomegaly (compared to untreated allograft-recipients) approximately 33%. Treatment. with the negative control mAb Ha4/8 had no effect, while treatment with anti-CD40L mAb MR1 blocked splenomegaly by nearly 70%. To investigate cell populations affected by treatment with anti-TWEAK mAb AB.D3 FACS analyses were performed on splenocytes taken from the recipient mice 14 days after graft injection. Spleen cells from 3-4 mice per group were isolated and pooled. Activation of recipient B cells is a defining feature of chronic GVHD. In untreated and control mAb treated mice a small but readily visible proportion of the B200+ B cells express the activation marker CD69 (FIG. 4 and Table 3). In contrast, virtually no B200+ B cells in MR1 or AD.B3 treated mice express CD69. Lack of measurable B cell activation in the spleen of AB.D3 mice could be due to one or more of several mechanisms of action, including failure of T cell activation, failure of B cell activation, or cell death (apoptosis). Next we measured total IgG in cultures of splenocytes in mice from different treatment groups to determine if the loss of the CD69 activation marker from the B cell populations correlated with a functional readout, ie. IgG production. Untreated control mice, MR1 treated mice, and AB.D3 treated mice produced dramatically lower amounts of total IgGs than did untreated or Ha4/8-treated allograft-recipient mice (Table 4). This result shows that Ig secretion by activated B cells, a defining feature of chronic GVHD, is blocked by treatment with anti-TWEAK mAb. The use of anti-TWEAK mAb to block the development of chronic GVHD is illustrated in Example 2.
- Other Antibody Mediated Diseases Many organ-specific and systemic autoimmune diseases involve pathological antibody responses. Such conditions include: Myasthenia Gravis, autoimmune hemolytic anemia, Chaga's disease, Grave's disease, idiopathic thrombocytopenia purpura (ITP) Systemic Lupus Erythematosus (SLE), Wegener's Granulomatosis, Poly-arteritis Nodosa and Rapidly Progressive Crescentic Glomerulonephritis (From Benjamini, et al.Immunology. A Short Course, (Wiley-Liss, New York 3d ed. (1996))
- Although the etiology of SLE is undefined, a fair amount is known about the immunologic mechanism responsible for the pathology observed. For unknown reasons, patients with SLE produce antibodies against nuclear components of the body (antinuclear antibodies (ANA) notably against native double stranded DNA. Clinically the presence of these antibodies correlates best with the renal pathology that develops in SLE. These antibodies complex with DNA apparently derived from the breakdown of normal tissue, and as in any immune-aggregate disease, such complexes form deposits trapped against the basement membrane of the glomeruli, in arteriolar walls and in joint synovial spaces. These complexes activate the complement cascade and attract granulocytes. The subsequent inflammatory reaction is characterized as glomerulonephritis, with resulting damage to the kidneys leading to proteinuria and hematuria.
- SLE has been studied in murine models for decades. The development of SLE can be blocked using reagents such as CTLA4-Ig fusion protein and anti-CD40L, which interrupt critical steps in T and B cell activation (Grewal and Flavell,Immunol. Rev. 153: 85-106 (1996)). Recently, the therapeutic efficacy of a reagent specific for the murine CD40 ligand was evaluated in several models (Mohan, et al., J. Immunol., 154, pp. 1470-1480 (1995)). The acceleration of lupus by the transfer of cells which induce the production of pathogenic antibodies in vivo was shown to be inhibited by administration of a monoclonal antibody which blocks CD40/CD40 ligand interactions. Moreover a brief treatment of lupus mice with anti-CD40 ligand antibody had a sustained beneficial effect on their spontaneous disease long after the antibody had been cleared from their systems. The experimentation indicated that pathogenic B cells could not produce antibody even 9 months after the therapy suggesting that there was a delay of the expansion of autoimmune memory B cells resulting in long-term therapeutic benefits. Moreover, anti CD40L treatment was able to halt or delay the progression of established SLE in a spontaneously occurring mouse model (Kalled, et al., J. Immunol. 160: 2158-2165 (1998)). As we have shown that reagents which modify TWEAK/TWEAK receptor(s) interaction in vivo inhibit B cell activation and Ig production, reagents of this invention will be useful for treating or preventing SLE.
- The normal immune response to some pathogenic infectious agents elicits autoantibody responses that can become excessive and present a medical problem. One example is Chagas'disease, an inflammatory cardiomyopathy which develops in humans and experimental animals with chronic Trypanosoma cruzi (T. cruzi) infection. Recently, several studies have identified anti-self antibodies in the sera of Chagas'disease patients (Bach-Elias et al.,Parasitol. Res. 84: 796-799 (1998)). Furthermore, induction of heart - specific autoimmune responses has recently received substantial experimental support as a possible mechanism involved in the pathogenesis of human Chagas'cardiomyopathy. A recent study (Tibbetts, et al., J. Immunol., 152, pp. 1493 -1499 (1994)) determined that cardiac antigen-specific antibodies are produced in T. Cruzi - infected C57BI/6 mice with heart disease. Upon infection with the Brazil strain of T. Cruzi, C57B1/6 mice develop a cardiomyopathy that is histologically similar to that observed in chronically infected humans. Antisera from these mice react with three cardiac antigens while C57B1/6 mice infected with the Guayas strain of T. Cruzi which do not develop cardiomyopathy did not produce such antibodies. These data indicate that these antibodies are specific markers of cardiomyopathy. The ability of TWEAK modifying agents to block B cell activation and Ig production will be useful in blocking the cardiac damage that occurs in Chagas'disease patients.
- Another example of cell destruction by autoantibodies generated as a consequence of certain infectious diseases or for other unknown reasons is idiopathic thrombocytopenia purpura (ITP). In this condition antibodies directed to platelets result in platelet destruction (by complement or phagocytic cells with Fc or C3b receptor) which may lead to bleeding. Therapeutics which will inhibit such antibody mediated autoimmune reactions in vivo such as the TWEAK modifying agents of this invention -- which inhibit antibody generation -- will be useful to treat or prevent these autoimmune diseases as well.
- The normal immune response to some pathogenic infectious agents can also elicit hypersensitivity reactions that can become excessive and present themselves as a medical problem. The most prevalent example of type I hypersensitivity is allergic reaction. These are mediated by IgE antibodies which bind via their Fc portion to receptors on mast cells and basophils to trigger the release of pharmacologically active agents that mediate anaphylaxis. ITP and Goodpasture's syndrome are sometimes thought to be Type II reactions which occur when IgM or IgG antibodies bind to antigen on the cell surface and activate the complement cascade. Granulocytes are then attracted to the site of activation, and damage from the release of lytic enzymes from their granules results in the destruction of cells. Rheumatic arthritis is thought to result from a type III hypersensitivity reaction mediated by immune complexes of antigen (in this case rheumatoid factor, an IgM autoantibody) that binds to the Fc portion of normal IgG. These immune complexes participate in causing inflammation of joints and the damage characteristic of this disease. As these pathologies are mediated in part by antibodies, therapeutics which will inhibit the generation of antibody, such as the TWEAK modifying agents of this invention, will be useful for treating or preventing these diseases as well.
- Additional examples of diseases which cause significant antibody-mediated damage to the patient include Graves' disease and acute hemolytic anemia. It is anticipated that TWEAK modifying agents will show efficacy in preventing or treating such diseases
- Inhibition of Cellular Immune Responses We have demonstrated that administration of reagents which modify the activity of TWEAK protein in vivo block the development of an antibody-mediated (humoral) immune disorder, chronic GVHD. Other potent immune system modifiers which are capable of blocking the development of chronic GVHD include anti-CD40L and CTLA4-Ig fusion protein. These reagents block critical steps in T and B cell activation (Grewal and Flavell,Immunol. Rev. 153: 85-106 (1996)). Therefore, therapeutic manipulation of these other potent immune system pathways has not been limited to the humoral immune responses. For example anti-CD40L and CTLA4-Ig have been used separately and together to control organ transplant rejection in animal models (Kirk et al., Proc. Natl. Acad. Sci. USA. 94 :8789-8794 (1997)). Much of the immune response to transplanted organs is Th1 T cell mediated, and consists of a cytotoxic cellular immune response. Such cellular immune responses are responsible for cell mediated damage in a variety of other immune disorders such as autoimmune diseases such as inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, diabetes, ulcerative colitis, and Crohn's disease, as examples. Based on the ability to block the development of chronic GVHD, our invention anticipates the use of TWEAK or TWEAK-receptor modifying reagents in the therapeutic treatment of cellular immune disorders.
