US20020172679A1 - Treatment of inflammatory bowel disease by inhibiting binding and/or signalling through alpha4beta7 and its ligands and MAdCAM - Google Patents
Treatment of inflammatory bowel disease by inhibiting binding and/or signalling through alpha4beta7 and its ligands and MAdCAM Download PDFInfo
- Publication number
- US20020172679A1 US20020172679A1 US10/118,600 US11860002A US2002172679A1 US 20020172679 A1 US20020172679 A1 US 20020172679A1 US 11860002 A US11860002 A US 11860002A US 2002172679 A1 US2002172679 A1 US 2002172679A1
- Authority
- US
- United States
- Prior art keywords
- monoclonal antibody
- antigen binding
- antibody
- fib
- binding fragment
- 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
- 208000022559 Inflammatory bowel disease Diseases 0.000 title claims abstract description 12
- 239000003446 ligand Substances 0.000 title claims description 6
- 238000011282 treatment Methods 0.000 title abstract description 14
- 230000002401 inhibitory effect Effects 0.000 title description 2
- 230000011664 signaling Effects 0.000 title 1
- 210000000265 leukocyte Anatomy 0.000 claims abstract description 29
- 201000010099 disease Diseases 0.000 claims abstract description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 15
- 230000007115 recruitment Effects 0.000 claims abstract description 13
- 210000001035 gastrointestinal tract Anatomy 0.000 claims abstract description 11
- 230000003511 endothelial effect Effects 0.000 claims abstract description 10
- 210000003038 endothelium Anatomy 0.000 claims abstract description 6
- 210000001519 tissue Anatomy 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 49
- 239000012634 fragment Substances 0.000 claims description 33
- 101150103244 ACT1 gene Proteins 0.000 claims description 28
- 101100161918 Glycine max SAC1 gene Proteins 0.000 claims description 28
- 239000000427 antigen Substances 0.000 claims description 25
- 102000036639 antigens Human genes 0.000 claims description 25
- 108091007433 antigens Proteins 0.000 claims description 25
- 210000004698 lymphocyte Anatomy 0.000 claims description 14
- 102000006495 integrins Human genes 0.000 claims description 12
- 108010044426 integrins Proteins 0.000 claims description 12
- 208000015943 Coeliac disease Diseases 0.000 claims description 7
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 7
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 7
- 208000011231 Crohn disease Diseases 0.000 claims description 5
- 208000002389 Pouchitis Diseases 0.000 claims description 4
- 230000000890 antigenic effect Effects 0.000 claims description 4
- 208000008609 collagenous colitis Diseases 0.000 claims description 4
- 201000001564 eosinophilic gastroenteritis Diseases 0.000 claims description 4
- 208000008275 microscopic colitis Diseases 0.000 claims description 4
- 206010062164 Seronegative arthritis Diseases 0.000 claims description 3
- 208000037902 enteropathy Diseases 0.000 claims description 3
- 208000028774 intestinal disease Diseases 0.000 claims description 3
- 210000001616 monocyte Anatomy 0.000 claims description 2
- 241001465754 Metazoa Species 0.000 description 35
- 210000001072 colon Anatomy 0.000 description 18
- 238000001574 biopsy Methods 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 14
- 229920003045 dextran sodium sulfate Polymers 0.000 description 14
- 241000699670 Mus sp. Species 0.000 description 13
- 206010009887 colitis Diseases 0.000 description 12
- 230000002962 histologic effect Effects 0.000 description 10
- 206010003694 Atrophy Diseases 0.000 description 9
- 241000288950 Callithrix jacchus Species 0.000 description 9
- 230000037444 atrophy Effects 0.000 description 9
- 230000003475 colitic effect Effects 0.000 description 9
- 210000004400 mucous membrane Anatomy 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- 230000002757 inflammatory effect Effects 0.000 description 8
- 210000004877 mucosa Anatomy 0.000 description 8
- 230000004927 fusion Effects 0.000 description 7
- 210000003622 mature neutrocyte Anatomy 0.000 description 7
- 206010012735 Diarrhoea Diseases 0.000 description 6
- 208000027418 Wounds and injury Diseases 0.000 description 6
- 230000006378 damage Effects 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 208000014674 injury Diseases 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 241000288960 Saguinus oedipus Species 0.000 description 5
- 108010000134 Vascular Cell Adhesion Molecule-1 Proteins 0.000 description 5
- 102100023543 Vascular cell adhesion protein 1 Human genes 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 238000009175 antibody therapy Methods 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- 210000005087 mononuclear cell Anatomy 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000011725 BALB/c mouse Methods 0.000 description 4
- 108010064593 Intercellular Adhesion Molecule-1 Proteins 0.000 description 4
- 102000015271 Intercellular Adhesion Molecule-1 Human genes 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 210000000981 epithelium Anatomy 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 230000002163 immunogen Effects 0.000 description 4
- 230000006872 improvement Effects 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000003651 drinking water Substances 0.000 description 3
- 235000020188 drinking water Nutrition 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 238000000684 flow cytometry Methods 0.000 description 3
- 238000009169 immunotherapy Methods 0.000 description 3
- 230000008595 infiltration Effects 0.000 description 3
- 238000001764 infiltration Methods 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 210000001165 lymph node Anatomy 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- 101100289995 Caenorhabditis elegans mac-1 gene Proteins 0.000 description 2
- 208000004232 Enteritis Diseases 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 241000282414 Homo sapiens Species 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 102100022339 Integrin alpha-L Human genes 0.000 description 2
- 108010008212 Integrin alpha4beta1 Proteins 0.000 description 2
- 108010064548 Lymphocyte Function-Associated Antigen-1 Proteins 0.000 description 2
- 102100028793 Mucosal addressin cell adhesion molecule 1 Human genes 0.000 description 2
- 101710139349 Mucosal addressin cell adhesion molecule 1 Proteins 0.000 description 2
- 241000288906 Primates Species 0.000 description 2
- 238000000692 Student's t-test Methods 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- 230000001174 ascending effect Effects 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 230000000112 colonic effect Effects 0.000 description 2
- 238000007405 data analysis Methods 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000003364 immunohistochemistry Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- PLYRYAHDNXANEG-QMWPFBOUSA-N (2s,3s,4r,5r)-5-(6-aminopurin-9-yl)-3,4-dihydroxy-n-methyloxolane-2-carboxamide Chemical compound O[C@@H]1[C@H](O)[C@@H](C(=O)NC)O[C@H]1N1C2=NC=NC(N)=C2N=C1 PLYRYAHDNXANEG-QMWPFBOUSA-N 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 108010062271 Acute-Phase Proteins Proteins 0.000 description 1
- 102000011767 Acute-Phase Proteins Human genes 0.000 description 1
- 108010032595 Antibody Binding Sites Proteins 0.000 description 1
- 108010074051 C-Reactive Protein Proteins 0.000 description 1
- 102100032752 C-reactive protein Human genes 0.000 description 1
- 241000288951 Callithrix <genus> Species 0.000 description 1
- 108010067225 Cell Adhesion Molecules Proteins 0.000 description 1
- 102000016289 Cell Adhesion Molecules Human genes 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- 206010012741 Diarrhoea haemorrhagic Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 101000994375 Homo sapiens Integrin alpha-4 Proteins 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 102100032818 Integrin alpha-4 Human genes 0.000 description 1
- UETNIIAIRMUTSM-UHFFFAOYSA-N Jacareubin Natural products CC1(C)OC2=CC3Oc4c(O)c(O)ccc4C(=O)C3C(=C2C=C1)O UETNIIAIRMUTSM-UHFFFAOYSA-N 0.000 description 1
- 206010025476 Malabsorption Diseases 0.000 description 1
- 208000004155 Malabsorption Syndromes Diseases 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 108090000526 Papain Proteins 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 206010038063 Rectal haemorrhage Diseases 0.000 description 1
- 241000288961 Saguinus imperator Species 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- SXEHKFHPFVVDIR-UHFFFAOYSA-N [4-(4-hydrazinylphenyl)phenyl]hydrazine Chemical compound C1=CC(NN)=CC=C1C1=CC=C(NN)C=C1 SXEHKFHPFVVDIR-UHFFFAOYSA-N 0.000 description 1
- 238000012084 abdominal surgery Methods 0.000 description 1
- 206010000269 abscess Diseases 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 102000019997 adhesion receptor Human genes 0.000 description 1
- 108010013985 adhesion receptor Proteins 0.000 description 1
- 239000004479 aerosol dispenser Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 230000003872 anastomosis Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 210000000628 antibody-producing cell Anatomy 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- 229960002170 azathioprine Drugs 0.000 description 1
- 238000004820 blood count Methods 0.000 description 1
- BPKIGYQJPYCAOW-FFJTTWKXSA-I calcium;potassium;disodium;(2s)-2-hydroxypropanoate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].C[C@H](O)C([O-])=O BPKIGYQJPYCAOW-FFJTTWKXSA-I 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000004534 cecum Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 238000012321 colectomy Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 210000001731 descending colon Anatomy 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 229940124589 immunosuppressive drug Drugs 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- RCRODHONKLSMIF-UHFFFAOYSA-N isosuberenol Natural products O1C(=O)C=CC2=C1C=C(OC)C(CC(O)C(C)=C)=C2 RCRODHONKLSMIF-UHFFFAOYSA-N 0.000 description 1
- 238000002350 laparotomy Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 241001515942 marmosets Species 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 210000002433 mononuclear leukocyte Anatomy 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229940055729 papain Drugs 0.000 description 1
- 235000019834 papain Nutrition 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 210000005105 peripheral blood lymphocyte Anatomy 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 210000001986 peyer's patch Anatomy 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000011886 postmortem examination Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 238000010880 proctocolectomy Methods 0.000 description 1
- 208000037821 progressive disease Diseases 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 0.000 description 1
- 229960001940 sulfasalazine Drugs 0.000 description 1
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 1
- 230000000153 supplemental effect Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000036642 wellbeing Effects 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
- C07K14/70503—Immunoglobulin superfamily
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2500/00—Screening for compounds of potential therapeutic value
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S424/00—Drug, bio-affecting and body treating compositions
- Y10S424/801—Drug, bio-affecting and body treating compositions involving antibody or fragment thereof produced by recombinant dna technology
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S424/00—Drug, bio-affecting and body treating compositions
- Y10S424/81—Drug, bio-affecting and body treating compositions involving autoimmunity, allergy, immediate hypersensitivity, delayed hypersensitivity, immunosuppression, immunotolerance, or anergy
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
- Y10S530/866—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof involving immunoglobulin or antibody fragment, e.g. fab', fab, fv, fc, heavy chain or light chain
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
- Y10S530/867—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof involving immunoglobulin or antibody produced via recombinant dna technology
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
- Y10S530/868—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof involving autoimmunity, allergy, immediate hypersensitivity, delayed hypersensitivity, immunosuppression, or immunotolerance
Definitions
- IBD Inflammatory bowel disease
- ulcerative colitis and Crohn's disease can be a debilitating and progressive disease involving inflammation of the gastrointestinal tract affecting an estimated two million people in the United States. Symptoms include abdominal pain, cramping, diarrhea and rectal bleeding. IBD treatments have included anti-inflammatory drugs (such as, corticosteroids and sulfasalazine), immunosuppressive drugs (such as, 6-mercaptopurine, cyclosporine and azathioprine) and surgery (such as, colectomy). Podolsky, The New England Journal of Medicine, 325:928-937 (1991) and Podolsky, The New England Journal of Medicine, 325:1008-1016 (1991).
