CA3020894A1 - Methods and compositions for the treatment of celiac disease, non-celiac gluten sensitivity, and refractory celiac disease - Google Patents
Methods and compositions for the treatment of celiac disease, non-celiac gluten sensitivity, and refractory celiac disease Download PDFInfo
- Publication number
- CA3020894A1 CA3020894A1 CA3020894A CA3020894A CA3020894A1 CA 3020894 A1 CA3020894 A1 CA 3020894A1 CA 3020894 A CA3020894 A CA 3020894A CA 3020894 A CA3020894 A CA 3020894A CA 3020894 A1 CA3020894 A1 CA 3020894A1
- Authority
- CA
- Canada
- Prior art keywords
- antibody
- sequence
- administered
- seq
- pharmaceutical composition
- 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.)
- Pending
Links
- 208000015943 Coeliac disease Diseases 0.000 title claims abstract description 90
- 238000000034 method Methods 0.000 title claims abstract description 76
- 108010068370 Glutens Proteins 0.000 title claims abstract description 67
- 235000021312 gluten Nutrition 0.000 title claims abstract description 67
- 208000021329 Refractory celiac disease Diseases 0.000 title claims abstract description 47
- 238000011282 treatment Methods 0.000 title claims abstract description 34
- 230000035945 sensitivity Effects 0.000 title claims abstract description 22
- 239000000203 mixture Substances 0.000 title description 48
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 74
- 239000012634 fragment Substances 0.000 claims description 57
- 239000000427 antigen Substances 0.000 claims description 56
- 108091007433 antigens Proteins 0.000 claims description 56
- 102000036639 antigens Human genes 0.000 claims description 56
- 230000027455 binding Effects 0.000 claims description 49
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 40
- 108010047041 Complementarity Determining Regions Proteins 0.000 claims description 15
- 238000010254 subcutaneous injection Methods 0.000 claims description 14
- 239000007929 subcutaneous injection Substances 0.000 claims description 12
- 238000010253 intravenous injection Methods 0.000 claims description 10
- 238000011068 loading method Methods 0.000 claims description 5
- 208000027866 inflammatory disease Diseases 0.000 abstract description 5
- 102000003812 Interleukin-15 Human genes 0.000 description 82
- 108090000172 Interleukin-15 Proteins 0.000 description 82
- 208000024891 symptom Diseases 0.000 description 47
- 210000005024 intraepithelial lymphocyte Anatomy 0.000 description 38
- 150000001875 compounds Chemical class 0.000 description 30
- 208000002460 Enteropathy-Associated T-Cell Lymphoma Diseases 0.000 description 22
- 230000001594 aberrant effect Effects 0.000 description 19
- 230000000968 intestinal effect Effects 0.000 description 18
- 230000001225 therapeutic effect Effects 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 17
- 238000007920 subcutaneous administration Methods 0.000 description 17
- 239000003814 drug Substances 0.000 description 16
- 235000006171 gluten free diet Nutrition 0.000 description 16
- 235000020884 gluten-free diet Nutrition 0.000 description 16
- 230000004044 response Effects 0.000 description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 14
- 229940079593 drug Drugs 0.000 description 14
- 238000001990 intravenous administration Methods 0.000 description 14
- 150000007523 nucleic acids Chemical group 0.000 description 14
- 239000000902 placebo Substances 0.000 description 14
- 229940068196 placebo Drugs 0.000 description 14
- 235000013305 food Nutrition 0.000 description 13
- 108020004707 nucleic acids Proteins 0.000 description 13
- 102000039446 nucleic acids Human genes 0.000 description 13
- 238000006467 substitution reaction Methods 0.000 description 13
- 230000008030 elimination Effects 0.000 description 12
- 238000003379 elimination reaction Methods 0.000 description 12
- 239000002502 liposome Substances 0.000 description 12
- 101001055157 Homo sapiens Interleukin-15 Proteins 0.000 description 11
- 108060003951 Immunoglobulin Proteins 0.000 description 11
- 235000001014 amino acid Nutrition 0.000 description 11
- 230000002496 gastric effect Effects 0.000 description 11
- 102000056003 human IL15 Human genes 0.000 description 11
- 102000018358 immunoglobulin Human genes 0.000 description 11
- 230000005764 inhibitory process Effects 0.000 description 10
- 239000002773 nucleotide Substances 0.000 description 10
- 125000003729 nucleotide group Chemical group 0.000 description 10
- 108090000623 proteins and genes Proteins 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- 238000001574 biopsy Methods 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 230000006378 damage Effects 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 210000000822 natural killer cell Anatomy 0.000 description 9
- 235000018102 proteins Nutrition 0.000 description 9
- 102000004169 proteins and genes Human genes 0.000 description 9
- 206010039073 rheumatoid arthritis Diseases 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 9
- 108091028043 Nucleic acid sequence Proteins 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 210000001744 T-lymphocyte Anatomy 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 8
- 210000001035 gastrointestinal tract Anatomy 0.000 description 8
- 238000001802 infusion Methods 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- 210000000056 organ Anatomy 0.000 description 8
- 108020003175 receptors Proteins 0.000 description 8
- 102000005962 receptors Human genes 0.000 description 8
- 230000009885 systemic effect Effects 0.000 description 8
- 102000000588 Interleukin-2 Human genes 0.000 description 7
- 108010002350 Interleukin-2 Proteins 0.000 description 7
- 201000004681 Psoriasis Diseases 0.000 description 7
- 206010042971 T-cell lymphoma Diseases 0.000 description 7
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 7
- 238000010521 absorption reaction Methods 0.000 description 7
- 230000002411 adverse Effects 0.000 description 7
- 239000003937 drug carrier Substances 0.000 description 7
- 230000014509 gene expression Effects 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 230000003285 pharmacodynamic effect Effects 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 208000023275 Autoimmune disease Diseases 0.000 description 6
- 102000004127 Cytokines Human genes 0.000 description 6
- 108090000695 Cytokines Proteins 0.000 description 6
- 206010025323 Lymphomas Diseases 0.000 description 6
- 108091008874 T cell receptors Proteins 0.000 description 6
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 6
- 241000209140 Triticum Species 0.000 description 6
- 235000021307 Triticum Nutrition 0.000 description 6
- 230000004913 activation Effects 0.000 description 6
- -1 coatings Substances 0.000 description 6
- 238000003745 diagnosis Methods 0.000 description 6
- 235000005911 diet Nutrition 0.000 description 6
- 239000006185 dispersion Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 230000035755 proliferation Effects 0.000 description 6
- 230000009261 transgenic effect Effects 0.000 description 6
- 241000282412 Homo Species 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 238000007792 addition Methods 0.000 description 5
- 125000000539 amino acid group Chemical group 0.000 description 5
- 230000006907 apoptotic process Effects 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- 238000012377 drug delivery Methods 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 238000011065 in-situ storage Methods 0.000 description 5
- 210000005025 intestinal intraepithelial lymphocyte Anatomy 0.000 description 5
- 238000012423 maintenance Methods 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- 238000012986 modification Methods 0.000 description 5
- 230000002085 persistent effect Effects 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 230000004083 survival effect Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 4
- 241000209219 Hordeum Species 0.000 description 4
- 235000007340 Hordeum vulgare Nutrition 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 241000209056 Secale Species 0.000 description 4
- 235000007238 Secale cereale Nutrition 0.000 description 4
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 4
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 4
- 208000006903 Wheat Hypersensitivity Diseases 0.000 description 4
- 230000005856 abnormality Effects 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 230000001419 dependent effect Effects 0.000 description 4
- 230000037213 diet Effects 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 238000000684 flow cytometry Methods 0.000 description 4
- 230000037406 food intake Effects 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 230000002068 genetic effect Effects 0.000 description 4
- 210000004602 germ cell Anatomy 0.000 description 4
- 210000000987 immune system Anatomy 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 210000004347 intestinal mucosa Anatomy 0.000 description 4
- 239000007951 isotonicity adjuster Substances 0.000 description 4
- 239000000787 lecithin Substances 0.000 description 4
- 235000010445 lecithin Nutrition 0.000 description 4
- 229940067606 lecithin Drugs 0.000 description 4
- 230000003211 malignant effect Effects 0.000 description 4
- 238000002703 mutagenesis Methods 0.000 description 4
- 231100000350 mutagenesis Toxicity 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 230000002035 prolonged effect Effects 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 241000894007 species Species 0.000 description 4
- 235000000346 sugar Nutrition 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 201000006520 wheat allergy Diseases 0.000 description 4
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 3
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 3
- 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 3
- 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 3
- 108020004414 DNA Proteins 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 206010067745 Intestinal mucosal atrophy Diseases 0.000 description 3
- 206010067994 Mucosal atrophy Diseases 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 108060008539 Transglutaminase Proteins 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 210000003719 b-lymphocyte Anatomy 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 230000008499 blood brain barrier function Effects 0.000 description 3
- 210000001218 blood-brain barrier Anatomy 0.000 description 3
- 235000013339 cereals Nutrition 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000011109 contamination Methods 0.000 description 3
- 238000012217 deletion Methods 0.000 description 3
- 230000037430 deletion Effects 0.000 description 3
- 239000002612 dispersion medium Substances 0.000 description 3
- 231100000673 dose–response relationship Toxicity 0.000 description 3
- 238000001839 endoscopy Methods 0.000 description 3
- 210000002919 epithelial cell Anatomy 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 230000028993 immune response Effects 0.000 description 3
- 239000007943 implant Substances 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 238000009533 lab test Methods 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 230000002018 overexpression Effects 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 230000007310 pathophysiology Effects 0.000 description 3
- 229920005862 polyol Polymers 0.000 description 3
- 150000003077 polyols Chemical class 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 238000004393 prognosis Methods 0.000 description 3
- 230000000770 proinflammatory effect Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 150000008163 sugars Chemical class 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 102000003601 transglutaminase Human genes 0.000 description 3
- 230000001960 triggered effect Effects 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 206010003694 Atrophy Diseases 0.000 description 2
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 2
- 108010074051 C-Reactive Protein Proteins 0.000 description 2
- 102100032752 C-reactive protein Human genes 0.000 description 2
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 2
- 241000699802 Cricetulus griseus Species 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
- 206010012735 Diarrhoea Diseases 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108010061711 Gliadin Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 102000003886 Glycoproteins Human genes 0.000 description 2
- 108090000288 Glycoproteins Proteins 0.000 description 2
- 208000009329 Graft vs Host Disease Diseases 0.000 description 2
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 2
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 2
- 108700005091 Immunoglobulin Genes Proteins 0.000 description 2
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 2
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 2
- 108010017535 Interleukin-15 Receptors Proteins 0.000 description 2
- 102000004556 Interleukin-15 Receptors Human genes 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 2
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 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
- 241000282567 Macaca fascicularis Species 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 206010028116 Mucosal inflammation Diseases 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- 208000018359 Systemic autoimmune disease Diseases 0.000 description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 2
- 239000004473 Threonine Substances 0.000 description 2
- 108700019146 Transgenes Proteins 0.000 description 2
- 206010052779 Transplant rejections Diseases 0.000 description 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 2
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 2
- 230000033289 adaptive immune response Effects 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 208000007502 anemia Diseases 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000003429 antifungal agent Substances 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 210000000612 antigen-presenting cell Anatomy 0.000 description 2
- 239000003435 antirheumatic agent Substances 0.000 description 2
- 230000037444 atrophy Effects 0.000 description 2
- 230000005784 autoimmunity Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000000090 biomarker Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000012876 carrier material Substances 0.000 description 2
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 229960002436 cladribine Drugs 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000002537 cosmetic Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000001934 delay Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 230000000378 dietary effect Effects 0.000 description 2
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000002988 disease modifying antirheumatic drug Substances 0.000 description 2
- 230000003828 downregulation Effects 0.000 description 2
- 239000012636 effector Substances 0.000 description 2
- 230000007717 exclusion Effects 0.000 description 2
- 208000024908 graft versus host disease Diseases 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 230000002962 histologic effect Effects 0.000 description 2
- 210000004408 hybridoma Anatomy 0.000 description 2
- 208000034783 hypoesthesia Diseases 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 230000005934 immune activation Effects 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000004968 inflammatory condition Effects 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 239000007972 injectable composition Substances 0.000 description 2
- 230000015788 innate immune response Effects 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 229960000310 isoleucine Drugs 0.000 description 2
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 2
- 238000011813 knockout mouse model Methods 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000001165 lymph node Anatomy 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 238000007726 management method Methods 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 238000002483 medication Methods 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 210000001616 monocyte Anatomy 0.000 description 2
- 230000000877 morphologic effect Effects 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 235000021590 normal diet Nutrition 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
- 230000035935 pregnancy Effects 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 230000008707 rearrangement Effects 0.000 description 2
- 210000003289 regulatory T cell Anatomy 0.000 description 2
- 238000002271 resection Methods 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 238000012819 small-bowel biopsy Methods 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 150000005846 sugar alcohols Polymers 0.000 description 2
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 2
- 230000004797 therapeutic response Effects 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 231100000027 toxicology Toxicity 0.000 description 2
- 238000011830 transgenic mouse model Methods 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- 239000004474 valine Substances 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 description 1
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N (R)-alpha-Tocopherol Natural products OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010008025 Cerebellar ataxia Diseases 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 241000938605 Crocodylia Species 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 208000005577 Gastroenteritis Diseases 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 206010017964 Gastrointestinal infection Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 206010022095 Injection Site reaction Diseases 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 108010038453 Interleukin-2 Receptors Proteins 0.000 description 1
- 102000010789 Interleukin-2 Receptors Human genes 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 206010022678 Intestinal infections Diseases 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 1
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 241000282553 Macaca Species 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 206010025476 Malabsorption Diseases 0.000 description 1
- 208000004155 Malabsorption Syndromes Diseases 0.000 description 1
- 208000029725 Metabolic bone disease Diseases 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010028391 Musculoskeletal Pain Diseases 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 108091005461 Nucleic proteins Chemical group 0.000 description 1
- 206010049088 Osteopenia Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 108700039882 Protein Glutamine gamma Glutamyltransferase 2 Proteins 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 102100038095 Protein-glutamine gamma-glutamyltransferase 2 Human genes 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 1
- 230000006052 T cell proliferation Effects 0.000 description 1
- 208000000389 T-cell leukemia Diseases 0.000 description 1
- 208000028530 T-cell lymphoblastic leukemia/lymphoma Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 230000002424 anti-apoptotic effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 230000009830 antibody antigen interaction Effects 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 159000000032 aromatic acids Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000010385 ascorbyl palmitate Nutrition 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 229960002170 azathioprine Drugs 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
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 210000004271 bone marrow stromal cell Anatomy 0.000 description 1
- 238000010322 bone marrow transplantation Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- 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 1
- 235000021240 caseins Nutrition 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
- 229960002023 chloroprocaine Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 230000004154 complement system Effects 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000009260 cross reactivity Effects 0.000 description 1
- 238000009109 curative therapy Methods 0.000 description 1
- 229960002433 cysteine Drugs 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 229960001305 cysteine hydrochloride Drugs 0.000 description 1
- 230000006240 deamidation Effects 0.000 description 1
- 230000009615 deamination Effects 0.000 description 1
- 238000006481 deamination reaction Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 210000003162 effector t lymphocyte Anatomy 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 208000028208 end stage renal disease Diseases 0.000 description 1
- 201000000523 end stage renal failure Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- 229940012017 ethylenediamine Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000011124 ex vivo culture Methods 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 206010016165 failure to thrive Diseases 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 230000003328 fibroblastic effect Effects 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 229940014144 folate Drugs 0.000 description 1
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 210000000285 follicular dendritic cell Anatomy 0.000 description 1
- 235000012041 food component Nutrition 0.000 description 1
- 239000005417 food ingredient Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 210000001102 germinal center b cell Anatomy 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000008935 histological improvement Effects 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 150000002433 hydrophilic molecules Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000008629 immune suppression Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 229940125721 immunosuppressive agent Drugs 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 208000000509 infertility Diseases 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 231100000535 infertility Toxicity 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 210000002490 intestinal epithelial cell Anatomy 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 150000008146 mannosides Chemical class 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 238000001471 micro-filtration Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000003147 molecular marker Substances 0.000 description 1
- 230000003562 morphometric effect Effects 0.000 description 1
- 238000013425 morphometry Methods 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000006320 pegylation Effects 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 230000001124 posttranscriptional effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 201000010434 protein-losing enteropathy Diseases 0.000 description 1
- 229940117820 purinethol Drugs 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 235000021067 refined food Nutrition 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 230000007727 signaling mechanism Effects 0.000 description 1
- 230000037432 silent mutation Effects 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 229940100996 sodium bisulfate Drugs 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229940001482 sodium sulfite Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 239000007921 spray Substances 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
- 238000012414 sterilization procedure Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 235000020790 strict gluten-free diet Nutrition 0.000 description 1
- 108010033090 surfactant protein A receptor Proteins 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000012250 transgenic expression Methods 0.000 description 1
- 239000002451 tumor necrosis factor inhibitor Substances 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000009777 vacuum freeze-drying Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
- C07K16/244—Interleukins [IL]
-
- 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
- A61P1/12—Antidiarrhoeals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Immunology (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Biochemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
Methods and pharmaceutical compositions are provided herein for the treatment of inflammatory disorders, in particular celiac disease, refractory celiac disease and non-celiac gluten sensitivity.
Description
Methods and Compositions for the Treatment of Celiac Disease, Non-Celiac Gluten Sensitivity, and Refractory Celiac Disease FIELD
[0001] The compositions and methods disclosed herein relate to the treatment of inflammatory disorders, in particular Celiac Disease, Refractory Celiac Disease and Non-celiac gluten sensitivity.
BACKGROUND
[0001] The compositions and methods disclosed herein relate to the treatment of inflammatory disorders, in particular Celiac Disease, Refractory Celiac Disease and Non-celiac gluten sensitivity.
BACKGROUND
[0002] Celiac disease (CD) is a systemic autoimmune disease triggered by gluten consumption in genetically susceptible individuals (Green and Cellier, 2007).
CD results in debilitating symptoms, including gut mucosal damage and potentially serious medical complications.
CD results in debilitating symptoms, including gut mucosal damage and potentially serious medical complications.
[0003] CD was the first autoimmune disease with an identified antigen, gluten, the main protein present in some of the most common cereals (e.g., wheat, barley, rye).
Humans lack enzymes to fully digest gluten, which, in the right genetic context, triggers inflammation and autoimmunity in the gut and other organs following deamination by the enzyme transglutaminase (tTG). CD presents in a several forms, presenting challenges for treatment.
Humans lack enzymes to fully digest gluten, which, in the right genetic context, triggers inflammation and autoimmunity in the gut and other organs following deamination by the enzyme transglutaminase (tTG). CD presents in a several forms, presenting challenges for treatment.
[0004] CD is the only common autoimmune disorder with no approved medication.
Currently, the only available strategy for the management of CD is a lifelong total avoidance of gluten. The ubiquitous presence of gluten makes total avoidance very difficult, if not impossible. As little as 50 mg/day (a normal diet contains greater than 10 g/day) triggers activation of T cells in the small bowel and causes intestinal mucosal damage (Catassi et al., 2007). For this reason, more than 50% of CD patients on a gluten free diet (GFD) continue to present with active disease and intestinal immune activation and mucosal atrophy (Lee et al., 2003; Cranney et al., 2007; Hopper et al., 2007;
Midhagen et al., 2003). Approximately 20% of individuals diagnosed with celiac disease have persistent symptoms or anemia with or without a positive tissue transglutaminase antibody (a molecular marker indicating celiac).
Currently, the only available strategy for the management of CD is a lifelong total avoidance of gluten. The ubiquitous presence of gluten makes total avoidance very difficult, if not impossible. As little as 50 mg/day (a normal diet contains greater than 10 g/day) triggers activation of T cells in the small bowel and causes intestinal mucosal damage (Catassi et al., 2007). For this reason, more than 50% of CD patients on a gluten free diet (GFD) continue to present with active disease and intestinal immune activation and mucosal atrophy (Lee et al., 2003; Cranney et al., 2007; Hopper et al., 2007;
Midhagen et al., 2003). Approximately 20% of individuals diagnosed with celiac disease have persistent symptoms or anemia with or without a positive tissue transglutaminase antibody (a molecular marker indicating celiac).
[0005] Non-Responsive Celiac Disease (NRCD) is defined by the persistent signs, symptoms or laboratory abnormalities typical of CD, despite abstaining from dietary gluten for six to twelve months (Rubio-Tapia et al., 2013). Currently there are no effective treatments for NRCD.
[0006] Refractory Celiac Disease (RCD) is characterized by a rare but specific complication of persistent exposure to gluten in CD, which affects approximately 1% of celiac patients (Lebwohl et al., 2013). RCD is characterized by severe intestinal mucosal atrophy and gastrointestinal symptoms in the absence of gluten consumption and in the presence of small bowel aberrant intestinal intra-epithelial lymphocytes (IELs) (Verbeek et al., 2008, vanWanrooij et al., 2014). The cut-off of 20% aberrant IELs in the small bowel separates RCD Type I (<20%) vs. RCD Type II (RCD-II, 20% or greater). While RCD-I can be treated symptomatically with steroids, there are no approved or curative treatments for RCD-I and RCD-II, and the latter evolves to overt lymphoma in 50% of the cases, with very poor prognosis (Nijeboer et al., 2015).
[0007] Enteropathy-Associated T Cell Lymphoma (EATL) is a high-grade, systemic, T cell lymphoma almost exclusively seen as a complication of RCD-II (Nijeboer et al., 2015).
Diagnosis includes imaging and histology to demonstrate the presence of malignant T cells in extra-epithelial locations such as lymph nodes or other organs. The treatment of EATL
relies on surgical resection and chemotherapy, but the prognosis is very poor, with a 5-year survival of less than 20% (Nijeboer et al., 2015).
Diagnosis includes imaging and histology to demonstrate the presence of malignant T cells in extra-epithelial locations such as lymph nodes or other organs. The treatment of EATL
relies on surgical resection and chemotherapy, but the prognosis is very poor, with a 5-year survival of less than 20% (Nijeboer et al., 2015).
[0008] Some of the CD-associated symptoms experienced in response to ingestion of wheat are also reported by individuals who do not have the typical serologic, histologic, or genetic markers of CD, and who also do not experience the immunoglobulin E (IgE) serologic response associated with wheat allergy. The term non-celiac gluten sensitivity (NCGS) has been proposed to refer to the spectrum of conditions reported by these patients (Lundin and Alaedini, 2012). Non-celiac gluten sensitivity is currently understood as a condition associated with the experiencing of various symptoms in response to ingestion of foods containing wheat, rye, and barley, and the resolution of symptoms on removal of those foods from diet in individuals in whom CD and wheat allergy have been ruled out (Lundin and Alaedini, 2012).
[0009] As such, effective treatments for CD, NRCD, RCD, EATL and NCGS are urgently needed.
SUMMARY
SUMMARY
[0010] In one aspect, the invention relates to a method of treating celiac disease or non-celiac gluten sensitivity in a subject in need thereof, comprising administering a therapeutically effective amount of an anti-IL-15 antibody or antigen-binding fragment thereof to the subject, wherein the therapeutically effective amount comprises 1-20 unit doses each administered at about 1-12 week intervals, each unit dose independently comprising about 50-1000 mg, preferably 75-600 mg, more preferably about 75 mg, about 150 mg, about 300 mg or about 600 mg of the anti-IL-15 antibody or antigen-binding fragment thereof In one embodiment, the therapeutically effective amount comprises 6 unit doses administered at about 2 week intervals. Each unit dose may be administered by subcutaneous injection or intravenous injection.
100111 In another aspect, the invention relates to a pharmaceutical composition for the treatment of, or a pharmaceutical composition for use in a method of treating, celiac disease or non-celiac gluten sensitivity, comprising a therapeutically effective amount of an anti-IL-15 antibody or antigen-binding fragment thereof, wherein the therapeutically effective amount comprises 1-20 unit doses each to be administered at about 1-12 week intervals, each unit dose independently comprising about 50-1000 mg, preferably 75-600 mg, more preferably about 75 mg, about 150 mg, about 300 mg or about 600 mg of the anti-IL-15 antibody or antigen-binding fragment thereof In one embodiment of the pharmaceutical composition, the therapeutically effective amount comprises 6 unit doses to be administered at 2 week intervals. Each unit dose can be administered by subcutaneous injection or intravenous injection.
[0012] Another aspect of the invention relates to a method of treating refractory celiac disease in a subject in need thereof, comprising administering a therapeutically effective amount of an anti-IL-15 antibody or antigen-binding fragment thereof to the subject, wherein the therapeutically effective amount comprises 1-20 unit doses each administered at about 1-12 week intervals, each unit dose independently comprising about 1-50 mg/kg, preferably about 4-16 mg/kg, more preferably about 4 mg/kg, about 8 mg/kg, about 12 mg/kg or about 16 mg/kg of the anti-IL-15 antibody or antigen-binding fragment thereof In one embodiment, the therapeutically effective amount comprises 6 unit doses administered at 2 week intervals, and an optional additional loading dose at week 1. Each unit dose is administered by subcutaneous injection or intravenous injection.
The refractory celiac disease is type I or type II refractory celiac disease.