- Treatments Using TWEAK and TWEAK-Receptor Modifying Agents The compositions of this invention will be administered at an effective dose to treat the particular clinical condition addressed. Determination of a preferred pharmaceutical formulation and a therapeutically efficient dose regiment for a given application is well within the skill of the art taking into consideration, for example, the condition and weight of the patient, the extent of desired treatment and the tolerance of the patient for the treatment.
- Doses of about 5 mg/kg of a TWEAK or TWEAK-Receptor modifying agent are expected to be suitable starting points for optimizing treatment doses.
- Determination of a therapeutically effective dose can also be assessed by performingin vitroexperiments that measure the concentration of the modifying agent required to coat target cells (TWEAK or TWEAK-Receptor-positive cells depending on the modifying agent) for suitable (therapeutic) time periods. The FACS and ELISA receptor-ligand binding assays described herein can be used to monitor the cell coating reaction. Based on the results of such in vitro binding assays, a range of suitable modifying agent concentrations can be selected to test in animals.
- Administration of the soluble modifying agents of this invention, alone or in combination, including isolated and purified forms of anti-TWEAK and anti-TWEAK-R antibodies, receptor-Ig fusion proteins, other TWEAK and TWEAK-receptor modifying reagents including naturally occurring or chemically derived reagents, and their salts or pharmaceutically acceptable derivatives thereof, may be accomplished using any of the conventionally accepted modes of administration of agents which exhibit immunosuppressive activity.
- The pharmaceutical compositions used in these therapies may also be in a variety of forms. These include, for example, solid, semi-solid and liquid dosage forms such as tablets, pills, powders, liquid solutions or suspensions, suppositories, and injectable and infusible solutions. The preferred form depends on the intended mode of administration and therapeutic application. Modes of administration may include oral, parenteral, subcutaneous, intravenous, intralesional or topical administration.
- The TWEAK and TWEAK-receptor modifying agents of this invention may, for example, be placed into sterile, isotonic formulations with or without cofactors which stimulate uptake or stability. The formulation is preferably liquid, or may be lyophilized powder. For example, the TWEAK and TWEAK-receptor modifying agents of this invention may be diluted with a formulation buffer comprising 5.0 mg/ml citric acid monohydrate, 2.7 mg/ml trisodium citrate, 41 mg/ml mannitol, 1 mg/ml glycine and 1 mg/ml polysorbate 20. This solution can be lyophilized, stored under refrigeration and reconstituted prior to administration with sterile Water-For-Injection (USP).
- The compositions also will preferably include conventional pharmaceutically acceptable carriers well known in the art (see for example Remington's Pharmaceutical Sciences, 16th Edition, 1980, Mac Publishing Company). Such pharmaceutically acceptable carriers may include other medicinal agents, carriers, genetic carriers, adjuvants, excipients, etc., such as human serum albumin or plasma preparations. The compositions are preferably in the form of a unit dose and will usually be administered one or more times a day.
- The pharmaceutical compositions of this invention may also be administered using microspheres, liposomes, other microparticulate delivery systems or sustained release formulations placed in, near, or otherwise in communication with affected tissues or the bloodstream. Suitable examples of sustained release carriers include semipermeable polymer matrices in the form of shaped articles such as suppositories or microcapsules. Implantable or microcapsular sustained release matrices include polylactides (U.S. Pat. No. 3,773,319; EP 58,481), copolymers of L-glutamic acid and ethyl-L-glutamate (Sidman et al.,Biopolymers, 22, pp. 547-56 (1985)); poly(2-hydroxyethyl-methacrylate) or ethylene vinyl acetate (Langer et al., J. Biomed. Mater. Res., 15, pp. 167-277 (1981); Langer, Chem. Tech., 12, pp. 98-105 (1982)).
- Advantages of Therapeutic Compositions Comprising TWEAK or TWEAK-Receptor Modifying agents The TWEAK and TWEAK-receptor modifying agents of this invention are capable of inhibiting immune responses, as shown by the inhibition of B cell activation and Ig production in the chronic GVHD model. The ability to selectively inhibit such immune mediated responses will be useful for treating immune disorders including various autoimmune diseases, organ transplant rejection, and acute and chronic inflammatory conditions. Treatment of such pathologic immune disorders generally employs immunomodulatory and immunosuppressive agents which have pleiotropic effects on a wide variety of cell types and immunological responses. These non-specific immunosuppressive agents are generally required in high and often cytotoxic doses that cause adverse side effects. For example, three general immunosuppressive agents currently used include steroids, cyclophosphamide and azathioprine. Steroids are pleiotropic anti-inflammatory agents which suppress activated macrophages and inhibit the activity of antigen presenting cells in ways which reverse many pathologic T cell effects. Cyclophosphamide, an alkylating agent, mediates cell death by inhibiting DNA replication and repair. Azathioprine is an anti-proliferative agent which inhibits DNA synthesis. These non-specific immunosuppressive agents are generally required in high doses which increase their toxicity (e.g. nephro-and hepatotoxicity) and cause adverse side effects. They are thus unsuitable for long term therapies.
- Thus, there is an unmet need for additional agents and therapies which overcome the problems caused by conventional treatments.
- The following are examples which illustrate the anti-TWEAK mAb of this invention, the methods used in the characterization of the mAb, and the use of the mAb to block an antigen-driven immunological disorder. These examples should not be construed as limiting: the examples are included for purposes of illustration and the present invention is limited only by the claims.
- Production of a monoclonal antibody to TWEAK protein.
- Monoclonal antibodies which recognizes human and murine TWEAK protein were generated in Armenian hamsters using soluble human TWEAK protein that had been generated in baculovirus as described (Chicheportiche et al.,J. Biol. Chem. 51: 32401-32410 (1997)). For the first immunization each hamster received 50 μgs TWEAK in complete Freund's adjuvant (CFA), injected ip. For the subsequent immunizations (days 14, 28, and 42 after the primary immunization) each hamster recieved 50 (days 14 and 28) or 33 (day 42) μgs TWEAK in Incomplete Freud's Adjuvant (IFA), ip. The final immunization before fusion of the spleen cell for hybridoma formation was with 100 μgs TWEAK without adjuvant, ip. Hybridoma generation was performed using standard procedures (Lerner, Yale J. Biol. Med. 54: 387-402 (1981)).
- Initial screening of mAb activity was done using ELISA format assays. Murine TWEAK protein was generated in baculovirus using methods similar to those described for human TWEAK protein (Chicheportiche et al.,J. Biol. Chem. 51: 32401-32410 (1997)). Purified human and murine TWEAK proteins were coated onto 96 well plates, and various hamster mAbs were tested for their ability to bind to these immobilized proteins. The capture of hamster mAb by the immobilized TWEAK proteins was visualized using HRP-coupled donkey anti-hamster IgG (Jackson ImmunoResearch, West Grove, Pa. USA), and an appropriate enzymatic reaction. Eight out of 23 mAbs recognized both murine and human TWEAK proteins (Table 1).
TABLE 1 FACS FACS Ligand Bind- Bind- Human Murine Block- ing to ing to m- TWEAK TWEAK ing hTWEAK/ TWEAK/ CLONE ELISA ELISA FACS 293 293 AB.D3.7.2 +++ +++ + + + AA.DB5 +++ − +/− + − AC.H5.24 +++ +++ − nd nd AA.G9 +++ − +/− + − AB.H12.1 +++ +++ − − − BA.F5.35.2* +++ +++ + + − BG.A12.5* ++ +++ + + − BE.D5 ++ − +/− + − AF.D4 ++ − + + − AB.G11.1* +++ +++ + + + BE.B3.6.1* ++ − − + − AA.AC2.3.2 +++ − +/− nd nd BB.B12.1.31.3 ++ − +/− + − AA.DG7.14* +++ +++ + + + BD.A3 ++ − − − − BC.B10.21* +++ +++ + + + BG.E8 +++ − +/− + − AE.C10.4* +++ − + + − AA.BB4.2* +++ − + + − AA.EC10.2* +++ − + + − AD.B5.9* +++ − − − − AB.D4.67.19 +++ − − − − - The conservation of antigenic epitopes across species lines was unsurprising given the extent of protein homology seen between the murine and human forms of TWEAK (FIG. 1). FACS analyses were used to determine if anti-TWEAK mAbs could bind to TWEAK proteins expressed on the surface of a cell. Human and murine TWEAK cDNA sequences were cloned into the expression vector CH269 (Chicheportiche et al.,J. Biol. Chem. 51: 32401-32410 (1997)), and these constructs were used in transfections to produce transient protein expression in EBNA 293 cells. Four mAbs, including AB.D3, bound well to EBNA293 cells expressing murine TWEAK (FIG. 2). These 4 mAbs were also capable of preventing the binding of human TWEAK to HT29 cells which are known to express one or more TWEAK-receptors (eg., FIG. 3). Together these FACS analyses indicated that anti-TWEAK mAbs specifically recognized TWEAK proteins, and were capable of modifying the ability of TWEAK proteins to bind to one or more TWEAK receptors.