- anti-inflammatory drugs such as, corticosteroids and sulfasalazine
- immunosuppressive drugs such as, 6-mercaptopurine, cyclosporine and azathioprine
- VCAM-1 vascular cell adhesion molecule-1
- VLA-4 vascular cell adhesion molecule-1
- IBD can be treated by blocking the interaction of ICAM-1 with LFA-1 or Mac-1 or VCAM-1 with ⁇ 4 ⁇ 1 (e.g., WO 93/15764).
- these therapeutic targets are likely involved in inflammatory processes in multiple organs, and a functional blockade would likely result in systemic immune dysfunction.
- Mucosal addressin MAdCAM a mucosal vascular adhesion molecule
- MAdCAM a mucosal vascular adhesion molecule
- MAdCAM In contrast to VCAM-1 and ICAM- 1, MAdCAM is preferentially expressed in the gastrointestinal tract, binds the ⁇ 4 ⁇ 7 integrin (also called LPAM-1 and CD49d/CD ⁇ ) found on lymphocytes, and participates in the homing of these cells to mucosal sites, such as Peyer's patches in the intestinal wall (Hamann et al., Journal of Immunology, 152:3282-3293 (1994)).
- ⁇ 4 ⁇ 7 integrin also called LPAM-1 and CD49d/CD ⁇
- the invention relates to the treatment of individuals suffering from a disease associated with leukocyte recruitment to the gastrointestinal tract as a result of binding of leukocytes to gut-associated endothelium expressing the molecule MAdCAM, comprising administering to the individual an effective amount of a compound, such as an antibody, which inhibits the binding of leukocytes to endothelial MAdCAM.
- a compound such as an antibody
- the antibody is preferably monoclonal, chimeric and/or humanized or an antigen binding fragment thereof, and inhibits adhesion of leukocytes expressing an integrin containing the ⁇ 7 chain (such as ⁇ 4 ⁇ 7) to endothelium expressing MAdCAM.
- the monoclonal antibody or antigen binding fragment thereof has the antigenic specificity of a monoclonal antibody selected from the group consisting of FIB 21, FIB 30, FIB 504 and ACT-1.
- Inflammatory bowel diseases such as but not limited to ulcerative colitis, Crohn's disease, Pouchitis, celiac disease, microscopic or collagenous colitis, and eosinophilic gastroenteritis can be treated according to the claimed method.
- FIGS. 1 a and 1 b are graphic illustrations of histologic scores of inflammatory activity and epithelial injury from left (descending) and right (ascending) colon of mice exposed to 10 days of DSS in their drinking water. Three groups of mice are shown, consisting of groups receiving an irrelevant rat IgG2a antibody, FIB21, or FIB30 antibodies.
- FIG. 2 is a graph of ⁇ counts per minute (cpm) ( ⁇ 1 SEM) as a percentage of input from mice given DSS in the drinking water for 10 days.
- Six groups consisted of negative controls given water alone, positive controls given DSS alone, test groups given irrelevant rat IgG2a antibody, FIB21, MECA-367, and FIB21 with MECA-367.
- FIG. 3 is a graph depicting the histologic scores ( ⁇ 1 SEM) for villus fusion obtained from jejunal biopsy samples of common marmosets before and on the 14th day of treatment with 2 mg/kg/day of ACT-1 monoclonal antibody.
- FIG. 4 is a graph depicting the histologic scores ( ⁇ 1 SEM) for villus atrophy obtained from jejunal biopsy samples of common marmosets before and on the 14th day of treatment with 2 mg/kg/day of ACT-1 monoclonal antibody.
- FIGS. 5 and 6 are graphic illustrations of the stool consistency and inflammatory activity in colitic animals (cotton-top tamarins) treated with ACT-1 antibody.
- the invention relates to the discovery that diseases associated with leukocyte recruitment to the gastrointestinal tract, such as IBD, or other mucosal tissues can be treated by inhibiting MAdCAM binding to the ⁇ 4 ⁇ 7 integrin or triggering of ⁇ 4 ⁇ 7-mediated cellular responses.
- Compounds which inhibit binding include antibodies or antigen binding fragments thereof which bind MAdCAM and/or the ⁇ 4 ⁇ 7 integrin.
- Antibodies which can be used in the method include recombinant or non-recombinant polyclonal, monoclonal, chimeric, humanized and/or anti-idiotypic antibodies.
- MECA 367 is an anti-MAdCAM antibody of the IgG2a subtype and is described in Gallatin et al., Nature, 304:30 (1983) and Michie et al., Am. J. Pathol. 143:1688-1698 (1993).
- ACT-1 is a monoclonal antibody which binds the ⁇ 4 ⁇ 7 integrin (Lazarovits et al., Journal of Immunology, 133:1857 (1984) and Schweighoffer et al., Journal of Immunology, 151:717-729 (1993)).
- FIB 21 binds the ⁇ 7 chain is described and characterized in Berlin et al., Cell 74:184-195 (1993); Andrew, D. P. et al., J. Immunol. 153:3847-3861 (1994)).
- Other monoclonal antibodies such as antibodies which bind to the same or similar epitopes as the antibodies described above, can be made according to methods known in the art, such as Kohler et al., Nature, 256:495-497 (1975), Harlow et al., 1988, Antibodies: A Laboratory Manual, (Cold Spring Harbor, N.Y.) or Current Protocols in Molecular Biology, Vol. 2 (Supplemental 27, Summer '94), Ausubel et al., Eds.
- antibodies can be raised against an appropriate immunogen in a suitable mammal.
- Immunogens include, for example, MAdCAM ⁇ 4 ⁇ 7 or immunogenic fragments thereof.
- the mammal can be a mouse, rat, rabbit or sheep, for example.
- the antibody-producing cell e.g., a lymphocyte
- the cell can then be fused to a suitable immortalized cell (e.g., a myeloma cell line), thereby forming a hybridoma.
- the fused cells can be isolated employing selective culturing techniques. Cells which produce antibodies with the desired specificity can be selected by a suitable assay (e.g., ELISA).
- the immunogen can be an antibody which binds, for example, MAdCAM ⁇ 4 ⁇ 7 or immunogenic fragments thereof.
- the antibody raised thereby can be an anti-idiotypic antibody, which can also be used in the present invention.
- Single chain antibodies, and chimeric, humanized or primatized (CDR-grafted or resurfaced, such as, according to EP 592406, Apr. 13, 1994) antibodies, as well as chimeric or CDR-grafted single chain antibodies, comprising portions derived from different species, can also be used in the invention.
- the various portions of these antibodies can be joined together chemically by conventional techniques, or can be prepared as a contiguous protein using genetic engineering techniques.
- nucleic acids encoding a chimeric or humanized chain can be expressed to produce a contiguous protein. See, e.g., Cabilly et al., U.S. Pat. No. 4,816,567; Cabilly et al., European Patent No.
- functional fragments of antibodies including fragments of chimeric, humanized, primatized or single chain antibodies, can also be produced.
- Functional fragments of the foregoing antibodies retain at least one binding function of the full-length antibody from which they are derived and, preferably, retains the ability to inhibit interaction.
- antibody fragments capable of binding to the ⁇ 4 ⁇ 7 integrin; MAdCAM or portion thereof include, but are not limited to, Fv, Fab, Fab′ and F(ab′) 2 fragments.
- Such fragments can be produced by enzymatic cleavage or by recombinant techniques. For instance, papain or pepsin cleavage can generate Fab or F(ab′) 2 fragments, respectively.
- antibodies can be produced in a variety of truncated forms using antibody genes in which one or more stop codons has been introduced upstream of the natural stop site.
- a chimeric gene encoding a F(ab′) 2 heavy chain portion can be designed to include DNA sequences encoding the CH 1 domain and hinge region of the heavy chain.
- Antibodies and antigen binding fragments thereof which can be used in the claimed method include antibodies which bind to MAdCAM and/or ⁇ 4 ⁇ 7, such as the ⁇ 7 chain.
- antibodies from the group including FIB 21, FIB 30, FIB 504 and ACT-1 and mixtures thereof can be administered.
- antigen fragments of these antibodies can be administered.
- Compounds which inhibit the binding of MAdCAM and the ⁇ 4 ⁇ 7 integrin can be administered according to the claimed method in the treatment of diseases which are associated with leukocyte (such as lymphocyte or monocyte) recruitment to the gastrointestinal tract or other tissues as a result of binding of leukocytes to gut-associated endothelium expressing the molecule MAdCAM.
- Diseases which can be treated accordingly include inflammatory bowel disease, such as ulcerative colitis, Crohn's disease, Celiac disease (nontropical Sprue), enteropathy associated with seronegative arthropathies, microscopic or collagenous colitis, eosinophilic gastroenteritis, or pouchitis resulting after proctocolectomy and ileoanal anastomosis.