[0013] Also provided herein is a pharmaceutical composition for the treatment of, or a pharmaceutical composition for use in a method of treating, refractory celiac disease, comprising a therapeutically effective amount of an anti-IL-15 antibody or antigen-binding fragment thereof, wherein the therapeutically effective amount comprises 1-20 unit doses each administered at about 1-12 week intervals, each unit dose independently comprising about 1-50 mg/kg, preferably about 4-16 mg/kg, more preferably about 4 mg/kg, about 8 mg/kg, about 12 mg/kg or about 16 mg/kg of the anti-IL-15 antibody or antigen-binding fragment thereof The therapeutically effective amount in some embodiments comprises 6 unit doses to be administered at 2 week intervals, and an optional additional loading dose to be administered at week 1. Each unit dose can be administered by subcutaneous injection or intravenous injection. The refractory celiac disease can be type I or type II.
[0014] In some embodiments of the methods and/or pharmaceutical compositions disclosed herein, the antibody may have a heavy chain variable region comprising one or more complementarity determining regions of SEQ ID NOs:5-7, or a sequence having at least 80% sequence identity thereto. The antibody may, in certain embodiments, have a light chain variable region comprising one or more complementarity determining regions of SEQ
ID NOs:8-10, or a sequence having at least 80% sequence identity thereto. The antibody in some embodiments has a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:2, or a sequence having at least 80% sequence identity thereto.
In certain embodiments, the antibody may have a light chain variable region comprising the amino acid sequence of SEQ ID NO:4, or a sequence having at least 80% sequence identity thereto.
BRIEF DESCRIPTION OF THE FIGURES
[0015] FIG. 1 illustrates a schematic structure of AMG 714.
[0016] FIG. 2 illustrates villi present in the gut of healthy subject and subjects with active celiac disease.
[0017] FIG. 3 illustrates a simplified schematic of celiac and refractory celiac disease pathophysiology.
[0018] FIG. 4 illustrates a simplified schematic of IL-15 signaling in RCD-II.
[0019] FIG. 5 illustrates a simplified schematic of the multiple roles of IL-15 in celiac and refractory celiac disease.
DETAILED DESCRIPTION
[0020] The compositions and methods disclosed herein relate to the treatment of gastrointestinal disorders such as CD, NRCD, RCD, EATL and NCGS by modulating an activity of IL-15 using, e.g., a therapeutically effective amount of an IL-15 antagonist. In some embodiments, the IL-15 antagonist is an antibody. In some embodiments, IL-15 can be blocked by AMG 714, a monoclonal antibody which can bind to, and inhibit the function of IL-15.
[0021] Pharmaceutical compositions provided herein can include a therapeutically effective amount of a recombinant monoclonal antibody or antigen-binding fragments against IL-15, in particular human IL-15. Suitable antibodies can include, for example, murine, chimeric, humanized and fully human antibodies, as well as other antibody forms known in the art. In some embodiments, the antibody can include but is not limited to those disclosed in U.S.
Patent Nos. 7,247,304, 7,329,405, 7,153,507, 7,597,892, 7,585,961 and 8,345,105, all of which are incorporated herein by reference in their entirety. The antibody can be provided in the form of a recombinantly expressed glycoprotein, using methods disclosed in, e.g., International Patent Application No. W02007/07087384, which is incorporated herein by reference in its entirety.
[0022] In one embodiment, the antibody is a fully human monoclonal antibody that binds IL-15. In a specific embodiment, the antibody is AMG 714 which has a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:2 and/or a light chain variable region comprising the amino acid sequence set forth in SEQ ID
NO:4. The antibody can also have amino acid sequences of about 80%, 85%, 90%, 95% or greater identity to SEQ ID NO: 2 and/or SEQ ID NO: 4.
[0023] In some embodiments, the antibody can include a light chain variable region comprising one or more complementarily determining regions (CDRs) set forth in SEQ ID
NOs:8-10, or homologous sequences thereof (e.g., having amino acid sequences of about 80%, 85%, 90%, 95% or greater identity to any of SEQ ID NOs: 8-10). The antibody can alternatively or additionally include a heavy chain variable region comprising one or more CDRs set forth in SEQ ID NOs:5-7, or homologous sequences thereof (e.g., having amino acid sequences of about 80%, 85%, 90%, 95% or greater identity to any of SEQ
ID NOs: 5-7). In a particular embodiment, a human monoclonal antibody that binds IL-15 or an antigen-binding fragment thereof, includes a light chain variable region comprising all three CDRs set forth in SEQ ID NOs:8-10, or conservative amino acid substitutions thereof, and a heavy chain variable region comprising all three CDRs set forth in SEQ ID NOs:
5-7, or conservative amino acid substitutions thereof [0024] The pharmaceutical compositions disclosed herein can include a therapeutically effective amount of an isolated monoclonal antibody that binds IL-15 or an antigen-binding fragment thereof and a pharmaceutically acceptable carrier. The pharmaceutical compositions can be used to treat or prevent a disorder associated with an overexpression of human IL-15 and/or in which a down regulation or inhibition of human IL-15 induced effects is beneficial.
[0025] Also provided herein is a method of treating or preventing a disorder associated with an overexpression of human IL-15 and/or in which a down regulation or inhibition of human IL-15 induced effects is beneficial, by administering to a subject a therapeutically effective amount of an isolated anti-IL-15 antibody, or an antigen-binding fragment thereof [0026] Exemplary disorders that can be treated or prevented using the presently disclosed methods or compositions include, but are not limited to, Celiac Disease, Non-Responsive Celiac Disease, Refractory Celiac Disease, Enteropathy-Associated T Cell Lymphoma, and Gluten-Sensitive Enteropathy. Other disorders that can be treated include vasculitis, psoriasis, multiple sclerosis, rheumatoid arthritis (RA), inflammatory disorders (e.g., inflammatory bowel disease), allograft rejection, graft versus host disease, T-cell lymphoma, and T-cell leukemia.
Definitions [0027] For convenience, certain terms employed in the specification, examples, and appended claims are collected here. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
[0028] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.
[0029] As used herein, the term "about" means within 20%, more preferably within 10%
and most preferably within 5%. The term "substantially" means more than 50%, preferably more than 80%, and most preferably more than 90% or 95%.
[0030] The terms "IL-15," "IL-15 antigen" and "interleukin 15" are used interchangeably herein, and include any variants or isoforms thereof which are naturally expressed by cells.
Interleukin 15 is a pro-inflammatory cytokine that serves as a potent growth, survival, and activation factor for T cells, particularly intestinal intraepithelial lymphocytes (IELs), and for natural killer (NK) cells. Increased expression of IL-15 has been demonstrated in a variety of inflammatory conditions, including CD, rheumatoid arthritis (RA), and psoriasis (Malamut et al., 2010). IL-15 is considered a central regulator of CD
immunopathology and a non-redundant driver of lymphomagenesis in RCD. Inhibition of IL-15 by an antagonist is an attractive therapeutic target for the treatment of CD. Targeting of IL-15 by a fully human monoclonal antibody to bind IL-15 has served to elucidate the signaling mechanism facilitated by IL-15 in CD and has established experimental proof principle for the advantages of modulating downstream effectors of IL-15 (Malamut et al., 2010).
[0031] The term "antibody" as referred to herein includes whole antibodies and any antigen (e.g., IL-15) binding fragment (i.e., "antigen-binding portion") or single chain thereof An "antibody" refers to a protein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, or an antigen binding portion thereof Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region is comprised of three domains, CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.
[0032] It should be understood that the term "antibody" also includes various antibody modification and/or derivative forms, including without limitation, an anti-IL-15 antibody, or antigen-binding fragment thereof, coupled with or linked to an additional molecular entity, such as one or more different antibodies or antigen-binding fragments thereof (e.g., a bi-specific, tri-specific, or multi-specific), pharmaceutical agents, peptides or proteins, and detection agent or labels. The term "antibody" also includes single chain antibodies, di abodies, domain antibodies, nanobodies, and tinibodies.
[0033] The terms "antigen-binding portion" and "antigen-binding fragment" of an antibody (or simply "antibody portion"), as used herein, refer to one or more fragments of an antibody that selectively bind to an antigen (e.g., IL-15). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of antigen-binding fragments encompassed within the term "antigen-binding portion" of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region;
(iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., Nature 341:544-546 (1989)), which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR) or (vii) a combination of two or more isolated CDRs which may optionally be joined by a synthetic linker. Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al., Science 242:423-426 (1988); and Huston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883 (1988)). Such single chain antibodies are also intended to be encompassed within the terms "antigen-binding portion"
and "antigen-binding fragment" of an antibody. These antibody fragments are obtained using conventional techniques known to those with skill in the art, and the fragments are screened for utility in the same manner as are intact antibodies.
[0034] The term "monoclonal antibody" as used herein, refers to an antibody which displays a single binding specificity and affinity for a particular epitope.
Accordingly, the term "human monoclonal antibody" refers to an antibody which displays a single binding specificity and which has variable and constant regions derived from human germline immunoglobulin sequences. In one embodiment, human monoclonal antibodies are produced by a hybridoma which includes a B cell obtained from a transgenic non-human animal, e.g., a transgenic mouse, having a genome comprising a human heavy chain transgene and a light chain transgene fused to an immortalized cell. In another embodiment, human monoclonal antibodies can be produced by Chinese hamster ovary (CHO) cells.
[0035] The term "recombinant human antibody," as used herein, includes all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as (a) antibodies isolated from an animal (e.g., a mouse) that is transgenic or transchromosomal for human immunoglobulin genes or a hybridoma prepared therefrom, (b) antibodies isolated from a host cell (e.g., CHO cell) transformed to express the antibody, e.g., from a transfectoma, (c) antibodies isolated from a recombinant, combinatorial human antibody library, and (d) antibodies prepared, expressed, created or isolated by any other means that involve splicing of human immunoglobulin gene sequences to other DNA
sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies can be subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.
[0036] As used herein, a "heterologous antibody" is defined in relation to the transgenic non-human organism producing such an antibody. This term refers to an antibody having an amino acid sequence or an encoding nucleic acid sequence corresponding to that found in an organism not consisting of the transgenic non-human animal, and generally from a species other than that of the transgenic non-human animal.
[0037] An "isolated antibody," as used herein, refers to an antibody which is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds to IL-15 is substantially free of antibodies that specifically bind antigens other than IL-15). An isolated antibody that specifically binds to an epitope of IL-15 may, however, have cross-reactivity to other related cytokines or to other IL-15 proteins from different species. However, the antibody preferably always binds to human IL-15. In addition, an isolated antibody is typically substantially free of other cellular material and/or chemicals. In a particular embodiment, a combination of "isolated" monoclonal antibodies having different IL-15 specificities are combined in a well-defined composition.
[0038] As used herein, "specific binding," "selective binding" and "selectively binds," refer to an antibody or a fragment thereof, binding to a predetermined antigen. For example, in one embodiment, the antibody binds with an affinity (KD) of approximately less than 10-7 M, such as approximately less than 10-8 M, 10-9 M or 10-19 M or even lower when determined by surface plasmon resonance (SPR) technology in a BIACORE 3000 instrument using recombinant human IL-15 as the analyte and the antibody as the ligand, and binds to the predetermined antigen with an affinity that is at least two-fold greater than its affinity for binding to a non-specific antigen (e.g., BSA, casein) other than the predetermined antigen or a closely-related antigen. The phrases "an antibody recognizing an antigen" and "an antibody specific for an antigen" are used interchangeably herein with the term "an antibody which selectively binds to an antigen."
[0039] The term "KD," as used herein, is intended to refer to the dissociation equilibrium constant of a particular antibody-antigen interaction.
[0040] The term "nucleic acid molecule," as used herein, refers to DNA and RNA
molecules. A nucleic acid molecule may be single-stranded or double-stranded, but preferably is double-stranded DNA.
[0041] The term "isolated nucleic acid molecule," as used herein in reference to nucleic acids encoding antibodies or antibody portions (e.g., VH, VL, CDR3) that selectively bind to IL-15, refer to a nucleic acid molecule in which the nucleotide sequences encoding the antibody or antibody portion are free of other nucleotide sequences encoding antibodies or antibody portions that bind antigens other than IL-15, which other sequences may naturally flank the nucleic acid in human genomic DNA.
[0042] In one embodiment, the human anti-IL-15 antibody can have a heavy chain variable region (VH) encoded by the nucleotide sequence set forth in SEQ ID NO: 1, or conservative nucleic acid substitutions (e.g., silent mutation) thereof, and/or a light chain variable region (VL) encoded by the nucleotide sequence set forth in SEQ ID NO: 3, or conservative nucleic acid substitutions thereof The antibody can also have VH and VL's encoded by nucleotide sequences having about 80%, 85%, 90%, 95% or greater identity to SEQ ID NO:
1 and/or SEQ ID NO: 3, respectively.
[0043] In one embodiment, the antibody can have a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 2, or conservative amino acid substitutions thereof, and/or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:4, or conservative amino acid substitutions thereof The antibody can also have amino acid sequences of about 80%, 85%, 90%, 95% or greater identity to SEQ ID NO: 2 and/or SEQ ID NO: 4.
[0044] In some embodiments, the antibody can include a light chain variable region comprising one or more complementarity determining regions (CDRs) set forth in SEQ ID
NOs: 8-10, or homologous sequences thereof (e.g., having amino acid sequences of about 80%, 85%, 90%, 95% or greater identity to any of SEQ ID NOs: 8-10, or having 1 or 2 or 3 or 4 amino acid substitutions or changes thereto). The antibody can alternatively or additionally include a heavy chain variable region comprising one or more CDRs set forth in SEQ ID NOs: 5-7, or homologous sequences thereof (e.g., having amino acid sequences of about 80%, 85%, 90%, 95% or greater identity to any of SEQ ID NOs: 5-7, or having 1 or 2 or 3 or 4 amino acid substitutions or changes thereto). In a particular embodiment, a human monoclonal antibody that binds IL-15 or an antigen-binding fragment thereof, includes a light chain variable region comprising all three CDRs set forth in SEQ ID NOs:
8-10, or conservative amino acid substitutions thereof, and a heavy chain variable region comprising all three CDRs set forth in SEQ ID NOs: 5-7, or conservative amino acid substitutions thereof [0045] One embodiment of the present invention also encompasses "conservative sequence modifications" or "conservative sequence substitutions" of the sequences set forth in SEQ
ID NOs: 1-10, i.e., nucleotide and amino acid sequence modifications which do not significantly affect or alter the binding characteristics of the antibody encoded by the nucleotide sequence or containing the amino acid sequence. Such conservative sequence modifications include nucleotide and amino acid substitutions, additions and deletions.
Modifications can be introduced into SEQ ID NOs: 1-10 by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis.
Conservative amino acid substitutions include ones in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, a predicted nonessential amino acid residue in a human anti-IL-15 antibody is preferably replaced with another amino acid residue from the same side chain family.
[0046] Alternatively, in another embodiment, mutations can be introduced randomly along all or part of an anti-IL-15 antibody coding sequence, such as by saturation mutagenesis, and the resulting modified anti-IL-15 antibodies can be screened for binding activity.
100111 In another aspect, the invention relates to a pharmaceutical composition for the treatment of, or a pharmaceutical composition for use in a method of treating, celiac disease or non-celiac gluten sensitivity, comprising a therapeutically effective amount of an anti-IL-15 antibody or antigen-binding fragment thereof, wherein the therapeutically effective amount comprises 1-20 unit doses each to be administered at about 1-12 week intervals, each unit dose independently comprising about 50-1000 mg, preferably 75-600 mg, more preferably about 75 mg, about 150 mg, about 300 mg or about 600 mg of the anti-IL-15 antibody or antigen-binding fragment thereof In one embodiment of the pharmaceutical composition, the therapeutically effective amount comprises 6 unit doses to be administered at 2 week intervals. Each unit dose can be administered by subcutaneous injection or intravenous injection.
[0012] Another aspect of the invention relates to a method of treating refractory celiac disease in a subject in need thereof, comprising administering a therapeutically effective amount of an anti-IL-15 antibody or antigen-binding fragment thereof to the subject, wherein the therapeutically effective amount comprises 1-20 unit doses each administered at about 1-12 week intervals, each unit dose independently comprising about 1-50 mg/kg, preferably about 4-16 mg/kg, more preferably about 4 mg/kg, about 8 mg/kg, about 12 mg/kg or about 16 mg/kg of the anti-IL-15 antibody or antigen-binding fragment thereof In one embodiment, the therapeutically effective amount comprises 6 unit doses administered at 2 week intervals, and an optional additional loading dose at week 1. Each unit dose is administered by subcutaneous injection or intravenous injection.
The refractory celiac disease is type I or type II refractory celiac disease.
[0013] Also provided herein is a pharmaceutical composition for the treatment of, or a pharmaceutical composition for use in a method of treating, refractory celiac disease, comprising a therapeutically effective amount of an anti-IL-15 antibody or antigen-binding fragment thereof, wherein the therapeutically effective amount comprises 1-20 unit doses each administered at about 1-12 week intervals, each unit dose independently comprising about 1-50 mg/kg, preferably about 4-16 mg/kg, more preferably about 4 mg/kg, about 8 mg/kg, about 12 mg/kg or about 16 mg/kg of the anti-IL-15 antibody or antigen-binding fragment thereof The therapeutically effective amount in some embodiments comprises 6 unit doses to be administered at 2 week intervals, and an optional additional loading dose to be administered at week 1. Each unit dose can be administered by subcutaneous injection or intravenous injection. The refractory celiac disease can be type I or type II.
[0014] In some embodiments of the methods and/or pharmaceutical compositions disclosed herein, the antibody may have a heavy chain variable region comprising one or more complementarity determining regions of SEQ ID NOs:5-7, or a sequence having at least 80% sequence identity thereto. The antibody may, in certain embodiments, have a light chain variable region comprising one or more complementarity determining regions of SEQ
ID NOs:8-10, or a sequence having at least 80% sequence identity thereto. The antibody in some embodiments has a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:2, or a sequence having at least 80% sequence identity thereto.
In certain embodiments, the antibody may have a light chain variable region comprising the amino acid sequence of SEQ ID NO:4, or a sequence having at least 80% sequence identity thereto.
BRIEF DESCRIPTION OF THE FIGURES
[0015] FIG. 1 illustrates a schematic structure of AMG 714.
[0016] FIG. 2 illustrates villi present in the gut of healthy subject and subjects with active celiac disease.
[0017] FIG. 3 illustrates a simplified schematic of celiac and refractory celiac disease pathophysiology.
[0018] FIG. 4 illustrates a simplified schematic of IL-15 signaling in RCD-II.
[0019] FIG. 5 illustrates a simplified schematic of the multiple roles of IL-15 in celiac and refractory celiac disease.
DETAILED DESCRIPTION
[0020] The compositions and methods disclosed herein relate to the treatment of gastrointestinal disorders such as CD, NRCD, RCD, EATL and NCGS by modulating an activity of IL-15 using, e.g., a therapeutically effective amount of an IL-15 antagonist. In some embodiments, the IL-15 antagonist is an antibody. In some embodiments, IL-15 can be blocked by AMG 714, a monoclonal antibody which can bind to, and inhibit the function of IL-15.
[0021] Pharmaceutical compositions provided herein can include a therapeutically effective amount of a recombinant monoclonal antibody or antigen-binding fragments against IL-15, in particular human IL-15. Suitable antibodies can include, for example, murine, chimeric, humanized and fully human antibodies, as well as other antibody forms known in the art. In some embodiments, the antibody can include but is not limited to those disclosed in U.S.
Patent Nos. 7,247,304, 7,329,405, 7,153,507, 7,597,892, 7,585,961 and 8,345,105, all of which are incorporated herein by reference in their entirety. The antibody can be provided in the form of a recombinantly expressed glycoprotein, using methods disclosed in, e.g., International Patent Application No. W02007/07087384, which is incorporated herein by reference in its entirety.
[0022] In one embodiment, the antibody is a fully human monoclonal antibody that binds IL-15. In a specific embodiment, the antibody is AMG 714 which has a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:2 and/or a light chain variable region comprising the amino acid sequence set forth in SEQ ID
NO:4. The antibody can also have amino acid sequences of about 80%, 85%, 90%, 95% or greater identity to SEQ ID NO: 2 and/or SEQ ID NO: 4.
[0023] In some embodiments, the antibody can include a light chain variable region comprising one or more complementarily determining regions (CDRs) set forth in SEQ ID
NOs:8-10, or homologous sequences thereof (e.g., having amino acid sequences of about 80%, 85%, 90%, 95% or greater identity to any of SEQ ID NOs: 8-10). The antibody can alternatively or additionally include a heavy chain variable region comprising one or more CDRs set forth in SEQ ID NOs:5-7, or homologous sequences thereof (e.g., having amino acid sequences of about 80%, 85%, 90%, 95% or greater identity to any of SEQ
ID NOs: 5-7). In a particular embodiment, a human monoclonal antibody that binds IL-15 or an antigen-binding fragment thereof, includes a light chain variable region comprising all three CDRs set forth in SEQ ID NOs:8-10, or conservative amino acid substitutions thereof, and a heavy chain variable region comprising all three CDRs set forth in SEQ ID NOs:
5-7, or conservative amino acid substitutions thereof [0024] The pharmaceutical compositions disclosed herein can include a therapeutically effective amount of an isolated monoclonal antibody that binds IL-15 or an antigen-binding fragment thereof and a pharmaceutically acceptable carrier. The pharmaceutical compositions can be used to treat or prevent a disorder associated with an overexpression of human IL-15 and/or in which a down regulation or inhibition of human IL-15 induced effects is beneficial.
[0025] Also provided herein is a method of treating or preventing a disorder associated with an overexpression of human IL-15 and/or in which a down regulation or inhibition of human IL-15 induced effects is beneficial, by administering to a subject a therapeutically effective amount of an isolated anti-IL-15 antibody, or an antigen-binding fragment thereof [0026] Exemplary disorders that can be treated or prevented using the presently disclosed methods or compositions include, but are not limited to, Celiac Disease, Non-Responsive Celiac Disease, Refractory Celiac Disease, Enteropathy-Associated T Cell Lymphoma, and Gluten-Sensitive Enteropathy. Other disorders that can be treated include vasculitis, psoriasis, multiple sclerosis, rheumatoid arthritis (RA), inflammatory disorders (e.g., inflammatory bowel disease), allograft rejection, graft versus host disease, T-cell lymphoma, and T-cell leukemia.
Definitions [0027] For convenience, certain terms employed in the specification, examples, and appended claims are collected here. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
[0028] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.
[0029] As used herein, the term "about" means within 20%, more preferably within 10%
and most preferably within 5%. The term "substantially" means more than 50%, preferably more than 80%, and most preferably more than 90% or 95%.
[0030] The terms "IL-15," "IL-15 antigen" and "interleukin 15" are used interchangeably herein, and include any variants or isoforms thereof which are naturally expressed by cells.
Interleukin 15 is a pro-inflammatory cytokine that serves as a potent growth, survival, and activation factor for T cells, particularly intestinal intraepithelial lymphocytes (IELs), and for natural killer (NK) cells. Increased expression of IL-15 has been demonstrated in a variety of inflammatory conditions, including CD, rheumatoid arthritis (RA), and psoriasis (Malamut et al., 2010). IL-15 is considered a central regulator of CD
immunopathology and a non-redundant driver of lymphomagenesis in RCD. Inhibition of IL-15 by an antagonist is an attractive therapeutic target for the treatment of CD. Targeting of IL-15 by a fully human monoclonal antibody to bind IL-15 has served to elucidate the signaling mechanism facilitated by IL-15 in CD and has established experimental proof principle for the advantages of modulating downstream effectors of IL-15 (Malamut et al., 2010).
[0031] The term "antibody" as referred to herein includes whole antibodies and any antigen (e.g., IL-15) binding fragment (i.e., "antigen-binding portion") or single chain thereof An "antibody" refers to a protein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, or an antigen binding portion thereof Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region is comprised of three domains, CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.
[0032] It should be understood that the term "antibody" also includes various antibody modification and/or derivative forms, including without limitation, an anti-IL-15 antibody, or antigen-binding fragment thereof, coupled with or linked to an additional molecular entity, such as one or more different antibodies or antigen-binding fragments thereof (e.g., a bi-specific, tri-specific, or multi-specific), pharmaceutical agents, peptides or proteins, and detection agent or labels. The term "antibody" also includes single chain antibodies, di abodies, domain antibodies, nanobodies, and tinibodies.
[0033] The terms "antigen-binding portion" and "antigen-binding fragment" of an antibody (or simply "antibody portion"), as used herein, refer to one or more fragments of an antibody that selectively bind to an antigen (e.g., IL-15). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of antigen-binding fragments encompassed within the term "antigen-binding portion" of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region;
(iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., Nature 341:544-546 (1989)), which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR) or (vii) a combination of two or more isolated CDRs which may optionally be joined by a synthetic linker. Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al., Science 242:423-426 (1988); and Huston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883 (1988)). Such single chain antibodies are also intended to be encompassed within the terms "antigen-binding portion"
and "antigen-binding fragment" of an antibody. These antibody fragments are obtained using conventional techniques known to those with skill in the art, and the fragments are screened for utility in the same manner as are intact antibodies.
[0034] The term "monoclonal antibody" as used herein, refers to an antibody which displays a single binding specificity and affinity for a particular epitope.
