WO2003028668A2 - Gammaglobulin treatment of immune disorders - Google Patents
Gammaglobulin treatment of immune disorders Download PDFInfo
- Publication number
- WO2003028668A2 WO2003028668A2 PCT/US2002/033322 US0233322W WO03028668A2 WO 2003028668 A2 WO2003028668 A2 WO 2003028668A2 US 0233322 W US0233322 W US 0233322W WO 03028668 A2 WO03028668 A2 WO 03028668A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- immunoglobulin
- subject
- disease
- immune
- immunoglobulin composition
- Prior art date
Links
- 238000011282 treatment Methods 0.000 title abstract description 33
- 108010074605 gamma-Globulins Proteins 0.000 title description 7
- 208000026278 immune system disease Diseases 0.000 title 1
- 108060003951 Immunoglobulin Proteins 0.000 claims abstract description 121
- 102000018358 immunoglobulin Human genes 0.000 claims abstract description 121
- 238000000034 method Methods 0.000 claims abstract description 71
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 36
- 201000010099 disease Diseases 0.000 claims abstract description 35
- 230000001404 mediated effect Effects 0.000 claims abstract description 35
- 239000000203 mixture Substances 0.000 claims description 79
- 208000029560 autism spectrum disease Diseases 0.000 claims description 32
- 230000006872 improvement Effects 0.000 claims description 29
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 21
- 230000004770 neurodegeneration Effects 0.000 claims description 20
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 17
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical class [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 15
- 229940069428 antacid Drugs 0.000 claims description 14
- 239000003159 antacid agent Substances 0.000 claims description 14
- 230000001458 anti-acid effect Effects 0.000 claims description 13
- 206010003805 Autism Diseases 0.000 claims description 11
- 208000020706 Autistic disease Diseases 0.000 claims description 11
- 210000000987 immune system Anatomy 0.000 claims description 8
- 230000001965 increasing effect Effects 0.000 claims description 7
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 229940099472 immunoglobulin a Drugs 0.000 claims description 6
- 229940027941 immunoglobulin g Drugs 0.000 claims description 6
- 230000001502 supplementing effect Effects 0.000 claims description 6
- 208000024827 Alzheimer disease Diseases 0.000 claims description 5
- 206010003246 arthritis Diseases 0.000 claims description 5
- 208000030172 endocrine system disease Diseases 0.000 claims description 5
- 229940096329 human immunoglobulin a Drugs 0.000 claims description 5
- 229940098197 human immunoglobulin g Drugs 0.000 claims description 5
- 201000006417 multiple sclerosis Diseases 0.000 claims description 5
- 208000019553 vascular disease Diseases 0.000 claims description 5
- 208000017520 skin disease Diseases 0.000 claims description 4
- 230000002708 enhancing effect Effects 0.000 claims description 2
- 230000016379 mucosal immune response Effects 0.000 claims description 2
- 208000035475 disorder Diseases 0.000 abstract 1
- 229940072221 immunoglobulins Drugs 0.000 description 27
- 230000002496 gastric effect Effects 0.000 description 25
- 238000002360 preparation method Methods 0.000 description 14
- 208000024891 symptom Diseases 0.000 description 14
- 239000000243 solution Substances 0.000 description 11
- 230000006399 behavior Effects 0.000 description 10
- 230000008859 change Effects 0.000 description 10
- -1 coatings Substances 0.000 description 10
- 208000023275 Autoimmune disease Diseases 0.000 description 9
- 108010010256 Dietary Proteins Proteins 0.000 description 8
- 102000015781 Dietary Proteins Human genes 0.000 description 8
- 206010061218 Inflammation Diseases 0.000 description 8
- 230000001363 autoimmune Effects 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 8
- 239000008280 blood Substances 0.000 description 8
- 235000021245 dietary protein Nutrition 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 230000004054 inflammatory process Effects 0.000 description 8
- 230000028327 secretion Effects 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- 238000011156 evaluation Methods 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 210000002966 serum Anatomy 0.000 description 7
- 238000002560 therapeutic procedure Methods 0.000 description 7
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 6
- 239000000427 antigen Substances 0.000 description 6
- 108091007433 antigens Proteins 0.000 description 6
- 102000036639 antigens Human genes 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 102000004127 Cytokines Human genes 0.000 description 5
- 108090000695 Cytokines Proteins 0.000 description 5
- 208000016192 Demyelinating disease Diseases 0.000 description 5
- 208000035895 Guillain-Barré syndrome Diseases 0.000 description 5
- 206010049567 Miller Fisher syndrome Diseases 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 230000002519 immonomodulatory effect Effects 0.000 description 5
- 230000001900 immune effect Effects 0.000 description 5
- 238000005067 remediation Methods 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 210000002784 stomach Anatomy 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 239000000829 suppository Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 206010061598 Immunodeficiency Diseases 0.000 description 4
- 208000029462 Immunodeficiency disease Diseases 0.000 description 4
- 230000001594 aberrant effect Effects 0.000 description 4
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 4
- 230000001684 chronic effect Effects 0.000 description 4
- 239000003599 detergent Substances 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 230000007813 immunodeficiency Effects 0.000 description 4
- 206010025135 lupus erythematosus Diseases 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 239000003381 stabilizer Substances 0.000 description 4
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 3
- 201000001320 Atherosclerosis Diseases 0.000 description 3
- 206010009900 Colitis ulcerative Diseases 0.000 description 3
- 208000011231 Crohn disease Diseases 0.000 description 3
- 206010011878 Deafness Diseases 0.000 description 3
- 208000003807 Graves Disease Diseases 0.000 description 3
- 208000015023 Graves' disease Diseases 0.000 description 3
- 208000023105 Huntington disease Diseases 0.000 description 3
- 108090001005 Interleukin-6 Proteins 0.000 description 3
- 208000018737 Parkinson disease Diseases 0.000 description 3
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 3
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 3
- 208000004732 Systemic Vasculitis Diseases 0.000 description 3
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 3
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 3
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 3
- 201000006704 Ulcerative Colitis Diseases 0.000 description 3
- 206010047115 Vasculitis Diseases 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 230000027455 binding Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 238000004891 communication Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005194 fractionation Methods 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 230000010370 hearing loss Effects 0.000 description 3
- 231100000888 hearing loss Toxicity 0.000 description 3
- 208000016354 hearing loss disease Diseases 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 210000004877 mucosa Anatomy 0.000 description 3
- 206010028417 myasthenia gravis Diseases 0.000 description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 description 3
- 230000035943 smell Effects 0.000 description 3
- 230000003997 social interaction Effects 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 108010074051 C-Reactive Protein Proteins 0.000 description 2
- 102100032752 C-reactive protein Human genes 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 206010012305 Demyelination Diseases 0.000 description 2
- 229930091371 Fructose Natural products 0.000 description 2
- 239000005715 Fructose Substances 0.000 description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 2
- 108010061711 Gliadin Proteins 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
- 239000004471 Glycine Substances 0.000 description 2
- 102000009490 IgG Receptors Human genes 0.000 description 2
- 108010073807 IgG Receptors Proteins 0.000 description 2
- 102100037850 Interferon gamma Human genes 0.000 description 2
- 108010074328 Interferon-gamma Proteins 0.000 description 2
- 102000014158 Interleukin-12 Subunit p40 Human genes 0.000 description 2
- 108010011429 Interleukin-12 Subunit p40 Proteins 0.000 description 2
- 108010002616 Interleukin-5 Proteins 0.000 description 2
- 102000000743 Interleukin-5 Human genes 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- 102000008192 Lactoglobulins Human genes 0.000 description 2
- 108010060630 Lactoglobulins Proteins 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 102000001109 Leukocyte L1 Antigen Complex Human genes 0.000 description 2
- 108010069316 Leukocyte L1 Antigen Complex Proteins 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 description 2
- 208000003435 Optic Neuritis Diseases 0.000 description 2
- 201000007737 Retinal degeneration Diseases 0.000 description 2
- 206010039710 Scleroderma Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 2
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 2
- 241000186514 Warburgia ugandensis Species 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 230000003302 anti-idiotype Effects 0.000 description 2
- 230000005784 autoimmunity Effects 0.000 description 2
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 239000005018 casein Substances 0.000 description 2
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 2
- 235000021240 caseins Nutrition 0.000 description 2
- 230000007969 cellular immunity Effects 0.000 description 2
- 230000008131 children development Effects 0.000 description 2
- 208000037976 chronic inflammation Diseases 0.000 description 2