- The use of anti-TWEAK mAb AB.D3 to block the development of splenomegaly, activated B cells, and Ig production in a murine model of chronic GVHD.
- Chronic GVHD was induced in 6-8 week old B6D2F1 female mice using DBA/2 splenocyte grafts as described in methods. Each recipient was injected with 500 μl (1×108) cells in the tail vein. Experimental groups recieved the DBA/2 graft (DBA/2>F1), while a set of control animals recieved a B6D2F1 graft (F1>F1). Mice received anti-TWEAK mAb AB.D3, anti-CD40L mAb MR1, control mAb Ha4/8, or no treatment. Animals were dosed with 250 μug mAb ip 4 hours prior to graft injection, and 2, 4, and 6 days afterwards. On day 14 of the experiment the mice were sacrificed and the spleen index was calculated as the ratio of spleen weight to body weight for each animal in the control F1>F1 group, averaged to give a value of one. The average spleen index for all other groups is normalized to the control value. The results from 2 independent experiments are shown in Table 2. Animals receiving the DBA/2 graft (DBA/2 >F1), and left untreated or treated with control mAb Ha4/8 showed a dramatic increase in spleen weight when compared to F1>F1 graft controls. This result is reflected in the spleen index, which showed an increase from the normalized control value of 1.0 to 2.6. Treatment of mice with anti-CD40L mAb MR1 reduced the spleen index nearly to control levels (1.1), and treatment with anti-TWEAK mAb AB.D3 reduced splenomegaly by 35% to 1.7 (Table 2).
TABLE 2 EXPERI- EXPERI- AVER- TREATMENT MENT 1 MENT 2AGE F1 > F1 (control) 1.0 1.0 1.0 DBA/2 > F1, untreated 2.7 2.6 2.65 DBA/2 > F1, Ha4/8 treated 2.9 2.6 2.75 DBA/2 > F1, MR1 treated 1.1 1.1 1.1 DBA/2 > F1, AB.D3 treated 1.8 1.7 1.75 - On day 14 of the experiment the mice were sacrificed and weighed. Then, the spleen was aseptically removed and weighed. The spleen index was calculated as the ratio of spleen to body weight for each animal in the control F1>F1 group, averaged to give a value of one. The average spleen index for all other groups is normalized to the control value.
- FACS analyses were employed to analyze the activation state of lymphocyte populations in the spleens of control and diseased mice, representing the various treatment groups. Initially we analyzed the amount of donor cell engraftment in the various group of mice. Donor cells were detected in the spleens of host mice at approximately the same percentage (average=6.2%) in all DBA/2>F1 treatment groups (Table 3). This result indicated that the different mAb treatments were not affecting donor cell engraftment.
TABLE 3 TREATMENT % H-2Kb negative (donor) cells F1 > Fl (control) 0.2 DBA/2 > F1, untreated 5.9 DBA/2 > F1, Ha4/8 treated 9.9 DBA/2 > F1, MR1 treated 5.5 DBA/2 > F1, AB.D3 treated 4.3 - For FACS analysis splenocytes from each group of mice were stained on ice for 1 h with PE-coupled anti-H2kb and FITC-coupled anti-H-2Dd to measure expression of MHC alleles. Host splenocytes are positive for both markers, but donor splenocytes are H-2kb negative. Percent values reflect events within the lymphocyte population, as determined by forward and side scatter characteristics.
- Next, two markers of lymphocyte activation were employed: CD69 expression on B220+ B cells, and L-selectin expression of CD4+ and CD8+ T cells. When control and untreated DBA/2 >Fl mice were compared we noted an increase in CD69+ B cells from 2.5% to 6.2% (Table 4). This increase in CD69+ B cell numbers was prevented by treatment with either MR1 (3.3%) or AB.D3 (2.1%) but not Ha4/8 (6.5%) (FIG. 4 and Table 3). Data from 2 experiments are shown in Table 4.
TABLE 4 % B220 +/ CD69 + (double positive) CELLS TREATMENT EXPERI- EXPERI- AVER- GROUP MENT 1 MENT 2AGE F1 > F1 (control) 2.5 2.0 2.25 DBA/2 > F1, untreated 6.2 5.5 5.9 DBA/2 > F1, Ha4/8 treated 6.5 4.7 5.6 DBA/2 > F1, MR1 treated 3.3 nd 3.3 DBA/2 > F1. AB.D3 treated 2.1 3.2 2.65 - Splenocytes were stained with PE-labelled anti-B220 and FITC labelled anti-CD69 for 1 h on ice, washed with FACS buffer, then analyzed. Percentages are based events collected within the lymphocyte population, as determined by forward and side scatter characteristics.
- For in vitro analysis of Ig secretion ELISA analysis was performed on splenocyte cell culture supernatants derived from spleens harvested from the various treatment groups. Results in Table 5 are from the second experiment, average of results from 3 mice per group. Treatment with
MR 1 or AB.D3 prevented the 4 - 6 fold increase in spontaneous IgG production observed in the untreated and Ha4/8 treated DBA/2 >F1 groups.TABLE 5 SPONTANEOUS TREATMENT GROUP IN VITRO IgG PRODUCTION F1 > F1, control 125 ng/ml +/− 20 ng/ml DBA/2 > F1, untreated 750 ng/ml +/− 65 ng/ml DBA/2 > F1, Ha4/8 treated 500 ng/ml +/− 150 ng/ml DBA/2 > F1, MR1 treated 0 DBA/2 > F1. AB.D3 treated 125 ng/ml +/− 20 ng/ml - For in vitro analysis of Ig secretion cells were pelleted and resuspended in DMEM containing 10% Fetal Bovine Serum (FBS)/4 mM glutamine, at a concentration of 1×107 cells/ml. One ml per well was distributed into 6 well plates. Cell supernatants were recovered after 24 hours. Values represent the average of 2 wells per mouse, with 3 mice represented for each treatment group.