- more than one monoclonal antibody which inhibits the binding of leukocytes to endothelial MAdCAM is administered.
- a monoclonal antibody which inhibits the binding of leukocytes to endothelial ligands is administered in addition to an anti-MAdCAM or anti- ⁇ 7 antibody.
- an antibody that inhibits the binding of leukocytes to an endothelial ligand other than MAdCAM such as an anti-ICAM-1 or anti-VCAM-1 antibody can also be administered.
- an additional pharmacologically active ingredient such as a steroid
- a variety of routes of administration are possible including, but not necessarily limited to parenteral (e.g., intravenous, intraarterial, intramuscular, subcutaneous injection), oral (e.g., dietary), topical, inhalation (e.g., intrabronchial, intranasal or oral inhalation, intranasal drops), or rectal, depending on the disease or condition to be treated.
- parenteral e.g., intravenous, intraarterial, intramuscular, subcutaneous injection
- oral e.g., dietary
- topical inhalation
- inhalation e.g., intrabronchial, intranasal or oral inhalation, intranasal drops
- rectal e.g., rectal, depending on the disease or condition to be treated.
- Parenteral administration is a preferred mode of administration.
- Formulation of a compound to be administered will vary according to the route of administration selected (e.g., solution, emulsion, capsule).
- An appropriate composition comprising the compound to be administered can be prepared in a physiologically acceptable vehicle or carrier.
- suitable carriers include, for example, aqueous or alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
- Parenteral vehicles can include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils.
- Intravenous vehicles can include various additives, preservatives, or fluid, nutrient or electrolyte replenishers (See, generally, Remington's Pharmaceutical Science, 16th Edition, Mack, Ed. 1980).
- a suitable dispenser for administration e.g., an atomizer, nebulizer or pressurized aerosol dispenser.
- the compound is administered in an amount which will inhibit binding of MAdCAM to the ⁇ 4 ⁇ 7 integrin.
- the compounds can be administered in a single dose or multiple doses.
- the dosage can be determined by methods known in the art and is dependent, for example, upon the individual's age, sensitivity, tolerance and overall well-being. Suitable dosages can be from 0.1-1.0 mg/kg body weight per treatment.
- mice were given access to a 5% solution of dextran sodium sulfate (DSS) in their drinking water for a period of 10 days, as previously described ( Lab. Invest. 69:238-249, 1993). During this time period, the mice developed clinical symptoms of colitis including softening of stools and bloody diarrhea. Multifocal epithelial injury and ulceration, similar to ulcerative colitis in humans, was evident on histologic examination of colonic mucosa from affected mice. Moreover, affected mice lost 20-30% of their initial body weight by day 10.
- DSS dextran sodium sulfate
- mice were given daily intraperitoneal (i.p.) injections of 100 ⁇ g of monoclonal antibodies against ⁇ 7, consisting of either FIB21 or FIB30 in saline, as previously characterized and described (Berlin, C., et al., Cell 74:185-195, 1993; Michie, S. A., et al, Am. J. Pathol. 143:1688-1698, 1993; Hamann, A., et al., J. Immunol. 152:3282-3293, 1994) or an isotype-matched control rat monoclonal antibody at the same dose (Andrew et al., supra) over the 10 day course of DSS treatment.
- FIB21 or FIB30 in saline
- mice were placed on 5% DSS for 9 days (instead of 10) and on day 8, mice were given i.p. injections of 100 ⁇ g of FIB21 (anti- ⁇ 7), MECA-367 (anti-MAdCAM), a mixture of both, or an isotype-matched control monoclonal antibody in saline.
- mesenteric lymph node cells were isolated from donor syngeneic BALB/c mice, labeled with 51 Cr, and 5.0 ⁇ 10 6 cells/mouse were incubated for 30 minutes at 37° C. with 500 ⁇ g control antibody, 250 ⁇ g of MECA-367, 500 ⁇ g FIB21, or both (total amount is 750 ⁇ g) in saline.
- the labeled cells and antibody were then injected intravenously (i.v.) into the DSS-treated recipient mice.
- Full-length colons were harvested from all experimental animals 1 hour after injection, and ⁇ -irradiation was measured using a ⁇ -counter.
- Lymphocyte recruitment to inflamed colon was then quantitatively assessed using radiolabeled mesenteric lymphocytes taken from syngeneic donors.
- radiolabeled mesenteric lymphocytes taken from syngeneic donors.
- One hour after injection of these cells in DSS-treated recipients there was a trend towards a reduction in the number of 51 Cr-labeled cells recruited to colon in mice that were treated with either ⁇ 7-specific antibodies or the MAdCAM-specific antibodies, but not in mice treated with the isotope-matched control antibodies (FIG. 2).
- Common marmosets ( Callithrix jacchus ) are a new world nonhuman primate that, under captive conditions at the New England Regional Primate Research Center (NERPRC), develop a steroid-nonresponsive, spontaneous malabsorption syndrome characterized by weight loss, diarrhea, and small intestinal mucosal changes consistent with loss of absorptive capacity. These histologic changes include small intestinal villus atrophy and fusion, and a mononuclear leukocyte infiltrate within the lamina intestinal similar to Celiac disease (nontropical sprue) in humans. Retrospective analysis from the pathology archive files at NERPRC demonstrated that up to 80% of common marmosets have, to various degrees, malabsorptive enteritis at the time of postmortem examination.
- NERPRC New England Regional Primate Research Center
- villus architecture was scored according to the following grading criteria: Villus atrophy 0 normal mucosal thickness and villus height 1 mild atrophy; slight shortening of villi; height approximately 75% of normal 2 moderate atrophy; villi approximately 33-50% normal height 3 severe atrophy; short ( ⁇ 33% normal) or no observable villi Villus fusion 0 normal; no fusion 1 1-2 villi in specimen fused 2 Between 1-2 and 50% of villi in specimen fused 3 >50% villi in specimen fused
- FIGS. 3 and 4 The mean scores for villus fusion and atrophy before and after antibody therapy with the ACT-1 monoclonal antibody are shown in FIGS. 3 and 4, respectively. As demonstrated, there was almost complete resolution of villus atrophy (P ⁇ 0.01) and a trend for improvement of villus fusion after a two-week course of therapy with the ACT-1 antibody. The effect was not secondary to nonspecific effects of exposure to foreign immunoglobulin since other animals treated with various monoclonal antibodies directed against epitopes other than that recognized by ACT-1 were ineffective in reducing villus fusion and atrophy scores.
- the cotton-top tamarin ( Saguinus oedipus ) is a New World nonhuman primate which develops a spontaneous colitis similar to ulcerative colitis in man.
- ACT-1 was known to cross-react in the tamarin because of immunohistologic staining with ACT-1 antibody of colitic mucosa from affected animals.
- Colitic animals were chosen from the colony-at-large based upon gross observation of diarrhea and weight loss. All candidate animals were then subjected to colon biopsy to confirm the presence of colitis, as defined as a histologic inflammatory activity score of 2 or 3.
- the scoring system used was originally described in Madara, J. L. et al., Gastroenterology 88:13-19 (1985). Briefly, inflammatory activity scores were based upon the relative numbers of neutrophils within the lamina intestinal, crypt lumena, crypt epithelium, and surface epithelium. All biopsy samples were scored and categorized into four groups, with 0 representing normal mucosa and 3 representing the most severe and inflamed mucosa. Scores of 0 and 1 do not represent symptomatic colitis, while scores of 2 to 3 represent mild to severe colitic activity. Within 5 days of confirmation of colitis, the animals began immunotherapy with ACT-1 monoclonal antibody.
- Colon biopsies were again obtained at the time of the first antibody infusion (Day 0) and on days 5, 10 and 20. The biopsies were evaluated by an independent pathologist. Additional colon biopsies were frozen for immunohistology. Animal caretakers evaluated stool consistency on a daily basis by categorizing stool as diarrhea, semi-solid, or solid. Animals were weighed every other day, while blood was drawn at the same intervals for flow cytometry, hematology, and storage of serum or plasma for further analyses, such as antibody concentration, anti-mouse IgG titer, clinical chemistry, or acute phase proteins.
- All four animals maintained either a grade 2 or 3 colitic inflammatory activity in both the pre-treatment and Day 0 biopsy samples, which for 3 animals was separated by 5 days.
- changes within the mucosal architecture of all four animals demonstrated that these four animals had colitis of a long-lasting nature. Therefore, all animals appeared to have a chronic disease course.
Abstract
The invention relates to the treatment of individuals suffering from a disease associated with leukocyte recruitment to the gastrointestinal tract or other tissues as a result of binding of leukocytes to gut-associated endothelium expressing the molecule MAdCAM (such as inflammatory bowel disease), comprising administering to the individual an effective amount of an antibody which inhibits the binding of leukocytes to endothelial MAdCAM.
Description
- This application is a continuation of U.S. application Ser. No. 08/386,857, filed Feb. 10, 1995. The entire teachings of the above application are incorporated herein by reference.
- Inflammatory bowel disease (IBD), such as ulcerative colitis and Crohn's disease, for example, can be a debilitating and progressive disease involving inflammation of the gastrointestinal tract affecting an estimated two million people in the United States. Symptoms include abdominal pain, cramping, diarrhea and rectal bleeding. IBD treatments have included anti-inflammatory drugs (such as, corticosteroids and sulfasalazine), immunosuppressive drugs (such as, 6-mercaptopurine, cyclosporine and azathioprine) and surgery (such as, colectomy). Podolsky,The New England Journal of Medicine, 325:928-937 (1991) and Podolsky, The New England Journal of Medicine, 325:1008-1016 (1991).