- 208000037893 chronic inflammatory disorder Diseases 0.000 description 2
- 229960001380 cimetidine Drugs 0.000 description 2
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 238000011461 current therapy Methods 0.000 description 2
- 230000016396 cytokine production Effects 0.000 description 2
- 238000004925 denaturation Methods 0.000 description 2
- 230000036425 denaturation Effects 0.000 description 2
- 201000001981 dermatomyositis Diseases 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000000378 dietary effect Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000006196 drop Substances 0.000 description 2
- 235000020883 elimination diet Nutrition 0.000 description 2
- 210000001842 enterocyte Anatomy 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 2
- 229930182830 galactose Natural products 0.000 description 2
- 229940009600 gammagard Drugs 0.000 description 2
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 2
- 235000020256 human milk Nutrition 0.000 description 2
- 210000004251 human milk Anatomy 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000036512 infertility Effects 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 2
- 239000000347 magnesium hydroxide Substances 0.000 description 2
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 210000003097 mucus Anatomy 0.000 description 2
- 229940039506 mylanta Drugs 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 230000008520 organization Effects 0.000 description 2
- 210000001986 peyer's patch Anatomy 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 229940096015 polygam s/d Drugs 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 210000000664 rectum Anatomy 0.000 description 2
- 238000009256 replacement therapy Methods 0.000 description 2
- 230000000241 respiratory effect Effects 0.000 description 2
- 230000004258 retinal degeneration Effects 0.000 description 2
- 210000003296 saliva Anatomy 0.000 description 2
- 210000000813 small intestine Anatomy 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 210000001138 tear Anatomy 0.000 description 2
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 2
- 230000003156 vasculitic effect Effects 0.000 description 2
- 230000001755 vocal effect Effects 0.000 description 2
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 108091008875 B cell receptors Proteins 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 231100000699 Bacterial toxin Toxicity 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 241000193163 Clostridioides difficile Species 0.000 description 1
- 208000002881 Colic Diseases 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- 208000035976 Developmental Disabilities Diseases 0.000 description 1
- 208000012239 Developmental disease Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 108010087819 Fc receptors Proteins 0.000 description 1
- 102000009109 Fc receptors Human genes 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 208000034826 Genetic Predisposition to Disease Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000913082 Homo sapiens IgGFc-binding protein Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 101710177940 IgG receptor FcRn large subunit p51 Proteins 0.000 description 1
- 102100026120 IgG receptor FcRn large subunit p51 Human genes 0.000 description 1
- 102100026103 IgGFc-binding protein Human genes 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 231100000757 Microbial toxin Toxicity 0.000 description 1
- 241000238367 Mya arenaria Species 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 102100037505 Secretin Human genes 0.000 description 1
- 108010086019 Secretin Proteins 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 101000874347 Streptococcus agalactiae IgA FC receptor Proteins 0.000 description 1
- 101710120037 Toxin CcdB Proteins 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229940024545 aluminum hydroxide Drugs 0.000 description 1
- 229940024546 aluminum hydroxide gel Drugs 0.000 description 1
- SMYKVLBUSSNXMV-UHFFFAOYSA-K aluminum;trihydroxide;hydrate Chemical compound O.[OH-].[OH-].[OH-].[Al+3] SMYKVLBUSSNXMV-UHFFFAOYSA-K 0.000 description 1
- 230000000578 anorexic effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003171 anti-complementary effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 210000000436 anus Anatomy 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 239000000688 bacterial toxin Substances 0.000 description 1
- 238000013542 behavioral therapy Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- VEZXCJBBBCKRPI-UHFFFAOYSA-N beta-propiolactone Chemical compound O=C1CCO1 VEZXCJBBBCKRPI-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000004820 blood count Methods 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 229960003563 calcium carbonate Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000001886 ciliary effect Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000001517 counterregulatory effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- GXGAKHNRMVGRPK-UHFFFAOYSA-N dimagnesium;dioxido-bis[[oxido(oxo)silyl]oxy]silane Chemical compound [Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O GXGAKHNRMVGRPK-UHFFFAOYSA-N 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 230000009144 enzymatic modification Effects 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 210000004837 gut-associated lymphoid tissue Anatomy 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 239000003485 histamine H2 receptor antagonist Substances 0.000 description 1
- 230000009215 host defense mechanism Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000009177 immunoglobulin therapy Methods 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000006882 induction of apoptosis Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000015788 innate immune response Effects 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 210000005210 lymphoid organ Anatomy 0.000 description 1
- 229940099076 maalox Drugs 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 229940031958 magnesium carbonate hydroxide Drugs 0.000 description 1
- 229960000816 magnesium hydroxide Drugs 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 229960000869 magnesium oxide Drugs 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 229940100377 micrhogam Drugs 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- 238000001728 nano-filtration Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229940021317 other blood product in atc Drugs 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 238000009928 pasteurization Methods 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 210000003800 pharynx Anatomy 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229920000867 polyelectrolyte Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 229960000380 propiolactone Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000003751 purification from natural source Methods 0.000 description 1
- 238000011046 pyrogen test Methods 0.000 description 1
- VMXUWOKSQNHOCA-LCYFTJDESA-N ranitidine Chemical compound [O-][N+](=O)/C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-LCYFTJDESA-N 0.000 description 1
- 229960000620 ranitidine Drugs 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 238000003259 recombinant expression Methods 0.000 description 1
- 108010043277 recombinant soluble CD4 Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 229940100381 rhogam Drugs 0.000 description 1
- 238000011076 safety test Methods 0.000 description 1
- 229960002101 secretin Drugs 0.000 description 1
- OWMZNFCDEHGFEP-NFBCVYDUSA-N secretin human Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(N)=O)[C@@H](C)O)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)C1=CC=CC=C1 OWMZNFCDEHGFEP-NFBCVYDUSA-N 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000006277 sulfonation reaction Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 230000024664 tolerance induction Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 210000003708 urethra Anatomy 0.000 description 1
- 238000002562 urinalysis Methods 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
- A61K2039/541—Mucosal route
- A61K2039/542—Mucosal route oral/gastrointestinal
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
Definitions
- the present invention relates to the fields of neurology and immunology. More particularly, the present invention relates to a method of treating immune-mediated neurodegenerative disease by administering to a subject via an alimentary route an immunoglobulin composition.
- the neurodegenerative disease is autistic spectrum disorder.
- Immune-mediated diseases are chronic inflammatory diseases perpetuated by antibodies and cellular immunity.
- the immune response damages healthy organs either inadvertently as a result of attacking foreign substances that have entered the body, or by attacking self tissues that happen to resemble foreign substances, a process called autoimmunity.
- arthritis e.g., rheumatoid arthritis and psoriatic arthritis
- inflammatory bowel diseases e.g., ulcerative colitis and Crohn's disease
- endocrinopathies e.g., type 1 diabetes and Graves disease
- neurodegenerative diseases e.g., multiple sclerosis, autistic spectrum disorder, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Huntington's Disease, Guillain-Barre syndrome, myasthenia gravis, and chronic idiopathic demyelinating disease (CH)
- vascular diseases e.g., autoimmune hearing loss, systemic vasculitis, and atherosclerosis.
- Immune-mediated diseases are complex and multifactorial. Recent research indicates that immune-mediated diseases require both a genetic predisposition and an environmental trigger. In many cases microbes have been implicated as a primary stimulus, and the gastrointestinal tract is a common source of these microbes. It is now recognized that some microbes implicated in autoimmune diseases may be ubiquitous, and the development of disease is determined by the genetic makeup of susceptible individuals.