Accordingly, the term "human monoclonal antibody" refers to an antibody which displays a single binding specificity and which has variable and constant regions derived from human germline immunoglobulin sequences. In one embodiment, human monoclonal antibodies are produced by a hybridoma which includes a B cell obtained from a transgenic non-human animal, e.g., a transgenic mouse, having a genome comprising a human heavy chain transgene and a light chain transgene fused to an immortalized cell. In another embodiment, human monoclonal antibodies can be produced by Chinese hamster ovary (CHO) cells.
[0035] The term "recombinant human antibody," as used herein, includes all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as (a) antibodies isolated from an animal (e.g., a mouse) that is transgenic or transchromosomal for human immunoglobulin genes or a hybridoma prepared therefrom, (b) antibodies isolated from a host cell (e.g., CHO cell) transformed to express the antibody, e.g., from a transfectoma, (c) antibodies isolated from a recombinant, combinatorial human antibody library, and (d) antibodies prepared, expressed, created or isolated by any other means that involve splicing of human immunoglobulin gene sequences to other DNA
sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies can be subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.
[0036] As used herein, a "heterologous antibody" is defined in relation to the transgenic non-human organism producing such an antibody. This term refers to an antibody having an amino acid sequence or an encoding nucleic acid sequence corresponding to that found in an organism not consisting of the transgenic non-human animal, and generally from a species other than that of the transgenic non-human animal.
[0037] An "isolated antibody," as used herein, refers to an antibody which is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds to IL-15 is substantially free of antibodies that specifically bind antigens other than IL-15). An isolated antibody that specifically binds to an epitope of IL-15 may, however, have cross-reactivity to other related cytokines or to other IL-15 proteins from different species. However, the antibody preferably always binds to human IL-15. In addition, an isolated antibody is typically substantially free of other cellular material and/or chemicals. In a particular embodiment, a combination of "isolated" monoclonal antibodies having different IL-15 specificities are combined in a well-defined composition.
[0038] As used herein, "specific binding," "selective binding" and "selectively binds," refer to an antibody or a fragment thereof, binding to a predetermined antigen. For example, in one embodiment, the antibody binds with an affinity (KD) of approximately less than 10-7 M, such as approximately less than 10-8 M, 10-9 M or 10-19 M or even lower when determined by surface plasmon resonance (SPR) technology in a BIACORE 3000 instrument using recombinant human IL-15 as the analyte and the antibody as the ligand, and binds to the predetermined antigen with an affinity that is at least two-fold greater than its affinity for binding to a non-specific antigen (e.g., BSA, casein) other than the predetermined antigen or a closely-related antigen. The phrases "an antibody recognizing an antigen" and "an antibody specific for an antigen" are used interchangeably herein with the term "an antibody which selectively binds to an antigen."
[0039] The term "KD," as used herein, is intended to refer to the dissociation equilibrium constant of a particular antibody-antigen interaction.
[0040] The term "nucleic acid molecule," as used herein, refers to DNA and RNA
molecules. A nucleic acid molecule may be single-stranded or double-stranded, but preferably is double-stranded DNA.
[0041] The term "isolated nucleic acid molecule," as used herein in reference to nucleic acids encoding antibodies or antibody portions (e.g., VH, VL, CDR3) that selectively bind to IL-15, refer to a nucleic acid molecule in which the nucleotide sequences encoding the antibody or antibody portion are free of other nucleotide sequences encoding antibodies or antibody portions that bind antigens other than IL-15, which other sequences may naturally flank the nucleic acid in human genomic DNA.
[0042] In one embodiment, the human anti-IL-15 antibody can have a heavy chain variable region (VH) encoded by the nucleotide sequence set forth in SEQ ID NO: 1, or conservative nucleic acid substitutions (e.g., silent mutation) thereof, and/or a light chain variable region (VL) encoded by the nucleotide sequence set forth in SEQ ID NO: 3, or conservative nucleic acid substitutions thereof The antibody can also have VH and VL's encoded by nucleotide sequences having about 80%, 85%, 90%, 95% or greater identity to SEQ ID NO:
1 and/or SEQ ID NO: 3, respectively.
[0043] In one embodiment, the antibody can have a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 2, or conservative amino acid substitutions thereof, and/or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:4, or conservative amino acid substitutions thereof The antibody can also have amino acid sequences of about 80%, 85%, 90%, 95% or greater identity to SEQ ID NO: 2 and/or SEQ ID NO: 4.
[0044] In some embodiments, the antibody can include a light chain variable region comprising one or more complementarity determining regions (CDRs) set forth in SEQ ID
NOs: 8-10, or homologous sequences thereof (e.g., having amino acid sequences of about 80%, 85%, 90%, 95% or greater identity to any of SEQ ID NOs: 8-10, or having 1 or 2 or 3 or 4 amino acid substitutions or changes thereto). The antibody can alternatively or additionally include a heavy chain variable region comprising one or more CDRs set forth in SEQ ID NOs: 5-7, or homologous sequences thereof (e.g., having amino acid sequences of about 80%, 85%, 90%, 95% or greater identity to any of SEQ ID NOs: 5-7, or having 1 or 2 or 3 or 4 amino acid substitutions or changes thereto). In a particular embodiment, a human monoclonal antibody that binds IL-15 or an antigen-binding fragment thereof, includes a light chain variable region comprising all three CDRs set forth in SEQ ID NOs:
8-10, or conservative amino acid substitutions thereof, and a heavy chain variable region comprising all three CDRs set forth in SEQ ID NOs: 5-7, or conservative amino acid substitutions thereof [0045] One embodiment of the present invention also encompasses "conservative sequence modifications" or "conservative sequence substitutions" of the sequences set forth in SEQ
ID NOs: 1-10, i.e., nucleotide and amino acid sequence modifications which do not significantly affect or alter the binding characteristics of the antibody encoded by the nucleotide sequence or containing the amino acid sequence. Such conservative sequence modifications include nucleotide and amino acid substitutions, additions and deletions.
Modifications can be introduced into SEQ ID NOs: 1-10 by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis.
Conservative amino acid substitutions include ones in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, a predicted nonessential amino acid residue in a human anti-IL-15 antibody is preferably replaced with another amino acid residue from the same side chain family.
[0046] Alternatively, in another embodiment, mutations can be introduced randomly along all or part of an anti-IL-15 antibody coding sequence, such as by saturation mutagenesis, and the resulting modified anti-IL-15 antibodies can be screened for binding activity.
11 [0047] Accordingly, antibodies encoded by the (heavy and light chain variable region) nucleotide sequences disclosed herein and/or containing the (heavy and light chain variable region) amino acid sequences disclosed herein (i.e., SEQ ID NOs: 1-4) include substantially similar antibodies encoded by or containing similar sequences, which have been conservatively modified. Further, discussion as to how such substantially similar antibodies can be generated based on the partial (i.e., heavy and light chain variable regions) sequences disclosed herein as SEQ ID Nos:1-4 is provided below.
[0048] For nucleic acids, the term "substantial homology" indicates that two nucleic acids, or designated sequences thereof, when optimally aligned and compared, are identical, with appropriate nucleotide insertions or deletions, in at least about 80% of the nucleotides, usually at least about 90% to 95%, and more preferably at least about 98% to 99.5% of the nucleotides. Alternatively, substantial homology exists when the segments will hybridize under selective hybridization conditions, to the complement of the strand.
[0049] For amino acid sequences, the term "homology" indicates the degree of identity between two amino acid sequences when optimally aligned and compared with appropriate insertions or deletions.
[0050] The percent identity between two sequences is a function of the number of identical positions shared by the sequences (i.e., % homology = # of identical positions/total # of positions x 100), taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm.
[0051] The percent identity between two nucleotide sequences can be determined using the GAP program in the GCG software package (available at www.gcg.com), using a NWSgapdna. CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. The percent identity between two nucleotide or amino acid sequences can also be determined using the algorithm of E. Meyers and W. Miller (CABIOS, 4:11-17 (1989)) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. In addition, the percent identity between two amino acid sequences can be determined using the Needleman and Wunsch (J. Mol. Biol. (48):444-453 (1970)) algorithm which has been incorporated into the GAP program in the GCG software package (available at
[0048] For nucleic acids, the term "substantial homology" indicates that two nucleic acids, or designated sequences thereof, when optimally aligned and compared, are identical, with appropriate nucleotide insertions or deletions, in at least about 80% of the nucleotides, usually at least about 90% to 95%, and more preferably at least about 98% to 99.5% of the nucleotides. Alternatively, substantial homology exists when the segments will hybridize under selective hybridization conditions, to the complement of the strand.
[0049] For amino acid sequences, the term "homology" indicates the degree of identity between two amino acid sequences when optimally aligned and compared with appropriate insertions or deletions.
[0050] The percent identity between two sequences is a function of the number of identical positions shared by the sequences (i.e., % homology = # of identical positions/total # of positions x 100), taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm.
[0051] The percent identity between two nucleotide sequences can be determined using the GAP program in the GCG software package (available at www.gcg.com), using a NWSgapdna. CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. The percent identity between two nucleotide or amino acid sequences can also be determined using the algorithm of E. Meyers and W. Miller (CABIOS, 4:11-17 (1989)) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. In addition, the percent identity between two amino acid sequences can be determined using the Needleman and Wunsch (J. Mol. Biol. (48):444-453 (1970)) algorithm which has been incorporated into the GAP program in the GCG software package (available at
12 www.gcg.com), using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6.
[0052] The nucleic acid and protein sequences of the present invention can further be used as a "query sequence" to perform a search against public databases to, for example, identify related sequences. Such searches can be performed using the NBLAST and XBLAST
programs (version 2.0) of Altschul, et al., J. Mol. Biol. 215:403-10 (1990).
BLAST
nucleotide searches can be performed with the NBLAST program, score = 100, wordlength = 12 to obtain nucleotide sequences homologous to the nucleic acid molecules of the invention. BLAST protein searches can be performed with the XBLAST program, score =
50, wordlength = 3 to obtain amino acid sequences homologous to the protein molecules of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., Nucleic Acids Res. 25(17):3389-3402 (1997).
When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. (See www.ncbi.nlm.nih.gov).
[0053] As used herein, the term "subject" includes any human or non-human animal. For example, the methods and compositions of the present invention can be used to treat a subject having an inflammatory disease, such as celiac disease, Refractory Celiac Disease, Enteropathy-Associated T Cell Lymphoma and Non-celiac gluten sensitivity. The term "non-human animal" includes all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dog, cow, chickens, amphibians, reptiles, etc.
[0054] A "therapeutically effective dosage" or "therapeutically effective amount" for inflammatory disorders, such as Celiac Disease, Refractory Celiac Disease, Gluten-Sensitive Enteropathy and/or Enteropathy-Associated T Cell Lymphoma, or the like, will preferably result in an improvement of patient's clinical outcome or otherwise ameliorate signs and/or symptoms in a subject. For example, a therapeutically effective dosage of AMG-714 can result in improved clinical outcomes and/or improve laboratory test results of patients receiving treatment, for example the parameters to be monitored in clinical trials and/or physician assessments, as set forth herein.
[0055] A "unit dose" refers to an amount of pharmaceutical composition, in particular the active ingredient therein (e.g., an anti-IL-15 antibody such as AMG 714) that is administered to a subject in one treatment session. A treatment session may be continuous,
[0052] The nucleic acid and protein sequences of the present invention can further be used as a "query sequence" to perform a search against public databases to, for example, identify related sequences. Such searches can be performed using the NBLAST and XBLAST
programs (version 2.0) of Altschul, et al., J. Mol. Biol. 215:403-10 (1990).
BLAST
nucleotide searches can be performed with the NBLAST program, score = 100, wordlength = 12 to obtain nucleotide sequences homologous to the nucleic acid molecules of the invention. BLAST protein searches can be performed with the XBLAST program, score =
50, wordlength = 3 to obtain amino acid sequences homologous to the protein molecules of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., Nucleic Acids Res. 25(17):3389-3402 (1997).
When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. (See www.ncbi.nlm.nih.gov).
[0053] As used herein, the term "subject" includes any human or non-human animal. For example, the methods and compositions of the present invention can be used to treat a subject having an inflammatory disease, such as celiac disease, Refractory Celiac Disease, Enteropathy-Associated T Cell Lymphoma and Non-celiac gluten sensitivity. The term "non-human animal" includes all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dog, cow, chickens, amphibians, reptiles, etc.
[0054] A "therapeutically effective dosage" or "therapeutically effective amount" for inflammatory disorders, such as Celiac Disease, Refractory Celiac Disease, Gluten-Sensitive Enteropathy and/or Enteropathy-Associated T Cell Lymphoma, or the like, will preferably result in an improvement of patient's clinical outcome or otherwise ameliorate signs and/or symptoms in a subject. For example, a therapeutically effective dosage of AMG-714 can result in improved clinical outcomes and/or improve laboratory test results of patients receiving treatment, for example the parameters to be monitored in clinical trials and/or physician assessments, as set forth herein.
[0055] A "unit dose" refers to an amount of pharmaceutical composition, in particular the active ingredient therein (e.g., an anti-IL-15 antibody such as AMG 714) that is administered to a subject in one treatment session. A treatment session may be continuous,
13 e.g., uninterrupted parenteral administration (e.g., subcutaneous or intravenous) of a single bolus for a duration of time (e.g., 1 hour, 2 hours). A treatment session can also be divided into two or more subsessions, such that one unit dose is administered over time (e.g., 12 hours, 24 hours) with each bolus followed by a break or recovery time.
[0056] As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. Preferably, the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion). Depending on the route of administration, the antibody may be coated in a material to protect the compound from the action of acids and other natural conditions that may inactivate the compound.
[0057] A "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects (see e.g., Berge, S.M., et al., J. Pharm. Sci. 66:1-19 (1977)).
Examples of such salts include acid addition salts and base addition salts. Acid addition salts include those derived from nontoxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like, as well as from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like. Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium and the like, as well as from nontoxic organic amines, such as N,N'-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine and the like.
[0058] Various aspects of the present invention are described in further detail in the following subsections.
Pharmaceutical Compositions and Preparations Thereof [0059] The present invention includes, in one aspect, a pharmaceutical composition having a therapeutically effective amount of a therapeutic antibody or an antigen-binding fragment thereof (e.g., a human monoclonal antibody that binds IL-15 or an antigen-binding fragment thereof), which can be formulated together with a pharmaceutically acceptable carrier.
[0060] In some embodiments, AMG 714, a fully human immunoglobulin (IgG1K)
[0056] As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. Preferably, the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion). Depending on the route of administration, the antibody may be coated in a material to protect the compound from the action of acids and other natural conditions that may inactivate the compound.
[0057] A "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects (see e.g., Berge, S.M., et al., J. Pharm. Sci. 66:1-19 (1977)).
Examples of such salts include acid addition salts and base addition salts. Acid addition salts include those derived from nontoxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like, as well as from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like. Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium and the like, as well as from nontoxic organic amines, such as N,N'-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine and the like.
[0058] Various aspects of the present invention are described in further detail in the following subsections.
Pharmaceutical Compositions and Preparations Thereof [0059] The present invention includes, in one aspect, a pharmaceutical composition having a therapeutically effective amount of a therapeutic antibody or an antigen-binding fragment thereof (e.g., a human monoclonal antibody that binds IL-15 or an antigen-binding fragment thereof), which can be formulated together with a pharmaceutically acceptable carrier.
[0060] In some embodiments, AMG 714, a fully human immunoglobulin (IgG1K)
14 monoclonal antibody (mAb) that binds to interleukin 15 (IL-15), is useful as a treatment for, e.g., celiac disease, gluten-free diet (GFD) non-responsive celiac disease (NRCD), non-celiac gluten sensitivity and Type II refractory celiac disease (RCD-II).
[0061] Interleukin 15 (IL-15), a glycoprotein of approximately 14-15 kDa, is a pro-inflammatory cytokine with structural similarities to IL-2. IL-15 exerts biological effects on many immunologically relevant cells (Fehniger and Caligiuri, 2001). While important differences are present across species, IL-15 generally acts as a development, homeostasis, and activation factor for NK cells and memory phenotype CD8+ T cells, including IELs. It also induces the production of chemokines and cytokines by these cell types.
IL-15 potently stimulates the production of pro-inflammatory cytokines such as IL-1, IL-6, and TNF-a by monocytes/macrophages. IL-15 produced by follicular dendritic cells is known to support germinal center B cell proliferation and immunoglobulin class switching (Park et al., 2004;
Litinskiy et al., 2002). Targeted disruption of either the IL-15 or IL-15Ra genes in mice has been shown to result in the loss of NK, NK-T, T cell receptor gamma delta (TCRy6+) IELs, and memory CD8+ T cells (Lodolce et al., 1998). In IL-15 knockout mice, these defects are reversible by the administration of exogenous IL-15 (Kennedy et al., 2000).
However, human NK cells are not entirely dependent on IL-15 (Lebrec et al., 2013).
[0062] IL-15 messenger RNA (mRNA) is expressed in a wide variety of tissues and cell types. However, expression of IL-15 protein is much more restricted and is subject to multiple post-transcriptional control mechanisms. Sources of IL-15 protein include monocytes, macrophages, epithelial and fibroblastic cells, and bone marrow stromal cells (Fehniger and Caligiuri, 2001). IL-15 and its receptor are also expressed in some organs outside the immune system; the role of IL-15 in these systems is less well understood. The absence of any overt defects outside the immune system in IL-15 and IL-15Ra knockout mice suggests that IL-15 may not be essential in any other system.
[0063] IL-15 binds to a heterotrimeric receptor that consists of a 13 chain that is shared with the IL-2 receptor (CD122 or IL-2/IL-15R13), the common y chain (yC) shared with IL-2, -4, -7, -9, and -21 receptors, and a unique a chain. IL-15 binds with high affinity to the IL-15Ra chain, which then interacts with the IL-2/IL-15R0 and the yC. The association of the IL-15/IL-15Ra complex with the other two components of the complete receptor complex can occur in a cis configuration, in which all three receptor components are present on the same cell, or in a trans configuration, in which the IL-15/IL-15Ra pair is on one cell and the receptor 13 and yC chains are on another (Schluns et al., 2005). IL-15 can also associate with IL-15Ra on the cell surface and then be cleaved into soluble cytokine/receptor complexes that have the potential to stimulate CD8+ T cells and NK cells (Anthony et al., 2015).
[0064] Increased expression of IL-15 has been demonstrated in a variety of inflammatory conditions, including RA, psoriasis, inflammatory bowel disease, graft-versus-host disease, solid organ transplant rejection (Blaser et al., 2005; Conti et al., 2003;
Gianfrani et al., 2005; McInnes and Gracie, 2004), and celiac disease (Gianfrani et al., 2005;
Meresse et al., 2012).
[0065] AMG 714, a fully human immunoglobulin (IgGlx) monoclonal antibody, binds to and inhibits the function of IL-15 in all its known forms (cis, trans, soluble IL-15 bound to IL-15 receptor alpha (IL-15Ra)). AMG 714 inhibits IL-15-induced T cell proliferation and shows a dose-dependent inhibition of IL-15-induced tumor necrosis factor alpha (TNF-a) production. The structure of AMG 714 is illustrated in FIG. 1.
[0066] AMG 714 can be produced by any antibody production methods generally known in the art. For example, AMG 714 may be produced from a B cell hybridoma cell line. AMG
714 can also be produced by a mammalian cell line such as Chinese hamster ovary (CHO) cell line. As one of ordinary skill in the art would understand, the heavy chain C-terminal lysine can be absent from the version produced by CHO cells (Dick Jr. et al., Biotechnol.
Bioeng. 2008;100: 1132-1143).
[0067] In nonclinical experiments, AMG 714 was found to recognize an epitope that is essential for the interaction between human IL-15 (hIL-15) and its receptor complex. AMG
714 showed a dose-dependent inhibition of IL-15-induced proliferation of peripheral blood T cells and cell lines expressing IL-15 receptors, as well as a dose-dependent inhibition of hIL-15-induced TNF-a production. AMG 714 was found to be efficacious in a mouse model of celiac disease triggered by the transgenic expression of human IL-15 in the gut epithelium. In this model, AMG 714 prevented IEL activation and proliferation, as well as histological abnormalities. In addition, AMG 714 was able to induce apoptosis of human IELs in ex vivo culture of small intestinal explants from patients with active celiac disease and RCD-II.
[0068] Due to low binding potency of AMG 714 for macaque IL-15, the safety profile of AMG 714 has been evaluated in nonclinical studies in non-human primates (NHPs), specifically cynomolgus monkeys, using the surrogate molecule Hu714MuXHu. In NHPs, the inhibition of IL-15 by Hu714MuXHu resulted in reversible NK cell reduction and associated gastrointestinal infections in some animals; however, NK cell depletion has not been observed in humans (Lebrec et al., 2013) and no corresponding gastroenteritis or enteric infections have been reported as a frequent adverse event (AE) in human studies. No other toxicology signals have been observed. The difference between this observation and the NK cell depletion seen in NHPs appears to be related to a difference between human and cynomolgus monkey in the sensitivity of NK cells to IL-15 blockade. Human NK cells are not dependent on IL-15 for their survival, possibly due to the redundant role of IL-2 on human NK cells.
[0069] Approximately 200 subjects have been exposed to AMG 714 to date for the treatment of RA and psoriasis, including approximately 140 subjects for 12 weeks of biweekly dosing. AMG 714 has been studied in four clinical trials, including one Phase 1 study in NHV (30 subjects on AMG 714, 10 on placebo, intravenous [IV] and subcutaneous [SC]), one Phase 1 study in RA (29 subjects on AMG 714, no placebo, IV), a Phase lb/2a in psoriasis (14 patients on AMG 714, 6 on placebo, SC), and a Phase 2b study in RA (121 subjects on AMG 714, 58 on placebo, SC). To date, AMG 714 has been well tolerated and its safety profile has been generally comparable to placebo with the exception of injection site reactions, which were more commonly reported in subjects exposed to AMG
714.
[0070] In RA clinical trials, AMG 714 demonstrated a response in approximately 60% of patients in both Phase 1 and Phase 2 studies versus a response of approximately 30% in the placebo group. AMG 714 also led to decreases in inflammatory biomarkers such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). AMG 714 did not demonstrate a response in clinical trials with psoriasis patients, suggesting AMG 714's action is selective, unlike that of broad systemic immune suppressants.
[0071] AMG 714 has a PK profile consistent with a typical human immunoglobulin antibody with no apparent target-mediated disposition and a half-life of 20 to 22 days.
Immunogenicity of AMG 714 has been reported in only one blood sample from one subject in the entire clinical program to date.
[0072] Pharmaceutical compositions of the present invention also can be administered in combination therapy, i.e., combined with other agents. For example, the combination therapy can include a composition of the present invention with at least one or more additional therapeutic agents, such as anti-inflammatory agents, DMARDs (disease-modifying anti-rheumatic drugs), immunosuppressive agents, chemotherapeutics, and psoriasis agents. The pharmaceutical compositions of the invention can also be administered in conjunction with radiation therapy. Co-administration with other antibodies, such as CD4 specific antibodies and IL-2 specific antibodies, are also encompassed by the invention. Such combinations with CD4 specific antibodies or IL-2 specific antibodies are considered particularly useful for treating autoimmune diseases and transplant rejections.
[0073] A composition of the present invention can be administered by a variety of methods known in the art. As will be appreciated by the skilled artisan, the route and/or mode of administration will vary depending upon the desired results. The active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are generally known to those skilled in the art. See, e.g., Sustained and Controlled Release Drug Delivery Systems, J.R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.
[0074] To administer a compound of the invention by certain routes of administration, it may be necessary to coat the compound with, or co-administer the compound with, a material to prevent its inactivation. For example, the compound may be administered to a subject in an appropriate carrier, for example, liposomes, or a diluent.
Pharmaceutically acceptable diluents include saline and aqueous buffer solutions. Liposomes include water-in-oil-in-water CGF emulsions as well as conventional liposomes (Strejan et al., J.
Neuroimmunol. 7:27 (1984)).
[0075] Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions of the invention is contemplated. Supplementary active compounds can also be incorporated into the compositions.
[0076] Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.
[0077] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by sterilization microfiltration.
Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying (lyophilization) that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof [0078] Dosage regimens can be adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. For example, the human antibodies of the invention may be administered once or twice weekly by subcutaneous injection or once or twice monthly by subcutaneous injection.
[0079] It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated;
each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.
[0080] Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
[0081] For the therapeutic compositions, formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dose form and may be prepared by any methods known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the subject being treated, and the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the composition which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 0.001 per cent to about ninety percent of active ingredient, preferably from about 0.005 per cent to about 70 per cent, most preferably from about 0.01 per cent to about 30 per cent.
[0082] Dosage forms for the topical or transdermal administration of compositions of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
[0083] Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
[0084] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of presence of microorganisms may be ensured both by sterilization procedures, supra, and by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions.
In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
[0085] When the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given alone or as a pharmaceutical composition containing, for example, 0.001 to 90% (more preferably, 0.005 to 70%, such as 0.01 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.
[0086] The phrases "parenteral administration" and "administered parenterally"
as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrastemal injection and infusion. In some embodiments, subcutaneous and/or intravenous administration can be used, certain advantages and disadvantages of which are summarized below.