-
1 2 1 225 PRT Murine 1 Val Leu Ser Leu Gly Leu Ala Leu Ala Cys Leu Gly Leu Leu Leu Val 1 5 10 15 Val Val Ser Leu Gly Ser Trp Ala Thr Leu Ser Ala Gln Glu Pro Ser 20 25 30 Gln Glu Glu Leu Thr Ala Glu Asp Arg Arg Glu Pro Pro Glu Leu Asn 35 40 45 Pro Gln Thr Glu Glu Ser Gln Asp Val Val Pro Phe Leu Glu Gln Leu 50 55 60 Val Arg Pro Arg Arg Ser Ala Pro Lys Gly Arg Lys Ala Arg Pro Arg 65 70 75 80 Arg Ala Ile Ala Ala His Tyr Glu Val His Pro Arg Pro Gly Gln Asp 85 90 95 Gly Ala Gln Ala Gly Val Asp Gly Thr Val Ser Gly Trp Glu Glu Thr 100 105 110 Lys Ile Asn Ser Ser Ser Pro Leu Arg Tyr Asp Arg Gln Ile Gly Glu 115 120 125 Phe Thr Val Ile Arg Ala Gly Leu Tyr Tyr Leu Tyr Cys Gln Val His 130 135 140 Phe Asp Glu Gly Lys Ala Val Tyr Leu Lys Leu Asp Leu Leu Val Asn 145 150 155 160 Gly Val Leu Ala Leu Arg Cys Leu Glu Glu Phe Ser Ala Thr Ala Ala 165 170 175 Ser Ser Pro Gly Pro Gln Leu Arg Leu Cys Gln Val Ser Gly Leu Leu 180 185 190 Pro Leu Arg Pro Gly Ser Ser Leu Arg Ile Arg Thr Leu Pro Trp Ala 195 200 205 His Leu Lys Ala Ala Pro Phe Leu Thr Tyr Phe Gly Leu Phe Gln Val 210 215 220 His 225 2 249 PRT Homo Sapien 2 Met Ala Ala Arg Arg Ser Gln Arg Arg Arg Gly Arg Arg Gly Glu Pro 1 5 10 15 Gly Thr Ala Leu Leu Val Pro Leu Ala Leu Gly Leu Gly Leu Ala Leu 20 25 30 Ala Cys Leu Gly Leu Leu Leu Ala Val Val Ser Leu Gly Ser Arg Ala 35 40 45 Ser Leu Ser Ala Gln Glu Pro Ala Gln Glu Glu Leu Val Ala Glu Glu 50 55 60 Asp Gln Asp Pro Ser Glu Leu Asn Pro Gln Thr Glu Glu Ser Gln Asp 65 70 75 80 Pro Ala Pro Phe Leu Asn Arg Leu Val Arg Pro Arg Arg Ser Ala Pro 85 90 95 Lys Gly Arg Lys Thr Arg Ala Arg Arg Ala Ile Ala Ala His Tyr Glu 100 105 110 Val His Pro Arg Pro Gly Gln Asp Gly Ala Gln Ala Gly Val Asp Gly 115 120 125 Thr Val Ser Gly Trp Glu Glu Ala Arg Ile Asn Ser Ser Ser Pro Leu 130 135 140 Arg Tyr Asn Arg Gln Ile Gly Glu Phe Ile Val Thr Arg Ala Gly Leu 145 150 155 160 Tyr Tyr Leu Tyr Cys Gln Val His Phe Asp Glu Gly Lys Ala Val Tyr 165 170 175 Leu Lys Leu Asp Leu Leu Val Asp Gly Val Leu Ala Leu Arg Cys Leu 180 185 190 Glu Glu Phe Ser Ala Thr Ala Ala Ser Ser Leu Gly Pro Gln Leu Arg 195 200 205 Leu Cys Gln Val Ser Gly Leu Leu Ala Leu Arg Pro Gly Ser Ser Leu 210 215 220 Arg Ile Arg Thr Leu Pro Trp Ala His Leu Lys Ala Ala Pro Phe Leu 225 230 235 240 Thr Tyr Phe Gly Leu Phe Gln Val His 245
Claims (22)
1. A method for blocking the development or treating or reducing the severity or effects of an immunological disorder in an animal comprising the step of administering a pharmaceutical composition which comprises a therapeutically effective amount of a TWEAK blocking agent and a pharmaceutically acceptable carrier.
2. A method for inhibiting an immune response in an animal comprising the step of administering a pharmaceutical composition which comprises an effective amount of a TWEAK blocking agent and a pharmaceutically effective carrier.
3. The method according to claim 1 or 2, wherein the TWEAK blocking agent is selected from the group consisting of:
(a) an antibody directed against the TWEAK ligand;
(b) an antibody directed against the TWEAK receptor;
(c) an agent that modifies the binding of the TWEAK ligand to the receptor;
(d) an agent that modifies the cell surface receptor clustering; and
(e) an agent that can interrupt the intra cellular signaling of the TWEAK receptor.
4. The method according to claim 1 or 2, wherein the animal is mammalian.
5. The method according to claim 4 , wherein the mammal is human.
6. The method according to claim 1 or 2, wherein the TWEAK blocking agent comprises a soluble TWEAK receptor having a ligand binding domain that can selectively bind to a surface TWEAK ligand.
7. The method of claim 6 , wherein the soluble TWEAK receptor comprises a human immunoglobulin IgG domain.
8. The method of claim 7 , wherein the human immunoglobulin IgG domain comprises regions responsible for specific antigen binding.
9. The method according to claim 1 or 2, wherein the antibody directed against the TWEAK receptor comprises a monoclonal antibody.
10. The method according to claim 1 or 2, wherein the TWEAK blocking agent comprises a monoclonal antibody directed against the TWEAK surface ligand.
11. The method according to claim 10 , wherein the antibody is directed against a subunit of the TWEAK ligand.
12. The method according to claim 2 , wherein the immune response is a Th1 cell-mediated immune response.
13. The method according to claim 2 , wherein the immune response is a Th2 cell-mediated immune response.
14. The method according to claim 2 , wherein the immune response includes both a Th1 and a Th2 cell-mediated immune response.
15. The method according to claim 2 , wherein the TWEAK blocking agent comprises a monoclonal antibody directed against the TWEAK receptor.
16. A pharmaceutical composition comprising a therapeutically effective amount of a TWEAK blocking agent and a pharmaceutically acceptable carrier.
17. The composition according to claim 16 , wherein the TWEAK blocking agent is selected from the group consisting of:
(a) an antibody directed against the TWEAK ligand;
(b) an antibody directed against the TWEAK receptor;
(c) an agent that modifies the binding of the TWEAK ligand to the receptor;
(d) an agent that modifies the cell surface receptor clustering; and
(e) an agent that can interrupt the intracellular signaling of the TWEAK receptor
18. The composition according to claim 16 , wherein the TWEAK blocking agent comprises a soluble TWEAK receptor having a ligand binding domain that can selectively bind to a surface TWEAK ligand.
19. The composition according to claim 18 , wherein the soluble TWEAK receptor comprises a human immunoglobulin IgG domain into which regions responsible for specific antigen binding have been inserted.
20. The composition of claim 16 , wherein the TWEAK blocking agent comprises a monoclonal antibody directed against the TWEAK receptor.
21. The composition according to claim 16 , wherein the TWEAK blocking agent comprises a monoclonal antibody directed against the TWEAK surface ligand.
22. The composition according to claim 21 , wherein the antibody is directed against a subunit of the TWEAK ligand.
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/905,810 US20020015703A1 (en) | 1999-01-15 | 2001-07-13 | Antagonists of tweak and of tweak receptor and their use to treat immunological disorders |
US10/916,141 US7169387B2 (en) | 1999-01-15 | 2004-08-11 | Antagonists of tweak and of tweak receptor and their use to treat immunological disorders |
US11/542,745 US7579001B2 (en) | 1999-01-15 | 2006-10-04 | Antagonists of TWEAK and of TWEAK receptor and their use to treat immunological disorders |
US12/506,006 US20100061985A1 (en) | 1999-01-15 | 2009-07-20 | Antagonists of tweak and of tweak receptor and their use to treat immunological disorders |
US13/173,604 US8440189B2 (en) | 1999-01-15 | 2011-06-30 | Antagonists of TWEAK and of TWEAK receptor and their use to treat immunological disorders |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11616899P | 1999-01-15 | 1999-01-15 | |
PCT/US2000/001044 WO2000042073A1 (en) | 1999-01-15 | 2000-01-14 | Antagonists of tweak and of tweak receptor and their use to treat immunological disorders |
USPCT/US00/01044 | 2000-01-14 | ||