- immunodeficiency A major clue to the cause of autoimmunity is its association with immunodeficiency.
- the most common immunodeficiency is the absence and/or decrease of IgA antibodies.
- IgA antibodies are secreted into the gastrointestinal tract as an important host defense mechanism. These antibodies protect us from numerous bacterial toxins by neutralizing them. Even in the presence of IgA, immunodeficiency may occur through mechanisms as subtle as a fortuitous similarity in appearance between self and microbe.
- Autistic spectrum disorder is a complex developmental disability. The disability affects social interaction and communication skills. Children and adults with autism have difficulties with verbal and non-verbal communication, social interactions and leisure activities.
- ASD children appear intolerant to common dietary protein antigens (Ag), suffering from a variety of gastrointestinal (GI) signs and symptoms including diarrhea, constipation, colic, gastroesophageal reflux (GER), and GI discomfort.
- GI gastrointestinal
- GER gastroesophageal reflux
- Parents of ASD children frequently report improvement of their GI symptoms as well as their aberrant behavior following implementation of an elimination diet (Berney 2001).
- the GI mucosa is important for inducing immunological tolerance against numerous dietary proteins.
- tolerance induction in the peripheral lymphoid organs is regulated by sophisticated and complex mechanisms (Krause et ah, 2000).
- Dysregulated activation of immune reactivity in the GI mucosa can lead to activation of autoreactive T cells and autoantibody production.
- microbial infection in the gut often precipitates disease exacerbation in inflammatory bowel diseases (EBD) and other systemic autoimmune disorders.
- EBD inflammatory bowel diseases
- the gut associated mucosal immune system may be crucial to maintain immunological tolerance.
- Intravenous gammaglobulin exerts various beneficial effects to attenuate autoimmune conditions via numerous direct and indirect (immunomodulatory) mechanisms of action (Kazatchkine and Kaveri, 2001). It has been reported that IVIG improved clinical features of autism in a small subset of ASD patients (Gupta et ah, 1996), although the mechanism of its action was unknown.
- the present invention is directed to a method for treating immune-mediated diseases.
- the method of treatment involves administration of immunoglobulin via an alimentary route, for example, oral, rectal, sublingual or buccal.
- the immune-mediated disease is a neurodegenerative disease, for example autistic spectrum disorder.
- the present invention also includes treatment of GI manifestations associated with neurodegenerative disorders.
- One embodiment of the present invention is a method of treating an immune- mediated neurodegenerative disease in a subject comprising the step of administering to the subject via an alimentary route an immunoglobulin composition in an amount sufficient to provide an improvement in the neurodegenerative disease in the subject.
- alimentary routes include, but are not limited to oral, buccal, rectal and sublingual. More particularly, the alimentary route is an oral route.
- the immunoglobulin composition is administered in conjunction with an antacid. Yet further, the antacid is administered prior to or simultaneously with the immunoglobulin composition.
- the neurodegenerative disease is selected from the group consisting of multiple sclerosis, autism and Alzheimer's disease.
- the immunoglobulin composition comprises human immunoglobulin that can be dispersed in a pharmaceutically acceptable carrier. More particularly, the human immunoglobulin is human immunoglobulin G, immunoglobulin A or a combination thereof.
- Another embodiment is a method of treating an autistic spectrum disorder in a subject comprising the step of administering to the subject via an alimentary route an immunoglobulin composition in an amount sufficient to provide an improvement in the autistic spectrum disorder in the subject.
- an embodiment is a method of treating an immune- mediated disease comprising the step of supplementing a mucosal immune system.
- the immune-mediated disease is an autistic spectrum disorder. More particularly, supplementing the mucosal immune system comprises increasing the amount of immunoglobulin G, immunoglobulin A or a combination thereof in the gastrointestinal tract. Yet further, in specific embodiments, the immunoglobulin G, immunoglobulin A or a combination thereof is administered to the subject via an alimentary route. In preferred embodiments, the alimentary route is an oral route.
- another embodiments is a method of enhancing a mucosal immune response in the gastrointestinal tract in a subject comprising the step of administering to the subject a composition comprising immunoglobulin G, immunoglobulin A or a combination thereof.
- the subject suffers from an immune-mediated disease, for example, but not limited to arthritis, inflammatory bowel disease, skin diseases, endocrinopathies, neurodegenerative diseases and vascular diseases.
- supplementing the mucosal immune system comprises increasing the presence of natural antibodies in the digestive tract.
- FIG. 1 shows the GI severity score after administration of oral IgG.
- alimentary route is defined as any route that pertains to the digestive tube from the mouth to the anus of the subject.
- the alimentary route includes, but is not limited to the mouth or buccal cavity, pharynx, esophagus, stomach, small intestine, large intestine or rectum.
- Exemplary alimentary routes of administration of drugs and/or compositions include, but are not limited to oral, rectal, sublingual or buccal.
- antibody as used herein is defined as a serum immunoglobulin that has specific binding sites to combine with antigens. All antibodies have the same overall structure and are known collectively as immunoglobulins. Thus, as used herein, the terms “antibody” and “immunoglobulin” are interchangeable.
- autism spectrum disorder or “ASD”, as used herein is defined as a complex developmental disorder diagnosed on the basis of clinical > characteristics (Diagnostic and Statistical Manual, 4th Edition, 1994, American Psychiatric Association). However, their condition may be influenced by various environmental factors.
- gammaglobulin as used herein is defined as the protein fraction of blood serum or antiserum that contains antibodies or immunoglobulins. It is well known in the art that antisera contain heterogeneous collections of antibodies or immunoglobulins. Thus, "gammaglobulin" contains IgA, IgG, IgD, IgM and/or IgE.
- Immune-mediated disease refers to chronic inflammatory diseases perpetuated by antibodies and cellular immunity.
- Immune-mediated diseases include, for example, but not limited to, arthritis (e.g., rheumatoid arthritis and psoriatic arthritis), inflammatory bowel diseases (e.g., ulcerative colitis and Crohn's disease), endocrinopathies (e.g., type 1 diabetes and Graves disease), neurodegenerative diseases (e.g., multiple sclerosis, autistic spectrum disorder, Alzheimer's disease, Guillain-Barre syndrome, obsessive-compulsive disorder, optic neuritis, retinal degeneration, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Huntington's Disease, Guillain-Barre syndrome, myasthenia gravis, and chronic idiopathic demyelinating disease (CID)), vascular diseases (e.g., autoimmune hearing loss, systemic vasculitis, and at
- Immunoglobulin or "Ig”, as used herein is defined as a class of plasma proteins, which functions as antibodies. Immunoglobulins include IgA, IgG, IgM, IgE, or IgD and/or their subtypes, for example IgGi, IgG 2 , IgG 3 , IgG 4 , IgAi or IgA 2 .
- IgA functions as the primary antibody that is present in body secretions, such as saliva, tears, breast milk, gastrointestinal secretions and mucus secretions of the respiratory and genitourinary tracts.
- IgG functions as the most common circulating antibody.
- the term "in conjunction with” as used herein refers to before or prior, substantially simultaneously with or after oral administration of an antacid.
- a composition such as, for example, immunoglobulin
- the administration of a composition can not precede or follow administration of an antacid by so long an interval of time that the relevant effects of the substance administered first have expired.
- the immunoglobulin composition is usually administered within a therapeutically effective time.
- oral administration includes oral, buccal, enteral or intragastric administration.
- pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
- the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the vectors or cells of the present invention, its use in therapeutic compositions is contemplated. Supplementary active ingredients also can be incorporated into the compositions.
- subject as used herein, is taken to mean any mammalian subject to which an immunoglobulin composition is orally administered according to the methods described herein, h a specific embodiment, the methods of the present invention are employed to treat a human subject. Another embodiment includes treating a human child.
- terapéuticaally effective time refers to a time frame in which the immunoglobulin composition and/or antacid is still active within the subject.