- Some studies have suggested that the cell adhesion molecule, ICAM-1, mediates leukocyte recruitment to inflammatory sites through adhesion to leukocyte surface ligands, i.e. Mac-1, LFA-1 or α4β2 (Springer,Nature, 346:425-434 (1990)). In addition, vascular cell adhesion molecule-1 (VCAM-1), recognizing the α4β1 integrin (VLA-4), has been reported to play a role in in vivo leukocyte recruitment as well (Silber et al., J. Clin. Invest. 93:1554-1563 (1994)). It has been proposed that IBD can be treated by blocking the interaction of ICAM-1 with LFA-1 or Mac-1 or VCAM-1 with α4β1 (e.g., WO 93/15764). However, these therapeutic targets are likely involved in inflammatory processes in multiple organs, and a functional blockade would likely result in systemic immune dysfunction.
- Mucosal addressin MAdCAM, a mucosal vascular adhesion molecule, is a 58-66K glycoprotein adhesion receptor for lymphocytes which is distinct from VCAM-1 and ICAM-1 (Briskin et al.,Nature, 363:461-463 (1993)). In contrast to VCAM-1 and ICAM- 1, MAdCAM is preferentially expressed in the gastrointestinal tract, binds the α4β7 integrin (also called LPAM-1 and CD49d/CD−) found on lymphocytes, and participates in the homing of these cells to mucosal sites, such as Peyer's patches in the intestinal wall (Hamann et al., Journal of Immunology, 152:3282-3293 (1994)). The use of inhibitors to the binding of MAdCAM to the receptor, α4β7, in the treatment of diseases such as IBD has not been suggested.
- The invention relates to the treatment of individuals suffering from a disease associated with leukocyte recruitment to the gastrointestinal tract as a result of binding of leukocytes to gut-associated endothelium expressing the molecule MAdCAM, comprising administering to the individual an effective amount of a compound, such as an antibody, which inhibits the binding of leukocytes to endothelial MAdCAM. The antibody is preferably monoclonal, chimeric and/or humanized or an antigen binding fragment thereof, and inhibits adhesion of leukocytes expressing an integrin containing the β7 chain (such as α4β7) to endothelium expressing MAdCAM. In one embodiment, the monoclonal antibody or antigen binding fragment thereof has the antigenic specificity of a monoclonal antibody selected from the group consisting of FIB 21, FIB 30, FIB 504 and ACT-1. Inflammatory bowel diseases, such as but not limited to ulcerative colitis, Crohn's disease, Pouchitis, celiac disease, microscopic or collagenous colitis, and eosinophilic gastroenteritis can be treated according to the claimed method.
- FIGS. 1a and 1 b are graphic illustrations of histologic scores of inflammatory activity and epithelial injury from left (descending) and right (ascending) colon of mice exposed to 10 days of DSS in their drinking water. Three groups of mice are shown, consisting of groups receiving an irrelevant rat IgG2a antibody, FIB21, or FIB30 antibodies.
- FIG. 2 is a graph of γ counts per minute (cpm) (±1 SEM) as a percentage of input from mice given DSS in the drinking water for 10 days. Six groups consisted of negative controls given water alone, positive controls given DSS alone, test groups given irrelevant rat IgG2a antibody, FIB21, MECA-367, and FIB21 with MECA-367.
- FIG. 3 is a graph depicting the histologic scores (±1 SEM) for villus fusion obtained from jejunal biopsy samples of common marmosets before and on the 14th day of treatment with 2 mg/kg/day of ACT-1 monoclonal antibody.
- FIG. 4 is a graph depicting the histologic scores (±1 SEM) for villus atrophy obtained from jejunal biopsy samples of common marmosets before and on the 14th day of treatment with 2 mg/kg/day of ACT-1 monoclonal antibody.
- FIGS.5 and 6 are graphic illustrations of the stool consistency and inflammatory activity in colitic animals (cotton-top tamarins) treated with ACT-1 antibody.
- The invention relates to the discovery that diseases associated with leukocyte recruitment to the gastrointestinal tract, such as IBD, or other mucosal tissues can be treated by inhibiting MAdCAM binding to the α4β7 integrin or triggering of α4β7-mediated cellular responses. Compounds which inhibit binding include antibodies or antigen binding fragments thereof which bind MAdCAM and/or the α4β7 integrin. Antibodies which can be used in the method include recombinant or non-recombinant polyclonal, monoclonal, chimeric, humanized and/or anti-idiotypic antibodies.
- Monoclonal antibodies that bind MAdCAM or α4β7 have been described. For example, MECA 367 is an anti-MAdCAM antibody of the IgG2a subtype and is described in Gallatin et al.,Nature, 304:30 (1983) and Michie et al., Am. J. Pathol. 143:1688-1698 (1993). ACT-1 is a monoclonal antibody which binds the α4β7 integrin (Lazarovits et al., Journal of Immunology, 133:1857 (1984) and Schweighoffer et al., Journal of Immunology, 151:717-729 (1993)). FIB 21 binds the β7 chain is described and characterized in Berlin et al., Cell 74:184-195 (1993); Andrew, D. P. et al., J. Immunol. 153:3847-3861 (1994)). Other monoclonal antibodies, such as antibodies which bind to the same or similar epitopes as the antibodies described above, can be made according to methods known in the art, such as Kohler et al., Nature, 256:495-497 (1975), Harlow et al., 1988, Antibodies: A Laboratory Manual, (Cold Spring Harbor, N.Y.) or Current Protocols in Molecular Biology, Vol. 2 (Supplemental 27, Summer '94), Ausubel et al., Eds. (John Wiley & Sons: New York, N.Y.), Chapter 11 (1991). For example, antibodies can be raised against an appropriate immunogen in a suitable mammal. Immunogens include, for example, MAdCAM α4β7 or immunogenic fragments thereof. The mammal can be a mouse, rat, rabbit or sheep, for example. The antibody-producing cell (e.g., a lymphocyte) can be isolated from, for example, the lymph nodes or spleen of the mammal. The cell can then be fused to a suitable immortalized cell (e.g., a myeloma cell line), thereby forming a hybridoma. The fused cells can be isolated employing selective culturing techniques. Cells which produce antibodies with the desired specificity can be selected by a suitable assay (e.g., ELISA).
- In one embodiment, the immunogen can be an antibody which binds, for example, MAdCAM α4β7 or immunogenic fragments thereof. The antibody raised thereby can be an anti-idiotypic antibody, which can also be used in the present invention.
- Single chain antibodies, and chimeric, humanized or primatized (CDR-grafted or resurfaced, such as, according to EP 592406, Apr. 13, 1994) antibodies, as well as chimeric or CDR-grafted single chain antibodies, comprising portions derived from different species, can also be used in the invention. The various portions of these antibodies can be joined together chemically by conventional techniques, or can be prepared as a contiguous protein using genetic engineering techniques. For example, nucleic acids encoding a chimeric or humanized chain can be expressed to produce a contiguous protein. See, e.g., Cabilly et al., U.S. Pat. No. 4,816,567; Cabilly et al., European Patent No. 0,125,023 B1; Boss et al., U.S. Pat. No. 4,816,397; Boss et al., European Patent No. 0,120,694 B1; Neuberger, M. S. et al., WO 86/01533; Neuberger, M. S. et al., European Patent No. 0,194,276 B1; Winter, U.S. Pat. No. 5,225,539; and Winter, European Patent No. 0,239,400 B1. See also, Newman, R. et al.,BioTechnology, 10:1455-1460 (1992), regarding primatized antibody, and Ladner et al., U.S. Pat. No. 4,946,778 and Bird, R. E. et al., Science, 242:423-426 (1988)) regarding single chain antibodies.
- In addition, functional fragments of antibodies, including fragments of chimeric, humanized, primatized or single chain antibodies, can also be produced. Functional fragments of the foregoing antibodies retain at least one binding function of the full-length antibody from which they are derived and, preferably, retains the ability to inhibit interaction. For example, antibody fragments capable of binding to the α4β7 integrin; MAdCAM or portion thereof include, but are not limited to, Fv, Fab, Fab′ and F(ab′)2 fragments. Such fragments can be produced by enzymatic cleavage or by recombinant techniques. For instance, papain or pepsin cleavage can generate Fab or F(ab′)2 fragments, respectively. Alternatively, antibodies can be produced in a variety of truncated forms using antibody genes in which one or more stop codons has been introduced upstream of the natural stop site. For example, a chimeric gene encoding a F(ab′)2 heavy chain portion can be designed to include DNA sequences encoding the CH1 domain and hinge region of the heavy chain.
- Antibodies and antigen binding fragments thereof which can be used in the claimed method include antibodies which bind to MAdCAM and/or α4β7, such as the β7 chain. For example, antibodies from the
group including FIB 21,FIB 30, FIB 504 and ACT-1 and mixtures thereof can be administered. Alternatively or in addition, antigen fragments of these antibodies can be administered. - Compounds which inhibit the binding of MAdCAM and the α4β7 integrin can be administered according to the claimed method in the treatment of diseases which are associated with leukocyte (such as lymphocyte or monocyte) recruitment to the gastrointestinal tract or other tissues as a result of binding of leukocytes to gut-associated endothelium expressing the molecule MAdCAM. Diseases which can be treated accordingly include inflammatory bowel disease, such as ulcerative colitis, Crohn's disease, Celiac disease (nontropical Sprue), enteropathy associated with seronegative arthropathies, microscopic or collagenous colitis, eosinophilic gastroenteritis, or pouchitis resulting after proctocolectomy and ileoanal anastomosis. In one embodiment, more than one monoclonal antibody which inhibits the binding of leukocytes to endothelial MAdCAM is administered. Alternatively, a monoclonal antibody which inhibits the binding of leukocytes to endothelial ligands is administered in addition to an anti-MAdCAM or anti-β7 antibody. For example, an antibody that inhibits the binding of leukocytes to an endothelial ligand other than MAdCAM, such as an anti-ICAM-1 or anti-VCAM-1 antibody can also be administered. In another embodiment, an additional pharmacologically active ingredient (such as a steroid) can be administered in conjunction with the antibody of the present invention.
- A variety of routes of administration are possible including, but not necessarily limited to parenteral (e.g., intravenous, intraarterial, intramuscular, subcutaneous injection), oral (e.g., dietary), topical, inhalation (e.g., intrabronchial, intranasal or oral inhalation, intranasal drops), or rectal, depending on the disease or condition to be treated. Parenteral administration is a preferred mode of administration.
- Formulation of a compound to be administered will vary according to the route of administration selected (e.g., solution, emulsion, capsule). An appropriate composition comprising the compound to be administered can be prepared in a physiologically acceptable vehicle or carrier. For solutions or emulsions, suitable carriers include, for example, aqueous or alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles can include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils. Intravenous vehicles can include various additives, preservatives, or fluid, nutrient or electrolyte replenishers (See, generally,Remington's Pharmaceutical Science, 16th Edition, Mack, Ed. 1980). For inhalation, the compound is solubilized and loaded into a suitable dispenser for administration (e.g., an atomizer, nebulizer or pressurized aerosol dispenser).
- The compound is administered in an amount which will inhibit binding of MAdCAM to the α4β7 integrin. The compounds can be administered in a single dose or multiple doses. The dosage can be determined by methods known in the art and is dependent, for example, upon the individual's age, sensitivity, tolerance and overall well-being. Suitable dosages can be from 0.1-1.0 mg/kg body weight per treatment.
- The subject invention will now be illustrated by the following examples, which are not intended to be limiting in any way.
- BALB/c mice were given access to a 5% solution of dextran sodium sulfate (DSS) in their drinking water for a period of 10 days, as previously described (Lab. Invest. 69:238-249, 1993). During this time period, the mice developed clinical symptoms of colitis including softening of stools and bloody diarrhea. Multifocal epithelial injury and ulceration, similar to ulcerative colitis in humans, was evident on histologic examination of colonic mucosa from affected mice. Moreover, affected mice lost 20-30% of their initial body weight by
day 10. - To determine the efficacy of β7-specific antibodies in blocking the recruitment of lymphocytes to the colon, BALB/c mice were given daily intraperitoneal (i.p.) injections of 100 μg of monoclonal antibodies against β7, consisting of either FIB21 or FIB30 in saline, as previously characterized and described (Berlin, C., et al.,Cell 74:185-195, 1993; Michie, S. A., et al, Am. J. Pathol. 143:1688-1698, 1993; Hamann, A., et al., J. Immunol. 152:3282-3293, 1994) or an isotype-matched control rat monoclonal antibody at the same dose (Andrew et al., supra) over the 10 day course of DSS treatment.
- Two methods were used to evaluate efficacy of the antibody therapy to inhibit leukocyte infiltration and mucosal injury in the colitic mouse. In the first method, treatment was judged histologically by two blinded observers using a scoring system for the evaluation of epithelial injury and degree of leukocyte cellular infiltration (Table 1). For this assessment, colon tissue was first fixed in 10% neutral buffered formalin, dehydrated, embedded in paraffin, sectioned, and the sections were stained with hematoxylin and eosin prior to examination.
TABLE PATHOLOGY EVALUATION Grade Definition INFLAMMATION Normal (0) Absence of clusters of polymorphonoclear leukocytes (PMNs) or mononuclear cells in the lamina propria; absence of intraepithelial PMNs Mild (1) Focal aggregates of PMNs and/or mononuclear cells in the lamina propria (equivocal or slight) or presence of isolated intraepithelial PMNs in 3 or fewer crypts per cross-section Moderate (2) Focal aggregates of PMNs and/or mononuclear cells in the lamina propria (multi-focal or diffuse 2-5X) or intraepithelial PMNs in more than 3 crypts per cross-section Severe (3) Diffuse infiltration of PMNs or mononuclear cells in the lamina propria (diffuse > 5X) or crypt abscesses STRUCTURAL OR EPITHELIAL ALTERATIONS Normal (0) Tight crypts, no erosion, columnar epithelial cells Mild (1) Epithelial immaturity; equivocal irregularity of epithelial surface Moderate (2) At least two foci of crypt branching or loss of crypts (<50%); loss of surface epithelium Severe (3) Diffuse or multifocal branching or loss of crypts (>50%); fibrosis; complete loss of epithelium (focal) # nonspecific antibody binding sites were blocked with 10% normal rabbit serum diluted in PBS for 10 min, followed in sequence with washes by FIB21 antibody at 20 μg/ml in PBS for 30 min at room temperature (RT), biotinylated rabbit anti-rat polyclonal antibody, avidinperoxidase complexes, and finally the chromogen, diaminobenzidine and hydrogen peroxide diluted in Tris buffer. - In the second method, recruitment of lymphocytes to the colon was quantitatively assessed using radiolabeled mesenteric lymph node lymphocytes from syngeneic donor mice. The experimental design of the animal experiments was similar to that described above except that BALB/c mice were placed on 5% DSS for 9 days (instead of 10) and on
day 8, mice were given i.p. injections of 100 μg of FIB21 (anti-β7), MECA-367 (anti-MAdCAM), a mixture of both, or an isotype-matched control monoclonal antibody in saline. On day 9, mesenteric lymph node cells were isolated from donor syngeneic BALB/c mice, labeled with 51Cr, and 5.0×106 cells/mouse were incubated for 30 minutes at 37° C. with 500 μg control antibody, 250 μg of MECA-367, 500 μg FIB21, or both (total amount is 750 μg) in saline. The labeled cells and antibody were then injected intravenously (i.v.) into the DSS-treated recipient mice. Full-length colons were harvested from allexperimental animals 1 hour after injection, and γ-irradiation was measured using a γ-counter. - Differences between mean scores obtained for each group of animals were assessed for statistical significance using a paired Student's t-test. Differences between means were considered significant when P<0.05.
- Histologically, inflammation and epithelial injury to the mucosa were most severe in the descending colon, rectum and cecum. Analysis of frozen tissue sections of colon by immunohistochemistry revealed that the most significant recruitment of β7+ lymphocytes was to the right colon. In addition, the level of expression of the mucosal vascular addressin, MAdCAM-1, was found to be expressed only at low levels in vessels in the intestinal mucosa early in DSS treatment (3 days), but increased dramatically after 9 days of DSS treatment, supporting the conclusion that β7 and MAdCAM-1 interactions are relevant to the inflammatory process in the colonic mucosa during DSS-induced colitis.
- Histologic evaluation of mice exposed to a 10-day course of DSS and daily therapy using β7-specific antibodies demonstrated that substantial reductions of leukocyte recruitment (P<0.01 for FIB30 and P<0.001 for FIB21) and epithelial injury (P<0.05) occurred in right (ascending) colon compared to animals receiving a control antibody at the same dose (FIGS. 1a and 1 b). Furthermore, analysis using immunohistochemistry of frozen sections from these animals suggested that the number of β7+ cells recruited to the right colon, but not other sections of colon, during DSS treatment was reduced.
- Lymphocyte recruitment to inflamed colon was then quantitatively assessed using radiolabeled mesenteric lymphocytes taken from syngeneic donors. One hour after injection of these cells in DSS-treated recipients, there was a trend towards a reduction in the number of51Cr-labeled cells recruited to colon in mice that were treated with either β7-specific antibodies or the MAdCAM-specific antibodies, but not in mice treated with the isotope-matched control antibodies (FIG. 2).
- Common marmosets (Callithrix jacchus) are a new world nonhuman primate that, under captive conditions at the New England Regional Primate Research Center (NERPRC), develop a steroid-nonresponsive, spontaneous malabsorption syndrome characterized by weight loss, diarrhea, and small intestinal mucosal changes consistent with loss of absorptive capacity. These histologic changes include small intestinal villus atrophy and fusion, and a mononuclear leukocyte infiltrate within the lamina propria similar to Celiac disease (nontropical sprue) in humans. Retrospective analysis from the pathology archive files at NERPRC demonstrated that up to 80% of common marmosets have, to various degrees, malabsorptive enteritis at the time of postmortem examination.
- Adult common marmosets were selected for study from the colony-at-large at NERPRC. Base-line studies on all animals included physical examination, complete blood count (CBC), blood chemistry profile, serum B12, c-reactive protein, and full-thickness jejunal biopsy by laparotomy. Following recovery from abdominal surgery, the animals were treated for 14 days with 2 mg/kg/day of ACT-1 monoclonal antibody, a blocking monoclonal antibody against a conformational epitope of α4β7 (Schweighoffer, T., et al.,J. Immunol. 151:717-729, 1993). Previous studies indicated that this antibody cross-reacted to Callithrix α4β7. All assessments that were performed prior to antibody therapy were repeated between the 10th and 14th day of antibody therapy.
- Full-thickness jejunal biopsies from each marmoset were evaluated histologically by two independent pathologists, and villus architecture was scored according to the following grading criteria:
Villus atrophy 0 normal mucosal thickness and villus height 1 mild atrophy; slight shortening of villi; height approximately 75% of normal 2 moderate atrophy; villi approximately 33-50% normal height 3 severe atrophy; short (<33% normal) or no observable villi Villus fusion 0 normal; no fusion 1 1-2 villi in specimen fused 2 Between 1-2 and 50% of villi in specimen fused 3 >50% villi in specimen fused - Differences between mean scores obtained for each group of animals were assessed for statistical significance using a paired Student's t-test. Differences between means were considered significant when P<0.05.
- The mean scores for villus fusion and atrophy before and after antibody therapy with the ACT-1 monoclonal antibody are shown in FIGS. 3 and 4, respectively. As demonstrated, there was almost complete resolution of villus atrophy (P<0.01) and a trend for improvement of villus fusion after a two-week course of therapy with the ACT-1 antibody. The effect was not secondary to nonspecific effects of exposure to foreign immunoglobulin since other animals treated with various monoclonal antibodies directed against epitopes other than that recognized by ACT-1 were ineffective in reducing villus fusion and atrophy scores.
- The cotton-top tamarin (Saguinus oedipus) is a New World nonhuman primate which develops a spontaneous colitis similar to ulcerative colitis in man.
- ACT-1 was known to cross-react in the tamarin because of immunohistologic staining with ACT-1 antibody of colitic mucosa from affected animals. These initial pilot studies demonstrated that from 40-80% of mononuclear cells within the lamina propria of colon from affected animals were α4β7+ similar to human colitic mucosa.
- Colitic animals were chosen from the colony-at-large based upon gross observation of diarrhea and weight loss. All candidate animals were then subjected to colon biopsy to confirm the presence of colitis, as defined as a histologic inflammatory activity score of 2 or 3. The scoring system used was originally described in Madara, J. L. et al.,Gastroenterology 88:13-19 (1985). Briefly, inflammatory activity scores were based upon the relative numbers of neutrophils within the lamina propria, crypt lumena, crypt epithelium, and surface epithelium. All biopsy samples were scored and categorized into four groups, with 0 representing normal mucosa and 3 representing the most severe and inflamed mucosa. Scores of 0 and 1 do not represent symptomatic colitis, while scores of 2 to 3 represent mild to severe colitic activity. Within 5 days of confirmation of colitis, the animals began immunotherapy with ACT-1 monoclonal antibody.
- Four colitic animals received ACT-1 monoclonal antibody at a dose of 2 mg/kg/day intravenously (I.V.) the first day followed by intramuscularly (I.M.) injections for 7 consecutive days thereafter. The dosing regime was the same as that used in the common marmoset study above.
- Colon biopsies were again obtained at the time of the first antibody infusion (Day 0) and on
days - All four animals maintained either a
grade Day 0 biopsy samples, which for 3 animals was separated by 5 days. In addition, changes within the mucosal architecture of all four animals demonstrated that these four animals had colitis of a long-lasting nature. Therefore, all animals appeared to have a chronic disease course. - With respect to stool consistency, diarrhea resolved in all four animals by
day 8 of ACT-1 immunotherapy (FIG. 4). All animals maintained solid stools for approximately 1 week after termination of antibody injections (FIG. 4). One animal (Sgo 63-93) has had solid stool fromDay 4 until the end of the protocol at Day 20 (FIG. 4). Two animals (Sgo 129-91 and Sgo 17-85) had slight relapses to semi-solid stools after Day 14 in the study (FIG. 4). The fourth animal (Sgo 326-84) showed a persistent improvement/resolution of diarrhea fromDay 6 toDay 20. - With respect to histologic changes, all four animals have shown improvement in inflammatory activity during or after ACT-1 immunotherapy. The colitis in two animals (Sgo 129-91 and Sgo 17-85) completely resolved by Day 10 (FIG. 6). Another animal (Sgo 63-93) did not show complete abrogation of colitis activity until Day 20 (FIG. 6), while mucosal biopsy scores from the fourth animal (Sgo 326-84) showed improvement during the entire study period (FIG. 6; two biopsies on
day 20 in Sgo 326-84 were scored as 0 and 1). Furthermore, animal 326-84 gained 20% of its original body weight during the study period. - To detect antibody administered in vivo, flow cytometry and immunohistology were performed. Flow cytometry without a primary antibody showed excellent labeling to peripheral blood lymphocytes in animals at all time points after antibody administration. Immunohistology on colon biopsies using no primary antibody in the sequence from three animals on samples up to and including
Day 10 showed excellent labeling of lymphocytes within the lamina propria on the samples fromDays Day 0 prior to antibody infusion. Collectively, these results showed that ACT-1 antibody localized to the target site, namely lymphocytes within the peripheral blood and specifically to the extravascular compartment within colitic mucosa. - By histologic criteria and stool consistency, ACT-1 was efficacious in improving colitis in the cotton top tamarin.
- There appeared to be a good correlation between histologic inflammatory activity scores and stool consistency. Noteworthy is the observation that stool consistency generally improved in 1-2 days in animals receiving ACT-1 antibody.
- Those skilled in the art will know, or be able to ascertain, using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. These and all other equivalents are intended to be encompassed by the following claims.
Claims (37)
1. A method for treating an individual having a disease associated with leukocyte recruitment to the gastrointestinal tract or other tissues as a result of binding of leukocytes to gut-associated endothelium expressing the molecule MAdCAM, comprising:
administering to the individual an effective amount of an antibody which inhibits the binding of leukocytes to endothelial MAdCAM.
2. The method of claim 1 wherein antibody is a monoclonal antibody or an antigen binding fragment thereof.
3. The method of claim 2 wherein the monoclonal antibody or antigen binding fragment thereof inhibits adhesion of leukocytes expressing an integrin containing the β7 chain and endothelium expressing MAdCAM.
4. The method of claim 3 wherein the monoclonal antibody or antigen binding fragment thereof binds α4β7 integrin.
5. The method of claim 4 wherein the monoclonal antibody or antigen binding fragment thereof binds β7.
6. The method of claim 3 wherein the monoclonal antibody or antigen binding fragment thereof binds MAdCAM.
7. The method of claim 3 wherein the monoclonal antibody or antigen binding fragment thereof has the antigenic specificity of a monoclonal antibody selected from the group consisting of FIB 21, FIB 30, FIB 504 and ACT-1.
8. The method of claim 7 wherein the monoclonal antibody or antigen binding fragment thereof is selected from the group consisting of FIB 21, FIB 30, FIB 504 and ACT-1 or antigen binding fragments thereof.
9. The method of claim 8 wherein the monoclonal antibody is ACT-1.
10. The method of claim 3 wherein the monoclonal antibody is selected from the group consisting of a chimeric antibody and a humanized antibody.
11. The method of claim 3 wherein the leukocytes are lymphocytes.
12. The method of claim 3 wherein the leukocytes are monocytes.
13. The method of claim 3 wherein the disease is inflammatory bowel disease.
14. The method of claim 13 wherein the disease is ulcerative colitis.
15. The method of claim 13 wherein the disease is Crohn's disease.
16. The method of claim 13 wherein the disease is Celiac disease, enteropathy associated with seronegative arthropathies, microscopic or collagenous colitis, eosinophilic gastroenteritis, or pouchitis.
17. The method of claim 13 wherein the monoclonal antibody or antigen binding fragment thereof binds α4β7.
18. The method of claim 13 wherein the monoclonal antibody or antigen binding fragment thereof binds MAdCAM.
19. The method of claim 13 wherein the monoclonal antibody or antigen binding fragment thereof has the antigenic specificity of a monoclonal antibody selected from the group consisting of FIB 21, FIB30, FIB 504 and ACT-1.
20. The method of claim 19 wherein the monoclonal antibody or antigen binding fragment thereof is selected from the group consisting of FIB 21, FIB30, FIB 504 and ACT-1 or antigen binding fragments thereof.
21. The method of claim 20 wherein the monoclonal antibody is ACT-1.
22. The method of claim 13 wherein the monoclonal antibody is selected from the group consisting of a chimeric antibody and a humanized antibody.
23. The method of claim 13 wherein more than one monoclonal antibody which inhibits the binding of leukocytes to endothelial MAdCAM is administered.
24. The method of claim 13 wherein more than one monoclonal antibody which inhibits the binding of leukocytes to endothelial ligands is administered.
25. The method of claim 24 wherein at least one monoclonal antibody inhibits the binding of leukocytes to an endothelial ligand other than MAdCAM.
26. A method for treating inflammatory bowel disease in an individual comprising administering to the individual an effective amount of an antibody which binds endothelial MAdCAM or the α4β7 integrin.
27. The method of claim 26 wherein antibody is a monoclonal antibody or an antigen binding fragment thereof.
28. The method of claim 27 wherein the monoclonal antibody or antigen binding fragment thereof binds α4β7 integrin.
29. The method of claim 28 wherein the monoclonal antibody or antigen binding fragment thereof binds β7.
30. The method of claim 27 wherein the monoclonal antibody or antigen binding fragment thereof binds MAdCAM.
31. The method of claim 27 wherein the monoclonal antibody or antigen binding fragment thereof has the antigenic specificity of a monoclonal antibody selected from the group consisting of FIB 21, FIB 30, FIB 504 and ACT-1.
32. The method of claim 31 wherein the monoclonal antibody or antigen binding fragment thereof is selected from the group consisting of FIB 21, FIB 30, FIB 504 and ACT-1 or antigen binding fragments thereof.
33. The method of claim 32 wherein the monoclonal antibody is ACT-1.
34. The method of claim 27 wherein the monoclonal antibody is selected from the group consisting of a chimeric antibody and a humanized antibody.