US09/905,810 US20020015703A1 (en) | 1999-01-15 | 2001-07-13 | Antagonists of tweak and of tweak receptor and their use to treat immunological disorders |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2000/001044 Continuation WO2000042073A1 (en) | 1999-01-15 | 2000-01-14 | Antagonists of tweak and of tweak receptor and their use to treat immunological disorders |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/916,141 Continuation US7169387B2 (en) | 1999-01-15 | 2004-08-11 | Antagonists of tweak and of tweak receptor and their use to treat immunological disorders |
Publications (1)
Publication Number | Publication Date |
---|---|
US20020015703A1 true US20020015703A1 (en) | 2002-02-07 |
Family
ID=22365656
Family Applications (5)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/905,810 Abandoned US20020015703A1 (en) | 1999-01-15 | 2001-07-13 | Antagonists of tweak and of tweak receptor and their use to treat immunological disorders |
US10/916,141 Expired - Lifetime US7169387B2 (en) | 1999-01-15 | 2004-08-11 | Antagonists of tweak and of tweak receptor and their use to treat immunological disorders |
US11/542,745 Expired - Fee Related US7579001B2 (en) | 1999-01-15 | 2006-10-04 | Antagonists of TWEAK and of TWEAK receptor and their use to treat immunological disorders |
US12/506,006 Abandoned US20100061985A1 (en) | 1999-01-15 | 2009-07-20 | Antagonists of tweak and of tweak receptor and their use to treat immunological disorders |
US13/173,604 Expired - Fee Related US8440189B2 (en) | 1999-01-15 | 2011-06-30 | Antagonists of TWEAK and of TWEAK receptor and their use to treat immunological disorders |
Family Applications After (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/916,141 Expired - Lifetime US7169387B2 (en) | 1999-01-15 | 2004-08-11 | Antagonists of tweak and of tweak receptor and their use to treat immunological disorders |
US11/542,745 Expired - Fee Related US7579001B2 (en) | 1999-01-15 | 2006-10-04 | Antagonists of TWEAK and of TWEAK receptor and their use to treat immunological disorders |
US12/506,006 Abandoned US20100061985A1 (en) | 1999-01-15 | 2009-07-20 | Antagonists of tweak and of tweak receptor and their use to treat immunological disorders |
US13/173,604 Expired - Fee Related US8440189B2 (en) | 1999-01-15 | 2011-06-30 | Antagonists of TWEAK and of TWEAK receptor and their use to treat immunological disorders |
Country Status (21)
Country | Link |
---|---|
US (5) | US20020015703A1 (en) |
EP (1) | EP1141027A1 (en) |
JP (3) | JP5550799B2 (en) |
KR (1) | KR20010102978A (en) |
CN (1) | CN1387538A (en) |
AU (1) | AU2507700A (en) |
BR (1) | BR0007556A (en) |
CA (1) | CA2358684C (en) |
CZ (1) | CZ20012548A3 (en) |
EA (1) | EA004590B1 (en) |
EE (1) | EE200100372A (en) |
HK (1) | HK1038755A1 (en) |
HU (1) | HUP0105044A3 (en) |
IL (1) | IL144007A0 (en) |
IS (1) | IS5986A (en) |
MX (1) | MXPA01007163A (en) |
NO (1) | NO20013340L (en) |
NZ (1) | NZ529355A (en) |
SK (1) | SK10042001A3 (en) |
TR (1) | TR200102021T2 (en) |
WO (1) | WO2000042073A1 (en) |
Cited By (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6727225B2 (en) | 1999-12-20 | 2004-04-27 | Immunex Corporation | TWEAK receptor |
US6824773B2 (en) | 1999-12-20 | 2004-11-30 | Immunex Corporation | TWEAK receptor |
US20050054047A1 (en) * | 2003-07-24 | 2005-03-10 | Wiley Steven R. | Compositions and methods relating to multimeric and oligomeric soluble fragments of the TWEAK receptor |
US20060240004A1 (en) * | 2002-04-09 | 2006-10-26 | Linda Burkly | Methods for treating tweak-related conditions |
US20070128184A1 (en) * | 2005-08-30 | 2007-06-07 | Eckhard Podack | Immunomodulating tumor necrosis factor receptor 25 (TNFR25) agonists, antagonists and immunotoxins |
WO2006096487A3 (en) * | 2005-03-07 | 2007-09-13 | Genentech Inc | Methods and compositions for modulating tweak and fn14 activity |
US20080003221A1 (en) * | 2003-08-20 | 2008-01-03 | Podack Eckhard R | Compositions and methods for treating inflammatory lung disease |
US20080187544A1 (en) * | 2005-05-10 | 2008-08-07 | Burkly Linda C | Treating and evaluating inflammatory disorders |
US20080241163A1 (en) * | 2005-05-27 | 2008-10-02 | Biogen Idec Ma Inc. | Tweak binding antibodies |
US20080279853A1 (en) * | 2005-05-27 | 2008-11-13 | Biogen Idec Ma Inc. | Treatment of cancer |
US20080292622A1 (en) * | 2005-06-13 | 2008-11-27 | Biogen Idec Ma Inc. | Methods of evaluating patients |
US20090068102A1 (en) * | 2005-02-17 | 2009-03-12 | Biogen Idec Ma Inc. | Treating stroke |
WO2006089095A3 (en) * | 2005-02-17 | 2009-04-16 | Biogen Idec Inc | Treating neurological disorders |
US20100061985A1 (en) * | 1999-01-15 | 2010-03-11 | Biogen Idec Ma Inc. | Antagonists of tweak and of tweak receptor and their use to treat immunological disorders |
US20100260761A1 (en) * | 1996-08-07 | 2010-10-14 | Biogen, Inc. | Antibodies specifically reactive with a tumor necrosis factor related ligand |
US20100284933A1 (en) * | 2006-10-16 | 2010-11-11 | Biogen Idec Ma Inc. | Biomarkers of Multiple Sclerosis |
WO2015006508A3 (en) * | 2013-07-09 | 2015-04-09 | The Translational Genomics Research Institute | Compositions and methods of screening for compounds that modulate activity at a tweak binding site on a crd of fn14 |
US20160328684A1 (en) * | 2008-10-02 | 2016-11-10 | ecoATM, Inc. | Method and apparatus for recycling electronic devices |
US9499627B2 (en) | 2009-08-03 | 2016-11-22 | University Of Miami | Method for in vivo expansion of T regulatory cells |
US9603925B2 (en) | 2013-01-09 | 2017-03-28 | University Of Miami | Compositions comprising TL1A-Ig fusion protein for the regulation of T regulatory cells, and methods for their use |
US9797882B2 (en) | 2013-07-09 | 2017-10-24 | The Translational Genomics Research Institute | Method of screening for a compound for inhibitory activity of FN14-tweak interaction |
Families Citing this family (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7001992B2 (en) * | 1997-05-30 | 2006-02-21 | Human Genome Sciences, Inc. | Antibodies to secreted protein HEMCM42 |
US7495086B2 (en) | 1999-12-20 | 2009-02-24 | Immunex Corporation | TWEAK receptor |
WO2001085193A2 (en) * | 2000-05-08 | 2001-11-15 | Biogen, Inc. | Method for promoting neovascularization using a tweak agonist and an angiogenic factor |
US7208151B2 (en) | 2001-09-12 | 2007-04-24 | Biogen Idec Ma Inc. | Tweak receptor agonists as anti-angiogenic agents |
ATE515271T1 (en) * | 2000-09-14 | 2011-07-15 | Biogen Idec Inc | TWEAK RECEPTOR AGONISTS AS ANTI-ANGIogenic AGENTS |
CN101899106A (en) | 2002-10-29 | 2010-12-01 | 阿纳福公司 | The binding proteins for trimeric of trimerization cytokine |
EP1566636A1 (en) * | 2004-02-23 | 2005-08-24 | AXARON Bioscience AG | Use of Tweak modulators and inhibitors for the treatment of neurological conditions |
WO2006052926A2 (en) * | 2004-11-08 | 2006-05-18 | University Of Maryland, Baltimore | Tweak as a therapeutic target for treating central nervous system diseases associated with cerebral edema and and cell death |
US7939490B2 (en) | 2004-12-13 | 2011-05-10 | University Of Maryland, Baltimore | TWEAK as a therapeutic target for treating central nervous system diseases associated with cerebral edema and cell death |
AU2013200995B2 (en) * | 2005-05-27 | 2016-08-04 | Biogen Ma Inc. | Tweak binding antibodies |