- terapéuticaally effective amount refers to an amount that results in an improvement or remediation of the symptoms of the disease or condition.
- treating and “treatment” as used herein refers to administering to a subject a therapeutically effective amount of an immunoglobulin composition so that the subject has an improvement in the immune-mediated neurodegenerative disease.
- the improvement is any improvement or remediation of the symptoms.
- the improvement is an observable or measurable improvement.
- a treatment may improve the disease condition, but may not be a complete cure for the disease.
- immunoglobulin compositions are acmiinistered to a subject via an alimentary route.
- the immunoglobulin compositions disclosed herein may be administered orally, buccally, rectally, or sublingually.
- the immunoglobulin composition of the present invention can be administered via inhalation.
- An immunoglobulin preparation suitable for practicing the present invention may contain varying amounts of IgA, IgG, IgM, IgE, or IgD and/or their subtypes (e.g., IgGi, IgG 2 , IgG 3 , IgG 4 , IgAi or IgA 2 ).
- the immunoglobulin composition is made up of predominantly IgG, IgA or a combination of IgG and IgA immunoglobulins.
- the immunoglobulin composition may comprise a specific subtype of IgG or IgA or a combination thereof.
- IgG or IgA include, but are not limited to IgGi, IgG 2 , IgG 3 , IgG 4 , IgAi or IgA 2 . More preferably, the immunoglobulin is a human immunoglobulin.
- fragments of immunoglobulins are also suitable for practicing the methods of the present invention. Fragments of immunoglobulins include, but are not limited to portions of intact immunoglobulins such as Fc, Fab, Fab', F(ab') 2 and single chain immunoglobulins.
- the immunoglobulins used according to the present invention can be obtained through isolation and purification from natural sources, for example, but not limited to blood and body secretions, such as saliva, tears, breast milk, gastrointestinal secretions and mucus secretions of the respiratory and genitourinary tracts.
- the immunoglobulins are produced recombinatly using genetic engineering techniques well known and used in the art, such as recombinant expression or direct production in genetically altered animals, or chemical synthesis.
- Isolation of native immunoglobulins for alimentary administration are prepared from blood by employing the procedures that are used in preparing immunoglobulins for parenteral * administration, e.g., immunoglobulins prepared for intravenous administration (also called IVIG).
- IVIG intravenous administration
- blood is collected and pooled from a number of healthy volunteers.
- the number of blood donors is at least about 5 or 10; preferably, at least about 100; more preferably, at least about 1000; yet more preferably, at least about 10,000.
- Immunoglobulins are isolated from the pooled human blood by a number of well-known methods. Such methods include, but are not limited to Cohn's alcohol fractionation (Cohn et al, 1946; Oncley et al, 1949), fractionation (Schneider et al, 1916), ulrracentrifugation (Barundern et al, 1962), or the method of Kistler and Nitschmann (1962), polyelectrolyte affinity adsorption, large scale electrophoresis, ion exchange adsorption, and polyethylene glycol fractionation. Any method which fractionates immunoglobulins from a human source is used to obtain immunoglobulins suitable for use in practicing the methods of the present invention.
- Immunoglobulins fractionated from pooled human blood contain predominantly IgG, smaller amounts of IgA, and yet smaller or trace amounts of IgM, IgE, IgD, with a diverse spectrum of antibody specificities and subclass distribution characteristic of the donor population.
- a preparation can also contain trace amounts of soluble CD4, CD8, and HLA molecules and certain cytokines from the plasma e.g. TGF- ⁇ .
- Additional preparative steps are used to enrich a particular class of immunoglobulin. For example, protein G sepharose treatment leads to an IgA predominant preparation (Leibl et al, 1996).
- conventional methods are employed for producing fragments of immunoglobulins. Such methods are taught by, e.g., Coligan et al, Current Protocols in Immunology, John Wiley & Sons Inc., New York, N . (1994).
- a commercial source of immunoglobulin appropriate for use in the methods of the present invention is Sandoglobulin IN.® (Sandoz Pharmaceuticals), which contains 96% IgG with traces of IgA and IgM.
- IgAbulin® immuno AG, Vienna, Austria
- Panglobulin® IVIG which contains primarily IgG, a small amount of IgA and traces of IgM.
- Oralgam Another commercial source of immunoglobulin.
- the safety standards of an immunoglobulin composition for oral administration are the same as those proposed for INIG.
- standards for the preparation of INIG were proposed in 1989 in a World Health Organization (WHO) bulletin and updated in 1989 to increase the safety of prepared immunoglobulins and other blood products.
- Safety tests which are performed may include, e.g., sterility test, Pyrogen test, Hepatitis B antigen test, anticomplementary activity test and the like. See, e.g., A. Gardi (1984).
- immunoglobulins isolated from pooled human blood are made into powders by conventional freeze-drying (or lyophilization) procedure.
- One or more stabilizing substances are added to the immunoglobulin preparation prior to the freeze- drying process.
- a variety of stabilizing substances are employed including, e.g., amino acids such as glycine and lysine, carbohydrates such as dextrose, mamiose, galactose, fructose, lactose, sucrose, maltose, sorbitol, mannitol and the like.
- An immunoglobulin preparation in lyophilized form for use in practicing the methods of the present invention are also obtained through commercial sources.
- Such sources include, but are not limited to: Gammagard S/D® (Baxter Healthcare), Sandoglobulin IN.® (Sandoz Pharmaceuticals), Polygam S/D® (American Red Cross), Nenoglobulin®-I (Alpha Therapeutic), NZIG® (American Red Cross), IgAbulin® (Immuno AG, Vienna, Austria) and Intraglobin-F® (Biotest Pharma GmbH, Frankfurt, Germany).
- the immunoglobulin preparation or composition suitable for oral administration is provided in a pharmaceutically acceptable carrier with or without an inert diluent.
- the carrier should be assimilable and edible and includes liquid, semi-solid, e.g., pastes, or solid carriers. Except insofar as any conventional media, agent, diluent or carrier is detrimental to the recipient or to the therapeutic effectiveness of an immunoglobulin preparation contained therein, its use in an administrable immunoglobulin for use in practicing the methods of the present invention is appropriate.
- carriers or diluents include fats, oils, water, saline solutions, lipids, liposomes, resins, binders, fillers and the like, or combinations thereof.
- the immunoglobulin composition is combined with the carrier in any convenient and practical manner, e.g., by solution, suspension, emulsification, admixture, encapsulation, absorption and the like. Such procedures are routine for those skilled in the art.
- an immunoglobulin composition in powder form is combined or mixed thoroughly with a semi-solid or solid carrier.
- the mixing can be carried out in any convenient manner such as grinding.
- Stabilizing agents can be also added in the mixing process in order to protect the immunoglobulin composition from loss of therapeutic activity through, e.g., denaturation in the stomach.
- stabilizers for use in an orally admimstrable immunoglobulin preparation include buffers, antagonists to the secretion of stomach acids, amino acids such as glycine and lysine, carbohydrates such as dextrose, mannose, galactose, fructose, lactose, sucrose, maltose, sorbitol, mannitol, etc., proteolytic enzyme inhibitors, and the like.
- an immunoglobulin composition which is combined with a semi- solid or solid carrier can be further formulated into hard or soft shell gelatin capsules, tablets, or pills. More preferably, gelatin capsules, tablets, or pills are enterically coated. Enteric coatings prevent denaturation of the immunoglobulin composition in the stomach or upper bowel where the pH is acidic. See, e.g., U.S. Pat. No. 5,629,001. Upon reaching the small intestines, the basic pH therein dissolves the coating and permits the immunoglobulin composition to be released and absorbed by specialized cells, e.g., epithelial enterocytes and Peyer's patch M cells.
- specialized cells e.g., epithelial enterocytes and Peyer's patch M cells.
- Panglobulin® is encapsulated in a gelatin capsule (IgPO, encapsulated Panglobulin ®).
- a powdered iimnunoglobulin composition is combined with a liquid carrier such as, e.g., water or a saline solution, with or without a stabilizing agent.