35. The method of claim 27 wherein the disease is ulcerative colitis.
36. The method of claim 27 wherein the disease is Crohn's disease.
37. The method of claim 27 wherein the disease is Celiac disease, enteropathy associated with seronegative arthropathies, microscopic or collagenous colitis, eosinophilic gastroenteritis, or pouchitis.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/118,600 US20020172679A1 (en) | 1995-02-10 | 2002-04-08 | Treatment of inflammatory bowel disease by inhibiting binding and/or signalling through alpha4beta7 and its ligands and MAdCAM |
US11/264,627 US20060057135A1 (en) | 1995-02-10 | 2005-11-01 | Mucosal vascular addressins and uses thereof |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/386,857 US6551593B1 (en) | 1995-02-10 | 1995-02-10 | Treatment of Inflammatory bowel disease by inhibiting binding and/or signalling through α 4 β 7 and its ligands and madcam |
US10/118,600 US20020172679A1 (en) | 1995-02-10 | 2002-04-08 | Treatment of inflammatory bowel disease by inhibiting binding and/or signalling through alpha4beta7 and its ligands and MAdCAM |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/386,857 Continuation US6551593B1 (en) | 1995-02-10 | 1995-02-10 | Treatment of Inflammatory bowel disease by inhibiting binding and/or signalling through α 4 β 7 and its ligands and madcam |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/264,627 Continuation-In-Part US20060057135A1 (en) | 1995-02-10 | 2005-11-01 | Mucosal vascular addressins and uses thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
US20020172679A1 true US20020172679A1 (en) | 2002-11-21 |
Family
ID=23527358
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/386,857 Expired - Fee Related US6551593B1 (en) | 1995-02-10 | 1995-02-10 | Treatment of Inflammatory bowel disease by inhibiting binding and/or signalling through α 4 β 7 and its ligands and madcam |
US10/118,600 Abandoned US20020172679A1 (en) | 1995-02-10 | 2002-04-08 | Treatment of inflammatory bowel disease by inhibiting binding and/or signalling through alpha4beta7 and its ligands and MAdCAM |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/386,857 Expired - Fee Related US6551593B1 (en) | 1995-02-10 | 1995-02-10 | Treatment of Inflammatory bowel disease by inhibiting binding and/or signalling through α 4 β 7 and its ligands and madcam |
Country Status (2)
Country | Link |
---|---|
US (2) | US6551593B1 (en) |
JP (1) | JP2008231112A (en) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040176304A1 (en) * | 1999-04-06 | 2004-09-09 | Nijkamp Franciscus Petrus | Compound for inhibiting the influx of polymorphonuclear leukocytes (PMNS) in a tissue, its selection, pharmaceutical compositions and use |
US20060057135A1 (en) * | 1995-02-10 | 2006-03-16 | Briskin Michael J | Mucosal vascular addressins and uses thereof |
US20070166308A1 (en) * | 2004-01-09 | 2007-07-19 | Nicholas Pullen | Antibodies to MAdCAM |
US9663579B2 (en) | 2011-05-02 | 2017-05-30 | Millennium Pharmaceuticals, Inc. | Formulation for anti-α4β7 antibody |
US10040855B2 (en) | 2011-05-02 | 2018-08-07 | Millennium Pharmaceuticals, Inc. | Formulation for anti-α4β7 antibody |
US10851163B2 (en) | 2015-01-09 | 2020-12-01 | Pfizer Inc. | Dosage regimen for MAdCAM antagonists |
CN114225025A (en) * | 2021-12-29 | 2022-03-25 | 北京创世客生物技术有限公司 | Use of probiotic-containing formulations for the treatment of gastrointestinal disorders |
US11802156B2 (en) | 2017-07-14 | 2023-10-31 | Pfizer Inc. | Antibodies to MAdCAM |
Families Citing this family (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6551593B1 (en) * | 1995-02-10 | 2003-04-22 | Millennium Pharmaceuticals, Inc. | Treatment of Inflammatory bowel disease by inhibiting binding and/or signalling through α 4 β 7 and its ligands and madcam |
US7147851B1 (en) * | 1996-08-15 | 2006-12-12 | Millennium Pharmaceuticals, Inc. | Humanized immunoglobulin reactive with α4β7 integrin |
US7090845B2 (en) * | 1998-05-13 | 2006-08-15 | Genentech, Inc. | Diagnosis and treatment of hepatic disorders |
US20010046496A1 (en) * | 2000-04-14 | 2001-11-29 | Brettman Lee R. | Method of administering an antibody |
US20040070518A1 (en) * | 2002-10-04 | 2004-04-15 | Carroll Whittle | Emergency vehicular traffic signal control |
AU2004207536B2 (en) | 2003-01-24 | 2010-05-20 | Elan Pharmaceuticals Inc. | Composition for and treatment of demyelinating diseases and paralysis by administration of remyelinating agents |
WO2005076843A2 (en) | 2004-02-06 | 2005-08-25 | Elan Pharmaceuticals, Inc. | Methods and compositions for treating tumors and metastatic disease |
PT1784426E (en) * | 2004-09-03 | 2012-03-06 | Genentech Inc | Humanized anti-beta7 antagonists and uses therefor |
CN101227923A (en) * | 2005-07-08 | 2008-07-23 | 辉瑞有限公司 | Use of anti-MAdCAM antibodies for the treatment of coeliac disease and tropical sprue |
WO2007007160A2 (en) * | 2005-07-11 | 2007-01-18 | Pfizer Limited | Anti-madcam antibodies to treat fever |
EP1948691A1 (en) * | 2005-11-17 | 2008-07-30 | Millennium Pharmaceuticals, Inc. | HUMANIZED IMMUNOGLOBULIN REACTIVE WITH a4ß7INTEGRIN |
JP2009528359A (en) | 2006-02-28 | 2009-08-06 | エラン ファーマシューティカルズ,インコーポレイテッド | Methods of treating inflammatory and autoimmune diseases with natalizumab |
EP2007392A4 (en) * | 2006-02-28 | 2010-04-07 | Elan Pharm Inc | Methods of treating inflammatory and autoimmune diseases with alpha-4 inhibitory compounds |
CA2644110A1 (en) | 2006-03-03 | 2007-09-13 | Elan Pharmaceuticals, Inc. | Methods of treating inflammatory and autoimmune diseases with natalizumab |
SI2279004T1 (en) * | 2008-05-16 | 2015-05-29 | F. Hoffmann-La Roche Ag | Use of biomarkers for assessing treatment of gastrointestinal inflammatory disorders with beta7integrin antagonists |
US20120258093A1 (en) | 2009-08-20 | 2012-10-11 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Vla-4 as a biomarker for prognosis and target for therapy in duchenne muscular dystrophy |
US11287423B2 (en) | 2010-01-11 | 2022-03-29 | Biogen Ma Inc. | Assay for JC virus antibodies |
RS63744B1 (en) | 2010-01-11 | 2022-12-30 | Biogen Ma Inc | Assay for jc virus antibodies |
US10119976B2 (en) | 2013-05-28 | 2018-11-06 | Biogen Ma Inc. | Method of assessing risk of PML |
CN107257693A (en) * | 2015-02-26 | 2017-10-17 | 豪夫迈·罗氏有限公司 | Treat the integrin beta 7 antagonists and method of Crohn diseases |
AU2018274749A1 (en) * | 2017-05-26 | 2019-12-19 | Millennium Pharmaceuticals, Inc. | Methods for the treatment of chronic pouchitis |
Citations (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4699880A (en) * | 1984-09-25 | 1987-10-13 | Immunomedics, Inc. | Method of producing monoclonal anti-idiotype antibody |
US4816567A (en) * | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US5223392A (en) * | 1988-01-25 | 1993-06-29 | Exocell, Inc. | Monoclonal antibodies against glycated albumin, hybrid cell lines producing these antibodies, and use therefore |
US5225539A (en) * | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
US5225538A (en) * | 1989-02-23 | 1993-07-06 | Genentech, Inc. | Lymphocyte homing receptor/immunoglobulin fusion proteins |
US5403919A (en) * | 1987-08-11 | 1995-04-04 | Board Of Trustees Of The Leland Stanford Junior University Stanford University | Method to control leukocyte extravasation |
US5530101A (en) * | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US5538724A (en) * | 1987-08-11 | 1996-07-23 | The Board Of Trustees For The Leland Stanford Junior Univ. | Method of control leukocyte extravasation |
US5558864A (en) * | 1991-03-06 | 1996-09-24 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Humanized and chimeric anti-epidermal growth factor receptor monoclonal antibodies |
US5565335A (en) * | 1987-10-02 | 1996-10-15 | Genentech, Inc. | Adhesion variants |
US5594120A (en) * | 1994-02-18 | 1997-01-14 | Brigham And Women's Hospital, Inc. | Integrin alpha subunit |
US5599676A (en) * | 1992-05-21 | 1997-02-04 | Center For Blood Research, Inc. | Method for isolating a novel receptor for α4 integrins |
US5610281A (en) * | 1994-05-03 | 1997-03-11 | Brigham & Women's Hospital, Inc. | Antibodies for modulating heterotypic E-cadherin interactions with human T lymphocytes |
US5624821A (en) * | 1987-03-18 | 1997-04-29 | Scotgen Biopharmaceuticals Incorporated | Antibodies with altered effector functions |
US5730978A (en) * | 1989-09-01 | 1998-03-24 | Fred Hutchinson Cancer Research Center | Inhibition of lymphocyte adherence with α4β1-specific antibodies |
US5840299A (en) * | 1994-01-25 | 1998-11-24 | Athena Neurosciences, Inc. | Humanized antibodies against leukocyte adhesion molecule VLA-4 |
US5932214A (en) * | 1994-08-11 | 1999-08-03 | Biogen, Inc. | Treatment for inflammatory bowel disease with VLA-4 blockers |
US6037324A (en) * | 1996-01-04 | 2000-03-14 | Leukosite, Inc. | Inhibitors of MAdCAM-1-mediated interactions and methods of use therefor |
US6551593B1 (en) * | 1995-02-10 | 2003-04-22 | Millennium Pharmaceuticals, Inc. | Treatment of Inflammatory bowel disease by inhibiting binding and/or signalling through α 4 β 7 and its ligands and madcam |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3852236T2 (en) | 1987-08-11 | 1995-04-06 | Univ Leland Stanford Junior | Procedure for controlling leukocyte extravasation. |
EP0462111A4 (en) | 1988-12-23 | 1992-07-08 | The Board Of Trustees Of The Leland Stanford Junior University | Homing sequences and their uses |
GB8928874D0 (en) | 1989-12-21 | 1990-02-28 | Celltech Ltd | Humanised antibodies |
GB9115364D0 (en) | 1991-07-16 | 1991-08-28 | Wellcome Found | Antibody |
ES2103468T3 (en) | 1992-02-12 | 1997-09-16 | Biogen Inc | TREATMENT OF INTESTINAL INFLAMMATION. |
AU5675794A (en) | 1992-12-15 | 1994-07-04 | Board Of Trustees Of The Leland Stanford Junior University | Mucosal vascular addressin, dna and expression |
CA2153692C (en) | 1993-01-12 | 2011-11-08 | Roy R. Lobb | Recombinant anti-vla4 antibody molecules |
DK0682529T4 (en) | 1993-02-09 | 2006-05-15 | Biogen Idec Inc | Antibody for the treatment of insulin-requiring diabetes |
JPH06303990A (en) | 1993-04-24 | 1994-11-01 | Kanebo Ltd | Monoclonal antibody, hybridoma capable of producing the same and production of the same antibody |
PT804237E (en) | 1994-01-25 | 2006-10-31 | Elan Pharm Inc | HUMANIZED ANTIBODIES AGAINST THE VLA-4 LEUCOCITARY ADHESION MOLECULE |
-
1995
- 1995-02-10 US US08/386,857 patent/US6551593B1/en not_active Expired - Fee Related
-
2002
- 2002-04-08 US US10/118,600 patent/US20020172679A1/en not_active Abandoned
-
2008
- 2008-04-08 JP JP2008100777A patent/JP2008231112A/en not_active Withdrawn
Patent Citations (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4816567A (en) * | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US4699880A (en) * | 1984-09-25 | 1987-10-13 | Immunomedics, Inc. | Method of producing monoclonal anti-idiotype antibody |
US5225539A (en) * | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
US5648260A (en) * | 1987-03-18 | 1997-07-15 | Scotgen Biopharmaceuticals Incorporated | DNA encoding antibodies with altered effector functions |
US5624821A (en) * | 1987-03-18 | 1997-04-29 | Scotgen Biopharmaceuticals Incorporated | Antibodies with altered effector functions |
US5403919A (en) * | 1987-08-11 | 1995-04-04 | Board Of Trustees Of The Leland Stanford Junior University Stanford University | Method to control leukocyte extravasation |
US5538724A (en) * | 1987-08-11 | 1996-07-23 | The Board Of Trustees For The Leland Stanford Junior Univ. | Method of control leukocyte extravasation |
US5565335A (en) * | 1987-10-02 | 1996-10-15 | Genentech, Inc. | Adhesion variants |
US5223392A (en) * | 1988-01-25 | 1993-06-29 | Exocell, Inc. | Monoclonal antibodies against glycated albumin, hybrid cell lines producing these antibodies, and use therefore |
US5530101A (en) * | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US5585089A (en) * | 1988-12-28 | 1996-12-17 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US5225538A (en) * | 1989-02-23 | 1993-07-06 | Genentech, Inc. | Lymphocyte homing receptor/immunoglobulin fusion proteins |
US5428130A (en) * | 1989-02-23 | 1995-06-27 | Genentech, Inc. | Hybrid immunoglobulins |
US5714147A (en) * | 1989-02-23 | 1998-02-03 | Genentech Inc. | Hybrid immunoglobulins |
US5730978A (en) * | 1989-09-01 | 1998-03-24 | Fred Hutchinson Cancer Research Center | Inhibition of lymphocyte adherence with α4β1-specific antibodies |
US5558864A (en) * | 1991-03-06 | 1996-09-24 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Humanized and chimeric anti-epidermal growth factor receptor monoclonal antibodies |
US5599676A (en) * | 1992-05-21 | 1997-02-04 | Center For Blood Research, Inc. | Method for isolating a novel receptor for α4 integrins |
US5840299A (en) * | 1994-01-25 | 1998-11-24 | Athena Neurosciences, Inc. | Humanized antibodies against leukocyte adhesion molecule VLA-4 |
US5594120A (en) * | 1994-02-18 | 1997-01-14 | Brigham And Women's Hospital, Inc. | Integrin alpha subunit |
US5610281A (en) * | 1994-05-03 | 1997-03-11 | Brigham & Women's Hospital, Inc. | Antibodies for modulating heterotypic E-cadherin interactions with human T lymphocytes |
US5932214A (en) * | 1994-08-11 | 1999-08-03 | Biogen, Inc. | Treatment for inflammatory bowel disease with VLA-4 blockers |
US6551593B1 (en) * | 1995-02-10 | 2003-04-22 | Millennium Pharmaceuticals, Inc. | Treatment of Inflammatory bowel disease by inhibiting binding and/or signalling through α 4 β 7 and its ligands and madcam |
US6037324A (en) * | 1996-01-04 | 2000-03-14 | Leukosite, Inc. | Inhibitors of MAdCAM-1-mediated interactions and methods of use therefor |
Cited By (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060057135A1 (en) * | 1995-02-10 | 2006-03-16 | Briskin Michael J | Mucosal vascular addressins and uses thereof |
US20070178089A1 (en) * | 1995-09-01 | 2007-08-02 | Briskin Michael J | Mucosal vascular addressins and uses thereof |
US8277808B2 (en) | 1995-09-01 | 2012-10-02 | Millennium Pharmaceuticals, Inc. | Mucosal vascular addressins and uses thereof |
US7410806B2 (en) | 1999-04-06 | 2008-08-12 | Fornix Biosciences N.V. | Compound for inhibiting the influx of polymorphonuclear leukocytes (PMNs) in a tissue, its selection, pharmaceutical compositions and use |
US6960565B2 (en) * | 1999-04-06 | 2005-11-01 | Fornix Biosciences N.V. | Compound for inhibiting the influx of polymorphonuclear leukocytes (PMNS) in a tissue, its selection, pharmaceutical compositions and use |
US20060046963A1 (en) * | 1999-04-06 | 2006-03-02 | Nijkamp Franciscus P | Compound for inhibiting the influx of polymorphonuclear leukocytes (PMNs) in a tissue, its selection, pharmaceutical compositions and use |
US20040176304A1 (en) * | 1999-04-06 | 2004-09-09 | Nijkamp Franciscus Petrus | Compound for inhibiting the influx of polymorphonuclear leukocytes (PMNS) in a tissue, its selection, pharmaceutical compositions and use |
USRE45847E1 (en) | 2004-01-09 | 2016-01-19 | Pfizer Inc. | Antibodies to MAdCAM |
US10259872B2 (en) | 2004-01-09 | 2019-04-16 | Pfizer, Inc. | Antibodies to MAdCAM |
US20080124339A1 (en) * | 2004-01-09 | 2008-05-29 | Nicholas Pullen | Antibodies to MAdCAM |
US20070166308A1 (en) * | 2004-01-09 | 2007-07-19 | Nicholas Pullen | Antibodies to MAdCAM |
US9328169B2 (en) | 2004-01-09 | 2016-05-03 | Pfizer Inc. | Human antibodies that bind human MAdCAM |
US7932372B2 (en) | 2004-01-09 | 2011-04-26 | Amgen Fremont Inc. | Antibodies to MAdCAM |
US9764033B2 (en) | 2011-05-02 | 2017-09-19 | Millennium Pharmaceuticals, Inc. | Formulation for anti-α4β7 antibody |
US10004808B2 (en) | 2011-05-02 | 2018-06-26 | Millennium Pharmaceuticals, Inc. | Methods of treating ulcerative colitis |
US10040855B2 (en) | 2011-05-02 | 2018-08-07 | Millennium Pharmaceuticals, Inc. | Formulation for anti-α4β7 antibody |
US10143752B2 (en) | 2011-05-02 | 2018-12-04 | Millennium Pharmaceuticals, Inc. | Methods of treating ulcerative colitis |
US9663579B2 (en) | 2011-05-02 | 2017-05-30 | Millennium Pharmaceuticals, Inc. | Formulation for anti-α4β7 antibody |
US11560434B2 (en) | 2011-05-02 | 2023-01-24 | Millennium Pharmaceuticals, Inc. | Formulation for anti-α4β7 antibody |
US10851163B2 (en) | 2015-01-09 | 2020-12-01 | Pfizer Inc. | Dosage regimen for MAdCAM antagonists |
US11884726B2 (en) | 2015-01-09 | 2024-01-30 | Pfizer Inc. | Dosage regimen for MAdCAM antagonists |
US11802156B2 (en) | 2017-07-14 | 2023-10-31 | Pfizer Inc. | Antibodies to MAdCAM |
CN114225025A (en) * | 2021-12-29 | 2022-03-25 | 北京创世客生物技术有限公司 | Use of probiotic-containing formulations for the treatment of gastrointestinal disorders |
Also Published As
Publication number | Publication date |
---|---|
JP2008231112A (en) | 2008-10-02 |
US6551593B1 (en) | 2003-04-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6551593B1 (en) | Treatment of Inflammatory bowel disease by inhibiting binding and/or signalling through α 4 β 7 and its ligands and madcam | |
Hesterberg et al. | Rapid resolution of chronic colitis in the cotton-top tamarin with an antibody to a gut-homing integrin a4b7 | |
Glassock et al. | Autologous immune complex nephritis induced with renal tubular antigen: II. The pathogenetic mechanism | |
Nishikawa et al. | Antibodies to intercellular adhesion molecule 1/lymphocyte function-associated antigen 1 prevent crescent formation in rat autoimmune glomerulonephritis. | |
Clagett et al. | Interstitial immune complex thyroiditis in mice: the role of autoantibody to thyroglobulin | |
Berden et al. | Analysis of vascular lesions in murine SLE. I. Association with serologic abnormalities. | |
US8277808B2 (en) | Mucosal vascular addressins and uses thereof | |
JP2015083603A (en) | ANTIBODY α4 β7 INTEGRIN AND ITS USE TO TREAT INFLAMMATORY BOWEL DISEASE | |
JP2703764B2 (en) | Monoclonal antibody against complement component C5a | |
JP2010280659A (en) | Diagnosis and treatment of hepatic disorders | |
Cunningham et al. | Glomerular complement regulation is overwhelmed in passive Heymann nephritis | |
World Health Organization | The role of immune complexes in disease: report of a WHO scientific group [meeting held in Geneva from 22 to 28 September 1976] | |
Niaudet | Nephrotic syndrome in children | |
Neale et al. | Spontaneous glomerulonephritis in rabbits: role of a glomerular capillary antigen | |
Kimura et al. | Monoclonal antibody against lymphocyte function‐associated antigen 1 inhibits the formation of primary biliary cirrhosis‐like lesions induced by murine graft‐versus‐host reaction | |
Kashgarian et al. | Renal disease. | |
Madaio et al. | Effect of antibody charge and concentration on deposition of antibody to glomerular basement membrane | |
Fujigaki et al. | Glomerular injury induced by cationic 70‐kD staphylococcal protein; specific immune response is not involved in early phase in rats | |
Péfaur et al. | Early and late humoral rejection: a clinicopathologic entity in two times | |
Gris et al. | Antiglomerular basement membrane nephritis induced by IgA1 antibodies | |
US7750137B2 (en) | Mucosal vascular addressins | |
Syre | IGA mesangial glomerulonephritis; significance and pathogenesis of segmental-focal glomerular lesions | |
Nakazawa et al. | Proteolytic enzyme treatment reduces glomerular immune deposits and proteinuria in passive Heymann nephritis. | |
Dantal et al. | Glomerulonephritis recurrences after kidney transplantation | |
Francis et al. | Membranous nephropathy and kidney transplantation |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- AFTER EXAMINER'S ANSWER OR BOARD OF APPEALS DECISION |