US9056908B2 (en) | 2007-08-03 | 2015-06-16 | Abbvie Biotherapeutics Inc. | Therapeutic use of anti-tweak receptor antibodies |
NZ590668A (en) * | 2008-07-02 | 2012-12-21 | Emergent Product Dev Seattle | TNF-alpha ANTAGONIST MULTI-TARGET BINDING PROTEINS |
KR20110044992A (en) * | 2008-07-02 | 2011-05-03 | 이머전트 프로덕트 디벨롭먼트 시애틀, 엘엘씨 | TVF-β antagonist multi-target binding protein |
US8093006B2 (en) | 2009-04-02 | 2012-01-10 | Hoffmann-La Roche Inc. | Antibodies against human tweak and uses thereof |
WO2011097500A2 (en) | 2010-02-04 | 2011-08-11 | University Of Louisville Research Foundation, Inc. | The tweak/fn14 system regulates skeletal muscle atrophy and regeneration |
AU2011311673B2 (en) * | 2010-10-05 | 2015-09-17 | F. Hoffmann-La Roche Ag | Antibodies against human TWEAK and uses thereof |
US8609818B2 (en) | 2011-03-10 | 2013-12-17 | Omeros Corporation | Generation of anti-FN14 monoclonal antibodies by ex-vivo accelerated antibody evolution |
US9456755B2 (en) | 2011-04-29 | 2016-10-04 | Medtronic, Inc. | Method and device to monitor patients with kidney disease |
EA201401077A1 (en) | 2012-04-05 | 2015-02-27 | Ф.Хоффманн-Ля Рош Аг | BISPECIFIC ANTIBODIES TO HUMAN TWEAK AND HUMAN IL17 AND THEIR APPLICATION |
JP2017029001A (en) * | 2013-12-19 | 2017-02-09 | 国立研究開発法人産業技術総合研究所 | Novel modified protein of extracellular domain of protein G |
GB201403775D0 (en) | 2014-03-04 | 2014-04-16 | Kymab Ltd | Antibodies, uses & methods |
US9512229B2 (en) | 2015-03-03 | 2016-12-06 | Kymab Limited | Synergistic combinations of OX40L antibodies for the treatment of GVHD |
WO2017131972A1 (en) * | 2016-01-25 | 2017-08-03 | Oxytec Llc | Soil and water remediation method and apparatus for treatment of recalcitrant halogenated substances |
WO2018083248A1 (en) | 2016-11-03 | 2018-05-11 | Kymab Limited | Antibodies, combinations comprising antibodies, biomarkers, uses & methods |
US11661360B2 (en) | 2020-06-18 | 2023-05-30 | Wp&E Technologies And Solutions, Llc | System for removing per- and polyfluorinated alkyl substances from contaminated aqueous streams, via chemical aided filtration, and methods of use thereof |
Family Cites Families (78)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5200313A (en) | 1983-08-05 | 1993-04-06 | Miles Inc. | Nucleic acid hybridization assay employing detectable anti-hybrid antibodies |
US4921698A (en) | 1984-05-25 | 1990-05-01 | Asahi Kasei Kogyo Kabushiki Kaisha | Polypeptide having gamma-interferon activity lacking amino acids coded by exon 4 |
US5225539A (en) | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
US5073492A (en) | 1987-01-09 | 1991-12-17 | The Johns Hopkins University | Synergistic composition for endothelial cell growth |
JP3101690B2 (en) | 1987-03-18 | 2000-10-23 | エス・ビィ・2・インコーポレイテッド | Modifications of or for denatured antibodies |
US5223409A (en) | 1988-09-02 | 1993-06-29 | Protein Engineering Corp. | Directed evolution of novel binding proteins |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US5859205A (en) | 1989-12-21 | 1999-01-12 | Celltech Limited | Humanised antibodies |
AT396939B (en) | 1990-05-29 | 1993-12-27 | Alois Dipl Ing Dr Jungbauer | COMPLEX VIRAL ANTIQUE OF HIV-1 BINDING RECOMBINANT PROTEIN |
ATE255131T1 (en) | 1991-06-14 | 2003-12-15 | Genentech Inc | HUMANIZED HEREGULIN ANTIBODIES |
ES2227512T3 (en) | 1991-12-02 | 2005-04-01 | Medical Research Council | PRODUCTION OF ANTIBODIES AGAINST SELF-ANTIGENS FROM REPERTORIES OF ANTIBODY SEGMENTS FIXED IN A PHOTO. |
CA2153480A1 (en) | 1993-11-12 | 1995-06-01 | Kenichi Matsubara | Gene signature |
US20030198640A1 (en) | 1994-11-07 | 2003-10-23 | Human Genome Sciences, Inc. | Methods and compositions for treating inflammatory bowel diseases relating to human tumor necrosis factor-gamma-beta |
DE69434926T2 (en) | 1994-12-13 | 2008-03-06 | Human Genome Sciences, Inc. | HUMAN TISSUE INHIBITOR OF METALOPROTEINASE-4 |
US6544761B2 (en) | 1994-12-13 | 2003-04-08 | Human Genome Sciences, Inc. | Human tissue inhibitor of metalloproteinase-4 |
DE69621940T2 (en) | 1995-08-18 | 2003-01-16 | Morphosys Ag | PROTEIN - / (POLY) PEPTIDE LIBRARIES |
US7129061B1 (en) | 1996-08-07 | 2006-10-31 | Biogen Idec Ma Inc. | Tumor necrosis factor related ligand |
SK288012B6 (en) * | 1996-08-07 | 2012-10-02 | Biogen Idec Ma Inc. | DNA coding ligand related to TNF, process for its preparation and method for inhibiting immune response |
US5858991A (en) | 1997-01-29 | 1999-01-12 | Vanderbilt University | Facilitation of wound healing with CM101/GBS toxin |
EP0977887A2 (en) * | 1997-02-12 | 2000-02-09 | Abbott Laboratories | Member of the tnf family useful for treatment and diagnosis of disease |
GB2339430A (en) | 1997-05-21 | 2000-01-26 | Biovation Ltd | Method for the production of non-immunogenic proteins |
JP2002512524A (en) | 1997-06-03 | 2002-04-23 | 財団法人相模中央化学研究所 | Human protein having transmembrane domain and DNA encoding the same |
AU9376498A (en) | 1997-09-05 | 1999-03-22 | University Of Washington | Tumor necrosis factor family receptors and ligands, encoding nucleic acids and related binding agents |
IL134578A0 (en) | 1997-09-18 | 2001-04-30 | Genentech Inc | DcR3 POLYPEPTIDE, A TNFR HOMOLOG |
ATE424459T1 (en) * | 1997-10-10 | 2009-03-15 | Genentech Inc | APO-3 LIGAND |
US20020072089A1 (en) | 1999-11-23 | 2002-06-13 | Holtzman Douglas A. | Novel ITALY, Lor-2, STRIFE, TRASH, BDSF, LRSG, and STMST protein and nucleic acid molecules and uses therefor |
US6046381A (en) | 1998-04-30 | 2000-04-04 | The Regents Of The University Of California | Apolipoprotein E transgenic mice and assay methods |
WO1999059614A1 (en) | 1998-05-20 | 1999-11-25 | Yale University | Modulation of angiogenesis and wound healing |
WO1999061471A2 (en) | 1998-05-29 | 1999-12-02 | Incyte Pharmaceuticals, Inc. | Human transmembrane proteins |
IL142539A0 (en) | 1998-10-16 | 2002-03-10 | Immunex Corp | Inhibitors of platelet activation and recruitment |
CN1202128C (en) | 1998-12-08 | 2005-05-18 | 拜奥威神有限公司 | Method for reducing immunogenicity of proteins |
AU768230B2 (en) | 1998-12-22 | 2003-12-04 | Genentech Inc. | Methods and compositions for inhibiting neoplastic cell growth |
EE200100372A (en) * | 1999-01-15 | 2002-10-15 | Biogen, Incorporated | TWEAK Protein and TWEAK Protein Receptor Antagonists and Their Use in the Treatment of Immune Diseases |
US20020004041A1 (en) | 1999-02-19 | 2002-01-10 | Albert Matthew L. | Methods for abrogating a cellular immune response |
DK1623989T3 (en) | 1999-03-08 | 2007-10-15 | Genentech Inc | Compositions and Methods for Diagnosing Tumors |
US6521424B2 (en) | 1999-06-07 | 2003-02-18 | Immunex Corporation | Recombinant expression of Tek antagonists |
KR100510795B1 (en) | 1999-08-31 | 2005-08-30 | Compositions and Methods for the Treatment of Tumor | |
US7495086B2 (en) | 1999-12-20 | 2009-02-24 | Immunex Corporation | TWEAK receptor |
EP1239869B1 (en) | 1999-12-20 | 2013-08-28 | Immunex Corporation | Tweak receptor |
US6727225B2 (en) * | 1999-12-20 | 2004-04-27 | Immunex Corporation | TWEAK receptor |
CA2395945C (en) | 2000-01-03 | 2013-12-24 | Tr Associates, L.L.C. | Novel chimeric proteins and methods for using the same |
US7927602B2 (en) | 2002-07-23 | 2011-04-19 | University Of Louisville Research Foundation, Inc. | Fas ligand-avidin/streptavidin fusion proteins |