- a liquid carrier such as, e.g., water or a saline solution
- stabilizing agent e.g., sodium bicarbonate
- Such commercial sources include BayRho-D® Full Dose (Bayer Biological), BahRho-D® Mini-Dose (Bayer Biological), Gamimune N®, 5% (Bayer Biological), Gamimune N®, 5% Solvent/Detergent Treated (Bayer Biological), Gamimune NO, 10% (Bayer Biological), Gamimmune N 5% (Miles), Gammagard S/D® (Baxter Healthcare), Isiven V.I.
- suppositories are solid dosage forms of various weights and shapes, usually medicated, for insertion into the rectum, vagina or urethra. After insertion, suppositories soften, melt or dissolve in the cavity fluids.
- traditional carriers may include, for example, polyalkylene glycols, triglycerides or combinations thereof.
- suppositories may be formed from mixtures containing, for example, the active ingredient in the range of about 0.5% to about 10%, and preferably about 1% to about 2%.
- nasal solutions are usually aqueous solutions designed to be administered to the nasal passages in drops or sprays.
- Nasal solutions are prepared so that they are similar in many respects to nasal secretions, so that normal ciliary action is maintained.
- the aqueous nasal solutions usually are isotonic or slightly buffered to maintain a pH of about 5.5 to about 6.5.
- antimicrobial preservatives similar to those used in ophthalmic preparations, drugs, or appropriate drug stabilizers, if required, may be included in the formulation.
- solutions are administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective to result in an improvement or remediation of signs and/or symptoms.
- the formulations are easily administered in a variety of dosage forms such as ingestible solutions, drug release capsules and the like. Some variation in dosage can occur depending on the condition of the subject being treated. The person responsible for administration can, in any event, determine the appropriate dose for the individual subject.
- preparations meet sterility, pyrogemcity, general safety and purity standards as required by FDA Office of Biologies standards.
- a subject that is suspected of an immune- mediated disease or a subject suffering from an immune-mediated disease is treated with the immunoglobulin composition of the present invention.
- the treatment comprises administering via an alimentary route to a subject a therapeutically effective amount of an immunoglobulin composition so that the subject has an improvement in the immune- mediated disease.
- Immune-mediated diseases of the present invention include, for example, but are not limited to, arthritis (e.g., rheumatoid arthritis and psoriatic arthritis), inflammatory bowel diseases (e.g., ulcerative colitis and Crohn's disease), endocrinopathies (e.g., type 1 diabetes and Graves disease), neurodegenerative diseases (e.g., multiple sclerosis, autistic spectrum disorder, Alzheimer's disease, Guillain-Barre syndrome, obsessive-compulsive disorder, optic neuritis, retinal degeneration, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Huntington's Disease, Guillain-Barre syndrome, myasthenia gravis, and chronic idiopathic demyelinating disease (CJJD)), vascular diseases (e.g., autoimmune hearing loss, systemic vasculitis, and atherosclerosis), and skin diseases (e.g., dermatomyositis, system
- a subject suspected of an immune-mediated neurodegenerative diseases such as autistic spectrum disorder (ASD)
- a subject suffering from an immune-mediated disease neurodegenerative diseases such as autistic spectrum disorder (ASD)
- ASD autistic spectrum disorder
- the treatment comprises administering via an alimentary route to a subject a therapeutically effective amount of an immunoglobulin composition so that the subject has an improvement in the immune-mediated disease neurodegenerative diseases, such as autistic spectrum disorder (ASD).
- the treatment of neurodegenerative diseases also includes treatment of the associated GI manifestations.
- the improvement is any remediation of the symptoms associated with the disease or condition.
- the therapeutic effects of an immunoglobulin composition are believed to result from a blockade of Fc-Receptors (Samuelsson et al, 2000), a neutralization of an autoantibody by anti-idiotype antibodies present in the immunoglobulin composition, binding and down-regulation by anti-idiotype antibodies of the B-cell receptor for an antigen thereby decreasing the autoantibody production (Dietrich et al, 1993), attenuation of complement mediated and immune complex-mediated tissue damage, increasing production of anti- inflammatory cytokine (Prasad et al, 1998), suppression of proliferation of antigen-specific T-cells (Aktas et al, 2001), induction of apoptosis of activated T and B cells (Prasad et al, 1998); neutralization of microbial toxins; or a combination thereof.
- an immunoglobulin composition provided in any of the above-described pharmaceutical carriers is administered via an alimentary route to a subject suspected of or having an immune mediated disease.
- the precise therapeutically effective amount of immunoglobulin composition to be administered is determined by a physician with consideration of individual differences in age, weight, disease severity and response to the therapy.
- Alimentary routes of administration include, but are not limited to oral, nasal, buccal, sublingual or rectal. More preferably, the alimentary route is oral.
- Oral administration of the immunoglobulin composition includes oral, buccal, enteral or intragastric administration. It is also envisioned that the composition is a food additive. For example, the composition is sprinkled on food or added to a liquid prior to ingestion.
- an immunoglobulin composition is administered about one to five times a day at a dose of about lOOmg/day-lOOOmg/day.
- the immunoglobulin composition is admimstered before, during, or after a meal.
- an immunoglobulin composition is admimstered once a day at a dose of 100- 1000 mg/day. Daily administration usually occurs before bedtime.
- an antacid is administered just prior or immediately after oral administration of the immunoglobulin composition.
- An antacid is also given simultaneously with the immunoglobulin composition.
- appropriate antacids include, but are not limited to sodium bicarbonate, magnesium oxide, magnesium hydroxide, calcium carbonate, magnesium trisilicate, magnesium carbonate, and aluminum hydroxide gel.
- the antacid is aluminum hydroxide or magnesium hydroxide such as Maalox® or Mylanta®, which are commercially available.
- the antacid is an H 2 blocker such as Cimetidine or Ranitidine. The dose ranges are between 15 ml and 30 ml for Mylanta, and between 400 and 800 mg per day for Cimetidine.
- the time needed to complete a course of the treatment is determined by a physician and may range from as short as one day to more than one week.
- a preferred course of treatment is from 2 to 8 weeks. More preferably, the course of treatment lasts for eight weeks.
- a course of treatment is repeated as often as necessary, as determined by a physician, in order to maintain or extend the therapeutic benefit to the patient.
- the subject is evaluated to determine if the treatment results in an improvement of the subject.
- the improvement is any improvement or remediation of signs or symptoms of the disease or condition.
- the improvement is an observable improvement, such as gastrointestinal signs or symptoms, social interaction, communication, and/or behavior. Such improvements are measured using evaluation systems, which are well known and used in the clinical field. It is also contemplated that the improvement is a measurable improvement, for example, immunological parameters.
- an ASD subject that is treated according to the methods described herein is evaluated using standard evaluation systems to determine an observable improvement, for example, evaluation of aberrant behavior (e.g., Abenant Behavior Check List (Aman et al, 1997); Childhood Autism Rating Scale (Coniglio et al, 2001); evaluation of child development (e.g., Clinical Global Impression (Sandier et al, 1999), Preschool Language Scale (Dunn-Geier et al, 2000)); or QTL assessment for children (Collier et al, 2000).
- Other clinical symptoms that are observed for ASD include, but are not limited to frequency of bowel movement, stool consistency, color and smells of stools, etc.
- immunological parameters are also measured using standard techniques known in the art. These parameters include, but are not limited to cytokine production in response to common dietary antigens (gliadin, casein, ⁇ -lactoalbumin, and ⁇ -lactoglobulin), LPS, and MBP, IFN- ⁇ , TNF- ⁇ , IL-5, IL-l ⁇ , IL-6, IL-10, sTNFRII, and IL-12p40, and markers for the gastrointestinal tract inflammation (e.g., calprotectin levels in the stool).