Administration Advantages Challenges form = shorter clinic/office visits =
pain-free administration of larger Subcutaneous for the patient fluid volumes (SC) = optimized use of resources = minimization of adverse events at = self-administration is the injection site possible = guarantee of good absorption and = less invasive than IV
bioavailability administration = administration of exact doses requires practice = suitable for substances that =
requires trained personnel in Intravenous can cause irritations special infusion settings (IV) = suitable for drugs that must = handling of port system (e.g., be administered in larger central port, Hickman catheter, volumes PICC) = placement of a peripheral cannula = longer clinic/office stays than with SC administration = risk of systemic infections [0087] Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.
[0088] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In general, a suitable daily dose of a composition of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. It is preferred that administration be intravenous, intramuscular, intraperitoneal, or subcutaneous, preferably administered proximal to the site of the target. If desired, the effective daily dose of a therapeutic composition may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dose forms. While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition).
[0089] Therapeutic compositions can be administered with medical devices known in the art. For example, in a preferred embodiment, a therapeutic composition of the invention can be administered with a needleless hypodermic injection device, such as the devices disclosed in U.S. Patent Nos. 5,399,163, 5,383,851, 5,312,335, 5,064,413, 4,941,880, 4,790,824, or 4,596,556. Examples of well-known implants and modules useful in the present invention include: U.S. Patent No. 4,487,603, which discloses an implantable micro-infusion pump for dispensing medication at a controlled rate; U.S.
Patent No. 4.,486,194, which discloses a therapeutic device for administering medicants through the skin; U.S. Patent No. 4,447,233, which discloses a medication infusion pump for delivering medication at a precise infusion rate; U.S. Patent No. 4,447,224, which discloses a variable flow implantable infusion apparatus for continuous drug delivery;
U.S. Patent No. 4,439,196, which discloses an osmotic drug delivery system having multi-chamber compartments; and U.S. Patent No. 4,475,196, which discloses an osmotic drug delivery system. Many other such implants, delivery systems, and modules are known to those skilled in the art.
[0090] The therapeutic antibodies of the present invention can be formulated to aid in proper distribution in vivo. For example, the blood-brain barrier (BBB) excludes many highly hydrophilic compounds. To aid therapeutic compounds of the invention in crossing the BBB (if desired), they can be formulated, for example, in liposomes. For methods of manufacturing liposomes, see, e.g., U.S. Patents 4,522,811; 5,374,548; and 5,399,331. The liposomes may comprise one or more moieties which are selectively transported into specific cells or organs, thus enhance targeted drug delivery (see, e.g., V.V.
Ranade J. Clin.
Pharmacol. 29:685 (1989). Exemplary targeting moieties include folate or biotin (see, e.g., U.S. Patent 5,416,016 to Low et al.); mannosides (Umezawa et al., Biochem.
Biophys. Res.
Commun. 153:1038 (1988)); antibodies (P.G. Bloeman et al., FEBS Lett. 357:140 (1995);
M. Owais et al., Antimicrob. Agents Chemother. 39:180 (1995)); surfactant protein A
receptor (Briscoe et al., Am. J. Physiol. 1233:134 (1995)), different species of which may comprise the formulations of the inventions, as well as components of the invented molecules; p120 (Schreier et al., J. Biol. Chem. 269:9090 (1994)); see also K.
Keinanen;
M.L. Laukkanen FEBS Lett. 346:123 (1994); J.J. Killion; I.J. Fidler Immunomethods 4:273 (1994). The therapeutic compounds of the present invention can be formulated in liposomes; and the liposomes can include a targeting moiety. The therapeutic compounds formulated in liposomes can be delivered by bolus injection to a site proximal to a tumor or infection. The composition must be fluid to the extent that the composition can be easily drawn into a syringe. The liposome composition can be stable under the conditions of manufacture and storage. The liposome composition can be preserved against the contaminating action of microorganisms such as bacteria and fungi.
[0091] The composition of the present invention can be formulated to prevent or reduce the transport across the placenta. This can be done by methods known in the art, e.g., by PEGylation of the antibody or by use of F(ab)2' fragments. Further references can be made to "Cunningham-Rundles C, Zhuo Z, Griffith B, Keenan J. (1992) Biological activities of polyethylene-glycol immunoglobulin conjugates." Resistance to enzymatic degradation. J
Immunol Methods. 152:177-190; and to Landor M. (1995) Maternal-fetal transfer of immunoglobulins, Ann Allergy Asthma Immunol 74:279-283.
[0092] The composition must be sterile and fluid to the extent that the composition is deliverable by syringe. In addition to water, the carrier can be an isotonic buffered saline solution, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof Proper fluidity can be maintained, for example, by use of coating such as lecithin, by maintenance of required particle size in the case of dispersion and by use of surfactants. In many cases, it is preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol or sorbitol, and sodium chloride in the composition. Long-term absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.
[0093] When the active compound is suitably protected, as described above, the compound may be orally administered, for example, with an inert diluent or an assimilable edible carrier.
Use of the Pharmaceutical Composition to Treat Celiac Disease and Non-celiac 2luten sensitivity [0094] Celiac disease is a systemic autoimmune disease triggered by gluten consumption in genetically susceptible individuals (Green and Cellier, 2007). Currently ¨1%
of the United States (US) and European Union (EU) populations are affected by celiac disease, albeit only 10-20% of celiac patients are diagnosed. Celiac was the first autoimmune disease with an identified antigen: gluten, the main protein present in some of the most common cereals (e.g., wheat, barley, rye). Modern diets are increasingly enriched with gluten and it is also used as an additive in processed foods, cosmetics, and oral medications.
Gluten is the second most common food ingredient after sugar and, in some countries, is present in up to 80% of foodstuff [0095] Humans lack enzymes to fully digest gluten, which, in the right genetic context (i.e., the presence of HLA-DQ2/8, Thl-prone immune system), triggers inflammation and autoimmunity in the gut and other organs following deamidation by the enzyme transglutaminase (tTG), which itself becomes a target for auto-antibodies. IL-
[0061] Interleukin 15 (IL-15), a glycoprotein of approximately 14-15 kDa, is a pro-inflammatory cytokine with structural similarities to IL-2. IL-15 exerts biological effects on many immunologically relevant cells (Fehniger and Caligiuri, 2001). While important differences are present across species, IL-15 generally acts as a development, homeostasis, and activation factor for NK cells and memory phenotype CD8+ T cells, including IELs. It also induces the production of chemokines and cytokines by these cell types.
IL-15 potently stimulates the production of pro-inflammatory cytokines such as IL-1, IL-6, and TNF-a by monocytes/macrophages. IL-15 produced by follicular dendritic cells is known to support germinal center B cell proliferation and immunoglobulin class switching (Park et al., 2004;
Litinskiy et al., 2002). Targeted disruption of either the IL-15 or IL-15Ra genes in mice has been shown to result in the loss of NK, NK-T, T cell receptor gamma delta (TCRy6+) IELs, and memory CD8+ T cells (Lodolce et al., 1998). In IL-15 knockout mice, these defects are reversible by the administration of exogenous IL-15 (Kennedy et al., 2000).
However, human NK cells are not entirely dependent on IL-15 (Lebrec et al., 2013).
[0062] IL-15 messenger RNA (mRNA) is expressed in a wide variety of tissues and cell types. However, expression of IL-15 protein is much more restricted and is subject to multiple post-transcriptional control mechanisms. Sources of IL-15 protein include monocytes, macrophages, epithelial and fibroblastic cells, and bone marrow stromal cells (Fehniger and Caligiuri, 2001). IL-15 and its receptor are also expressed in some organs outside the immune system; the role of IL-15 in these systems is less well understood. The absence of any overt defects outside the immune system in IL-15 and IL-15Ra knockout mice suggests that IL-15 may not be essential in any other system.
[0063] IL-15 binds to a heterotrimeric receptor that consists of a 13 chain that is shared with the IL-2 receptor (CD122 or IL-2/IL-15R13), the common y chain (yC) shared with IL-2, -4, -7, -9, and -21 receptors, and a unique a chain. IL-15 binds with high affinity to the IL-15Ra chain, which then interacts with the IL-2/IL-15R0 and the yC. The association of the IL-15/IL-15Ra complex with the other two components of the complete receptor complex can occur in a cis configuration, in which all three receptor components are present on the same cell, or in a trans configuration, in which the IL-15/IL-15Ra pair is on one cell and the receptor 13 and yC chains are on another (Schluns et al., 2005). IL-15 can also associate with IL-15Ra on the cell surface and then be cleaved into soluble cytokine/receptor complexes that have the potential to stimulate CD8+ T cells and NK cells (Anthony et al., 2015).
[0064] Increased expression of IL-15 has been demonstrated in a variety of inflammatory conditions, including RA, psoriasis, inflammatory bowel disease, graft-versus-host disease, solid organ transplant rejection (Blaser et al., 2005; Conti et al., 2003;
Gianfrani et al., 2005; McInnes and Gracie, 2004), and celiac disease (Gianfrani et al., 2005;
Meresse et al., 2012).
[0065] AMG 714, a fully human immunoglobulin (IgGlx) monoclonal antibody, binds to and inhibits the function of IL-15 in all its known forms (cis, trans, soluble IL-15 bound to IL-15 receptor alpha (IL-15Ra)). AMG 714 inhibits IL-15-induced T cell proliferation and shows a dose-dependent inhibition of IL-15-induced tumor necrosis factor alpha (TNF-a) production. The structure of AMG 714 is illustrated in FIG. 1.
[0066] AMG 714 can be produced by any antibody production methods generally known in the art. For example, AMG 714 may be produced from a B cell hybridoma cell line. AMG
714 can also be produced by a mammalian cell line such as Chinese hamster ovary (CHO) cell line. As one of ordinary skill in the art would understand, the heavy chain C-terminal lysine can be absent from the version produced by CHO cells (Dick Jr. et al., Biotechnol.
Bioeng. 2008;100: 1132-1143).
[0067] In nonclinical experiments, AMG 714 was found to recognize an epitope that is essential for the interaction between human IL-15 (hIL-15) and its receptor complex. AMG
714 showed a dose-dependent inhibition of IL-15-induced proliferation of peripheral blood T cells and cell lines expressing IL-15 receptors, as well as a dose-dependent inhibition of hIL-15-induced TNF-a production. AMG 714 was found to be efficacious in a mouse model of celiac disease triggered by the transgenic expression of human IL-15 in the gut epithelium. In this model, AMG 714 prevented IEL activation and proliferation, as well as histological abnormalities. In addition, AMG 714 was able to induce apoptosis of human IELs in ex vivo culture of small intestinal explants from patients with active celiac disease and RCD-II.
[0068] Due to low binding potency of AMG 714 for macaque IL-15, the safety profile of AMG 714 has been evaluated in nonclinical studies in non-human primates (NHPs), specifically cynomolgus monkeys, using the surrogate molecule Hu714MuXHu. In NHPs, the inhibition of IL-15 by Hu714MuXHu resulted in reversible NK cell reduction and associated gastrointestinal infections in some animals; however, NK cell depletion has not been observed in humans (Lebrec et al., 2013) and no corresponding gastroenteritis or enteric infections have been reported as a frequent adverse event (AE) in human studies. No other toxicology signals have been observed. The difference between this observation and the NK cell depletion seen in NHPs appears to be related to a difference between human and cynomolgus monkey in the sensitivity of NK cells to IL-15 blockade. Human NK cells are not dependent on IL-15 for their survival, possibly due to the redundant role of IL-2 on human NK cells.
[0069] Approximately 200 subjects have been exposed to AMG 714 to date for the treatment of RA and psoriasis, including approximately 140 subjects for 12 weeks of biweekly dosing. AMG 714 has been studied in four clinical trials, including one Phase 1 study in NHV (30 subjects on AMG 714, 10 on placebo, intravenous [IV] and subcutaneous [SC]), one Phase 1 study in RA (29 subjects on AMG 714, no placebo, IV), a Phase lb/2a in psoriasis (14 patients on AMG 714, 6 on placebo, SC), and a Phase 2b study in RA (121 subjects on AMG 714, 58 on placebo, SC). To date, AMG 714 has been well tolerated and its safety profile has been generally comparable to placebo with the exception of injection site reactions, which were more commonly reported in subjects exposed to AMG
714.
[0070] In RA clinical trials, AMG 714 demonstrated a response in approximately 60% of patients in both Phase 1 and Phase 2 studies versus a response of approximately 30% in the placebo group. AMG 714 also led to decreases in inflammatory biomarkers such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). AMG 714 did not demonstrate a response in clinical trials with psoriasis patients, suggesting AMG 714's action is selective, unlike that of broad systemic immune suppressants.
[0071] AMG 714 has a PK profile consistent with a typical human immunoglobulin antibody with no apparent target-mediated disposition and a half-life of 20 to 22 days.
Immunogenicity of AMG 714 has been reported in only one blood sample from one subject in the entire clinical program to date.
[0072] Pharmaceutical compositions of the present invention also can be administered in combination therapy, i.e., combined with other agents. For example, the combination therapy can include a composition of the present invention with at least one or more additional therapeutic agents, such as anti-inflammatory agents, DMARDs (disease-modifying anti-rheumatic drugs), immunosuppressive agents, chemotherapeutics, and psoriasis agents. The pharmaceutical compositions of the invention can also be administered in conjunction with radiation therapy. Co-administration with other antibodies, such as CD4 specific antibodies and IL-2 specific antibodies, are also encompassed by the invention. Such combinations with CD4 specific antibodies or IL-2 specific antibodies are considered particularly useful for treating autoimmune diseases and transplant rejections.
[0073] A composition of the present invention can be administered by a variety of methods known in the art. As will be appreciated by the skilled artisan, the route and/or mode of administration will vary depending upon the desired results. The active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are generally known to those skilled in the art. See, e.g., Sustained and Controlled Release Drug Delivery Systems, J.R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.
[0074] To administer a compound of the invention by certain routes of administration, it may be necessary to coat the compound with, or co-administer the compound with, a material to prevent its inactivation. For example, the compound may be administered to a subject in an appropriate carrier, for example, liposomes, or a diluent.
Pharmaceutically acceptable diluents include saline and aqueous buffer solutions. Liposomes include water-in-oil-in-water CGF emulsions as well as conventional liposomes (Strejan et al., J.
Neuroimmunol. 7:27 (1984)).
[0075] Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions of the invention is contemplated. Supplementary active compounds can also be incorporated into the compositions.
[0076] Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.
[0077] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by sterilization microfiltration.
Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying (lyophilization) that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof [0078] Dosage regimens can be adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. For example, the human antibodies of the invention may be administered once or twice weekly by subcutaneous injection or once or twice monthly by subcutaneous injection.
[0079] It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated;
each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.
[0080] Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
[0081] For the therapeutic compositions, formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dose form and may be prepared by any methods known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the subject being treated, and the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the composition which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 0.001 per cent to about ninety percent of active ingredient, preferably from about 0.005 per cent to about 70 per cent, most preferably from about 0.01 per cent to about 30 per cent.
[0082] Dosage forms for the topical or transdermal administration of compositions of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
[0083] Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
[0084] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of presence of microorganisms may be ensured both by sterilization procedures, supra, and by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions.
In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
[0085] When the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given alone or as a pharmaceutical composition containing, for example, 0.001 to 90% (more preferably, 0.005 to 70%, such as 0.01 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.
[0086] The phrases "parenteral administration" and "administered parenterally"
as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrastemal injection and infusion. In some embodiments, subcutaneous and/or intravenous administration can be used, certain advantages and disadvantages of which are summarized below.
Administration Advantages Challenges form = shorter clinic/office visits =
pain-free administration of larger Subcutaneous for the patient fluid volumes (SC) = optimized use of resources = minimization of adverse events at = self-administration is the injection site possible = guarantee of good absorption and = less invasive than IV
bioavailability administration = administration of exact doses requires practice = suitable for substances that =
requires trained personnel in Intravenous can cause irritations special infusion settings (IV) = suitable for drugs that must = handling of port system (e.g., be administered in larger central port, Hickman catheter, volumes PICC) = placement of a peripheral cannula = longer clinic/office stays than with SC administration = risk of systemic infections [0087] Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.
[0088] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In general, a suitable daily dose of a composition of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. It is preferred that administration be intravenous, intramuscular, intraperitoneal, or subcutaneous, preferably administered proximal to the site of the target. If desired, the effective daily dose of a therapeutic composition may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dose forms. While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition).
[0089] Therapeutic compositions can be administered with medical devices known in the art. For example, in a preferred embodiment, a therapeutic composition of the invention can be administered with a needleless hypodermic injection device, such as the devices disclosed in U.S. Patent Nos. 5,399,163, 5,383,851, 5,312,335, 5,064,413, 4,941,880, 4,790,824, or 4,596,556. Examples of well-known implants and modules useful in the present invention include: U.S. Patent No. 4,487,603, which discloses an implantable micro-infusion pump for dispensing medication at a controlled rate; U.S.
Patent No. 4.,486,194, which discloses a therapeutic device for administering medicants through the skin; U.S. Patent No. 4,447,233, which discloses a medication infusion pump for delivering medication at a precise infusion rate; U.S. Patent No. 4,447,224, which discloses a variable flow implantable infusion apparatus for continuous drug delivery;
U.S. Patent No. 4,439,196, which discloses an osmotic drug delivery system having multi-chamber compartments; and U.S. Patent No. 4,475,196, which discloses an osmotic drug delivery system. Many other such implants, delivery systems, and modules are known to those skilled in the art.
[0090] The therapeutic antibodies of the present invention can be formulated to aid in proper distribution in vivo. For example, the blood-brain barrier (BBB) excludes many highly hydrophilic compounds. To aid therapeutic compounds of the invention in crossing the BBB (if desired), they can be formulated, for example, in liposomes. For methods of manufacturing liposomes, see, e.g., U.S. Patents 4,522,811; 5,374,548; and 5,399,331. The liposomes may comprise one or more moieties which are selectively transported into specific cells or organs, thus enhance targeted drug delivery (see, e.g., V.V.
Ranade J. Clin.
Pharmacol. 29:685 (1989). Exemplary targeting moieties include folate or biotin (see, e.g., U.S. Patent 5,416,016 to Low et al.); mannosides (Umezawa et al., Biochem.
Biophys. Res.
Commun. 153:1038 (1988)); antibodies (P.G. Bloeman et al., FEBS Lett. 357:140 (1995);
M. Owais et al., Antimicrob. Agents Chemother. 39:180 (1995)); surfactant protein A
receptor (Briscoe et al., Am. J. Physiol. 1233:134 (1995)), different species of which may comprise the formulations of the inventions, as well as components of the invented molecules; p120 (Schreier et al., J. Biol. Chem. 269:9090 (1994)); see also K.
Keinanen;
M.L. Laukkanen FEBS Lett. 346:123 (1994); J.J. Killion; I.J. Fidler Immunomethods 4:273 (1994). The therapeutic compounds of the present invention can be formulated in liposomes; and the liposomes can include a targeting moiety. The therapeutic compounds formulated in liposomes can be delivered by bolus injection to a site proximal to a tumor or infection. The composition must be fluid to the extent that the composition can be easily drawn into a syringe. The liposome composition can be stable under the conditions of manufacture and storage. The liposome composition can be preserved against the contaminating action of microorganisms such as bacteria and fungi.
[0091] The composition of the present invention can be formulated to prevent or reduce the transport across the placenta. This can be done by methods known in the art, e.g., by PEGylation of the antibody or by use of F(ab)2' fragments. Further references can be made to "Cunningham-Rundles C, Zhuo Z, Griffith B, Keenan J. (1992) Biological activities of polyethylene-glycol immunoglobulin conjugates." Resistance to enzymatic degradation. J
Immunol Methods. 152:177-190; and to Landor M. (1995) Maternal-fetal transfer of immunoglobulins, Ann Allergy Asthma Immunol 74:279-283.
[0092] The composition must be sterile and fluid to the extent that the composition is deliverable by syringe. In addition to water, the carrier can be an isotonic buffered saline solution, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof Proper fluidity can be maintained, for example, by use of coating such as lecithin, by maintenance of required particle size in the case of dispersion and by use of surfactants. In many cases, it is preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol or sorbitol, and sodium chloride in the composition. Long-term absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.
[0093] When the active compound is suitably protected, as described above, the compound may be orally administered, for example, with an inert diluent or an assimilable edible carrier.
Use of the Pharmaceutical Composition to Treat Celiac Disease and Non-celiac 2luten sensitivity [0094] Celiac disease is a systemic autoimmune disease triggered by gluten consumption in genetically susceptible individuals (Green and Cellier, 2007). Currently ¨1%
of the United States (US) and European Union (EU) populations are affected by celiac disease, albeit only 10-20% of celiac patients are diagnosed. Celiac was the first autoimmune disease with an identified antigen: gluten, the main protein present in some of the most common cereals (e.g., wheat, barley, rye). Modern diets are increasingly enriched with gluten and it is also used as an additive in processed foods, cosmetics, and oral medications.
Gluten is the second most common food ingredient after sugar and, in some countries, is present in up to 80% of foodstuff [0095] Humans lack enzymes to fully digest gluten, which, in the right genetic context (i.e., the presence of HLA-DQ2/8, Thl-prone immune system), triggers inflammation and autoimmunity in the gut and other organs following deamidation by the enzyme transglutaminase (tTG), which itself becomes a target for auto-antibodies. IL-
15 is believed to be a key mediator in both the adaptive immune response, leading to extra-intestinal manifestations, and the innate immune response, leading to intestinal mucosal atrophy and gastrointestinal symptoms.
[0096] Celiac disease causes debilitating symptoms and potentially serious medical complications. In many patients, gastrointestinal symptoms derived from gut mucosal damage dominate the patient-reported symptoms at diagnosis. As illustrated in FIG. 2, the normal villi (absorptive finger-like prolongations) present in the gut of healthy individuals (left) are lost in active celiac disease (right) as a result of mucosal atrophy and crypt enlargement. The ratio of the villous height (VH) to the intestinal crypt depth (CD), the VH:CD ratio, is one of the main descriptors of the severity of celiac disease (Taavela et al., 2013). Small bowel damage often leads to nutrient malabsorption that can result in a range of further clinical manifestations (e.g., anemia, osteopenia, failure to thrive in children). In addition, extra-intestinal symptoms and systemic manifestations are often present, such as dermatitis, infertility, neurological disorders, and skeletal disorders (Green and Cellier, 2007).
[0097] Despite this considerable morbidity, celiac disease is the only common autoimmune disorder with no approved medication. Currently, the only available strategy for the management of celiac disease is a lifelong total avoidance of gluten. While simple in theory, in practice, the ubiquity of gluten in foodstuffs, medications, household substances, cosmetics, and even gluten-free items makes total avoidance of gluten difficult, if not impossible.
[0098] The main challenge to the successful maintenance of a gluten free diet (GFD) is that cereal flours are widely used in the food industry and are present in most food products either naturally or as additives. Although gluten-free products can be purchased, commercially manufactured gluten-free products may be difficult to find, tend to be less flavorful, and are more expensive than regular gluten-containing foods, which can sometimes deter patients from adhering to a GFD. In addition, many countries are deficient in the appropriate labeling of food products. Even in countries with superior labeling guidelines, foods labeled "gluten-free" may nevertheless contain gluten. For example, in northern European countries, gluten amounts of up to 100 parts per million (ppm) are permitted in gluten-free products designated for celiac sufferers (Gibert et al., 2006).
[0099] For these reasons, celiac sufferers are regularly exposed to gluten contamination when consuming food and beverages. This exposure to gluten contamination and the associated physiological and psychological consequences result in a self-limitation of social activities and/or a reduction in the variety of foods consumed. Thus, a GFD
presents both a considerable challenge and substantial burden for patients. A study by Shah et al., (2014) found that the burden of celiac disease and a GFD on patients' quality of life was ranked second only to end-stage renal disease, a condition that requires multiple weekly dialysis treatments.
[0100] As discussed above, the ubiquitous presence of gluten makes total avoidance very difficult, if not impossible. As little as 50 mg/day (a normal diet contains greater than 10 g/day) triggers activation of T cells in the small bowel and causes intestinal mucosal damage (Catassi et al., 2007). For this reason, more than 50% of celiac patients on a GFD
continue to present with active disease and intestinal immune activation and mucosal atrophy (Lee et al., 2003; Cranney et al., 2007; Hopper et al., 2007; Midhagen et al., 2003).
[0101] Patients who continue to have symptoms despite attempting to maintain a GFD are deemed to have NRCD. NRCD has been defined as "persistent symptoms, signs or laboratory abnormalities typical of celiac disease, despite 6-12 months of dietary gluten avoidance" (Rubio-Tapia et al., 2013). Patient support groups and experts agree that alternative treatment options independent of, or in combination with, GFD are urgently needed to improve the quality of life for celiac patients.
[0102] Substantial experimental data support multiple actions of IL-15 in the pathophysiology of CD and RCD (Abadie and Jabri et al., 2014) as illustrated in FIG. 5.
For example, within the innate immune response IL-15 is an essential, non-redundant growth and activation factor for the IELs which destroy the intestinal mucosa.
Further, the expression of IL-15 in the intestinal epithelium is necessary for villous atrophy.
Additionally, in some patients, IL-15 drives progression towards lymphomagenesis and potentially fatal RCD-II (Malamut et al., 2010).
[0103] Experimental data suggest IL-15 mediates the adaptive immune response as well.
For example, IL-15 enhances the presentation of deamidated gluten peptides (DGP) by antigen-presenting cells (APCs). Further, IL-15 renders the activated CD4+ T
cells resistant to inhibition by regulatory T cell.
[0104] By activating the IELs, IL-15 is believed to be the main mediator in the mucosal damage that ensues in response to gluten exposure in celiac disease (Korneychuk et al., 2014). The expression of IL-15 in the intestinal epithelium is necessary for villous atrophy in animal models of celiac disease and circumstantial evidence suggests this to be the case in humans as well. In addition, IL-15 renders effector T cells resistant to inhibition by regulatory T cells (Tõg) (Abadie and Jabri 2014), promoting the loss of tolerance to food antigens (DePaolo et al., 2011; Korneychuk et al., 2014).
[0105] One of the mouse models of celiac disease is an IL-15-transgenic mouse, in which IL-15 overexpression by gut epithelial cells leads to celiac-like presentations, including T
and B cell-mediated pathology (Yokoyama et al., 2009 and 2011). TEL apoptosis has been observed in this animal model after treatment with the anti-IL-15 mAb AMG 714 (Malamut et al., 2010) or anti-IL-15R mAbs (Yokoyama et al., 2009). IL-15 has been proven to be a key factor in the loss of tolerance to food antigens (DePaolo et al., 2011;
Korneychuk, et al., 2014).
[0106] Some of the CD-associated symptoms experienced in response to ingestion of wheat are also reported by individuals who do not have the typical serologic, histologic, or genetic markers of CD, and who also do not experience the immunoglobulin E (IgE) serologic response associated with wheat allergy. The term Non-celiac gluten sensitivity or non-celiac gluten sensitivity (NCGS) has been proposed to refer to the spectrum of conditions reported by these patients (Lundin and Alaedini, 2012). Non-celiac gluten sensitivity is currently understood as a condition associated with the experiencing of various symptoms in response to ingestion of foods containing wheat, rye, and barley, and the resolution of symptoms on removal of those foods from diet in individuals in whom CD and wheat allergy have been ruled out (Lundin and Alaedini, 2012). The symptoms may be accompanied with an increase in levels of antibody to gluten. The majority of symptoms associated with NCGS
are subjective, including abdominal pain, headache, "brain fog," tingling and/or numbness in hands and feet, fatigue, and musculoskeletal pain. However, other symptoms such as rash and diarrhea, as well as more severe neurologic and psychiatric conditions including schizophrenia and cerebellar ataxia, have also been reported to be associated with NCGS.
[0107] The present invention provides methods and compositions for treating celiac disease or non-celiac gluten sensitivity by administering a therapeutically effective amount of an anti-IL-15 antibody or antigen-binding fragment thereof disclosed herein. In some embodiments, a therapeutically effective amount of the anti-IL-15 antibody or antigen-binding fragment thereof can achieve, e.g., for the treatment of CD or NCGS
one or more of, (1) attenuation of gluten-induced small intestinal mucosal morphological injury, (2) reduction of villous height to crypt depth (VH:CD) ratio, (3) attenuation of gluten-induced small intestinal mucosal inflammation measured as intraepithelial lymphocyte (IELs) density, (4) attenuation of gluten-induced small intestinal mucosal morphological injury using a grouped classification of Marsh score, (5) attenuation of gluten-induced serum antibodies by measuring of anti-tissue transglutaminase antibodies (anti-tTG
IgA) and anti-deamidated gliadin peptide (anti-DGP) IgA and IgG, and/or (6) attenuation of gluten-induced clinical symptoms as assessed by the Bristol Stool Form Scale (BSFS) and the Gastrointestinal Symptom Rating Scale (GSRS) and celiac disease GSRS (CeD-GSRS).
Additional endpoints for NCGS include an ad-hoc list of symptoms (Di Sabatino et al., Clinical Gastroenterology and Hepatology 2015;13:1604-1612) or a severity patient-reported outcome like a visual analogue scale (VAS) (Elli et al., Nutrients 2016, 8, 84;
doi:10.3390/nu8020084).
[0108] One of ordinary skill in the art would be able to determine such therapeutically effective amounts based on additional factors as the subject's size, the severity of the subject's symptoms, and the particular composition or route of administration selected.
[0109] In some embodiments, the amount or unit dose of the pharmaceutical compositions disclosed herein can include about 50-1000 mg of the anti-IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof In some embodiments, the unit dose can be:
about 50-100 mg, about 100-150 mg, about 150-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, about 450-500 mg, about 550 mg, about 550-600 mg, about 600-700 mg, about 700-800 mg, about 800-900 mg or about 900-1000 mg, or higher or lower, or any numerical value therebetween, of the anti-IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof disclosed herein.
[0110] In some embodiments, the amount or unit dose can be: about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-110 mg, about mg, about 120-130 mg, about 130-140 mg, about 140-150 mg, about 150-160 mg, about 160-170 mg, about 170-180 mg, about 180-190 mg, about 190-200 mg, about 200-210 mg, about 210-220 mg, about 220-230 mg, about 230-240 mg, about 240-250 mg, about 260 mg, about 260-270 mg, about 270-280 mg, about 280-290 mg, about 290-300 mg, about 300-310 mg, about 310-320 mg, about 320-330 mg, about 330-340 mg, about 350 mg, about 350-360 mg, about 360-370 mg, about 370-380 mg, about 380-390 mg, about 390-400 mg, about 400-410 mg, about 410-420 mg, about 420-430 mg, about 440 mg, about 440-450 mg, about 450-460 mg, about 460-470 mg, about 470-480 mg, about 480-490 mg, about 490-500 mg, about 500-510 mg, about 510-520 mg, about 530 mg, about 530-540 mg, about 540-550 mg, about 550-560 mg, about 560-570 mg, about 570-580 mg, about 580-590 mg, about 590-600 mg, about 600-610 mg, about 620 mg, about 630-640 mg, about 640-650 mg, about 650-660 mg, about 660-670 mg, about 670-680 mg, about 680-690 mg, or 690-700 mg, of the anti-IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof disclosed herein.
101111 In some embodiments, the amount or unit dose can be: about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 205, about 210, about 220, about 225, about 230, about 235, about 240, about 245, about 250, about 255, about 260, about 265, about 270, about 275, about 280, about 285, about 290, about 295, about 300, about 305, about 310, about 315, about 320, about 325, about 330, about 335, about 340, about 345, about 350, about 355, about 360, about 365, about 370, about 375, about 380, about 385, about 390, about 395, about 400, about 405, about 410, about 415, about 420, about 425, about 430, about 435, about 440, about 445, about 450, about 455, about 460, about 465, about 470, about 475, about 480, about 485, about 490, about 495, about 500, about 505, about 510, about 515, about 520, about 525, about 530, about 535, about 540, about 545, about 550, about 555, about 560, about 565, about 570, about 575, about 580, about 585, about 590, about 595, about 600, about 605, about 610, about 615, about 620, about 625, about 630, about 635, about 640, about 645, about 650, about 655, about 660, about 665, about 670, about 675, about 680, about 685, about 690, about 695, or about 700 mg, or any numerical value in between any two of the foregoing, of the anti-IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof disclosed herein.
[0112] In some embodiments, the amount or unit dose of the pharmaceutical compositions disclosed herein can include about 1-50 mg/kg (patient weight) of the anti-IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof In some embodiments, the unit dose can be: about 1-10 mg/kg, about 10-20 mg/kg, about 20-30 mg/kg, about 30-40 mg/kg, or about 40-50 mg/kg, or higher or lower, or any numerical value therebetween, of the anti-IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof disclosed herein.
[0113] In some embodiments, the amount or unit dose can be: about 1-5 mg/kg, about 5-10 mg/kg, about 10-15 mg/kg, about 15-20 mg/kg, about 20-25 mg/kg, about 25-30 mg/kg, about 30-35 mg/kg, about 35-40 mg/kg, about 40-45 mg/kg, or about 45-50 mg/kg.
In some embodiments, a preferred dosage can include: about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about
[0096] Celiac disease causes debilitating symptoms and potentially serious medical complications. In many patients, gastrointestinal symptoms derived from gut mucosal damage dominate the patient-reported symptoms at diagnosis. As illustrated in FIG. 2, the normal villi (absorptive finger-like prolongations) present in the gut of healthy individuals (left) are lost in active celiac disease (right) as a result of mucosal atrophy and crypt enlargement. The ratio of the villous height (VH) to the intestinal crypt depth (CD), the VH:CD ratio, is one of the main descriptors of the severity of celiac disease (Taavela et al., 2013). Small bowel damage often leads to nutrient malabsorption that can result in a range of further clinical manifestations (e.g., anemia, osteopenia, failure to thrive in children). In addition, extra-intestinal symptoms and systemic manifestations are often present, such as dermatitis, infertility, neurological disorders, and skeletal disorders (Green and Cellier, 2007).
[0097] Despite this considerable morbidity, celiac disease is the only common autoimmune disorder with no approved medication. Currently, the only available strategy for the management of celiac disease is a lifelong total avoidance of gluten. While simple in theory, in practice, the ubiquity of gluten in foodstuffs, medications, household substances, cosmetics, and even gluten-free items makes total avoidance of gluten difficult, if not impossible.
[0098] The main challenge to the successful maintenance of a gluten free diet (GFD) is that cereal flours are widely used in the food industry and are present in most food products either naturally or as additives. Although gluten-free products can be purchased, commercially manufactured gluten-free products may be difficult to find, tend to be less flavorful, and are more expensive than regular gluten-containing foods, which can sometimes deter patients from adhering to a GFD. In addition, many countries are deficient in the appropriate labeling of food products. Even in countries with superior labeling guidelines, foods labeled "gluten-free" may nevertheless contain gluten. For example, in northern European countries, gluten amounts of up to 100 parts per million (ppm) are permitted in gluten-free products designated for celiac sufferers (Gibert et al., 2006).
[0099] For these reasons, celiac sufferers are regularly exposed to gluten contamination when consuming food and beverages. This exposure to gluten contamination and the associated physiological and psychological consequences result in a self-limitation of social activities and/or a reduction in the variety of foods consumed. Thus, a GFD
presents both a considerable challenge and substantial burden for patients. A study by Shah et al., (2014) found that the burden of celiac disease and a GFD on patients' quality of life was ranked second only to end-stage renal disease, a condition that requires multiple weekly dialysis treatments.
[0100] As discussed above, the ubiquitous presence of gluten makes total avoidance very difficult, if not impossible. As little as 50 mg/day (a normal diet contains greater than 10 g/day) triggers activation of T cells in the small bowel and causes intestinal mucosal damage (Catassi et al., 2007). For this reason, more than 50% of celiac patients on a GFD
continue to present with active disease and intestinal immune activation and mucosal atrophy (Lee et al., 2003; Cranney et al., 2007; Hopper et al., 2007; Midhagen et al., 2003).
[0101] Patients who continue to have symptoms despite attempting to maintain a GFD are deemed to have NRCD. NRCD has been defined as "persistent symptoms, signs or laboratory abnormalities typical of celiac disease, despite 6-12 months of dietary gluten avoidance" (Rubio-Tapia et al., 2013). Patient support groups and experts agree that alternative treatment options independent of, or in combination with, GFD are urgently needed to improve the quality of life for celiac patients.
[0102] Substantial experimental data support multiple actions of IL-15 in the pathophysiology of CD and RCD (Abadie and Jabri et al., 2014) as illustrated in FIG. 5.
For example, within the innate immune response IL-15 is an essential, non-redundant growth and activation factor for the IELs which destroy the intestinal mucosa.
Further, the expression of IL-15 in the intestinal epithelium is necessary for villous atrophy.
Additionally, in some patients, IL-15 drives progression towards lymphomagenesis and potentially fatal RCD-II (Malamut et al., 2010).
[0103] Experimental data suggest IL-15 mediates the adaptive immune response as well.
For example, IL-15 enhances the presentation of deamidated gluten peptides (DGP) by antigen-presenting cells (APCs). Further, IL-15 renders the activated CD4+ T
cells resistant to inhibition by regulatory T cell.
[0104] By activating the IELs, IL-15 is believed to be the main mediator in the mucosal damage that ensues in response to gluten exposure in celiac disease (Korneychuk et al., 2014). The expression of IL-15 in the intestinal epithelium is necessary for villous atrophy in animal models of celiac disease and circumstantial evidence suggests this to be the case in humans as well. In addition, IL-15 renders effector T cells resistant to inhibition by regulatory T cells (Tõg) (Abadie and Jabri 2014), promoting the loss of tolerance to food antigens (DePaolo et al., 2011; Korneychuk et al., 2014).
[0105] One of the mouse models of celiac disease is an IL-15-transgenic mouse, in which IL-15 overexpression by gut epithelial cells leads to celiac-like presentations, including T
and B cell-mediated pathology (Yokoyama et al., 2009 and 2011). TEL apoptosis has been observed in this animal model after treatment with the anti-IL-15 mAb AMG 714 (Malamut et al., 2010) or anti-IL-15R mAbs (Yokoyama et al., 2009). IL-15 has been proven to be a key factor in the loss of tolerance to food antigens (DePaolo et al., 2011;
Korneychuk, et al., 2014).
[0106] Some of the CD-associated symptoms experienced in response to ingestion of wheat are also reported by individuals who do not have the typical serologic, histologic, or genetic markers of CD, and who also do not experience the immunoglobulin E (IgE) serologic response associated with wheat allergy. The term Non-celiac gluten sensitivity or non-celiac gluten sensitivity (NCGS) has been proposed to refer to the spectrum of conditions reported by these patients (Lundin and Alaedini, 2012). Non-celiac gluten sensitivity is currently understood as a condition associated with the experiencing of various symptoms in response to ingestion of foods containing wheat, rye, and barley, and the resolution of symptoms on removal of those foods from diet in individuals in whom CD and wheat allergy have been ruled out (Lundin and Alaedini, 2012). The symptoms may be accompanied with an increase in levels of antibody to gluten. The majority of symptoms associated with NCGS
are subjective, including abdominal pain, headache, "brain fog," tingling and/or numbness in hands and feet, fatigue, and musculoskeletal pain. However, other symptoms such as rash and diarrhea, as well as more severe neurologic and psychiatric conditions including schizophrenia and cerebellar ataxia, have also been reported to be associated with NCGS.
[0107] The present invention provides methods and compositions for treating celiac disease or non-celiac gluten sensitivity by administering a therapeutically effective amount of an anti-IL-15 antibody or antigen-binding fragment thereof disclosed herein. In some embodiments, a therapeutically effective amount of the anti-IL-15 antibody or antigen-binding fragment thereof can achieve, e.g., for the treatment of CD or NCGS
one or more of, (1) attenuation of gluten-induced small intestinal mucosal morphological injury, (2) reduction of villous height to crypt depth (VH:CD) ratio, (3) attenuation of gluten-induced small intestinal mucosal inflammation measured as intraepithelial lymphocyte (IELs) density, (4) attenuation of gluten-induced small intestinal mucosal morphological injury using a grouped classification of Marsh score, (5) attenuation of gluten-induced serum antibodies by measuring of anti-tissue transglutaminase antibodies (anti-tTG
IgA) and anti-deamidated gliadin peptide (anti-DGP) IgA and IgG, and/or (6) attenuation of gluten-induced clinical symptoms as assessed by the Bristol Stool Form Scale (BSFS) and the Gastrointestinal Symptom Rating Scale (GSRS) and celiac disease GSRS (CeD-GSRS).
Additional endpoints for NCGS include an ad-hoc list of symptoms (Di Sabatino et al., Clinical Gastroenterology and Hepatology 2015;13:1604-1612) or a severity patient-reported outcome like a visual analogue scale (VAS) (Elli et al., Nutrients 2016, 8, 84;
doi:10.3390/nu8020084).
[0108] One of ordinary skill in the art would be able to determine such therapeutically effective amounts based on additional factors as the subject's size, the severity of the subject's symptoms, and the particular composition or route of administration selected.
[0109] In some embodiments, the amount or unit dose of the pharmaceutical compositions disclosed herein can include about 50-1000 mg of the anti-IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof In some embodiments, the unit dose can be:
about 50-100 mg, about 100-150 mg, about 150-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, about 450-500 mg, about 550 mg, about 550-600 mg, about 600-700 mg, about 700-800 mg, about 800-900 mg or about 900-1000 mg, or higher or lower, or any numerical value therebetween, of the anti-IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof disclosed herein.
[0110] In some embodiments, the amount or unit dose can be: about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-110 mg, about mg, about 120-130 mg, about 130-140 mg, about 140-150 mg, about 150-160 mg, about 160-170 mg, about 170-180 mg, about 180-190 mg, about 190-200 mg, about 200-210 mg, about 210-220 mg, about 220-230 mg, about 230-240 mg, about 240-250 mg, about 260 mg, about 260-270 mg, about 270-280 mg, about 280-290 mg, about 290-300 mg, about 300-310 mg, about 310-320 mg, about 320-330 mg, about 330-340 mg, about 350 mg, about 350-360 mg, about 360-370 mg, about 370-380 mg, about 380-390 mg, about 390-400 mg, about 400-410 mg, about 410-420 mg, about 420-430 mg, about 440 mg, about 440-450 mg, about 450-460 mg, about 460-470 mg, about 470-480 mg, about 480-490 mg, about 490-500 mg, about 500-510 mg, about 510-520 mg, about 530 mg, about 530-540 mg, about 540-550 mg, about 550-560 mg, about 560-570 mg, about 570-580 mg, about 580-590 mg, about 590-600 mg, about 600-610 mg, about 620 mg, about 630-640 mg, about 640-650 mg, about 650-660 mg, about 660-670 mg, about 670-680 mg, about 680-690 mg, or 690-700 mg, of the anti-IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof disclosed herein.
101111 In some embodiments, the amount or unit dose can be: about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 205, about 210, about 220, about 225, about 230, about 235, about 240, about 245, about 250, about 255, about 260, about 265, about 270, about 275, about 280, about 285, about 290, about 295, about 300, about 305, about 310, about 315, about 320, about 325, about 330, about 335, about 340, about 345, about 350, about 355, about 360, about 365, about 370, about 375, about 380, about 385, about 390, about 395, about 400, about 405, about 410, about 415, about 420, about 425, about 430, about 435, about 440, about 445, about 450, about 455, about 460, about 465, about 470, about 475, about 480, about 485, about 490, about 495, about 500, about 505, about 510, about 515, about 520, about 525, about 530, about 535, about 540, about 545, about 550, about 555, about 560, about 565, about 570, about 575, about 580, about 585, about 590, about 595, about 600, about 605, about 610, about 615, about 620, about 625, about 630, about 635, about 640, about 645, about 650, about 655, about 660, about 665, about 670, about 675, about 680, about 685, about 690, about 695, or about 700 mg, or any numerical value in between any two of the foregoing, of the anti-IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof disclosed herein.
[0112] In some embodiments, the amount or unit dose of the pharmaceutical compositions disclosed herein can include about 1-50 mg/kg (patient weight) of the anti-IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof In some embodiments, the unit dose can be: about 1-10 mg/kg, about 10-20 mg/kg, about 20-30 mg/kg, about 30-40 mg/kg, or about 40-50 mg/kg, or higher or lower, or any numerical value therebetween, of the anti-IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof disclosed herein.
[0113] In some embodiments, the amount or unit dose can be: about 1-5 mg/kg, about 5-10 mg/kg, about 10-15 mg/kg, about 15-20 mg/kg, about 20-25 mg/kg, about 25-30 mg/kg, about 30-35 mg/kg, about 35-40 mg/kg, about 40-45 mg/kg, or about 45-50 mg/kg.
In some embodiments, a preferred dosage can include: about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about
16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, or about 50 mg/kg, of the anti-IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof disclosed herein.
[0114] In some embodiments, each subject can receive at least one (e.g., 1-100) unit dose disclosed herein, depending on the severity of the disease and/or effectiveness of the treatment. For example, the subject may receive 2-20 unit doses which can be the same or different (e.g., one or more initial unit doses can be smaller or larger than later unit dose(s)) from one another.
[0115] In some embodiments, the pharmaceutical compositions disclosed herein can be administered, in unit doses disclosed herein, by subcutaneous or intravenous injection every 1-20 weeks. In one embodiment, the pharmaceutical composition is administered subcutaneously. In another embodiment, the pharmaceutical composition is administered intravenously. In certain embodiments, administration can occur every 1-5, 5-10, 10-15, or 15-20 weeks. In some embodiments, administration can occur every 1-2, 2-4, 4-6, 6-8, 8-10, 10-12, 12-14, 14-16, 16-18, or 18-20 weeks. In some embodiments, administration can occur every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks. The unit doses can be given at the same intervals (e.g., every 1-20 weeks).
Alternatively, at least a portion of the unit doses are given at different (e.g., shortened or prolonged) intervals than the other unit doses.
[0116] In other aspects, the present invention relates to a pharmaceutical composition, as described herein, for use in treating celiac or non-celiac gluten sensitivity, wherein the pharmaceutical composition comprises an anti-IL-15 antibody (e.g., AMG 714).
In other embodiments, the pharmaceutical composition comprises 75 mg, 150 mg, 300 mg, 600 mg, 4 mg/kg, 8 mg/kg or 12 mg/kg of an anti-IL-15 antibody (e.g., AMG 714). In certain embodiments, the pharmaceutical composition comprises 150 mg or 300 mg of an anti-IL-15 antibody (e.g., AMG 714). In some embodiments, the pharmaceutical composition is administered subcutaneously every 1, 2 or 4 weeks, until, e.g., alleviation or elimination of signs and/or symptoms. In one embodiment, the pharmaceutical composition is administered subcutaneously every 2 weeks. In another particular embodiment, the pharmaceutical composition is administered intravenously every 1, 2 or 4 weeks until, e.g., alleviation or elimination of signs and/or symptoms. In another particular embodiment, the pharmaceutical composition is administered intravenously every 2 weeks.
[0117] In some aspects, the present invention relates to a pharmaceutical composition, as described herein, for use in a method of treating celiac or non-celiac gluten sensitivity, wherein the method comprises administering (e.g., subcutaneously) an anti-IL-15 antibody (e.g., AMG 714). In some embodiments, the method comprises administering (e.g., subcutaneously) 75 mg, 150 mg, 300 mg, 600 mg, 4 mg/kg, 8 mg/kg or 12 mg/kg of an anti-IL-15 antibody (e.g., AMG 714). In certain embodiments, the method comprises administering (e.g., subcutaneously) 150 mg or 300 mg of an anti-IL-15 antibody (e.g., AMG 714). In some embodiments, the method comprises administering the pharmaceutical composition subcutaneously every 1, 2 or 4 weeks, until, e.g., alleviation or elimination of signs and/or symptoms. In one embodiment, the method comprises administering subcutaneously every 2 weeks. In another particular embodiment, the method comprises administering intravenously every 1, 2 or 4 weeks until, e.g., alleviation or elimination of signs and/or symptoms. In another particular embodiment, the method comprises administering intravenously every 2 weeks.
[0118] In another aspect, the present invention relates to a method of treating celiac or non-celiac gluten sensitivity, wherein the method comprises administering (e.g., subcutaneously) an anti-IL-15 antibody (e.g., AMG 714). In some embodiments, the method comprises administering (e.g., subcutaneously) 75 mg, 150 mg, 300 mg, 600 mg, 4 mg/kg, 8 mg/kg or 12 mg/kg of an anti-IL-15 antibody (e.g., AMG 714). In certain embodiments, the method comprises administering (e.g., subcutaneously) 150 mg or 300 mg of an anti-IL-15 antibody (e.g., AMG 714). In some embodiments, the method comprises administering the pharmaceutical composition subcutaneously every 1, 2 or 4 weeks, until, e.g., alleviation or elimination of signs and/or symptoms. In one embodiment, the method comprises administering subcutaneously every 2 weeks. In another particular embodiment, the method comprises administering intravenously every 1, 2 or 4 weeks until, e.g., alleviation or elimination of signs and/or symptoms. In another particular embodiment, the method comprises administering intravenously every 2 weeks.
[0119] In particular embodiments of the pharmaceutical compositions and methods described herein, 150 or 300 mg of an anti-IL 15 antibody (e.g., AMG 714) is administered once every 2 weeks (q2w) via subcutaneous injection.
Use of the Pharmaceutical Composition to Treat Refractory Celiac Disease [0120] A rare but specific complication of persistent exposure to gluten in celiac disease is the development of refractory celiac disease (RCD), which affects approximately 1% of celiac patients (Lebwohl et al., 2013). RCD is characterized by severe intestinal mucosal atrophy and gastrointestinal symptoms in the absence of gluten consumption and in the presence of small bowel aberrant IELs (Verbeek et al., 2008, vanWanrooij et al., 2014).
[0121] RCD patients can be further classified according to the proportion and characteristics of aberrant IELs. Patients with a low proportion of aberrant IELs, defined as less than 20% of total IELs (less than 20 IELs per 100 epithelial cells), as determined by flow cytometry, are referred to as Type I RCD (RCD-I). These aberrant IELs are generally polyclonal, and RCD-I patients are not at increased risk of developing overt extra epithelial lymphoma (i.e., enteropathy-associated T cell lymphoma [EATL]) and have a typical 5-year survival (vanWanrooij et al., 2014). To treat RCD-I, corticosteroids (local or systemic), azathioprine, purinethol, anti-TNF agents, or cladribine may be used (Brar et al., 2007;
Goerres et al., 2003) with clinical and histological improvement. FIG. 3 illustrates the pathophysiology of celiac and refractory celiac disease, as described by Schuppan et al.
[0122] When the proportion of aberrant IELs reaches or exceeds 20%, patients are diagnosed with Type II RCD (RCD-II). In RCD-II, the IELs are typically monoclonal and the risk of developing EATL is dramatically increased to greater than 50%
(Nijeboer et al., 2015). The aberrant IELs proliferate in the absence of gluten due to accumulation of anti-apoptotic mechanisms, hence the term "refractory" indicating that the disease, a non-Hodgkin slow-growing intraepithelial lymphoma, appears not to be dependent on gluten since it is not responsive to the strictest GFD. As illustrated in FIG. 4, IL-15 is believed to be the main driver of transformation and maintenance of the aberrant IELs (Meresse et al., 2012). Experimental proof of principle has been established for IL-15 inhibition in RCD-II
by the finding that blocking IL-15 with the anti-IL-15 mAb AMG 714 induces IEL
apoptosis in human small bowel biopsies from active celiac and RCD-II patients (Malamut et al., 2010). Also, IEL apoptosis has been observed in animal models of celiac disease treated with anti-IL-15 AMG 714 (Malamut et al., 2010) or anti-IL-15-receptor mAbs (Yokoyama et al., 2009).
[0123] The aberrant monoclonal IELs have been demonstrated to be precursors of EATL
based on the observation that the T cell receptor (TCR) re-arrangement repertoire is similar in sequential biopsies from RCD-II patients who develop EATL. RCD-II is considered to be an in situ low-grade T cell lymphoma of the small bowel. A thorough study of the low grade IEL proliferation in RCD-II has revealed a characteristic phenotype with the presence of intracellular CD3 without surface CD3 or TCR and generally no CD8 expression with expression of CD103, which is shared by high grade EATL proliferations. This phenotype is distinct from the normal phenotype of IELs in uncomplicated celiac disease and, together with the common presence of a clonal TCR re-arrangement in the intestinal biopsy, confirms the diagnosis of RCD and allows follow-up of the expansion.
[0124] The treatment of RCD-II is difficult as aberrant lymphocytes are scattered throughout the whole small intestinal epithelium and, usually, in the stomach and colon, thereby precluding surgery. In addition, there is no standard of care for RCD-II. Attempts of chemotherapies have been mostly ineffective and/or dangerous for patients.
Cladribine (Tack et al., 2011a; Tack et al., 2011b) and autologous bone marrow transplantation have been used and shown to transiently improve the digestive symptoms and histology but not monoclonal proliferation. The prognosis of RCD-II is poor, with death occurring within 3-years mainly due to intractable diarrhea, EATL, or the rare dissemination of low grade lymphocyte proliferation to other tissues (e.g., skin, lungs).
[0125] EATL is a high-grade, systemic, T cell lymphoma almost exclusively seen as a complication of RCD-II (Nijeboer et al., 2015). Diagnosis includes imaging and histology to demonstrate the presence of malignant T cells in extra-epithelial locations such as lymph nodes or other organs. The treatment of EATL relies on surgical resection and chemotherapy, but the prognosis is very poor, with a 5-year survival of less than 20%
(Nijeboer et al., 2015).
[0126] The incidence of EATL is increasing, and this increase could be related to the rising prevalence of gluten contamination in the diet over prolonged periods of time (Sharaiha et al., 2012). An effective treatment for RCD-II that could alleviate the presence of aberrant IELs, the histological abnormalities, and/or the symptoms remains the highest priority. A
summary of the characteristics of CD, RCD, and ETCL are summarized in Table 1 below.
Table 1. Characteristics of Celiac Disease, Refractory Celiac Disease, and Enteropathy-associated T cell Lymphoma Type Nature of the Gluten Aberrant Clonality Progression disease dependence IELs to overt systemic lymphoma Non- Autoimmune Yes No Poly clonal No Responsive Celiac Disease Refractory Unknown Probably Yes, less than Oligoclonal No Type I 20%
Refractory Malignant, slow Probably Yes, greater Monoclonal greater than Type II growing independent than 20% (in situ 50%
lymphoma) EATL Malignant, rapid No Yes, greater Monoclonal N/A
progression than 20% (systemic lymphoma) [0127] The present invention provides methods and compositions for treating Type I or Type II Refractory Celiac Disease by administering a therapeutically effective amount of an anti-IL-15 antibody (e.g., AMG 714) or antigen-binding fragment thereof disclosed herein.
In some embodiments, a therapeutically effective amount of the anti-IL-15 antibody (e.g., AMG 714) or antigen-binding fragment thereof can achieve, e.g., for the treatment of RCD-I or RCD-II one or more of, (1) a measure of the immunological response by quantification of the reduction from baseline in the % of aberrant intestinal intraepithelial lymphocytes (IELs) vs. total IELs as assessed by flow-cytometry, (2) the measure of the immunological response by quantification of the reduction from baseline in the % of aberrant IELs vs.
intestinal epithelial cells, (3) histological response: Improvement from baseline in small intestinal villous height to crypt depth (VH:CD) ratio, Marsh score or total TEL counts, and/or (4) clinical response: Change from baseline in clinical symptoms by the Bristol Stool Form Scale (BSFS) and Gastrointestinal Symptom Rating Scale (GSRS), including the celiac disease GSRS (CeD-GSRS).
[0128] In some embodiments, the amount or unit dose of the pharmaceutical compositions disclosed herein can include about 1-50 mg/kg (patient weight) of the anti-IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof In some embodiments, the unit dose can be: about 1-10 mg/kg, about 10-20 mg/kg, about 20-30 mg/kg, about 30-40 mg/kg, or about 40-50 mg/kg, or higher or lower, or any numerical value therebetween, of the anti-IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof disclosed herein.
[0129] In some embodiments, the amount or unit dose can be: about 1-5 mg/kg, about 5-10 mg/kg, about 10-15 mg/kg, about 15-20 mg/kg, about 20-25 mg/kg, about 25-30 mg/kg, about 30-35 mg/kg, about 35-40 mg/kg, about 40-45 mg/kg, or about 45-50 mg/kg.
In some embodiments, a preferred dosage can include: about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, or about 50 mg/kg, of the anti-IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof disclosed herein.
[0130] In some embodiments, the amount or unit dose of the pharmaceutical compositions disclosed herein can include about 50-1000 mg of the anti-IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof In some embodiments, the unit dose can be:
about 50-100 mg, about 100-150 mg, about 150-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, about 450-500 mg, about 550 mg, about 550-600 mg, about 600-700 mg, about 700-800 mg, about 800-900 mg or about 900-1000 mg, or higher or lower, or any numerical value therebetween, of the anti-IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof disclosed herein.
[0131] In some embodiments, the amount or unit dose can be: about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-110 mg, about mg, about 120-130 mg, about 130-140 mg, about 140-150 mg, about 150-160 mg, about 160-170 mg, about 170-180 mg, about 180-190 mg, about 190-200 mg, about 200-210 mg, about 210-220 mg, about 220-230 mg, about 230-240 mg, about 240-250 mg, about 260 mg, about 260-270 mg, about 270-280 mg, about 280-290 mg, about 290-300 mg, about 300-310 mg, about 310-320 mg, about 320-330 mg, about 330-340 mg, about 350 mg, about 350-360 mg, about 360-370 mg, about 370-380 mg, about 380-390 mg, about 390-400 mg, about 400-410 mg, about 410-420 mg, about 420-430 mg, about 440 mg, about 440-450 mg, about 450-460 mg, about 460-470 mg, about 470-480 mg, about 480-490 mg, about 490-500 mg, about 500-510 mg, about 510-520 mg, about 530 mg, about 530-540 mg, about 540-550 mg, about 550-560 mg, about 560-570 mg, about 570-580 mg, about 580-590 mg, about 590-600 mg, about 600-610 mg, about 620 mg, about 630-640 mg, about 640-650 mg, about 650-660 mg, about 660-670 mg, about 670-680 mg, about 680-690 mg, or 690-700 mg, of the anti-IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof disclosed herein.
[0132] In some embodiments, the amount or unit dose can be: about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 205, about 210, about 220, about 225, about 230, about 235, about 240, about 245, about 250, about 255, about 260, about 265, about 270, about 275, about 280, about 285, about 290, about 295, about 300, about 305, about 310, about 315, about 320, about 325, about 330, about 335, about 340, about 345, about 350, about 355, about 360, about 365, about 370, about 375, about 380, about 385, about 390, about 395, about 400, about 405, about 410, about 415, about 420, about 425, about 430, about 435, about 440, about 445, about 450, about 455, about 460, about 465, about 470, about 475, about 480, about 485, about 490, about 495, about 500, about 505, about 510, about 515, about 520, about 525, about 530, about 535, about 540, about 545, about 550, about 555, about 560, about 565, about 570, about 575, about 580, about 585, about 590, about 595, about 600, about 605, about 610, about 615, about 620, about 625, about 630, about 635, about 640, about 645, about 650, about 655, about 660, about 665, about 670, about 675, about 680, about 685, about 690, about 695, or about 700 mg, or any numerical value in between any two of the foregoing, of the anti-IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof disclosed herein.
[0133] In some embodiments, each subject can receive at least one (e.g., 1-100) unit dose disclosed herein, depending on the severity of the disease and/or effectiveness of the treatment. For example, the subject may receive 2-20 unit doses which can be the same or different (e.g., one or more initial unit doses can be smaller or larger than later unit dose(s)) from one another.
[0134] In some embodiments, the pharmaceutical compositions disclosed herein can be administered, in unit doses disclosed herein, by subcutaneous or intravenous injection every 1-20 weeks. In one embodiment, the pharmaceutical composition is administered subcutaneously. In another embodiment, the pharmaceutical composition is administered intravenously. In certain embodiments, administration can occur every 1-5, 5-10, 10-15, or 15-20 weeks. In some embodiments, administration can occur every 1-2, 2-4, 4-6, 6-8, 8-10, 10-12, 12-14, 14-16, 16-18, or 18-20 weeks. In some embodiments, administration can occur every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks. The unit doses can be given at the same intervals (e.g., every 1-20 weeks).
Alternatively, at least a portion of the unit doses are given at different (e.g., shortened or prolonged) intervals than the other unit doses. In one example, one or more additional loading doses can be given at, e.g., week 1 or any other time to boost the dosage.
[0135] In other aspects, the present invention relates to a pharmaceutical composition, as described herein, for use in treating Type II refractory celiac disease patients, e.g., patients with in situ small bowel T Cell lymphoma, wherein the pharmaceutical composition comprises an anti-IL-15 antibody (e.g., AMG 714). In other embodiments, the pharmaceutical composition comprises 75 mg, 150 mg, 300 mg, 600 mg, 4 mg/kg, 8 mg/kg or 12 mg/kg of an anti-IL-15 antibody (e.g., AMG 714). In a particular embodiment, the pharmaceutical composition comprises 8 mg/kg of AMG 714. In some embodiments, the pharmaceutical composition is administered (e.g., intravenously) every 1, 2 or 4 weeks, until, e.g., alleviation or elimination of signs and/or symptoms. In another particular embodiment, pharmaceutical composition is administered (e.g., intravenously) every 2 weeks. In another particular embodiment, the pharmaceutical composition is administered subcutaneously every 1, 2 or 4 weeks until, e.g., alleviation or elimination of signs and/or symptoms. In another particular embodiment, the pharmaceutical composition is administered subcutaneously every 2 weeks.
[0136] In some aspects, the present invention relates to a pharmaceutical composition, as described herein, for use in a method of treating Type II refractory celiac disease patients e.g., patients with in situ small bowel T Cell lymphoma, wherein the method comprises administering (e.g., intravenously) an anti-IL-15 antibody (e.g., AMG 714). In some embodiments, the method comprises administering (e.g., intravenously) 75 mg, 150 mg, 300 mg, 600 mg, 4 mg/kg, 8 mg/kg or 12 mg/kg of an anti-IL-15 antibody (e.g., AMG 714).
In certain embodiments, the method comprises administering (e.g., intravenously) 8 mg/kg of an anti-IL-15 antibody (e.g., AMG 714). In some embodiments, the method comprises administering the pharmaceutical composition subcutaneously every 1, 2 or 4 weeks, until, e.g., alleviation or elimination of signs and/or symptoms. In one embodiment, the method comprises administering subcutaneously every 2 weeks. In another particular embodiment, the method comprises administering intravenously every 1, 2 or 4 weeks until, e.g., alleviation or elimination of signs and/or symptoms. In another particular embodiment, the method comprises administering intravenously every 2 weeks.
[0137] In another aspect, the present invention relates to a method of treating Type II
refractory celiac disease patients or patients with in situ small bowel T Cell lymphoma, wherein the method comprises administering (e.g., intravenously) an anti-IL-15 antibody (e.g., AMG 714). In some embodiments, the method comprises administering (e.g., intravenously) 75 mg, 150 mg, 300 mg, 600 mg, 4 mg/kg, 8 mg/kg or 12 mg/kg of an anti-IL-15 antibody (e.g., AMG 714). In certain embodiments, the method comprises administering (e.g., intravenously) 8 mg/kg of an anti-IL-15 antibody (e.g., AMG 714). In some embodiments, the method comprises administering the pharmaceutical composition subcutaneously every 1, 2 or 4 weeks, until, e.g., alleviation or elimination of signs and/or symptoms. In one embodiment, the method comprises administering subcutaneously every 2 weeks. In another particular embodiment, the method comprises administering intravenously every 1, 2 or 4 weeks until, e.g., alleviation or elimination of signs and/or symptoms. In another particular embodiment, the method comprises administering intravenously every 2 weeks.
[0138] In particular embodiments of the pharmaceutical compositions and methods described herein, 8 mg/kg of an anti-IL-15 antibody (e.g., AMG 714) is administered once every 2 weeks (q2w) intravenously. In other particular embodiments of the pharmaceutical compositions and methods described herein, 8 mg/kg of an anti-IL 15 antibody (e.g., AMG
714) is administered intravenously at week 0, week 1, and once every 2 weeks (q2w) thereafter.
EXAMPLES
Example 1: Phase 2a, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate Efficacy and Safety of AMG714 in Adult Patients with Celiac Disease [0139] In an exemplary clinical trial AMG 714 can be administered to adult patients with CD. The primary objective of this study is to assess the efficacy of AMG 714 in attenuating the effects of gluten exposure in adults with CD. The secondary objective is to assess the safety and tolerability of AMG 714 when administered to adult patients with celiac disease exposed to a gluten challenge. The exploratory objectives are to assess the pharmacokinetics (PK), pharmacodynamics (PD), and PK/PD correlations of AMG
714.
[0140] Primary outcome/endpoint measures: Attenuation of gluten-induced small intestinal mucosal injury as assessed by the change from baseline to Week 12 in VH:CD
ratio. Time Frame: Baseline and 12 weeks. The VH:CD is the morphometric measure of the length of the small intestinal villi with respect to the depth of the crypts.
[0141] Secondary outcome/endpoint measures:
(1) Attenuation of gluten-induced small intestinal mucosal inflammation at Week 12 compared to baseline, as measured by the enumeration of intraepithelial lymphocytes (IELs) in histological sections. Time Frame: Baseline and 12 weeks. Small bowel biopsies can be processed and stained with hematoxylin-eosin stains, and the IELs counted per epithelial cells.
(2) Attenuation of gluten-induced serum antibodies at Week 12 compared to baseline (anti-deamidated gliadin peptides, DGP) and autoantibodies (anti-transglutaminase, ATG). Time Frame: Baseline and 12 weeks. DGP and ATG antibodies can be measured in serum by ELISA technique.
(3) Attenuation at Week 12 compared to baseline, of gluten-induced clinical symptoms as measured by the Gastrointestinal Symptom Rating Scale (GSRS). Time Frame:
Baseline and 12 weeks. The GSRS questionnaire can be filled at every visit (approximately monthly).
[0142] Other outcome/endpoint measures: Safety and Tolerability of AMG 714 as assessed by the proportion of subjects with drug related adverse events. Time Frame: 12 weeks.
Adverse events and serious adverse events can be captured on an on-going basis from screening to study end.
Study Design [0143] The protocol is designed to be a Phase 2a, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of AMG
714 for the attenuation of the effects of gluten exposure in adult patients with celiac disease during a gluten challenge.
[0144] All subjects are randomized at a 1:1:1 ratio to receive 150 mg or 300 mg AMG 714 or placebo once every two weeks for 10 weeks. Randomization is stratified by sex. The study drug (AMG 714 or placebo) can be administered at the clinical site in a double-blind fashion via subcutaneous (SC) injection.
[0145] In addition to receiving study medication or placebo, all subjects will be required to consume either placebo gluten or active gluten administered in a single-blind fashion.
[0146] All study subjects can undergo upper gastrointestinal endoscopy and biopsy prior to baseline (Visit 1, Week 0/Day 0) and at the end of the 12-week study period while still on the gluten challenge and within 5 days before Visit 7 (Week 12/Day 84) in order to assess changes from baseline in VH:CD ratio, IELs, and Marsh score.
[0147] Safety will be monitored on an ongoing basis and subjects may undergo unscheduled visits if needed for safety reasons. Safety will be assessed throughout the study by clinical laboratory tests, physical examination, vital signs, and AE
monitoring.
[0148] Subject Inclusion Criteria:
= Diagnosis of celiac disease by intestinal biopsy at least 12 months prior to screening = On a gluten-free diet for at least 12 months = Negative celiac serology = Avoidance of pregnancy [0149] Exclusion Criteria:
e Severe complications of celiac disease, such as refractory celiac disease Celiac symptoms = Other concomitant autoimmune disease = Chronic, active GI disease = Infections, concomitant diseases Prohibited medications [0150] The selection of dosing levels for the celiac disease study, in one embodiment, is 150 and 300 mg once every 2 weeks (q2w) via subcutaneous injection (SC). While there is no prior experience with AMG 714 in celiac disease nor any understanding of the potential PK/PD relationship in this disease, toxicology and human studies to date support the dosing regimen selected for this study. The highest doses of AMG 714 studied in previous clinical trials were a single SC dose of 700 mg and SC doses of 300 mg every two weeks for 12 weeks, with no safety signals identified to date.
[0151] The dosing regimen is expected to provide trough levels above the concentration of AMG 714 used in vitro (10 [tg/mL) to induce apoptosis of activated IELs in biopsies of patients with active celiac disease (Malamut et al., 2010).
[0152] Serum exposure can be monitored with frequent PK sampling. Tissue effects can be monitored with experimental biomarkers to be measured in the biopsies to be obtained throughout the study.
Example 2: Phase 2a Study to Evaluate Efficacy and Safety of AMG 714 in Adult Patients with Type II Refractory Celiac Disease [0153] In an exemplary clinical trial the efficacy and safety of AMG 714 can be studied in adult patients with Type II Refractory Celiac Disease. The primary objective of this study will be to assess the efficacy of AMG 714 in treating RCD-II in adult patients. The secondary object of this study will be to assess the safety and tolerability of AMG 714 when administered to adult patients with RCD-II. The exploratory objectives of this study will be to assess the pharmacokinetics (PK), pharmacodynamics (PD), and PK/PD
correlations of AMG 714.
[0154] Primary outcome/endpoint measures include immunological response, e.g., reduction from baseline in the % of aberrant small bowel intestinal intraepithelial lymphocytes (surface CD3- intracellular CD3+). Time Frame: Baseline and 12 weeks.
Reduction from baseline in the % of aberrant intestinal intraepithelial lymphocytes can be measured by, e.g., flow cytometry after small intestinal biopsy collection.
[0155] Secondary outcome/endpoint measures:
(1) Histological response: Improvement from baseline in small intestinal morphology as measured by the Villous Height to Crypt Depth (VH:CD) ratio in intestinal biopsy material. Time Frame: Baseline and 12 weeks.
(2) Clinical response: Change from baseline in clinical symptoms as measured by the Gastrointestinal Symptom Rating Scale (GSRS). Time Frame: Baseline and 12 weeks.
[0156] Other outcome/endpoint measures include safety and tolerability: Number of participants with treatment-related adverse events as assessed by Common Terminology Criteria for Adverse Events (CTCAE). Time Frame: 12 weeks. The frequency and nature of adverse events can be collected and analyzed.
Study Design [0157] The protocol is designed to be a Phase 2a randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy and safety of AMG
714 for the treatment of adult patients with RCD-II.
[0158] All subjects who meet the study entry criteria can be randomized at a 2:1 ratio to receive either 8 mg/kg AMG 714 or placebo every 2 weeks for a total of 7 times over 10 weeks, with evaluation of the primary endpoint at Week 12. AMG 714 or placebo can be administered at the clinical site in a double-blind fashion via intravenous (IV) infusion over 120 minutes.
[0159] Subjects will be expected to maintain total adherence to a strict gluten-free diet (GFD) from 6 months before randomization through the final study visit (Visit 9, Week 16/Day 112).
[0160] The final study dose will be administered at Visit 7 (Week 10/Day 70).
An end-of-study efficacy visit will be conducted at Visit 8 (Week 12/Day 84). The final study visit will be conducted 6 weeks after the last dose of study drug at Visit 9 (Week 16/Day 112).
[0161] All study subjects can undergo upper gastrointestinal endoscopy with mucosal biopsy prior to baseline (i.e., prior to Visit 1, Week 0/Day 0) and within 7 days of Visit 8 (Week 12/Day 84) in order to assess changes from baseline in aberrant and abnormal IELs, VH:CD ratio, TCR clonality, Marsh score and total TEL counts.
[0162] Safety can be monitored on an ongoing basis and subjects may undergo unscheduled visits for safety reasons, if needed. Safety will be assessed throughout the study by clinical laboratory tests, physical examination, vital sign and AE monitoring.
[0163] Subject Inclusion Criteria:
Confirmed diagnosis of refractory celiac disease Type 2 (RCD-II) O Greater than 20% aberrant intraepithelial lymphocytes (TEL) as assessed by flow cytometry = On a gluten-free diet for at least 6 months ^ Avoid pregnancy [0164] Exclusion Criteria:
= Enteropathy-Associated T cell Lymphoma (EATL) O Infections O Immune suppression O Clinically significant co-morbidities [0165] The proposed dose of 8 mg/kg IV for 10 weeks, once every 2 weeks (q2w) with an extra dose at week 1, can account for the presumed protein-losing enteropathy typical of RCD-II (up to 40% protein loss can be expected based on albumin levels in RCD-II
patients) and for the larger target organ area (small bowel as compared to more localized joints).
[0166] Various aspects of the present disclosure may be used alone, in combination, or in a variety of arrangements not specifically discussed in the embodiments described in the foregoing and is therefore not limited in its application to the details and arrangement of components set forth in the foregoing description or illustrated in the drawings. For example, aspects described in one embodiment may be combined in any manner with aspects described in other embodiments. Also, the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting.
[0167] Use of ordinal terms such as "first," "second," "third," etc., in the claims to modify a claim element does not by itself connote any priority, precedence, or order of one claim element over another or the temporal order in which acts of a method are performed, but are used merely as labels to distinguish one claim element having a certain name from another element having a same name (but for the use of the ordinal term) to distinguish the claim elements.
[0168] Also, the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of "including," "comprising,"
or "having,"
"containing," "involving," and variations thereof herein, is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.
"Consisting essentially of" means inclusion of the items listed thereafter and which is open to unlisted items that do not materially affect the basic and novel properties of the invention.
INCORPORATION BY REFERENCE
[0169] The ASCII text file submitted herewith via EFS-Web, entitled "A2082PCT.txt"
created on June 15, 2016, having a size of 4,623 bytes, is hereby incorporated by reference in its entirety.
101701 All publications, patents and sequence database entries mentioned herein are hereby incorporated by reference in their entireties as if each individual publication or patent was specifically and individually indicated to be incorporated by reference.
References:
Abadie V, Jabri B. Immunol Rev. 2014;260:221-34.
Anthony SM, Howard ME, Hailemichael Y, et al. PLoS One. 2015;10:e0120274.
Baslund B, Tvede N, Danneskiold-Samsoe B, et al. Arthritis Rheum.
2005;52(9):2686-92.
Blaser BW, Roychowdhury S, Kim DJ, et al. Blood. 2005;105(2):894-901.
Brar P, Lee S, Lewis S, et al. Am J Gastroenterol. 2007;102:2265-9.
Catassi C, Fabiani E, Iacono G, et al. Am J Clin Nutr. 2007;85(1):160-6.
Conti F, Frappier J, Dharancy S, et al Transplantation. 2003;76(1):210-6.
Cranney A, Zarkadas M, Graham ID, et al. Dig Dis Sci. 2007;52(4):1087-95.
DePaolo RW, Abadie V, Tang F, et al. Nature. 2011; 471:220-4.
Fehniger TA, Caligiuri MA. Blood. 2001;97:14-32.
Gianfrani C, Auricchio S, Troncone R. Immunol Lett. 2005;99(2):141-145.
Gibert A, Espadaler M, Canela A, et al. Eur J Gastroenterol Hepatol 2006;
18:1187-1195.
Goerres MS, Meijer JW, Wahab PJ, et al. Aliment Pharmacol Ther 2003;18:487-94.
Green PH, Cellier C. N Engl J Med. 2007;357(17):1731-43 Hopper AD, Cross SS, Hurlstone DP, et al. Br Med Journal. 2007;334(7596):729 Kennedy MK, Glaccum M, Brown SN, et al. J Exp Med. 2000;191:771-780.
Komeychuk N, Ramiro-Puig E, Ettersperger J, et al. Gastroenterology.
2014;146:1017-27.
Lebrec H, Homer MJ, Gorski KS, et al. J Immunol. 2013;191(11):5551-8.
Lebwohl B, Granath F, Ekbom A, etal. Ann Intern Med. 2013;159(3):169-75.
Lee SK, Lo W, Memeo L, Rotterdam H, Green PH. Gastrointest Endosc.
2003;57(2):187-91.
Litinskiy MB, Nardelli B, Hilbert DM, He B, Schaffer A, Casali P, Cerutti A.
Nat Immunol.
2002;3(9):822-829.
Lodolce JP, Boone DL, Chai S, Swain RE, Dassopoulos T, Trettin S, Ma A.
Immunity.
1998;9(5):669-676.
Lundin, Knut E.a., and Armin Alaedini. Gastrointestinal Endoscopy Clinics of North America 22.4 (2012): 723-34.
Malamut G, El Machhour R, Montcuquet N, et al. J Clin Invest. 2010;120:2131-43.
McInnes TB, Gracie JA. Curr Opin Pharmacol. 2004;4(4):392-397.
Meresse B, Malamut G, Cerf-Bensussan N. Immunity. 2012; 36:907-19.
Midhagen G, Hallert C. Am J Gastroenterol. 2003;98:2023-6.
Nijeboer P, Malamut G, Bouma G, et al. Dig Dis. 2015;33:227-230.
Park CS, Yoon SO, Armitage RJ, Choi YS. J Immunol. 2004;173(11):6676- 6683.
Rubio-Tapia A, Hill ID, Kelly CP, et al. Am J Gastroenterol. 2013;108:656-76.
Shah S, Akbari M, Vanga R, etal. Am J Gastroenterol. 2014;109(9):1304-11.
Sharaiha RZ, Lebwohl B, Reimers L, etal. Cancer. 2012; 118:3786-92.
Schluns KS, Stoklasek T, Lefrancois L. Int J Biochem Cell Biol.
2005;37(8):1567-1571.
Taavela, Juha, Kalle Kurppa, Pekka Collin, et al. Clinical Gastroenterology and Hepatology 11.2 (2013): 166-71.
Tack GJ, Verbeek WH, Al-Toma A, et al. World J Gastroenterol 2011;17:506-13.
Tack GJ, Wondergem MJ, Al-Toma A, et al. Bone Marrow Transplant 2011;46:840-6.
van Wanrooij RL, Mtiller DM, Neefjes-Borst EA, et al. J Clin Immunol 2014;34:828-35.
Verbeek WH, Schreurs MW, Visser OJ, et al. Expert Rev Clin Immunol 2008;4:205-19.
Yokoyama S, Watanabe N, Sato N, et al. Proc Nat! Acad Sci USA 2009; 106: 15849-15854.
Yokoyama S, Takada K, Hirasawa M, et al. J Clin Immunol. 2011;31(6):1038-44.
[0114] In some embodiments, each subject can receive at least one (e.g., 1-100) unit dose disclosed herein, depending on the severity of the disease and/or effectiveness of the treatment. For example, the subject may receive 2-20 unit doses which can be the same or different (e.g., one or more initial unit doses can be smaller or larger than later unit dose(s)) from one another.
[0115] In some embodiments, the pharmaceutical compositions disclosed herein can be administered, in unit doses disclosed herein, by subcutaneous or intravenous injection every 1-20 weeks. In one embodiment, the pharmaceutical composition is administered subcutaneously. In another embodiment, the pharmaceutical composition is administered intravenously. In certain embodiments, administration can occur every 1-5, 5-10, 10-15, or 15-20 weeks. In some embodiments, administration can occur every 1-2, 2-4, 4-6, 6-8, 8-10, 10-12, 12-14, 14-16, 16-18, or 18-20 weeks. In some embodiments, administration can occur every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks. The unit doses can be given at the same intervals (e.g., every 1-20 weeks).
Alternatively, at least a portion of the unit doses are given at different (e.g., shortened or prolonged) intervals than the other unit doses.
[0116] In other aspects, the present invention relates to a pharmaceutical composition, as described herein, for use in treating celiac or non-celiac gluten sensitivity, wherein the pharmaceutical composition comprises an anti-IL-15 antibody (e.g., AMG 714).
In other embodiments, the pharmaceutical composition comprises 75 mg, 150 mg, 300 mg, 600 mg, 4 mg/kg, 8 mg/kg or 12 mg/kg of an anti-IL-15 antibody (e.g., AMG 714). In certain embodiments, the pharmaceutical composition comprises 150 mg or 300 mg of an anti-IL-15 antibody (e.g., AMG 714). In some embodiments, the pharmaceutical composition is administered subcutaneously every 1, 2 or 4 weeks, until, e.g., alleviation or elimination of signs and/or symptoms. In one embodiment, the pharmaceutical composition is administered subcutaneously every 2 weeks. In another particular embodiment, the pharmaceutical composition is administered intravenously every 1, 2 or 4 weeks until, e.g., alleviation or elimination of signs and/or symptoms. In another particular embodiment, the pharmaceutical composition is administered intravenously every 2 weeks.
[0117] In some aspects, the present invention relates to a pharmaceutical composition, as described herein, for use in a method of treating celiac or non-celiac gluten sensitivity, wherein the method comprises administering (e.g., subcutaneously) an anti-IL-15 antibody (e.g., AMG 714). In some embodiments, the method comprises administering (e.g., subcutaneously) 75 mg, 150 mg, 300 mg, 600 mg, 4 mg/kg, 8 mg/kg or 12 mg/kg of an anti-IL-15 antibody (e.g., AMG 714). In certain embodiments, the method comprises administering (e.g., subcutaneously) 150 mg or 300 mg of an anti-IL-15 antibody (e.g., AMG 714). In some embodiments, the method comprises administering the pharmaceutical composition subcutaneously every 1, 2 or 4 weeks, until, e.g., alleviation or elimination of signs and/or symptoms. In one embodiment, the method comprises administering subcutaneously every 2 weeks. In another particular embodiment, the method comprises administering intravenously every 1, 2 or 4 weeks until, e.g., alleviation or elimination of signs and/or symptoms. In another particular embodiment, the method comprises administering intravenously every 2 weeks.
[0118] In another aspect, the present invention relates to a method of treating celiac or non-celiac gluten sensitivity, wherein the method comprises administering (e.g., subcutaneously) an anti-IL-15 antibody (e.g., AMG 714). In some embodiments, the method comprises administering (e.g., subcutaneously) 75 mg, 150 mg, 300 mg, 600 mg, 4 mg/kg, 8 mg/kg or 12 mg/kg of an anti-IL-15 antibody (e.g., AMG 714). In certain embodiments, the method comprises administering (e.g., subcutaneously) 150 mg or 300 mg of an anti-IL-15 antibody (e.g., AMG 714). In some embodiments, the method comprises administering the pharmaceutical composition subcutaneously every 1, 2 or 4 weeks, until, e.g., alleviation or elimination of signs and/or symptoms. In one embodiment, the method comprises administering subcutaneously every 2 weeks. In another particular embodiment, the method comprises administering intravenously every 1, 2 or 4 weeks until, e.g., alleviation or elimination of signs and/or symptoms. In another particular embodiment, the method comprises administering intravenously every 2 weeks.
[0119] In particular embodiments of the pharmaceutical compositions and methods described herein, 150 or 300 mg of an anti-IL 15 antibody (e.g., AMG 714) is administered once every 2 weeks (q2w) via subcutaneous injection.
Use of the Pharmaceutical Composition to Treat Refractory Celiac Disease [0120] A rare but specific complication of persistent exposure to gluten in celiac disease is the development of refractory celiac disease (RCD), which affects approximately 1% of celiac patients (Lebwohl et al., 2013). RCD is characterized by severe intestinal mucosal atrophy and gastrointestinal symptoms in the absence of gluten consumption and in the presence of small bowel aberrant IELs (Verbeek et al., 2008, vanWanrooij et al., 2014).
[0121] RCD patients can be further classified according to the proportion and characteristics of aberrant IELs. Patients with a low proportion of aberrant IELs, defined as less than 20% of total IELs (less than 20 IELs per 100 epithelial cells), as determined by flow cytometry, are referred to as Type I RCD (RCD-I). These aberrant IELs are generally polyclonal, and RCD-I patients are not at increased risk of developing overt extra epithelial lymphoma (i.e., enteropathy-associated T cell lymphoma [EATL]) and have a typical 5-year survival (vanWanrooij et al., 2014). To treat RCD-I, corticosteroids (local or systemic), azathioprine, purinethol, anti-TNF agents, or cladribine may be used (Brar et al., 2007;
Goerres et al., 2003) with clinical and histological improvement. FIG. 3 illustrates the pathophysiology of celiac and refractory celiac disease, as described by Schuppan et al.
[0122] When the proportion of aberrant IELs reaches or exceeds 20%, patients are diagnosed with Type II RCD (RCD-II). In RCD-II, the IELs are typically monoclonal and the risk of developing EATL is dramatically increased to greater than 50%
(Nijeboer et al., 2015). The aberrant IELs proliferate in the absence of gluten due to accumulation of anti-apoptotic mechanisms, hence the term "refractory" indicating that the disease, a non-Hodgkin slow-growing intraepithelial lymphoma, appears not to be dependent on gluten since it is not responsive to the strictest GFD. As illustrated in FIG. 4, IL-15 is believed to be the main driver of transformation and maintenance of the aberrant IELs (Meresse et al., 2012). Experimental proof of principle has been established for IL-15 inhibition in RCD-II
by the finding that blocking IL-15 with the anti-IL-15 mAb AMG 714 induces IEL
apoptosis in human small bowel biopsies from active celiac and RCD-II patients (Malamut et al., 2010). Also, IEL apoptosis has been observed in animal models of celiac disease treated with anti-IL-15 AMG 714 (Malamut et al., 2010) or anti-IL-15-receptor mAbs (Yokoyama et al., 2009).
[0123] The aberrant monoclonal IELs have been demonstrated to be precursors of EATL
based on the observation that the T cell receptor (TCR) re-arrangement repertoire is similar in sequential biopsies from RCD-II patients who develop EATL. RCD-II is considered to be an in situ low-grade T cell lymphoma of the small bowel. A thorough study of the low grade IEL proliferation in RCD-II has revealed a characteristic phenotype with the presence of intracellular CD3 without surface CD3 or TCR and generally no CD8 expression with expression of CD103, which is shared by high grade EATL proliferations. This phenotype is distinct from the normal phenotype of IELs in uncomplicated celiac disease and, together with the common presence of a clonal TCR re-arrangement in the intestinal biopsy, confirms the diagnosis of RCD and allows follow-up of the expansion.
[0124] The treatment of RCD-II is difficult as aberrant lymphocytes are scattered throughout the whole small intestinal epithelium and, usually, in the stomach and colon, thereby precluding surgery. In addition, there is no standard of care for RCD-II. Attempts of chemotherapies have been mostly ineffective and/or dangerous for patients.
Cladribine (Tack et al., 2011a; Tack et al., 2011b) and autologous bone marrow transplantation have been used and shown to transiently improve the digestive symptoms and histology but not monoclonal proliferation. The prognosis of RCD-II is poor, with death occurring within 3-years mainly due to intractable diarrhea, EATL, or the rare dissemination of low grade lymphocyte proliferation to other tissues (e.g., skin, lungs).
[0125] EATL is a high-grade, systemic, T cell lymphoma almost exclusively seen as a complication of RCD-II (Nijeboer et al., 2015). Diagnosis includes imaging and histology to demonstrate the presence of malignant T cells in extra-epithelial locations such as lymph nodes or other organs. The treatment of EATL relies on surgical resection and chemotherapy, but the prognosis is very poor, with a 5-year survival of less than 20%
(Nijeboer et al., 2015).
[0126] The incidence of EATL is increasing, and this increase could be related to the rising prevalence of gluten contamination in the diet over prolonged periods of time (Sharaiha et al., 2012). An effective treatment for RCD-II that could alleviate the presence of aberrant IELs, the histological abnormalities, and/or the symptoms remains the highest priority. A
summary of the characteristics of CD, RCD, and ETCL are summarized in Table 1 below.
Table 1. Characteristics of Celiac Disease, Refractory Celiac Disease, and Enteropathy-associated T cell Lymphoma Type Nature of the Gluten Aberrant Clonality Progression disease dependence IELs to overt systemic lymphoma Non- Autoimmune Yes No Poly clonal No Responsive Celiac Disease Refractory Unknown Probably Yes, less than Oligoclonal No Type I 20%
Refractory Malignant, slow Probably Yes, greater Monoclonal greater than Type II growing independent than 20% (in situ 50%
lymphoma) EATL Malignant, rapid No Yes, greater Monoclonal N/A
progression than 20% (systemic lymphoma) [0127] The present invention provides methods and compositions for treating Type I or Type II Refractory Celiac Disease by administering a therapeutically effective amount of an anti-IL-15 antibody (e.g., AMG 714) or antigen-binding fragment thereof disclosed herein.
In some embodiments, a therapeutically effective amount of the anti-IL-15 antibody (e.g., AMG 714) or antigen-binding fragment thereof can achieve, e.g., for the treatment of RCD-I or RCD-II one or more of, (1) a measure of the immunological response by quantification of the reduction from baseline in the % of aberrant intestinal intraepithelial lymphocytes (IELs) vs. total IELs as assessed by flow-cytometry, (2) the measure of the immunological response by quantification of the reduction from baseline in the % of aberrant IELs vs.
intestinal epithelial cells, (3) histological response: Improvement from baseline in small intestinal villous height to crypt depth (VH:CD) ratio, Marsh score or total TEL counts, and/or (4) clinical response: Change from baseline in clinical symptoms by the Bristol Stool Form Scale (BSFS) and Gastrointestinal Symptom Rating Scale (GSRS), including the celiac disease GSRS (CeD-GSRS).
[0128] In some embodiments, the amount or unit dose of the pharmaceutical compositions disclosed herein can include about 1-50 mg/kg (patient weight) of the anti-IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof In some embodiments, the unit dose can be: about 1-10 mg/kg, about 10-20 mg/kg, about 20-30 mg/kg, about 30-40 mg/kg, or about 40-50 mg/kg, or higher or lower, or any numerical value therebetween, of the anti-IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof disclosed herein.
[0129] In some embodiments, the amount or unit dose can be: about 1-5 mg/kg, about 5-10 mg/kg, about 10-15 mg/kg, about 15-20 mg/kg, about 20-25 mg/kg, about 25-30 mg/kg, about 30-35 mg/kg, about 35-40 mg/kg, about 40-45 mg/kg, or about 45-50 mg/kg.
In some embodiments, a preferred dosage can include: about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, or about 50 mg/kg, of the anti-IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof disclosed herein.
[0130] In some embodiments, the amount or unit dose of the pharmaceutical compositions disclosed herein can include about 50-1000 mg of the anti-IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof In some embodiments, the unit dose can be:
about 50-100 mg, about 100-150 mg, about 150-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, about 450-500 mg, about 550 mg, about 550-600 mg, about 600-700 mg, about 700-800 mg, about 800-900 mg or about 900-1000 mg, or higher or lower, or any numerical value therebetween, of the anti-IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof disclosed herein.
[0131] In some embodiments, the amount or unit dose can be: about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-110 mg, about mg, about 120-130 mg, about 130-140 mg, about 140-150 mg, about 150-160 mg, about 160-170 mg, about 170-180 mg, about 180-190 mg, about 190-200 mg, about 200-210 mg, about 210-220 mg, about 220-230 mg, about 230-240 mg, about 240-250 mg, about 260 mg, about 260-270 mg, about 270-280 mg, about 280-290 mg, about 290-300 mg, about 300-310 mg, about 310-320 mg, about 320-330 mg, about 330-340 mg, about 350 mg, about 350-360 mg, about 360-370 mg, about 370-380 mg, about 380-390 mg, about 390-400 mg, about 400-410 mg, about 410-420 mg, about 420-430 mg, about 440 mg, about 440-450 mg, about 450-460 mg, about 460-470 mg, about 470-480 mg, about 480-490 mg, about 490-500 mg, about 500-510 mg, about 510-520 mg, about 530 mg, about 530-540 mg, about 540-550 mg, about 550-560 mg, about 560-570 mg, about 570-580 mg, about 580-590 mg, about 590-600 mg, about 600-610 mg, about 620 mg, about 630-640 mg, about 640-650 mg, about 650-660 mg, about 660-670 mg, about 670-680 mg, about 680-690 mg, or 690-700 mg, of the anti-IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof disclosed herein.
[0132] In some embodiments, the amount or unit dose can be: about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 205, about 210, about 220, about 225, about 230, about 235, about 240, about 245, about 250, about 255, about 260, about 265, about 270, about 275, about 280, about 285, about 290, about 295, about 300, about 305, about 310, about 315, about 320, about 325, about 330, about 335, about 340, about 345, about 350, about 355, about 360, about 365, about 370, about 375, about 380, about 385, about 390, about 395, about 400, about 405, about 410, about 415, about 420, about 425, about 430, about 435, about 440, about 445, about 450, about 455, about 460, about 465, about 470, about 475, about 480, about 485, about 490, about 495, about 500, about 505, about 510, about 515, about 520, about 525, about 530, about 535, about 540, about 545, about 550, about 555, about 560, about 565, about 570, about 575, about 580, about 585, about 590, about 595, about 600, about 605, about 610, about 615, about 620, about 625, about 630, about 635, about 640, about 645, about 650, about 655, about 660, about 665, about 670, about 675, about 680, about 685, about 690, about 695, or about 700 mg, or any numerical value in between any two of the foregoing, of the anti-IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof disclosed herein.
[0133] In some embodiments, each subject can receive at least one (e.g., 1-100) unit dose disclosed herein, depending on the severity of the disease and/or effectiveness of the treatment. For example, the subject may receive 2-20 unit doses which can be the same or different (e.g., one or more initial unit doses can be smaller or larger than later unit dose(s)) from one another.
[0134] In some embodiments, the pharmaceutical compositions disclosed herein can be administered, in unit doses disclosed herein, by subcutaneous or intravenous injection every 1-20 weeks. In one embodiment, the pharmaceutical composition is administered subcutaneously. In another embodiment, the pharmaceutical composition is administered intravenously. In certain embodiments, administration can occur every 1-5, 5-10, 10-15, or 15-20 weeks. In some embodiments, administration can occur every 1-2, 2-4, 4-6, 6-8, 8-10, 10-12, 12-14, 14-16, 16-18, or 18-20 weeks. In some embodiments, administration can occur every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks. The unit doses can be given at the same intervals (e.g., every 1-20 weeks).
Alternatively, at least a portion of the unit doses are given at different (e.g., shortened or prolonged) intervals than the other unit doses. In one example, one or more additional loading doses can be given at, e.g., week 1 or any other time to boost the dosage.
[0135] In other aspects, the present invention relates to a pharmaceutical composition, as described herein, for use in treating Type II refractory celiac disease patients, e.g., patients with in situ small bowel T Cell lymphoma, wherein the pharmaceutical composition comprises an anti-IL-15 antibody (e.g., AMG 714). In other embodiments, the pharmaceutical composition comprises 75 mg, 150 mg, 300 mg, 600 mg, 4 mg/kg, 8 mg/kg or 12 mg/kg of an anti-IL-15 antibody (e.g., AMG 714). In a particular embodiment, the pharmaceutical composition comprises 8 mg/kg of AMG 714. In some embodiments, the pharmaceutical composition is administered (e.g., intravenously) every 1, 2 or 4 weeks, until, e.g., alleviation or elimination of signs and/or symptoms. In another particular embodiment, pharmaceutical composition is administered (e.g., intravenously) every 2 weeks. In another particular embodiment, the pharmaceutical composition is administered subcutaneously every 1, 2 or 4 weeks until, e.g., alleviation or elimination of signs and/or symptoms. In another particular embodiment, the pharmaceutical composition is administered subcutaneously every 2 weeks.
[0136] In some aspects, the present invention relates to a pharmaceutical composition, as described herein, for use in a method of treating Type II refractory celiac disease patients e.g., patients with in situ small bowel T Cell lymphoma, wherein the method comprises administering (e.g., intravenously) an anti-IL-15 antibody (e.g., AMG 714). In some embodiments, the method comprises administering (e.g., intravenously) 75 mg, 150 mg, 300 mg, 600 mg, 4 mg/kg, 8 mg/kg or 12 mg/kg of an anti-IL-15 antibody (e.g., AMG 714).
In certain embodiments, the method comprises administering (e.g., intravenously) 8 mg/kg of an anti-IL-15 antibody (e.g., AMG 714). In some embodiments, the method comprises administering the pharmaceutical composition subcutaneously every 1, 2 or 4 weeks, until, e.g., alleviation or elimination of signs and/or symptoms. In one embodiment, the method comprises administering subcutaneously every 2 weeks. In another particular embodiment, the method comprises administering intravenously every 1, 2 or 4 weeks until, e.g., alleviation or elimination of signs and/or symptoms. In another particular embodiment, the method comprises administering intravenously every 2 weeks.
[0137] In another aspect, the present invention relates to a method of treating Type II
refractory celiac disease patients or patients with in situ small bowel T Cell lymphoma, wherein the method comprises administering (e.g., intravenously) an anti-IL-15 antibody (e.g., AMG 714). In some embodiments, the method comprises administering (e.g., intravenously) 75 mg, 150 mg, 300 mg, 600 mg, 4 mg/kg, 8 mg/kg or 12 mg/kg of an anti-IL-15 antibody (e.g., AMG 714). In certain embodiments, the method comprises administering (e.g., intravenously) 8 mg/kg of an anti-IL-15 antibody (e.g., AMG 714). In some embodiments, the method comprises administering the pharmaceutical composition subcutaneously every 1, 2 or 4 weeks, until, e.g., alleviation or elimination of signs and/or symptoms. In one embodiment, the method comprises administering subcutaneously every 2 weeks. In another particular embodiment, the method comprises administering intravenously every 1, 2 or 4 weeks until, e.g., alleviation or elimination of signs and/or symptoms. In another particular embodiment, the method comprises administering intravenously every 2 weeks.
[0138] In particular embodiments of the pharmaceutical compositions and methods described herein, 8 mg/kg of an anti-IL-15 antibody (e.g., AMG 714) is administered once every 2 weeks (q2w) intravenously. In other particular embodiments of the pharmaceutical compositions and methods described herein, 8 mg/kg of an anti-IL 15 antibody (e.g., AMG
714) is administered intravenously at week 0, week 1, and once every 2 weeks (q2w) thereafter.
EXAMPLES
Example 1: Phase 2a, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate Efficacy and Safety of AMG714 in Adult Patients with Celiac Disease [0139] In an exemplary clinical trial AMG 714 can be administered to adult patients with CD. The primary objective of this study is to assess the efficacy of AMG 714 in attenuating the effects of gluten exposure in adults with CD. The secondary objective is to assess the safety and tolerability of AMG 714 when administered to adult patients with celiac disease exposed to a gluten challenge. The exploratory objectives are to assess the pharmacokinetics (PK), pharmacodynamics (PD), and PK/PD correlations of AMG
714.
[0140] Primary outcome/endpoint measures: Attenuation of gluten-induced small intestinal mucosal injury as assessed by the change from baseline to Week 12 in VH:CD
ratio. Time Frame: Baseline and 12 weeks. The VH:CD is the morphometric measure of the length of the small intestinal villi with respect to the depth of the crypts.
[0141] Secondary outcome/endpoint measures:
(1) Attenuation of gluten-induced small intestinal mucosal inflammation at Week 12 compared to baseline, as measured by the enumeration of intraepithelial lymphocytes (IELs) in histological sections. Time Frame: Baseline and 12 weeks. Small bowel biopsies can be processed and stained with hematoxylin-eosin stains, and the IELs counted per epithelial cells.
(2) Attenuation of gluten-induced serum antibodies at Week 12 compared to baseline (anti-deamidated gliadin peptides, DGP) and autoantibodies (anti-transglutaminase, ATG). Time Frame: Baseline and 12 weeks. DGP and ATG antibodies can be measured in serum by ELISA technique.
(3) Attenuation at Week 12 compared to baseline, of gluten-induced clinical symptoms as measured by the Gastrointestinal Symptom Rating Scale (GSRS). Time Frame:
Baseline and 12 weeks. The GSRS questionnaire can be filled at every visit (approximately monthly).
[0142] Other outcome/endpoint measures: Safety and Tolerability of AMG 714 as assessed by the proportion of subjects with drug related adverse events. Time Frame: 12 weeks.
Adverse events and serious adverse events can be captured on an on-going basis from screening to study end.
Study Design [0143] The protocol is designed to be a Phase 2a, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of AMG
714 for the attenuation of the effects of gluten exposure in adult patients with celiac disease during a gluten challenge.
[0144] All subjects are randomized at a 1:1:1 ratio to receive 150 mg or 300 mg AMG 714 or placebo once every two weeks for 10 weeks. Randomization is stratified by sex. The study drug (AMG 714 or placebo) can be administered at the clinical site in a double-blind fashion via subcutaneous (SC) injection.
[0145] In addition to receiving study medication or placebo, all subjects will be required to consume either placebo gluten or active gluten administered in a single-blind fashion.
[0146] All study subjects can undergo upper gastrointestinal endoscopy and biopsy prior to baseline (Visit 1, Week 0/Day 0) and at the end of the 12-week study period while still on the gluten challenge and within 5 days before Visit 7 (Week 12/Day 84) in order to assess changes from baseline in VH:CD ratio, IELs, and Marsh score.
[0147] Safety will be monitored on an ongoing basis and subjects may undergo unscheduled visits if needed for safety reasons. Safety will be assessed throughout the study by clinical laboratory tests, physical examination, vital signs, and AE
monitoring.
[0148] Subject Inclusion Criteria:
= Diagnosis of celiac disease by intestinal biopsy at least 12 months prior to screening = On a gluten-free diet for at least 12 months = Negative celiac serology = Avoidance of pregnancy [0149] Exclusion Criteria:
e Severe complications of celiac disease, such as refractory celiac disease Celiac symptoms = Other concomitant autoimmune disease = Chronic, active GI disease = Infections, concomitant diseases Prohibited medications [0150] The selection of dosing levels for the celiac disease study, in one embodiment, is 150 and 300 mg once every 2 weeks (q2w) via subcutaneous injection (SC). While there is no prior experience with AMG 714 in celiac disease nor any understanding of the potential PK/PD relationship in this disease, toxicology and human studies to date support the dosing regimen selected for this study. The highest doses of AMG 714 studied in previous clinical trials were a single SC dose of 700 mg and SC doses of 300 mg every two weeks for 12 weeks, with no safety signals identified to date.
[0151] The dosing regimen is expected to provide trough levels above the concentration of AMG 714 used in vitro (10 [tg/mL) to induce apoptosis of activated IELs in biopsies of patients with active celiac disease (Malamut et al., 2010).
[0152] Serum exposure can be monitored with frequent PK sampling. Tissue effects can be monitored with experimental biomarkers to be measured in the biopsies to be obtained throughout the study.
Example 2: Phase 2a Study to Evaluate Efficacy and Safety of AMG 714 in Adult Patients with Type II Refractory Celiac Disease [0153] In an exemplary clinical trial the efficacy and safety of AMG 714 can be studied in adult patients with Type II Refractory Celiac Disease. The primary objective of this study will be to assess the efficacy of AMG 714 in treating RCD-II in adult patients. The secondary object of this study will be to assess the safety and tolerability of AMG 714 when administered to adult patients with RCD-II. The exploratory objectives of this study will be to assess the pharmacokinetics (PK), pharmacodynamics (PD), and PK/PD
correlations of AMG 714.
[0154] Primary outcome/endpoint measures include immunological response, e.g., reduction from baseline in the % of aberrant small bowel intestinal intraepithelial lymphocytes (surface CD3- intracellular CD3+). Time Frame: Baseline and 12 weeks.
Reduction from baseline in the % of aberrant intestinal intraepithelial lymphocytes can be measured by, e.g., flow cytometry after small intestinal biopsy collection.
[0155] Secondary outcome/endpoint measures:
(1) Histological response: Improvement from baseline in small intestinal morphology as measured by the Villous Height to Crypt Depth (VH:CD) ratio in intestinal biopsy material. Time Frame: Baseline and 12 weeks.
(2) Clinical response: Change from baseline in clinical symptoms as measured by the Gastrointestinal Symptom Rating Scale (GSRS). Time Frame: Baseline and 12 weeks.
[0156] Other outcome/endpoint measures include safety and tolerability: Number of participants with treatment-related adverse events as assessed by Common Terminology Criteria for Adverse Events (CTCAE). Time Frame: 12 weeks. The frequency and nature of adverse events can be collected and analyzed.
Study Design [0157] The protocol is designed to be a Phase 2a randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy and safety of AMG
714 for the treatment of adult patients with RCD-II.
[0158] All subjects who meet the study entry criteria can be randomized at a 2:1 ratio to receive either 8 mg/kg AMG 714 or placebo every 2 weeks for a total of 7 times over 10 weeks, with evaluation of the primary endpoint at Week 12. AMG 714 or placebo can be administered at the clinical site in a double-blind fashion via intravenous (IV) infusion over 120 minutes.
[0159] Subjects will be expected to maintain total adherence to a strict gluten-free diet (GFD) from 6 months before randomization through the final study visit (Visit 9, Week 16/Day 112).
[0160] The final study dose will be administered at Visit 7 (Week 10/Day 70).
An end-of-study efficacy visit will be conducted at Visit 8 (Week 12/Day 84). The final study visit will be conducted 6 weeks after the last dose of study drug at Visit 9 (Week 16/Day 112).
[0161] All study subjects can undergo upper gastrointestinal endoscopy with mucosal biopsy prior to baseline (i.e., prior to Visit 1, Week 0/Day 0) and within 7 days of Visit 8 (Week 12/Day 84) in order to assess changes from baseline in aberrant and abnormal IELs, VH:CD ratio, TCR clonality, Marsh score and total TEL counts.
[0162] Safety can be monitored on an ongoing basis and subjects may undergo unscheduled visits for safety reasons, if needed. Safety will be assessed throughout the study by clinical laboratory tests, physical examination, vital sign and AE monitoring.
[0163] Subject Inclusion Criteria:
Confirmed diagnosis of refractory celiac disease Type 2 (RCD-II) O Greater than 20% aberrant intraepithelial lymphocytes (TEL) as assessed by flow cytometry = On a gluten-free diet for at least 6 months ^ Avoid pregnancy [0164] Exclusion Criteria:
= Enteropathy-Associated T cell Lymphoma (EATL) O Infections O Immune suppression O Clinically significant co-morbidities [0165] The proposed dose of 8 mg/kg IV for 10 weeks, once every 2 weeks (q2w) with an extra dose at week 1, can account for the presumed protein-losing enteropathy typical of RCD-II (up to 40% protein loss can be expected based on albumin levels in RCD-II
patients) and for the larger target organ area (small bowel as compared to more localized joints).
[0166] Various aspects of the present disclosure may be used alone, in combination, or in a variety of arrangements not specifically discussed in the embodiments described in the foregoing and is therefore not limited in its application to the details and arrangement of components set forth in the foregoing description or illustrated in the drawings. For example, aspects described in one embodiment may be combined in any manner with aspects described in other embodiments. Also, the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting.
[0167] Use of ordinal terms such as "first," "second," "third," etc., in the claims to modify a claim element does not by itself connote any priority, precedence, or order of one claim element over another or the temporal order in which acts of a method are performed, but are used merely as labels to distinguish one claim element having a certain name from another element having a same name (but for the use of the ordinal term) to distinguish the claim elements.
[0168] Also, the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of "including," "comprising,"
or "having,"
"containing," "involving," and variations thereof herein, is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.
"Consisting essentially of" means inclusion of the items listed thereafter and which is open to unlisted items that do not materially affect the basic and novel properties of the invention.
INCORPORATION BY REFERENCE
[0169] The ASCII text file submitted herewith via EFS-Web, entitled "A2082PCT.txt"
created on June 15, 2016, having a size of 4,623 bytes, is hereby incorporated by reference in its entirety.
101701 All publications, patents and sequence database entries mentioned herein are hereby incorporated by reference in their entireties as if each individual publication or patent was specifically and individually indicated to be incorporated by reference.
References:
Abadie V, Jabri B. Immunol Rev. 2014;260:221-34.
Anthony SM, Howard ME, Hailemichael Y, et al. PLoS One. 2015;10:e0120274.
Baslund B, Tvede N, Danneskiold-Samsoe B, et al. Arthritis Rheum.
2005;52(9):2686-92.
Blaser BW, Roychowdhury S, Kim DJ, et al. Blood. 2005;105(2):894-901.
Brar P, Lee S, Lewis S, et al. Am J Gastroenterol. 2007;102:2265-9.
Catassi C, Fabiani E, Iacono G, et al. Am J Clin Nutr. 2007;85(1):160-6.
Conti F, Frappier J, Dharancy S, et al Transplantation. 2003;76(1):210-6.
Cranney A, Zarkadas M, Graham ID, et al. Dig Dis Sci. 2007;52(4):1087-95.
DePaolo RW, Abadie V, Tang F, et al. Nature. 2011; 471:220-4.
Fehniger TA, Caligiuri MA. Blood. 2001;97:14-32.
Gianfrani C, Auricchio S, Troncone R. Immunol Lett. 2005;99(2):141-145.
Gibert A, Espadaler M, Canela A, et al. Eur J Gastroenterol Hepatol 2006;
18:1187-1195.
Goerres MS, Meijer JW, Wahab PJ, et al. Aliment Pharmacol Ther 2003;18:487-94.
Green PH, Cellier C. N Engl J Med. 2007;357(17):1731-43 Hopper AD, Cross SS, Hurlstone DP, et al. Br Med Journal. 2007;334(7596):729 Kennedy MK, Glaccum M, Brown SN, et al. J Exp Med. 2000;191:771-780.
Komeychuk N, Ramiro-Puig E, Ettersperger J, et al. Gastroenterology.
2014;146:1017-27.
Lebrec H, Homer MJ, Gorski KS, et al. J Immunol. 2013;191(11):5551-8.
Lebwohl B, Granath F, Ekbom A, etal. Ann Intern Med. 2013;159(3):169-75.
Lee SK, Lo W, Memeo L, Rotterdam H, Green PH. Gastrointest Endosc.
2003;57(2):187-91.
Litinskiy MB, Nardelli B, Hilbert DM, He B, Schaffer A, Casali P, Cerutti A.
Nat Immunol.
2002;3(9):822-829.
Lodolce JP, Boone DL, Chai S, Swain RE, Dassopoulos T, Trettin S, Ma A.
Immunity.
1998;9(5):669-676.
Lundin, Knut E.a., and Armin Alaedini. Gastrointestinal Endoscopy Clinics of North America 22.4 (2012): 723-34.
Malamut G, El Machhour R, Montcuquet N, et al. J Clin Invest. 2010;120:2131-43.
McInnes TB, Gracie JA. Curr Opin Pharmacol. 2004;4(4):392-397.
Meresse B, Malamut G, Cerf-Bensussan N. Immunity. 2012; 36:907-19.
Midhagen G, Hallert C. Am J Gastroenterol. 2003;98:2023-6.
Nijeboer P, Malamut G, Bouma G, et al. Dig Dis. 2015;33:227-230.
Park CS, Yoon SO, Armitage RJ, Choi YS. J Immunol. 2004;173(11):6676- 6683.
Rubio-Tapia A, Hill ID, Kelly CP, et al. Am J Gastroenterol. 2013;108:656-76.
Shah S, Akbari M, Vanga R, etal. Am J Gastroenterol. 2014;109(9):1304-11.
Sharaiha RZ, Lebwohl B, Reimers L, etal. Cancer. 2012; 118:3786-92.
Schluns KS, Stoklasek T, Lefrancois L. Int J Biochem Cell Biol.
2005;37(8):1567-1571.
Taavela, Juha, Kalle Kurppa, Pekka Collin, et al. Clinical Gastroenterology and Hepatology 11.2 (2013): 166-71.
Tack GJ, Verbeek WH, Al-Toma A, et al. World J Gastroenterol 2011;17:506-13.
Tack GJ, Wondergem MJ, Al-Toma A, et al. Bone Marrow Transplant 2011;46:840-6.
van Wanrooij RL, Mtiller DM, Neefjes-Borst EA, et al. J Clin Immunol 2014;34:828-35.
Verbeek WH, Schreurs MW, Visser OJ, et al. Expert Rev Clin Immunol 2008;4:205-19.
Yokoyama S, Watanabe N, Sato N, et al. Proc Nat! Acad Sci USA 2009; 106: 15849-15854.
Yokoyama S, Takada K, Hirasawa M, et al. J Clin Immunol. 2011;31(6):1038-44.
Claims (30)
1. A method of treating celiac disease or non-celiac gluten sensitivity in a subject in need thereof, comprising administering a therapeutically effective amount of an anti-IL-15 antibody or antigen-binding fragment thereof to the subject, wherein the therapeutically effective amount comprises 1-20 unit doses each administered at about 1-12 week intervals, each unit dose independently comprising about 50-1000 mg, preferably 75-600 mg, more preferably about 75 mg, about 150 mg, about 300 mg or about 600 mg of the anti-IL-15 antibody or antigen-binding fragment thereof
2. The method of claim 1, wherein the antibody has a heavy chain variable region comprising one or more complementarity determining regions of SEQ ID NOs:5-7, or a sequence having at least 80% sequence identity thereto.
3. The method of claim 1 or 2, wherein the antibody has a light chain variable region comprising one or more complementarity determining regions of SEQ ID NOs:8-10, or a sequence having at least 80% sequence identity thereto.
4. The method of claim 1 or 2, wherein the antibody has a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:2, or a sequence having at least 80% sequence identity thereto.
5. The method of claim 3, wherein the antibody has a light chain variable region comprising the amino acid sequence of SEQ ID NO:4, or a sequence having at least 80% sequence identity thereto.
6. The method of claim 1, wherein the therapeutically effective amount comprises 6 unit doses administered at about 2 week intervals.
7. The method of claim 1 or 6, wherein each unit dose is administered by subcutaneous injection or intravenous injection.
8. A pharmaceutical composition for the treatment of celiac disease or non-celiac gluten sensitivity, comprising a therapeutically effective amount of an anti-IL-15 antibody or antigen-binding fragment thereof, wherein the therapeutically effective amount comprises 1-20 unit doses each to be administered at about 1-12 week intervals, each unit dose independently comprising about 50-1000 mg, preferably 75-600 mg, more preferably about 75 mg, about 150 mg, about 300 mg or about 600 mg of the anti-IL-15 antibody or antigen-binding fragment thereof
9. The pharmaceutical composition of claim 8, wherein the antibody has a heavy chain variable region comprising one or more complementarity determining regions of SEQ
ID NOs:5-7, or a sequence having at least 80% sequence identity thereto.
ID NOs:5-7, or a sequence having at least 80% sequence identity thereto.
10. The pharmaceutical composition of claim 8 or 9, wherein the antibody has a light chain variable region comprising one or more complementarity determining regions of SEQ ID NOs:8-10, or a sequence having at least 80% sequence identity thereto.
11. The pharmaceutical composition of claim 8 or 9, wherein the antibody has a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:2, or a sequence having at least 80% sequence identity thereto.
12. The pharmaceutical composition of claim 10, wherein the antibody has a light chain variable region comprising the amino acid sequence of SEQ ID NO:4, or a sequence having at least 80% sequence identity thereto.
13. The pharmaceutical composition of claim 8, wherein the therapeutically effective amount comprises 6 unit doses to be administered at 2 week intervals.
14. The pharmaceutical composition of claim 8 or 13, wherein each unit dose is administered by subcutaneous injection or intravenous injection.
15. A method of treating refractory celiac disease in a subject in need thereof, comprising administering a therapeutically effective amount of an anti-IL-15 antibody or antigen-binding fragment thereof to the subject, wherein the therapeutically effective amount comprises 1-20 unit doses each administered at about 1-12 week intervals, each unit dose independently comprising about 1-50 mg/kg, preferably about 4-16 mg/kg, more preferably about 4 mg/kg, about 8 mg/kg, about 12 mg/kg or about 16 mg/kg of the anti-IL-15 antibody or antigen-binding fragment thereof
16. The method of claim 15, wherein the antibody has a heavy chain variable region comprising one or more complementarity determining regions of SEQ ID NOs:5-7, or a sequence having at least 80% sequence identity thereto.
17. The method of claim 15 or 16, wherein the antibody has a light chain variable region comprising one or more complementarity determining regions of SEQ ID NOs:8-10, or a sequence having at least 80% sequence identity thereto.
18. The method of claim 15 or 16, wherein the antibody has a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:2, or a sequence having at least 80% sequence identity thereto.
19. The method of claim 17, wherein the antibody has a light chain variable region comprising the amino acid sequence of SEQ ID NO:4, or a sequence having at least 80% sequence identity thereto.
20. The method of claim 15, wherein the therapeutically effective amount comprises 6 unit doses administered at 2 week intervals, and an optional additional loading dose at week 1.
21. The method of claim 15 or 20, wherein each unit dose is administered by subcutaneous injection or intravenous injection.
22. The method of claim 15, wherein the refractory celiac disease is type I or type II.
23. A pharmaceutical composition for the treatment of refractory celiac disease, comprising a therapeutically effective amount of an anti-IL-15 antibody or antigen-binding fragment thereof, wherein the therapeutically effective amount comprises 1-20 unit doses each administered at about 1-12 week intervals, each unit dose independently comprising about 1-50 mg/kg, preferably about 4-16 mg/kg, more preferably about 4 mg/kg, about 8 mg/kg, about 12 mg/kg or about 16 mg/kg of the anti-IL-15 antibody or antigen-binding fragment thereof
24. The pharmaceutical composition of claim 23, wherein the antibody has a heavy chain variable region comprising one or more complementarity determining regions of SEQ
ID NOs:5-7, or a sequence having at least 80% sequence identity thereto.
ID NOs:5-7, or a sequence having at least 80% sequence identity thereto.
25. The pharmaceutical composition of claim 23 or 24, wherein the antibody has a light chain variable region comprising one or more complementarity determining regions of SEQ ID NOs:8-10, or a sequence having at least 80% sequence identity thereto.
26. The pharmaceutical composition of claim 23 or 24, wherein the antibody has a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:2, or a sequence having at least 80% sequence identity thereto.
27. The pharmaceutical composition of claim 25, wherein the antibody has a light chain variable region comprising the amino acid sequence of SEQ ID NO:4, or a sequence having at least 80% sequence identity thereto.
28. The pharmaceutical composition of claim 23, wherein the therapeutically effective amount comprises 6 unit doses to be administered at 2 week intervals, and an optional additional loading dose to be administered at week 1.
29. The pharmaceutical composition of claim 23 or 28, wherein each unit dose is administered by subcutaneous injection or intravenous injection.
30. The method of claim 23, wherein the refractory celiac disease is type I or type II.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/US2016/037708 WO2017217985A1 (en) | 2016-06-15 | 2016-06-15 | Methods and compositions for the treatment of celiac disease, non-celiac gluten sensitivity, and refractory celiac disease |
Publications (1)
Publication Number | Publication Date |
---|---|
CA3020894A1 true CA3020894A1 (en) | 2017-12-21 |
Family
ID=56292925
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA3020894A Pending CA3020894A1 (en) | 2016-06-15 | 2016-06-15 | Methods and compositions for the treatment of celiac disease, non-celiac gluten sensitivity, and refractory celiac disease |
Country Status (11)
Country | Link |
---|---|
EP (1) | EP3472202A1 (en) |
JP (2) | JP2019521981A (en) |
CN (1) | CN109311972A (en) |
AR (1) | AR108790A1 (en) |
AU (1) | AU2016411388A1 (en) |
BR (1) | BR112018076287A2 (en) |
CA (1) | CA3020894A1 (en) |
EA (1) | EA201892707A1 (en) |
MX (1) | MX2018015363A (en) |
TW (2) | TW201803591A (en) |
WO (1) | WO2017217985A1 (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BR112019012570A8 (en) * | 2016-12-21 | 2023-01-24 | Cephalon Inc | ANTIBODIES SPECIFICALLY BINDING HUMAN IL-15 AND THEIR USES, COMPOSITION, IN VITRO METHOD FOR DETECTION OF IL-15 OR A COMPLEX OF IL-15 AND IL-15-ALPHA RECEPTOR, POLYNUCLEOTIDE, VECTOR AND METHOD OF PRODUCTION OF SAID ANTIBODY |
US20220008533A1 (en) * | 2018-10-31 | 2022-01-13 | Tiziana Life Sciences Plc | Composition and methods of treating inflammatory and autoimmune diseases |
AU2022325870A1 (en) | 2021-08-12 | 2024-02-08 | Amgen Inc. | Antibody formulations |
WO2024028448A1 (en) | 2022-08-04 | 2024-02-08 | Calypso Biotech Sa | Il-15 inhibitors useful for the treatment of atopic dermatitis |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7247304B2 (en) * | 2001-08-23 | 2007-07-24 | Genmab A/S | Methods of treating using anti-IL-15 antibodies |
ZA200506724B (en) * | 2003-02-26 | 2007-03-28 | Genmab As | Human antibodies specific for interleukin 15 (IL-15) |
AU2010208637A1 (en) * | 2009-01-29 | 2011-08-04 | Abbvie Inc. | IL-1 binding proteins |
WO2011031986A1 (en) * | 2009-09-10 | 2011-03-17 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Office Of Technology Transfer, National Institutes Of Health | Assays for soluble il-15 receptor alpha |
EP2963057A1 (en) * | 2014-07-02 | 2016-01-06 | Calypso Biotech SA | Antibodies to IL-15 |
-
2016
- 2016-06-15 BR BR112018076287-3A patent/BR112018076287A2/en active Search and Examination
- 2016-06-15 CN CN201680086774.8A patent/CN109311972A/en active Pending
- 2016-06-15 AU AU2016411388A patent/AU2016411388A1/en active Pending
- 2016-06-15 WO PCT/US2016/037708 patent/WO2017217985A1/en unknown
- 2016-06-15 EP EP16733804.5A patent/EP3472202A1/en active Pending
- 2016-06-15 JP JP2018565345A patent/JP2019521981A/en active Pending
- 2016-06-15 CA CA3020894A patent/CA3020894A1/en active Pending
- 2016-06-15 MX MX2018015363A patent/MX2018015363A/en unknown
- 2016-06-15 EA EA201892707A patent/EA201892707A1/en unknown
-
2017
- 2017-06-15 TW TW106119998A patent/TW201803591A/en unknown
- 2017-06-15 TW TW111144466A patent/TW202327653A/en unknown
- 2017-06-15 AR ARP170101652A patent/AR108790A1/en unknown
-
2021
- 2021-09-24 JP JP2021155175A patent/JP2022001577A/en active Pending
Also Published As
Publication number | Publication date |
---|---|
MX2018015363A (en) | 2019-04-15 |
BR112018076287A2 (en) | 2019-03-26 |
EP3472202A1 (en) | 2019-04-24 |
CN109311972A (en) | 2019-02-05 |
EA201892707A1 (en) | 2019-05-31 |
WO2017217985A1 (en) | 2017-12-21 |
JP2019521981A (en) | 2019-08-08 |
TW202327653A (en) | 2023-07-16 |
AR108790A1 (en) | 2018-09-26 |
JP2022001577A (en) | 2022-01-06 |
TW201803591A (en) | 2018-02-01 |
AU2016411388A1 (en) | 2018-11-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20210214455A1 (en) | Anti-human 4-1bb antibodies and uses thereof | |
JP6248024B2 (en) | Binding molecule for human OX40 receptor | |
CN113056285A (en) | Anti-tumor immune checkpoint modulator antagonists | |
TWI359671B (en) | Cd40 antibody formulation and methods | |
JP7102670B2 (en) | Fusion of anti-PD-L1 antibody and IL-7 | |
US10983128B2 (en) | CXCL11 and SMICA as predictive biomarkers for efficacy of anti-CTLA4 immunotherapy | |
JP7274426B2 (en) | Treatment of cancer with anti-GITR agonist antibodies | |
JP2022001577A (en) | Methods and compositions for treatment of celiac disease, non-celiac gluten sensitivity, and refractory celiac disease | |
CN110546163A (en) | anti-TIGIT antigen binding proteins and methods of use thereof | |
EP4130037A1 (en) | Conditional agonists of immune responses | |
WO2021088838A1 (en) | Binding molecule specifically for cd39 and use thereof | |
JP2021500916A (en) | Anti-TIM-3 antibody and its use | |
KR20210030406A (en) | FC binding fragment comprising the CD137 antigen-binding site | |
US20230312701A1 (en) | Methods and Compositions for the Treatment of Celiac Disease, Non-Celiac Gluten Sensitivity, and Refractory Celiac Disease | |
US20140065154A1 (en) | Tlr3 binding agents | |
WO2022242758A1 (en) | Anti-cd73 antibody and use thereof | |
TW202330027A (en) | Anti-cd47 antibody formulation | |
WO2022095970A1 (en) | Bispecific antibody and use thereof | |
JPWO2015186823A1 (en) | Treatment method and medicine for cancer patient with FOLR1 target drug and antifolate | |
CN117500833A (en) | Double-antibody combination and application thereof | |
CN117098778A (en) | Formulations of DR5 binding polypeptides | |
KR20080017088A (en) | Use of anti-madcam antibodies for the treatment of coeliac disease and tropical sprue | |
JP2021500320A (en) | Combination drug for the treatment of cancer | |
US20240158510A1 (en) | Antibodies against integrin heterodimers and uses thereof | |
WO2023192489A2 (en) | Anti-adenosine receptor (a2ar) antibodies and the use thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request |
Effective date: 20210611 |
|
EEER | Examination request |
Effective date: 20210611 |
|
EEER | Examination request |
Effective date: 20210611 |
|
EEER | Examination request |
Effective date: 20210611 |
|
EEER | Examination request |
Effective date: 20210611 |
|
EEER | Examination request |
Effective date: 20210611 |
|
EEER | Examination request |
Effective date: 20210611 |
|
EEER | Examination request |
Effective date: 20210611 |