US7074408B2 (en) | 2000-02-25 | 2006-07-11 | Immunex Corporation | Use of integrin antagonists to inhibit angiogenesis |
WO2001085193A2 (en) | 2000-05-08 | 2001-11-15 | Biogen, Inc. | Method for promoting neovascularization using a tweak agonist and an angiogenic factor |
US20040047854A1 (en) | 2001-07-27 | 2004-03-11 | Black Roy A. | Human disintegrin protein |
ATE515271T1 (en) | 2000-09-14 | 2011-07-15 | Biogen Idec Inc | TWEAK RECEPTOR AGONISTS AS ANTI-ANGIogenic AGENTS |
US7208151B2 (en) * | 2001-09-12 | 2007-04-24 | Biogen Idec Ma Inc. | Tweak receptor agonists as anti-angiogenic agents |
JP4344519B2 (en) | 2000-12-28 | 2009-10-14 | 旭化成ファーマ株式会社 | NF-κB activating gene |
EP1381622A2 (en) | 2001-03-21 | 2004-01-21 | Human Genome Sciences, Inc. | Human secreted proteins |
US20040203083A1 (en) | 2001-04-13 | 2004-10-14 | Biosite, Inc. | Use of thrombus precursor protein and monocyte chemoattractant protein as diagnostic and prognostic indicators in vascular diseases |
US20040076955A1 (en) | 2001-07-03 | 2004-04-22 | Eos Biotechnology, Inc. | Methods of diagnosis of bladder cancer, compositions and methods of screening for modulators of bladder cancer |
US6756101B2 (en) | 2001-07-16 | 2004-06-29 | Specialty Tapes, Division Of Rsw | Tape for use with high-speed webs and method of use thereof |
US20040091473A1 (en) | 2001-07-27 | 2004-05-13 | Dubose Robert F. | Metalloproteinase-disintegrin polypeptides and methods of making and use thereof |
WO2003040307A2 (en) | 2001-07-27 | 2003-05-15 | Human Genome Sciences, Inc. | Heteromultimeric tnf ligand family members |
US20030148314A1 (en) | 2001-08-01 | 2003-08-07 | Millennium Pharmaceuticals, Inc. | Compositions, kits, and methods for identification, assessment, prevention, and therapy of colon cancer |
US20040033495A1 (en) | 2001-08-03 | 2004-02-19 | Eos Biotechnology, Inc. | Methods of diagnosis of angiogenesis, compositions and methods of screening for angiogenesis modulators |
CN106421778A (en) | 2002-04-09 | 2017-02-22 | 比奥根Ma公司 | Methods for treating tweak-related conditions |
WO2004063355A2 (en) | 2003-01-10 | 2004-07-29 | Protein Design Labs, Inc. | Novel methods of diagnosis of metastatic cancer, compositions and methods of screening for modulators of matastatic cancer |
WO2004065416A2 (en) | 2003-01-16 | 2004-08-05 | Genentech, Inc. | Synthetic antibody phage libraries |
US20050008625A1 (en) | 2003-02-13 | 2005-01-13 | Kalobios, Inc. | Antibody affinity engineering by serial epitope-guided complementarity replacement |
WO2004074506A2 (en) | 2003-02-13 | 2004-09-02 | Mergen Ltd | Polynucleotide sequences and corresponding encoded polypeptides of particular secreted and membrane-bound proteins overexpressed in certain cancers |
EP1599607A2 (en) | 2003-03-04 | 2005-11-30 | Arcturus Bioscience, Inc. | Signatures of er status in breast cancer |
CA2531526C (en) * | 2003-07-24 | 2012-08-21 | Amgen Inc. | Compositions and methods relating to multimeric and oligomeric soluble fragments of the tweak receptor |
EP1566636A1 (en) | 2004-02-23 | 2005-08-24 | AXARON Bioscience AG | Use of Tweak modulators and inhibitors for the treatment of neurological conditions |
WO2006052926A2 (en) | 2004-11-08 | 2006-05-18 | University Of Maryland, Baltimore | Tweak as a therapeutic target for treating central nervous system diseases associated with cerebral edema and and cell death |
US7939490B2 (en) * | 2004-12-13 | 2011-05-10 | University Of Maryland, Baltimore | TWEAK as a therapeutic target for treating central nervous system diseases associated with cerebral edema and cell death |
WO2006088890A2 (en) | 2005-02-17 | 2006-08-24 | Biogen Idec Ma Inc. | Treating stroke |
WO2006089095A2 (en) | 2005-02-17 | 2006-08-24 | Biogen Idec Ma Inc. | Treating neurological disorders |
US20080286271A1 (en) * | 2005-03-07 | 2008-11-20 | Ashkenazi Avi J | Methods and Compositions for Modulating Tweak and Fn14 Activity |
AU2006244014B2 (en) * | 2005-05-10 | 2011-03-17 | Biogen Ma Inc. | Treating and evaluating inflammatory disorders |
CN102441163A (en) | 2005-05-27 | 2012-05-09 | 比奥根艾迪克Ma公司 | Tweak binding antibodies |
WO2006130429A2 (en) | 2005-05-27 | 2006-12-07 | Biogen Idec Ma Inc. | Treatment of cancer |
WO2006138219A2 (en) * | 2005-06-13 | 2006-12-28 | Biogen Idec Ma Inc. | Methods of diagnosis / prognosis of inflammatory conditions |
WO2008048924A2 (en) | 2006-10-16 | 2008-04-24 | Biogen Idec Ma Inc. | Biomarkers of multiple sclerosis |
EP2294089A2 (en) | 2008-05-15 | 2011-03-16 | Biogen Idec MA Inc. | Anti-fn14 antibodies and uses thereof |
WO2010085648A2 (en) | 2009-01-23 | 2010-07-29 | Linda Burkly C | Methods for reducing radiation-induced tissue damage |
AU2010208123A1 (en) | 2009-01-30 | 2011-08-18 | Biogen Idec Ma Inc. | Methods for pancreatic tissue regeneration |
AU2011311673B2 (en) * | 2010-10-05 | 2015-09-17 | F. Hoffmann-La Roche Ag | Antibodies against human TWEAK and uses thereof |
-
2000
- 2000-01-14 EE EEP200100372A patent/EE200100372A/en unknown
- 2000-01-14 TR TR2001/02021T patent/TR200102021T2/en unknown
- 2000-01-14 BR BR0007556-6A patent/BR0007556A/en not_active Application Discontinuation
- 2000-01-14 EP EP00903307A patent/EP1141027A1/en not_active Withdrawn
- 2000-01-14 AU AU25077/00A patent/AU2507700A/en not_active Abandoned
- 2000-01-14 MX MXPA01007163A patent/MXPA01007163A/en unknown
- 2000-01-14 CN CN00804735A patent/CN1387538A/en active Pending
- 2000-01-14 CA CA2358684A patent/CA2358684C/en not_active Expired - Lifetime
- 2000-01-14 IL IL14400700A patent/IL144007A0/en unknown
- 2000-01-14 KR KR1020017008956A patent/KR20010102978A/en not_active Application Discontinuation
- 2000-01-14 CZ CZ20012548A patent/CZ20012548A3/en unknown
- 2000-01-14 WO PCT/US2000/001044 patent/WO2000042073A1/en not_active Application Discontinuation
- 2000-01-14 SK SK1004-2001A patent/SK10042001A3/en unknown
- 2000-01-14 HU HU0105044A patent/HUP0105044A3/en unknown
- 2000-01-14 JP JP2000593639A patent/JP5550799B2/en not_active Expired - Fee Related
- 2000-01-14 NZ NZ529355A patent/NZ529355A/en not_active IP Right Cessation
- 2000-01-14 EA EA200100780A patent/EA004590B1/en not_active IP Right Cessation
-
2001
- 2001-06-29 IS IS5986A patent/IS5986A/en unknown
- 2001-07-05 NO NO20013340A patent/NO20013340L/en not_active Application Discontinuation
- 2001-07-13 US US09/905,810 patent/US20020015703A1/en not_active Abandoned
-
2002
- 2002-01-10 HK HK02100180.8A patent/HK1038755A1/en unknown
-
2004
- 2004-08-11 US US10/916,141 patent/US7169387B2/en not_active Expired - Lifetime
-
2006
- 2006-10-04 US US11/542,745 patent/US7579001B2/en not_active Expired - Fee Related
-
2009
- 2009-07-20 US US12/506,006 patent/US20100061985A1/en not_active Abandoned
-
2010
- 2010-08-25 JP JP2010188938A patent/JP5592195B2/en not_active Expired - Lifetime
-
2011
- 2011-06-30 US US13/173,604 patent/US8440189B2/en not_active Expired - Fee Related
-
2013
- 2013-01-17 JP JP2013006243A patent/JP2013075916A/en not_active Withdrawn
Cited By (44)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100260761A1 (en) * | 1996-08-07 | 2010-10-14 | Biogen, Inc. | Antibodies specifically reactive with a tumor necrosis factor related ligand |