- immunoglobulins that are administered via an alimentary route are absorbed and processed by specialized cells in the mucosa tissues of the digestive tract, e.g., epithelial enterocytes and Peyer's patch M cells in the gut-associated lymphoid tissue, which permits the establishment of self-tolerance and inhibition of autoimmune reactions in the subjects.
- administered immunoglobulins can bind intestinal immunoglobulin G receptors, i.e., Fc ⁇ R, and such binding initiate modulation of autoimmune disorders, that is, Fc-mediated immunomodulation.
- This Fc-mediated immunomodulation can occur via immunoglobulin binding of, but not limited to, the intestinal Fc ⁇ RBP, i.e., Fc ⁇ Binding Protein (Harada et al, 1991), which plays an important role in inflammation and immunomodulation in humans (Harada et al, 1997) with autoimmune diseases (Kobayashi et al, 2001); the IgG receptor FcRn in the intestinal epithelium (Israel et al, 1997) which prevents IgG catabolism (Junghans and Anderson, 1996) and thus, has a role in modulating the increased serum immunoglobulin of some autoimmune disorders (Bleeker et al, 2001).
- the intestinal Fc ⁇ RBP i.e., Fc ⁇ Binding Protein
- the present invention contemplates administering immunoglobulins via an alimentary route to stimulate, enhance or supplement the mucosal immune system and modulate autoimmune disorders resulting in a treatment for immune-mediated diseases. 4. Combination treatments
- immunoglobulin compositions in combination with a known treatment for the immune- mediated disease that is being treated.
- oral immunoglobulin is administered to an ASD patient in combination with a therapy for dietary protein intolerance or a behavioral therapy program. It is well within the knowledge of those of skill in the art to determine the appropriate therapies to use in combination with the oral immunoglobulin therapy.
- Subjects are administered the immunoglobulin composition orally once a day before bedtime, as an add-on to their background therapy for ASD and dietary protein intolerance.
- Subjects receive capsules containing IgG and IgA once daily for 8 weeks (420 mg/day).
- Immunological parameters are measured, for example, cytokine production in response to common dietary antigens (gliadin, casein, ⁇ - lactoalbumin, and ⁇ -lactoglobulin), LPS, and MBP. Cytokine levels are determined at protein and mRNA levels.
- Other parameters that are measured include IFN- ⁇ , TNF- ⁇ , IL-5, IL-l ⁇ , IL-6, IL-10, sTNFRII, and IL-12p40.
- Markers for the GI tract inflammation are measured, such as calprotectin levels in the stool.
- Clinical symptoms such as frequency of bowel movement, stool consistency, color and smells of stools, etc. are documented.
- Subjects were administered the immunoglobulin composition orally once a day before bedtime, as an add-on to their background therapy for ASD and dietary protein intolerance.
- Clinical assessments were carried out at prior to treatment (baseline), 4 weeks, 8 weeks, and 12 weeks. Each assessment consisted of a physical examination and an assessment of clinical activity (GI severity score, Physician global assessment, Patient global assessment, and Autism Behavior Checklist). Clinical symptoms, such as frequency of bowel movement, stool consistency, color and smells of stools, etc. were documented.
- Laboratory testing consisted of urinalysis, cell blood count (CBC) with manual differential, Westergren erythrocyte sedimentation rate (ESR), C reactive protein (CRP), chemistry 14 panel, Quantitative Immunoglobulins (QIGs), a stool culture for Clostridium difficile, and freezing of a serum aliquot. After 8 weeks, the same parameters were evaluated and the results were compared to those obtained prior to treatment.
- a clinical response was defined as a drop in the GI severity index score of at least 4 points from baseline.
- a clinical remission was defined by a GI Severity score of ⁇ 4 with an overall improvement of at least 4 points from baseline.
- Table 1 and Fig. 1 show that 55% of the patients had remission of GI symptoms and 78% of the patents had improvement of GI signs and symptoms. Yet further, Table 2 shows that there was a 21.8 point decrease in the ABC average score, which suggested an improvement in behavior. TABLE 2.
- a subject was diagnosed as "autistic" at the age of 2.5 years. At that time, a MRI or CNS showed localized demyelination. The subject also suffered an additional major regression following a VZV vaccination at age 3.75 years. An MRI following this episode of major regression showed increased demyelination. An elimination diet, secretin, numerous supplements and behavioral therapy have been tried with limited responses.
- autoimmune/inflammatory condition in the cerebral spinal fluid indicated autoimmune/inflammatory condition in the cerebral spinal fluid (CSF).
- the subject was positive for anti-MBP antibodies in serum and CSF.
- the subject was also noted to have elevated serum levels of proinflammatory (IL-l ⁇ , IL-6, IL-12 ⁇ 40, IL-18 and TNF- ⁇ ) and counter-regulatory cytokines (IL-lra, TGF- ⁇ , sTNFRI, and sTNFRII levels in the serum). More importantly, these cytokine levels were elevated in CSF as like seen in MS patients, indicating autoimmune conditions in the CNS. STNFRI and sTNFRII were notably elevated.
- the patient was administered 400 mg of an immunoglobulin composition daily in the form of Panglobulin (IVIg) dissolved in about 10 cc of water and taken orally at bedtime.
- IVIg Panglobulin
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Immunology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Microbiology (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Mycology (AREA)
- Psychiatry (AREA)
- Biophysics (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Hospice & Palliative Care (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002462682A CA2462682A1 (en) | 2001-10-04 | 2002-10-04 | The use of gammaglobulin for the treatment of immune-mediated diseases |
JP2003532004A JP2005508338A (en) | 2001-10-04 | 2002-10-04 | Use of gamma globulin to treat immune diseases |
EP02782181A EP1463527A4 (en) | 2001-10-04 | 2002-10-04 | The use of gammaglobulin for the treatment of immune-mediated diseases |
MXPA04003156A MXPA04003156A (en) | 2001-10-04 | 2002-10-04 | The use of gammaglobulin for the treatment of immune-mediated diseases. |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US32704301P | 2001-10-04 | 2001-10-04 | |
US60/327,043 | 2001-10-04 | ||
US38096002P | 2002-05-16 | 2002-05-16 | |
US60/380,960 | 2002-05-16 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2003028668A2 true WO2003028668A2 (en) | 2003-04-10 |
WO2003028668A3 WO2003028668A3 (en) | 2004-07-22 |
Family
ID=26985697
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2002/033322 WO2003028668A2 (en) | 2001-10-04 | 2002-10-04 | Gammaglobulin treatment of immune disorders |
Country Status (6)
Country | Link |
---|---|
US (1) | US20030099635A1 (en) |
EP (1) | EP1463527A4 (en) |
JP (1) | JP2005508338A (en) |
CA (1) | CA2462682A1 (en) |
MX (1) | MXPA04003156A (en) |
WO (1) | WO2003028668A2 (en) |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006011485A1 (en) * | 2004-07-27 | 2006-02-02 | Osaka Bioscience Institute | Protein inhibiting amyloid peptide aggregation and effect of the same |
WO2010128265A3 (en) * | 2009-05-07 | 2011-04-21 | Stallergenes S.A. | Use of igg1 immunoglobulins and/or ligands of the cd32 receptor for treating inflammatory diseases and incidents via the mucosa |
WO2014134070A1 (en) | 2013-02-26 | 2014-09-04 | Baxter International Inc. | Treatment of central nervous system disorders by intranasal administration of immunoglobulin g |
WO2014182631A1 (en) | 2013-05-06 | 2014-11-13 | Baxter International Inc. | Treatment of alzheimer's disease subpopulations with pooled immunoglobulin g |
US9062101B2 (en) | 2010-08-14 | 2015-06-23 | AbbVie Deutschland GmbH & Co. KG | Amyloid-beta binding proteins |
US9822171B2 (en) | 2010-04-15 | 2017-11-21 | AbbVie Deutschland GmbH & Co. KG | Amyloid-beta binding proteins |
US9951125B2 (en) | 2006-11-30 | 2018-04-24 | Abbvie Inc. | Aβ conformer selective anti-Aβ globulomer monoclonal antibodies |
US10208109B2 (en) | 2005-11-30 | 2019-02-19 | Abbvie Inc. | Monoclonal antibodies against amyloid beta protein and uses thereof |
US10464976B2 (en) | 2003-01-31 | 2019-11-05 | AbbVie Deutschland GmbH & Co. KG | Amyloid β(1-42) oligomers, derivatives thereof and antibodies thereto, methods of preparation thereof and use thereof |
US10538581B2 (en) | 2005-11-30 | 2020-01-21 | Abbvie Inc. | Anti-Aβ globulomer 4D10 antibodies |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050101520A1 (en) * | 2002-03-29 | 2005-05-12 | Harumi Jyonouchi | CTLA4 compositions in the treatment of autism |
US20090280114A1 (en) * | 2002-04-12 | 2009-11-12 | Ramot At Tel Aviv University Ltd. | Prevention of brain inflammation as a result of induced autoimmune response |
WO2006014911A2 (en) * | 2004-07-26 | 2006-02-09 | Kossor David C | Treatment of inflammatory, autoimmune, or other disorders, using agents that reduce the sequestering of zinc by calprotectin |
WO2006073682A2 (en) | 2004-12-09 | 2006-07-13 | Meso Scale Technologies, Llc | Diagnostic test |
EP2124952A2 (en) | 2007-02-27 | 2009-12-02 | Abbott GmbH & Co. KG | Method for the treatment of amyloidoses |
US7968293B2 (en) | 2007-08-13 | 2011-06-28 | Baxter International Inc. | IVIG modulation of chemokines for treatment of multiple sclerosis, alzheimer's disease, and parkinson's disease |
US20100158893A1 (en) * | 2008-12-19 | 2010-06-24 | Baxter International Inc. | Systems and methods for obtaining immunoglobulin from blood |
SG176256A1 (en) | 2009-05-27 | 2012-01-30 | Baxter Int | A method to produce a highly concentrated immunoglobulin preparation for subcutaneous use |
EP2560678A4 (en) * | 2010-04-23 | 2013-09-18 | Probiotec Ltd | Pharmaceutical compositions |
US8796430B2 (en) | 2010-05-26 | 2014-08-05 | Baxter International Inc. | Method to produce an immunoglobulin preparation with improved yield |
WO2011150284A2 (en) | 2010-05-26 | 2011-12-01 | Baxter International Inc. | Removal of serine proteases by treatment with finely divided silicon dioxide |
AU2010202125B1 (en) | 2010-05-26 | 2010-09-02 | Takeda Pharmaceutical Company Limited | A method to produce an immunoglobulin preparation with improved yield |
US10478493B2 (en) | 2015-08-31 | 2019-11-19 | Stolle Milk Biologics, Inc. | Method of treating protozoal gastrointestinal disorders in immunocompromised patients |
ES2690178A1 (en) * | 2017-05-18 | 2018-11-19 | Apc Europe Slu | PLASMA OF ANIMAL OR FRACTIONS OF THE SAME FOR ITS USE IN THE TREATMENT OF DISORDERS OF COGNITIVE DETERIORATION IN HUMAN BEINGS AND ANIMALS OF COMPANY (Machine-translation by Google Translate, not legally binding) |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
USRE33565E (en) * | 1978-02-06 | 1991-04-02 | Stolle Research And Development Corporation | Prevention and treatment of rheumatioid arthritis |
US4477432A (en) * | 1981-05-01 | 1984-10-16 | Cutter Laboratories, Inc. | Oral immune globulin |
US5242691A (en) * | 1982-06-03 | 1993-09-07 | Stolle Research & Development Corporation | Anti-inflammatory factor, method of isolation, and use |
US4897265A (en) * | 1983-10-27 | 1990-01-30 | Stolle Research & Development Corporation | Method for treating disorders of the vascular and pulmonary systems |
US5106618A (en) * | 1987-07-02 | 1992-04-21 | Stolle Research And Development Corporation | Method of treating protozoal gastrointestinal disorders by administering hyperimmune milk product |
AU664561B2 (en) * | 1991-06-21 | 1995-11-23 | University Of Cincinnati, The | Orally administrable therapeutic proteins and method of making |
US5888511A (en) * | 1993-02-26 | 1999-03-30 | Advanced Biotherapy Concepts, Inc. | Treatment of autoimmune diseases, including AIDS |
US5455160A (en) * | 1993-05-27 | 1995-10-03 | Fagerhol; Magne K. | Diagnostic test and kit for disease or disorders in the digestive system |
US5681571A (en) * | 1993-10-08 | 1997-10-28 | Duotol Ab | Immunological tolerance-inducing agent |
US6090380A (en) * | 1994-01-12 | 2000-07-18 | Research Corporation Technologies, Inc. | Treatment of rheumatoid arthritis by oral administration of pooled human immunoglobulin |
JPH10212246A (en) * | 1997-01-30 | 1998-08-11 | Nippon Zoki Pharmaceut Co Ltd | Preparation for oral administration |
DE69830185D1 (en) * | 1997-05-19 | 2005-06-16 | Repligen Corp | METHOD FOR SUPPORTING DIFFERENTIAL DIAGNOSTICS AND TREATING AUTISTIC SYNDROMES |
US20020114802A1 (en) * | 1998-02-10 | 2002-08-22 | Tjellstrom Bo Arthur Einar | Oral immunoglobulin treatment for inflammatory bowel disease |
WO1999057152A1 (en) * | 1998-05-07 | 1999-11-11 | Research Corporation Technologies, Inc. | Oral administration of immunoglobulins for treating autoimmune hearing loss |
EP1109821A4 (en) * | 1998-08-25 | 2002-04-03 | Human Genome Sciences Inc | 49 human secreted proteins |
EP1171161A1 (en) * | 1999-04-19 | 2002-01-16 | Richard Weisbart | Treatment of adult rheumatoid arthritis by oral administration of pooled human immunoglobulin and an antacid |
US6187309B1 (en) * | 1999-09-14 | 2001-02-13 | Milkaus Laboratory, Inc. | Method for treatment of symptoms of central nervous system disorders |
-
2002
- 2002-10-04 JP JP2003532004A patent/JP2005508338A/en active Pending
- 2002-10-04 US US10/264,564 patent/US20030099635A1/en not_active Abandoned
- 2002-10-04 MX MXPA04003156A patent/MXPA04003156A/en unknown
- 2002-10-04 CA CA002462682A patent/CA2462682A1/en not_active Abandoned
- 2002-10-04 EP EP02782181A patent/EP1463527A4/en not_active Withdrawn
- 2002-10-04 WO PCT/US2002/033322 patent/WO2003028668A2/en not_active Application Discontinuation
Non-Patent Citations (11)
Title |
---|
ACHIRON A. ET AL: 'Immunoglobulin treatment in multiple sclerosis and experimental autoimmune encephalomyelitis' MULT. SCLER. vol. 6, no. SUPPL. 2, October 2000, pages S6 - S8, S33, XP002978574 * |
ACHIRON A. ET AL: 'Intravenous immunoglobulin treatment in multiple sclerosis' NEUROLOGY vol. 50, no. 2, February 1998, pages 398 - 402, XP002978547 * |
DEL GIUDICE-ASCH G. ET AL: 'Brief report: a pilot open clinical trial of intravenous immunoglobulin in childhood autism' J. AUTISM DEV DISORD vol. 29, no. 2, April 1999, pages 157 - 160, XP002978522 * |
DURELLI ET AL: 'Immunoglobulin treatment of multiple sclerosis: future prospects' NEUROL SCI vol. 24, no. SUPPL. 4, October 2003, pages S234 - S238, XP002978371 * |
EGG R. ET AL: 'Anti-MOG and anti-MBP antibody subclasses in multiple sclerosis' MULTIPLE SCLEROSIS vol. 7, no. 5, October 2001, pages 285 - 289, XP002978546 * |
GUPTA S.: 'Immunological treatments for autism' J. AUTISM. DEV. DISORD. vol. 30, no. 5, October 2000, pages 475 - 479, XP002978523 * |
PLIOPLYS A.V.: 'Intravenous immunoglobulin treatment in autism' J. AUTISM DEV. DISORD. vol. 30, no. 1, February 2000, pages 73 - 74, XP002978521 * |
RESKE D. ET AL: 'The immunomodulatory properties of in vitro immunoglobulins are dose-dependent' ACTA NEUROL SCAND vol. 108, no. 4, October 2003, pages 267 - 273, XP002978370 * |
SCHENK D. ET AL: 'Immunization with amyloid-b attenuates Alzheimer-disease-like pathology in the PDAPP mouse' NATURE vol. 400, 08 July 1999, pages 173 - 177, XP002906872 * |
SCHULLER E. ET AL: 'Long-term treatment of multiple sclerosis with IgG immunotherapy' PATHOLOGIE BIOLOGIE vol. 44, no. 8, October 1996, pages 710 - 715, XP002978537 * |
See also references of EP1463527A2 * |
Cited By (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10464976B2 (en) | 2003-01-31 | 2019-11-05 | AbbVie Deutschland GmbH & Co. KG | Amyloid β(1-42) oligomers, derivatives thereof and antibodies thereto, methods of preparation thereof and use thereof |
WO2006011485A1 (en) * | 2004-07-27 | 2006-02-02 | Osaka Bioscience Institute | Protein inhibiting amyloid peptide aggregation and effect of the same |
US10208109B2 (en) | 2005-11-30 | 2019-02-19 | Abbvie Inc. | Monoclonal antibodies against amyloid beta protein and uses thereof |
US10538581B2 (en) | 2005-11-30 | 2020-01-21 | Abbvie Inc. | Anti-Aβ globulomer 4D10 antibodies |
US10323084B2 (en) | 2005-11-30 | 2019-06-18 | Abbvie Inc. | Monoclonal antibodies against amyloid beta protein and uses thereof |
US9951125B2 (en) | 2006-11-30 | 2018-04-24 | Abbvie Inc. | Aβ conformer selective anti-Aβ globulomer monoclonal antibodies |
WO2010128265A3 (en) * | 2009-05-07 | 2011-04-21 | Stallergenes S.A. | Use of igg1 immunoglobulins and/or ligands of the cd32 receptor for treating inflammatory diseases and incidents via the mucosa |
US20120171198A1 (en) * | 2009-05-07 | 2012-07-05 | Stallergenes S.A. | Use of igg1 immunoglobulins and/or ligands of the cd32 receptor for treating inflammatory diseases and manifestations via the mucosal route |
US9187568B2 (en) | 2009-05-07 | 2015-11-17 | Stallergenes S.A. | Use of IgG1 immunoglobulins and/or ligands of the CD32 receptor for treating inflammatory diseases and manifestations via the mucosal route |
US9822185B2 (en) | 2009-05-07 | 2017-11-21 | Stallergenes | Use of IGG1 immunoglobulins and/or ligands of the CD32 receptor for treating inflammatory diseases and incidents via the mucosa |
US9822171B2 (en) | 2010-04-15 | 2017-11-21 | AbbVie Deutschland GmbH & Co. KG | Amyloid-beta binding proteins |
US9062101B2 (en) | 2010-08-14 | 2015-06-23 | AbbVie Deutschland GmbH & Co. KG | Amyloid-beta binding proteins |
US10047121B2 (en) | 2010-08-14 | 2018-08-14 | AbbVie Deutschland GmbH & Co. KG | Amyloid-beta binding proteins |
US10144776B2 (en) | 2013-02-26 | 2018-12-04 | Baxalta Incorporated | Treatment of central nervous system disorders by intranasal administration of immunoglobulin G |
US9556260B2 (en) | 2013-02-26 | 2017-01-31 | Baxalta Incorporated | Treatment of central nervous system disorders by intranasal administration of immunoglobulin G |
WO2014134070A1 (en) | 2013-02-26 | 2014-09-04 | Baxter International Inc. | Treatment of central nervous system disorders by intranasal administration of immunoglobulin g |
EP3597220A1 (en) | 2013-02-26 | 2020-01-22 | Baxalta GmbH | Treatment of central nervous system disorders by intranasal administration of immunoglobulin g |
US11851481B2 (en) | 2013-02-26 | 2023-12-26 | Takeda Pharmaceutical Company Limited | Treatment of central nervous system disorders by intranasal administration of immunoglobulin g |
EP3552624A1 (en) | 2013-05-06 | 2019-10-16 | Baxalta Incorporated | Treatment of alzheimer's disease subpopulations with pooled immunoglobulin g |
WO2014182631A1 (en) | 2013-05-06 | 2014-11-13 | Baxter International Inc. | Treatment of alzheimer's disease subpopulations with pooled immunoglobulin g |
Also Published As
Publication number | Publication date |
---|---|
US20030099635A1 (en) | 2003-05-29 |
EP1463527A4 (en) | 2005-05-11 |
WO2003028668A3 (en) | 2004-07-22 |
EP1463527A2 (en) | 2004-10-06 |
CA2462682A1 (en) | 2003-04-10 |
JP2005508338A (en) | 2005-03-31 |
MXPA04003156A (en) | 2005-01-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20030099635A1 (en) | Use of oral gammaglobulin for the treatment of immune-mediated diseases | |
US10912955B2 (en) | Treatment of celiac disease, C. difficile infection, food intolerance and food allergy with secretory IgA/IgM | |
US6187309B1 (en) | Method for treatment of symptoms of central nervous system disorders | |
US20170218056A1 (en) | Humanized antibodies specific for hsp65-derived peptide-6, methods and uses thereof | |
AU2003218206B2 (en) | Methods for alleviating symptoms associated with neuropathic conditions comprising administration of low levels of antibodies | |
US20040202660A1 (en) | Methods and compositions for treatment of immune dysfunction disorders | |
US7771725B2 (en) | Medicinal concentrate of arbovirus specific immunoglobulins and F(ab)'2 and/or Fab fragments | |
AU2018213127A1 (en) | Therapies for treating inflammatory disorders | |
AU2002348464A1 (en) | Gammaglobulin treatment of immune disorders | |
US6200565B1 (en) | Oral administration of immunoglobulins for treating autoimmune hearing loss | |
US11319361B2 (en) | Treatment of intestinal dysbiosis with immunoglobin | |
WO2024151506A1 (en) | Process for preparation of secretory iga and secretory igm and use thereof for treating necrotizing enterocolitis | |
CA2370268A1 (en) | Treatment of adult rheumatoid arthritis by oral administration of pooled human immunoglobulin and an antacid | |
WO2006036213A2 (en) | The use of gammaglobulin for the treatment of periodontal disease | |
CA2423805A1 (en) | Treatment of immune-mediated diseases by oral administration of plasma fractions enriched in immunoglobulin g | |
CA2424623A1 (en) | Treatment of juvenile rheumatioid arthritis by oral administration of pooled human immunoglobulin and an antacid |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BY BZ CA CH CN CO CR CU CZ DE DM DZ EC EE ES FI GB GD GE GH HR HU ID IL IN IS JP KE KG KP KR LC LK LR LS LT LU LV MA MD MG MN MW MX MZ NO NZ OM PH PL PT RU SD SE SG SI SK SL TJ TM TN TR TZ UA UG US UZ VN YU ZA ZM |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): GH GM KE LS MW MZ SD SL SZ UG ZM ZW AM AZ BY KG KZ RU TJ TM AT BE BG CH CY CZ DK EE ES FI FR GB GR IE IT LU MC PT SE SK TR BF BJ CF CG CI GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: PA/a/2004/003156 Country of ref document: MX Ref document number: 2003532004 Country of ref document: JP Ref document number: 2462682 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2002348464 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2002782181 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 2002782181 Country of ref document: EP |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
WWW | Wipo information: withdrawn in national office |
Ref document number: 2002782181 Country of ref document: EP |