US8440189B2 (en) | 1999-01-15 | 2013-05-14 | Biogen Idec Ma Inc. | Antagonists of TWEAK and of TWEAK receptor and their use to treat immunological disorders |
US20100061985A1 (en) * | 1999-01-15 | 2010-03-11 | Biogen Idec Ma Inc. | Antagonists of tweak and of tweak receptor and their use to treat immunological disorders |
US6824773B2 (en) | 1999-12-20 | 2004-11-30 | Immunex Corporation | TWEAK receptor |
US6727225B2 (en) | 1999-12-20 | 2004-04-27 | Immunex Corporation | TWEAK receptor |
US20060240004A1 (en) * | 2002-04-09 | 2006-10-26 | Linda Burkly | Methods for treating tweak-related conditions |
US8506958B2 (en) * | 2002-04-09 | 2013-08-13 | Biogen Idec Ma Inc. | Methods for treating TWEAK-related conditions |
US20120015024A1 (en) * | 2002-04-09 | 2012-01-19 | Biogen Idec Ma Inc. | Methods for treating tweak-related conditions |
US20130216496A1 (en) * | 2002-04-09 | 2013-08-22 | Biogen Idec Ma Inc. | Methods for treating tweak-related conditions |
CN106421778A (en) * | 2002-04-09 | 2017-02-22 | 比奥根Ma公司 | Methods for treating tweak-related conditions |
US9011859B2 (en) * | 2002-04-09 | 2015-04-21 | Biogen Idec Ma Inc. | Methods for treating TWEAK-related conditions |
US20090311313A1 (en) * | 2002-04-09 | 2009-12-17 | Biogen Idec Ma Inc. | Methods for treating tweak-related conditions |
US20050054047A1 (en) * | 2003-07-24 | 2005-03-10 | Wiley Steven R. | Compositions and methods relating to multimeric and oligomeric soluble fragments of the TWEAK receptor |
US7482430B2 (en) | 2003-07-24 | 2009-01-27 | Amgen Inc. | Compositions and methods relating to multimeric and oligomeric soluble fragments of the TWEAK receptor |
US20080003221A1 (en) * | 2003-08-20 | 2008-01-03 | Podack Eckhard R | Compositions and methods for treating inflammatory lung disease |
US20080233119A2 (en) * | 2003-08-20 | 2008-09-25 | University Of Miami | Compositions and methods for treating inflammatory lung disease |
WO2006089095A3 (en) * | 2005-02-17 | 2009-04-16 | Biogen Idec Inc | Treating neurological disorders |
US20090124993A1 (en) * | 2005-02-17 | 2009-05-14 | Burkly Linda C | Treating neurological disorders |
US20090068102A1 (en) * | 2005-02-17 | 2009-03-12 | Biogen Idec Ma Inc. | Treating stroke |
US9775899B2 (en) | 2005-02-17 | 2017-10-03 | Biogen Ma Inc. | Treating neurological disorders |
US20080286271A1 (en) * | 2005-03-07 | 2008-11-20 | Ashkenazi Avi J | Methods and Compositions for Modulating Tweak and Fn14 Activity |
WO2006096487A3 (en) * | 2005-03-07 | 2007-09-13 | Genentech Inc | Methods and compositions for modulating tweak and fn14 activity |
WO2006122187A3 (en) * | 2005-05-10 | 2009-04-16 | Biogen Idec Inc | Treating and evaluating inflammatory disorders |
US8728475B2 (en) | 2005-05-10 | 2014-05-20 | Biogen Idec Ma Inc. | Methods for treating inflammatory bowel disease |
US20080187544A1 (en) * | 2005-05-10 | 2008-08-07 | Burkly Linda C | Treating and evaluating inflammatory disorders |
US8048422B2 (en) | 2005-05-27 | 2011-11-01 | Biogen Idec Ma Inc. | Tweak binding antibodies |
US20080241163A1 (en) * | 2005-05-27 | 2008-10-02 | Biogen Idec Ma Inc. | Tweak binding antibodies |
US20080279853A1 (en) * | 2005-05-27 | 2008-11-13 | Biogen Idec Ma Inc. | Treatment of cancer |
US8048635B2 (en) | 2005-06-13 | 2011-11-01 | Biogen Idec Ma Inc. | Measurement of soluble Tweak levels for evaluation of lupus patients |
US20080292622A1 (en) * | 2005-06-13 | 2008-11-27 | Biogen Idec Ma Inc. | Methods of evaluating patients |
US9730947B2 (en) | 2005-06-13 | 2017-08-15 | Biogen Ma Inc. | Method of treating lupus nephritis |
US20070128184A1 (en) * | 2005-08-30 | 2007-06-07 | Eckhard Podack | Immunomodulating tumor necrosis factor receptor 25 (TNFR25) agonists, antagonists and immunotoxins |
US9017679B2 (en) | 2005-08-30 | 2015-04-28 | University Of Miami | Immunomodulating tumor necrosis factor receptor 25 (TNFR25) agonists, antagonists, and immunotoxins |
US9839670B2 (en) | 2005-08-30 | 2017-12-12 | University Of Miami | Immunomodulating tumor necrosis factor receptor 25 (TNFR25) agonists, antagonists, and immunotoxins |
US11395846B2 (en) | 2005-08-30 | 2022-07-26 | University Of Miami | Immunomodulating tumor necrosis factor receptor 25 (TNFR25) agonists, antagonists, and immunotoxins |
US20100284933A1 (en) * | 2006-10-16 | 2010-11-11 | Biogen Idec Ma Inc. | Biomarkers of Multiple Sclerosis |
US20160328684A1 (en) * | 2008-10-02 | 2016-11-10 | ecoATM, Inc. | Method and apparatus for recycling electronic devices |
US9499627B2 (en) | 2009-08-03 | 2016-11-22 | University Of Miami | Method for in vivo expansion of T regulatory cells |
US10934364B2 (en) | 2009-08-03 | 2021-03-02 | University Of Miami | Method for in vivo expansion of T regulatory cells |
US9603925B2 (en) | 2013-01-09 | 2017-03-28 | University Of Miami | Compositions comprising TL1A-Ig fusion protein for the regulation of T regulatory cells, and methods for their use |
USRE48599E1 (en) | 2013-01-09 | 2021-06-22 | University Of Miami | Compositions comprising TLIA-Ig fusion protein for the regulation of T regulatory cells, and methods for their use |
US9238034B2 (en) | 2013-07-09 | 2016-01-19 | The Translational Genomics Research Institute | FN14 antagonists and therapeutic uses thereof |
WO2015006508A3 (en) * | 2013-07-09 | 2015-04-09 | The Translational Genomics Research Institute | Compositions and methods of screening for compounds that modulate activity at a tweak binding site on a crd of fn14 |
US9797882B2 (en) | 2013-07-09 | 2017-10-24 | The Translational Genomics Research Institute | Method of screening for a compound for inhibitory activity of FN14-tweak interaction |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7579001B2 (en) | Antagonists of TWEAK and of TWEAK receptor and their use to treat immunological disorders | |
US8287874B2 (en) | Soluble lymphotoxin-beta receptors and anti-lymphotoxin receptor and ligand antibodies as therapeutic agents for the treatment of immunological diseases | |
CA2227477A1 (en) | Soluble lymphotoxin-.beta. receptors and anti-lymphotoxin receptor and ligand antibodies, as therapeutic agents for the treatment of immunological disease | |
KR100584704B1 (en) | Soluble lymphotoxin-beta receptors, anti-lymphotoxin receptor antibodies, and anti-lymphotoxin ligand antibodies as therapeutic agents for the treatment of immunological diseases | |
WO1998017313A9 (en) | Soluble lymphotoxin-beta receptors, anti-lymphotoxin receptor antibodies, and anti-lymphotoxin ligand antibodies as therapeutic agents for the treatment of immunological diseases | |
BG64436B1 (en) | Cd154 blockade therapy for the treatment of protein inhibition syndrome | |
EP1723967A2 (en) | Soluble lymphotoxin-beta receptors, anti-lymphotoxin receptor antibodies and anti-lymphotoxin ligand antibodies as therapeutic agents for the treatment of immunological diseases |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: BIOGEN IDEC MA INC., MASSACHUSETTS Free format text: CHANGE OF NAME;ASSIGNOR:BIOGEN IDEC MA, INC.;REEL/FRAME:014520/0982 Effective date: 20031203 |
|
AS | Assignment |
Owner name: BIOGEN IDEC MA INC., MASSACHUSETTS Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:RENNERT, PAUL;REEL/FRAME:015723/0314 Effective date: 20050208 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |