JP7302990B2 - ヒト及び非ヒトcd3に結合可能なcd3結合分子 - Google Patents
ヒト及び非ヒトcd3に結合可能なcd3結合分子 Download PDFInfo
- Publication number
- JP7302990B2 JP7302990B2 JP2019043220A JP2019043220A JP7302990B2 JP 7302990 B2 JP7302990 B2 JP 7302990B2 JP 2019043220 A JP2019043220 A JP 2019043220A JP 2019043220 A JP2019043220 A JP 2019043220A JP 7302990 B2 JP7302990 B2 JP 7302990B2
- Authority
- JP
- Japan
- Prior art keywords
- binding
- mab2
- antibody
- cancer
- seq
- 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.)
- Active
Links
- 230000027455 binding Effects 0.000 title claims description 310
- 241000282414 Homo sapiens Species 0.000 title claims description 191
- 239000000427 antigen Substances 0.000 claims description 203
- 102000036639 antigens Human genes 0.000 claims description 196
- 108091007433 antigens Proteins 0.000 claims description 196
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 119
- 206010028980 Neoplasm Diseases 0.000 claims description 114
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 111
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 99
- 229920001184 polypeptide Polymers 0.000 claims description 92
- 239000012634 fragment Substances 0.000 claims description 79
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 76
- 201000011510 cancer Diseases 0.000 claims description 72
- 150000001413 amino acids Chemical class 0.000 claims description 55
- 238000011282 treatment Methods 0.000 claims description 54
- 208000023275 Autoimmune disease Diseases 0.000 claims description 47
- 238000006467 substitution reaction Methods 0.000 claims description 46
- 108010047041 Complementarity Determining Regions Proteins 0.000 claims description 41
- 210000004881 tumor cell Anatomy 0.000 claims description 39
- 239000003814 drug Substances 0.000 claims description 38
- 230000000694 effects Effects 0.000 claims description 37
- 210000003719 b-lymphocyte Anatomy 0.000 claims description 34
- 230000002829 reductive effect Effects 0.000 claims description 26
- 108060003951 Immunoglobulin Proteins 0.000 claims description 24
- 102000018358 immunoglobulin Human genes 0.000 claims description 24
- 102000005962 receptors Human genes 0.000 claims description 24
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 claims description 18
- 108010001857 Cell Surface Receptors Proteins 0.000 claims description 18
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 claims description 18
- 102000009109 Fc receptors Human genes 0.000 claims description 16
- 108010087819 Fc receptors Proteins 0.000 claims description 16
- 239000012636 effector Substances 0.000 claims description 16
- 239000003446 ligand Substances 0.000 claims description 16
- 238000004519 manufacturing process Methods 0.000 claims description 16
- -1 IGF-1R Proteins 0.000 claims description 15
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 15
- 230000001363 autoimmune Effects 0.000 claims description 12
- 208000032839 leukemia Diseases 0.000 claims description 12
- 208000027866 inflammatory disease Diseases 0.000 claims description 10
- 210000000056 organ Anatomy 0.000 claims description 10
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 9
- 206010025323 Lymphomas Diseases 0.000 claims description 9
- 101710160107 Outer membrane protein A Proteins 0.000 claims description 9
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 claims description 8
- 208000009329 Graft vs Host Disease Diseases 0.000 claims description 8
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 8
- 208000024908 graft versus host disease Diseases 0.000 claims description 8
- 238000002054 transplantation Methods 0.000 claims description 8
- 206010006187 Breast cancer Diseases 0.000 claims description 7
- 208000026310 Breast neoplasm Diseases 0.000 claims description 7
- 101150029707 ERBB2 gene Proteins 0.000 claims description 7
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 7
- 102100029205 Low affinity immunoglobulin gamma Fc region receptor II-b Human genes 0.000 claims description 7
- 201000004681 Psoriasis Diseases 0.000 claims description 7
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 7
- 125000000539 amino acid group Chemical group 0.000 claims description 7
- 208000029742 colonic neoplasm Diseases 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 7
- 201000001441 melanoma Diseases 0.000 claims description 7
- 201000006417 multiple sclerosis Diseases 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 claims description 6
- 102100038080 B-cell receptor CD22 Human genes 0.000 claims description 6
- 206010009944 Colon cancer Diseases 0.000 claims description 6
- 101000884305 Homo sapiens B-cell receptor CD22 Proteins 0.000 claims description 6
- 101000917824 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor II-b Proteins 0.000 claims description 6
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 6
- 206010038389 Renal cancer Diseases 0.000 claims description 6
- 201000010982 kidney cancer Diseases 0.000 claims description 6
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 6
- 102220005411 rs35873730 Human genes 0.000 claims description 6
- 208000011231 Crohn disease Diseases 0.000 claims description 5
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 5
- 201000005202 lung cancer Diseases 0.000 claims description 5
- 208000020816 lung neoplasm Diseases 0.000 claims description 5
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 5
- 206010028417 myasthenia gravis Diseases 0.000 claims description 5
- 201000002528 pancreatic cancer Diseases 0.000 claims description 5
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 5
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 5
- 206010005003 Bladder cancer Diseases 0.000 claims description 4
- 206010005949 Bone cancer Diseases 0.000 claims description 4
- 208000018084 Bone neoplasm Diseases 0.000 claims description 4
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 4
- 101150013553 CD40 gene Proteins 0.000 claims description 4
- 108010084313 CD58 Antigens Proteins 0.000 claims description 4
- 108010066687 Epithelial Cell Adhesion Molecule Proteins 0.000 claims description 4
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 4
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 claims description 4
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 claims description 4
- 101000878605 Homo sapiens Low affinity immunoglobulin epsilon Fc receptor Proteins 0.000 claims description 4
- 206010023825 Laryngeal cancer Diseases 0.000 claims description 4
- 102100038007 Low affinity immunoglobulin epsilon Fc receptor Human genes 0.000 claims description 4
- 208000003445 Mouth Neoplasms Diseases 0.000 claims description 4
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 4
- 206010033128 Ovarian cancer Diseases 0.000 claims description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 4
- 208000009565 Pharyngeal Neoplasms Diseases 0.000 claims description 4
- 206010034811 Pharyngeal cancer Diseases 0.000 claims description 4
- 206010060862 Prostate cancer Diseases 0.000 claims description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 4
- 208000015634 Rectal Neoplasms Diseases 0.000 claims description 4
- 208000021386 Sjogren Syndrome Diseases 0.000 claims description 4
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 4
- 206010041969 Steatorrhoea Diseases 0.000 claims description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 4
- 208000024313 Testicular Neoplasms Diseases 0.000 claims description 4
- 206010057644 Testis cancer Diseases 0.000 claims description 4
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 4
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 claims description 4
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 4
- 208000006673 asthma Diseases 0.000 claims description 4
- 201000004101 esophageal cancer Diseases 0.000 claims description 4
- 206010017758 gastric cancer Diseases 0.000 claims description 4
- 208000005017 glioblastoma Diseases 0.000 claims description 4
- 206010023841 laryngeal neoplasm Diseases 0.000 claims description 4
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 claims description 4
- 201000007270 liver cancer Diseases 0.000 claims description 4
- 208000014018 liver neoplasm Diseases 0.000 claims description 4
- 206010038038 rectal cancer Diseases 0.000 claims description 4
- 201000001275 rectum cancer Diseases 0.000 claims description 4
- 201000000849 skin cancer Diseases 0.000 claims description 4
- 208000001162 steatorrhea Diseases 0.000 claims description 4
- 201000011549 stomach cancer Diseases 0.000 claims description 4
- 201000003120 testicular cancer Diseases 0.000 claims description 4
- 201000002510 thyroid cancer Diseases 0.000 claims description 4
- 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 claims description 4
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 4
- 206010046766 uterine cancer Diseases 0.000 claims description 4
- 102100031585 ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Human genes 0.000 claims description 3
- 208000023328 Basedow disease Diseases 0.000 claims description 3
- 102100027207 CD27 antigen Human genes 0.000 claims description 3
- 208000015023 Graves' disease Diseases 0.000 claims description 3
- 101000777636 Homo sapiens ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Proteins 0.000 claims description 3
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 claims description 3
- 201000001263 Psoriatic Arthritis Diseases 0.000 claims description 3
- 208000036824 Psoriatic arthropathy Diseases 0.000 claims description 3
- 206010039085 Rhinitis allergic Diseases 0.000 claims description 3
- 201000010105 allergic rhinitis Diseases 0.000 claims description 3
- 210000001185 bone marrow Anatomy 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 206010003827 Autoimmune hepatitis Diseases 0.000 claims description 2
- 229920001481 poly(stearyl methacrylate) Polymers 0.000 claims description 2
- 102000018651 Epithelial Cell Adhesion Molecule Human genes 0.000 claims 1
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 claims 1
- 102100022339 Integrin alpha-L Human genes 0.000 claims 1
- 108010064548 Lymphocyte Function-Associated Antigen-1 Proteins 0.000 claims 1
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 claims 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 claims 1
- 210000004027 cell Anatomy 0.000 description 128
- 101100476210 Caenorhabditis elegans rnt-1 gene Proteins 0.000 description 105
- 238000000034 method Methods 0.000 description 94
- 235000001014 amino acid Nutrition 0.000 description 59
- 229940024606 amino acid Drugs 0.000 description 52
- 108091033319 polynucleotide Proteins 0.000 description 44
- 102000040430 polynucleotide Human genes 0.000 description 44
- 239000002157 polynucleotide Substances 0.000 description 44
- 108091008874 T cell receptors Proteins 0.000 description 37
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 37
- 239000000203 mixture Substances 0.000 description 36
- 230000004048 modification Effects 0.000 description 33
- 238000012986 modification Methods 0.000 description 33
- 235000004279 alanine Nutrition 0.000 description 29
- 230000004044 response Effects 0.000 description 29
- 241000282567 Macaca fascicularis Species 0.000 description 27
- 229940079593 drug Drugs 0.000 description 27
- 230000006870 function Effects 0.000 description 27
- 230000002147 killing effect Effects 0.000 description 27
- 238000002560 therapeutic procedure Methods 0.000 description 27
- 108090000623 proteins and genes Proteins 0.000 description 26
- 210000001519 tissue Anatomy 0.000 description 25
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 23
- 229940126619 mouse monoclonal antibody Drugs 0.000 description 23
- 239000003795 chemical substances by application Substances 0.000 description 22
- 235000018102 proteins Nutrition 0.000 description 22
- 102000004169 proteins and genes Human genes 0.000 description 22
- 201000010099 disease Diseases 0.000 description 21
- 102100038078 CD276 antigen Human genes 0.000 description 19
- 241001465754 Metazoa Species 0.000 description 17
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 17
- 230000001225 therapeutic effect Effects 0.000 description 17
- 238000002965 ELISA Methods 0.000 description 16
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 16
- 230000001506 immunosuppresive effect Effects 0.000 description 16
- 238000000375 direct analysis in real time Methods 0.000 description 15
- 238000012063 dual-affinity re-targeting Methods 0.000 description 15
- 238000000338 in vitro Methods 0.000 description 15
- 238000001727 in vivo Methods 0.000 description 15
- 230000003993 interaction Effects 0.000 description 15
- 125000005647 linker group Chemical group 0.000 description 15
- 231100000205 reproductive and developmental toxicity Toxicity 0.000 description 15
- 208000024891 symptom Diseases 0.000 description 15
- 102000001301 EGF receptor Human genes 0.000 description 14
- 230000004913 activation Effects 0.000 description 14
- 238000001802 infusion Methods 0.000 description 14
- 230000001404 mediated effect Effects 0.000 description 14
- 210000000130 stem cell Anatomy 0.000 description 14
- 102100035360 Cerebellar degeneration-related antigen 1 Human genes 0.000 description 13
- 102000004127 Cytokines Human genes 0.000 description 13
- 108090000695 Cytokines Proteins 0.000 description 13
- 102000009490 IgG Receptors Human genes 0.000 description 13
- 108010073807 IgG Receptors Proteins 0.000 description 13
- 238000004458 analytical method Methods 0.000 description 13
- 238000003556 assay Methods 0.000 description 13
- 210000004408 hybridoma Anatomy 0.000 description 13
- 230000001965 increasing effect Effects 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- 108060006698 EGF receptor Proteins 0.000 description 12
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 12
- 210000000612 antigen-presenting cell Anatomy 0.000 description 12
- 239000003153 chemical reaction reagent Substances 0.000 description 12
- 238000002648 combination therapy Methods 0.000 description 12
- 230000002354 daily effect Effects 0.000 description 12
- 230000028993 immune response Effects 0.000 description 12
- 101710185679 CD276 antigen Proteins 0.000 description 11
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 11
- 241000283984 Rodentia Species 0.000 description 11
- 230000009977 dual effect Effects 0.000 description 11
- 235000013922 glutamic acid Nutrition 0.000 description 11
- 239000004220 glutamic acid Substances 0.000 description 11
- 239000005557 antagonist Substances 0.000 description 10
- 210000004369 blood Anatomy 0.000 description 10
- 239000008280 blood Substances 0.000 description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 101000884279 Homo sapiens CD276 antigen Proteins 0.000 description 9
- 206010062016 Immunosuppression Diseases 0.000 description 9
- 241001529936 Murinae Species 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000005516 engineering process Methods 0.000 description 9
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 9
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 9
- 235000004554 glutamine Nutrition 0.000 description 9
- 229940125396 insulin Drugs 0.000 description 9
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 9
- 102200074783 rs144422014 Human genes 0.000 description 9
- 238000012216 screening Methods 0.000 description 9
- 229940124597 therapeutic agent Drugs 0.000 description 9
- 208000003950 B-cell lymphoma Diseases 0.000 description 8
- 102100031940 Epithelial cell adhesion molecule Human genes 0.000 description 8
- 102000004877 Insulin Human genes 0.000 description 8
- 108090001061 Insulin Proteins 0.000 description 8
- 230000006044 T cell activation Effects 0.000 description 8
- 230000022534 cell killing Effects 0.000 description 8
- 230000000295 complement effect Effects 0.000 description 8
- 230000003013 cytotoxicity Effects 0.000 description 8
- 231100000135 cytotoxicity Toxicity 0.000 description 8
- 210000000987 immune system Anatomy 0.000 description 8
- 230000036210 malignancy Effects 0.000 description 8
- 108020003175 receptors Proteins 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- VOUAQYXWVJDEQY-QENPJCQMSA-N 33017-11-7 Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)NCC(=O)NCC(=O)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N1[C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)CCC1 VOUAQYXWVJDEQY-QENPJCQMSA-N 0.000 description 7
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 7
- 108010075254 C-Peptide Proteins 0.000 description 7
- 102100025137 Early activation antigen CD69 Human genes 0.000 description 7
- 241000282412 Homo Species 0.000 description 7
- 101000934374 Homo sapiens Early activation antigen CD69 Proteins 0.000 description 7
- 206010061218 Inflammation Diseases 0.000 description 7
- 102100029204 Low affinity immunoglobulin gamma Fc region receptor II-a Human genes 0.000 description 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 230000009824 affinity maturation Effects 0.000 description 7
- 235000009582 asparagine Nutrition 0.000 description 7
- 229960001230 asparagine Drugs 0.000 description 7
- 238000012512 characterization method Methods 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 238000003745 diagnosis Methods 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 230000001976 improved effect Effects 0.000 description 7
- 230000004054 inflammatory process Effects 0.000 description 7
- 230000000977 initiatory effect Effects 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 210000004698 lymphocyte Anatomy 0.000 description 7
- 238000002483 medication Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 230000008685 targeting Effects 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 6
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 6
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 6
- 241000288906 Primates Species 0.000 description 6
- 239000000556 agonist Substances 0.000 description 6
- 239000002246 antineoplastic agent Substances 0.000 description 6
- 230000001419 dependent effect Effects 0.000 description 6
- 206010012601 diabetes mellitus Diseases 0.000 description 6
- 229940000406 drug candidate Drugs 0.000 description 6
- 125000000404 glutamine group Chemical group N[C@@H](CCC(N)=O)C(=O)* 0.000 description 6
- 238000003018 immunoassay Methods 0.000 description 6
- 230000002163 immunogen Effects 0.000 description 6
- 238000001990 intravenous administration Methods 0.000 description 6
- 210000003734 kidney Anatomy 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 230000000069 prophylactic effect Effects 0.000 description 6
- 238000003127 radioimmunoassay Methods 0.000 description 6
- 210000002966 serum Anatomy 0.000 description 6
- 230000009870 specific binding Effects 0.000 description 6
- 241000196324 Embryophyta Species 0.000 description 5
- 101000920667 Homo sapiens Epithelial cell adhesion molecule Proteins 0.000 description 5
- 108090000467 Interferon-beta Proteins 0.000 description 5
- 108010074328 Interferon-gamma Proteins 0.000 description 5
- 108010002350 Interleukin-2 Proteins 0.000 description 5
- 102000000588 Interleukin-2 Human genes 0.000 description 5
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 5
- 102000043131 MHC class II family Human genes 0.000 description 5
- 108091054438 MHC class II family Proteins 0.000 description 5
- 206010035226 Plasma cell myeloma Diseases 0.000 description 5
- 241000700605 Viruses Species 0.000 description 5
- 230000033289 adaptive immune response Effects 0.000 description 5
- 230000002411 adverse Effects 0.000 description 5
- 238000009175 antibody therapy Methods 0.000 description 5
- 230000009286 beneficial effect Effects 0.000 description 5
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 5
- 239000002299 complementary DNA Substances 0.000 description 5
- 229940127089 cytotoxic agent Drugs 0.000 description 5
- 230000003247 decreasing effect Effects 0.000 description 5
- 230000000779 depleting effect Effects 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 239000012893 effector ligand Substances 0.000 description 5
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 230000004927 fusion Effects 0.000 description 5
- 102000037865 fusion proteins Human genes 0.000 description 5
- 108020001507 fusion proteins Proteins 0.000 description 5
- 229940072221 immunoglobulins Drugs 0.000 description 5
- 239000003018 immunosuppressive agent Substances 0.000 description 5
- 230000002757 inflammatory effect Effects 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000003550 marker Substances 0.000 description 5
- 230000035772 mutation Effects 0.000 description 5
- 201000000050 myeloid neoplasm Diseases 0.000 description 5
- 230000000263 nonmitogenic effect Effects 0.000 description 5
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 5
- 230000003389 potentiating effect Effects 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 102220053806 rs121918461 Human genes 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 241000894007 species Species 0.000 description 5
- 239000003053 toxin Substances 0.000 description 5
- 231100000765 toxin Toxicity 0.000 description 5
- 108700012359 toxins Proteins 0.000 description 5
- 230000009261 transgenic effect Effects 0.000 description 5
- 239000013598 vector Substances 0.000 description 5
- 102100025475 Carcinoembryonic antigen-related cell adhesion molecule 5 Human genes 0.000 description 4
- 241000606161 Chlamydia Species 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 108010021468 Fc gamma receptor IIA Proteins 0.000 description 4
- 208000009889 Herpes Simplex Diseases 0.000 description 4
- 101000998953 Homo sapiens Immunoglobulin heavy variable 1-2 Proteins 0.000 description 4
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 4
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 4
- 102100036887 Immunoglobulin heavy variable 1-2 Human genes 0.000 description 4
- 102000003996 Interferon-beta Human genes 0.000 description 4
- 102100029193 Low affinity immunoglobulin gamma Fc region receptor III-A Human genes 0.000 description 4
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 description 4
- 102100034256 Mucin-1 Human genes 0.000 description 4
- 208000002193 Pain Diseases 0.000 description 4
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Chemical group OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 4
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 4
- 241000606701 Rickettsia Species 0.000 description 4
- 230000005867 T cell response Effects 0.000 description 4
- 206010052779 Transplant rejections Diseases 0.000 description 4
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 4
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 4
- 241000700647 Variola virus Species 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000001042 affinity chromatography Methods 0.000 description 4
- 230000006472 autoimmune response Effects 0.000 description 4
- 230000005784 autoimmunity Effects 0.000 description 4
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 230000001413 cellular effect Effects 0.000 description 4
- 238000010367 cloning Methods 0.000 description 4
- 239000011248 coating agent Substances 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 238000011443 conventional therapy Methods 0.000 description 4
- 230000009089 cytolysis Effects 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 238000012217 deletion Methods 0.000 description 4
- 230000037430 deletion Effects 0.000 description 4
- 238000013461 design Methods 0.000 description 4
- 230000004069 differentiation Effects 0.000 description 4
- 238000010494 dissociation reaction Methods 0.000 description 4
- 230000005593 dissociations Effects 0.000 description 4
- 210000003162 effector t lymphocyte Anatomy 0.000 description 4
- 210000003743 erythrocyte Anatomy 0.000 description 4
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 4
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 230000002519 immonomodulatory effect Effects 0.000 description 4
- 229940125721 immunosuppressive agent Drugs 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 4
- 238000002372 labelling Methods 0.000 description 4
- 201000005296 lung carcinoma Diseases 0.000 description 4
- 238000013507 mapping Methods 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- 239000003607 modifier Substances 0.000 description 4
- 102000039446 nucleic acids Human genes 0.000 description 4
- 108020004707 nucleic acids Proteins 0.000 description 4
- 150000007523 nucleic acids Chemical class 0.000 description 4
- 230000008520 organization Effects 0.000 description 4
- 238000002823 phage display Methods 0.000 description 4
- 230000026731 phosphorylation Effects 0.000 description 4
- 238000006366 phosphorylation reaction Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 230000000284 resting effect Effects 0.000 description 4
- 150000003839 salts Chemical group 0.000 description 4
- 230000011664 signaling Effects 0.000 description 4
- 238000010532 solid phase synthesis reaction Methods 0.000 description 4
- 230000000638 stimulation Effects 0.000 description 4
- 208000011580 syndromic disease Diseases 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000002626 targeted therapy Methods 0.000 description 4
- 229950010127 teplizumab Drugs 0.000 description 4
- 238000011285 therapeutic regimen Methods 0.000 description 4
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 3
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 3
- 239000004475 Arginine Substances 0.000 description 3
- 206010012735 Diarrhoea Diseases 0.000 description 3
- 206010061818 Disease progression Diseases 0.000 description 3
- 102000003886 Glycoproteins Human genes 0.000 description 3
- 108090000288 Glycoproteins Proteins 0.000 description 3
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 3
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 3
- 206010019233 Headaches Diseases 0.000 description 3
- 101000913074 Homo sapiens High affinity immunoglobulin gamma Fc receptor I Proteins 0.000 description 3
- 101000935040 Homo sapiens Integrin beta-2 Proteins 0.000 description 3
- 101000917826 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor II-a Proteins 0.000 description 3
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 description 3
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 3
- 102100025390 Integrin beta-2 Human genes 0.000 description 3
- 102000006992 Interferon-alpha Human genes 0.000 description 3
- 108010047761 Interferon-alpha Proteins 0.000 description 3
- 102000008070 Interferon-gamma Human genes 0.000 description 3
- 102000004388 Interleukin-4 Human genes 0.000 description 3
- 108090000978 Interleukin-4 Proteins 0.000 description 3
- 102000004889 Interleukin-6 Human genes 0.000 description 3
- 108090001005 Interleukin-6 Proteins 0.000 description 3
- DEFJQIDDEAULHB-IMJSIDKUSA-N L-alanyl-L-alanine Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(O)=O DEFJQIDDEAULHB-IMJSIDKUSA-N 0.000 description 3
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 3
- 231100000416 LDH assay Toxicity 0.000 description 3
- 101710099301 Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 3
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 206010027476 Metastases Diseases 0.000 description 3
- 229940122985 Peptide agonist Drugs 0.000 description 3
- 229940083963 Peptide antagonist Drugs 0.000 description 3
- 108010004729 Phycoerythrin Proteins 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 3
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 3
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 3
- 239000004473 Threonine Substances 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 108010056243 alanylalanine Proteins 0.000 description 3
- 230000000781 anti-lymphocytic effect Effects 0.000 description 3
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 3
- 239000012472 biological sample Substances 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 210000004899 c-terminal region Anatomy 0.000 description 3
- 230000005880 cancer cell killing Effects 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 238000002405 diagnostic procedure Methods 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 230000005750 disease progression Effects 0.000 description 3
- 239000013604 expression vector Substances 0.000 description 3
- 230000013595 glycosylation Effects 0.000 description 3
- 238000006206 glycosylation reaction Methods 0.000 description 3
- 231100000869 headache Toxicity 0.000 description 3
- 230000005965 immune activity Effects 0.000 description 3
- 230000001900 immune effect Effects 0.000 description 3
- 230000002055 immunohistochemical effect Effects 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 206010022000 influenza Diseases 0.000 description 3
- 238000003780 insertion Methods 0.000 description 3
- 230000037431 insertion Effects 0.000 description 3
- 229940028885 interleukin-4 Drugs 0.000 description 3
- 229940100601 interleukin-6 Drugs 0.000 description 3
- 238000002843 lactate dehydrogenase assay Methods 0.000 description 3
- 210000000265 leukocyte Anatomy 0.000 description 3
- 230000004807 localization Effects 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 210000002540 macrophage Anatomy 0.000 description 3
- 230000003211 malignant effect Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000009401 metastasis Effects 0.000 description 3
- 235000013336 milk Nutrition 0.000 description 3
- 239000008267 milk Substances 0.000 description 3
- 210000004080 milk Anatomy 0.000 description 3
- 229920001542 oligosaccharide Polymers 0.000 description 3
- 150000002482 oligosaccharides Chemical class 0.000 description 3
- 238000004091 panning Methods 0.000 description 3
- 244000052769 pathogen Species 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 230000002285 radioactive effect Effects 0.000 description 3
- 102200024594 rs9657963 Human genes 0.000 description 3
- 238000012289 standard assay Methods 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 238000011269 treatment regimen Methods 0.000 description 3
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 3
- 241000701161 unidentified adenovirus Species 0.000 description 3
- MFRNYXJJRJQHNW-DEMKXPNLSA-N (2s)-2-[[(2r,3r)-3-methoxy-3-[(2s)-1-[(3r,4s,5s)-3-methoxy-5-methyl-4-[methyl-[(2s)-3-methyl-2-[[(2s)-3-methyl-2-(methylamino)butanoyl]amino]butanoyl]amino]heptanoyl]pyrrolidin-2-yl]-2-methylpropanoyl]amino]-3-phenylpropanoic acid Chemical compound CN[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MFRNYXJJRJQHNW-DEMKXPNLSA-N 0.000 description 2
- WOWDZACBATWTAU-FEFUEGSOSA-N (2s)-2-[[(2s)-2-(dimethylamino)-3-methylbutanoyl]amino]-n-[(3r,4s,5s)-1-[(2s)-2-[(1r,2r)-3-[[(1s,2r)-1-hydroxy-1-phenylpropan-2-yl]amino]-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl]-3-methoxy-5-methyl-1-oxoheptan-4-yl]-n,3-dimethylbutanamide Chemical compound CC(C)[C@H](N(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)C1=CC=CC=C1 WOWDZACBATWTAU-FEFUEGSOSA-N 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 102100030310 5,6-dihydroxyindole-2-carboxylic acid oxidase Human genes 0.000 description 2
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 2
- 102100040149 Adenylyl-sulfate kinase Human genes 0.000 description 2
- 108010054404 Adenylyl-sulfate kinase Proteins 0.000 description 2
- 101100067974 Arabidopsis thaliana POP2 gene Proteins 0.000 description 2
- 206010003445 Ascites Diseases 0.000 description 2
- 230000003844 B-cell-activation Effects 0.000 description 2
- 241000193738 Bacillus anthracis Species 0.000 description 2
- 241000589969 Borreliella burgdorferi Species 0.000 description 2
- 108010008629 CA-125 Antigen Proteins 0.000 description 2
- 102000007269 CA-125 Antigen Human genes 0.000 description 2
- 102100024217 CAMPATH-1 antigen Human genes 0.000 description 2
- 102100032912 CD44 antigen Human genes 0.000 description 2
- 108010065524 CD52 Antigen Proteins 0.000 description 2
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 2
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 2
- 229940045513 CTLA4 antagonist Drugs 0.000 description 2
- 108010022366 Carcinoembryonic Antigen Proteins 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- 108010067225 Cell Adhesion Molecules Proteins 0.000 description 2
- 102000016289 Cell Adhesion Molecules Human genes 0.000 description 2
- 102000000844 Cell Surface Receptors Human genes 0.000 description 2
- 206010008479 Chest Pain Diseases 0.000 description 2
- 206010008469 Chest discomfort Diseases 0.000 description 2
- 201000006082 Chickenpox Diseases 0.000 description 2
- 206010008631 Cholera Diseases 0.000 description 2
- 241000224483 Coccidia Species 0.000 description 2
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- 206010010144 Completed suicide Diseases 0.000 description 2
- 241000701022 Cytomegalovirus Species 0.000 description 2
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 208000001490 Dengue Diseases 0.000 description 2
- 206010012310 Dengue fever Diseases 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 238000012286 ELISA Assay Methods 0.000 description 2
- 241001466953 Echovirus Species 0.000 description 2
- 206010014612 Encephalitis viral Diseases 0.000 description 2
- 241000709661 Enterovirus Species 0.000 description 2
- 241000991587 Enterovirus C Species 0.000 description 2
- 108010055196 EphA2 Receptor Proteins 0.000 description 2
- 102100030340 Ephrin type-A receptor 2 Human genes 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 108010021472 Fc gamma receptor IIB Proteins 0.000 description 2
- 102000004641 Fetal Proteins Human genes 0.000 description 2
- 108010003471 Fetal Proteins Proteins 0.000 description 2
- 201000008808 Fibrosarcoma Diseases 0.000 description 2
- 108010014663 Glycated Hemoglobin A Proteins 0.000 description 2
- 102000017011 Glycated Hemoglobin A Human genes 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 208000031886 HIV Infections Diseases 0.000 description 2
- 102000006354 HLA-DR Antigens Human genes 0.000 description 2
- 108010058597 HLA-DR Antigens Proteins 0.000 description 2
- 208000005176 Hepatitis C Diseases 0.000 description 2
- 102100026122 High affinity immunoglobulin gamma Fc receptor I Human genes 0.000 description 2
- 101000773083 Homo sapiens 5,6-dihydroxyindole-2-carboxylic acid oxidase Proteins 0.000 description 2
- 101000868273 Homo sapiens CD44 antigen Proteins 0.000 description 2
- 101000914324 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 5 Proteins 0.000 description 2
- 101000914321 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 7 Proteins 0.000 description 2
- 101100118549 Homo sapiens EGFR gene Proteins 0.000 description 2
- 101001008255 Homo sapiens Immunoglobulin kappa variable 1D-8 Proteins 0.000 description 2
- 101001047628 Homo sapiens Immunoglobulin kappa variable 2-29 Proteins 0.000 description 2
- 101001008321 Homo sapiens Immunoglobulin kappa variable 2D-26 Proteins 0.000 description 2
- 101001047619 Homo sapiens Immunoglobulin kappa variable 3-20 Proteins 0.000 description 2
- 101001008263 Homo sapiens Immunoglobulin kappa variable 3D-15 Proteins 0.000 description 2
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 2
- 101000798109 Homo sapiens Melanotransferrin Proteins 0.000 description 2
- 101001133056 Homo sapiens Mucin-1 Proteins 0.000 description 2
- 101000623901 Homo sapiens Mucin-16 Proteins 0.000 description 2
- 101000934338 Homo sapiens Myeloid cell surface antigen CD33 Proteins 0.000 description 2
- 101001024605 Homo sapiens Next to BRCA1 gene 1 protein Proteins 0.000 description 2
- 101000617725 Homo sapiens Pregnancy-specific beta-1-glycoprotein 2 Proteins 0.000 description 2
- 208000008454 Hyperhidrosis Diseases 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 208000001953 Hypotension Diseases 0.000 description 2
- 102100034980 ICOS ligand Human genes 0.000 description 2
- 101710093458 ICOS ligand Proteins 0.000 description 2
- 102100026120 IgG receptor FcRn large subunit p51 Human genes 0.000 description 2
- 101710177940 IgG receptor FcRn large subunit p51 Proteins 0.000 description 2
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 2
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 2
- 102100022964 Immunoglobulin kappa variable 3-20 Human genes 0.000 description 2
- 206010022095 Injection Site reaction Diseases 0.000 description 2
- 108010005716 Interferon beta-1a Proteins 0.000 description 2
- 102100037850 Interferon gamma Human genes 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- 108010065805 Interleukin-12 Proteins 0.000 description 2
- 102000013462 Interleukin-12 Human genes 0.000 description 2
- 101800003050 Interleukin-16 Proteins 0.000 description 2
- 102000049772 Interleukin-16 Human genes 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-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
- 241000589248 Legionella Species 0.000 description 2
- 208000007764 Legionnaires' Disease Diseases 0.000 description 2
- 241000222722 Leishmania <genus> Species 0.000 description 2
- 208000004852 Lung Injury Diseases 0.000 description 2
- 206010025327 Lymphopenia Diseases 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
- 241000712079 Measles morbillivirus Species 0.000 description 2
- 102100032239 Melanotransferrin Human genes 0.000 description 2
- 102000018697 Membrane Proteins Human genes 0.000 description 2
- 108010052285 Membrane Proteins Proteins 0.000 description 2
- 206010027260 Meningitis viral Diseases 0.000 description 2
- 108010008707 Mucin-1 Proteins 0.000 description 2
- 102100023123 Mucin-16 Human genes 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- 208000000112 Myalgia Diseases 0.000 description 2
- 241000204031 Mycoplasma Species 0.000 description 2
- 102100025243 Myeloid cell surface antigen CD33 Human genes 0.000 description 2
- 102100029527 Natural cytotoxicity triggering receptor 3 ligand 1 Human genes 0.000 description 2
- 206010028813 Nausea Diseases 0.000 description 2
- 241000588653 Neisseria Species 0.000 description 2
- XDMCWZFLLGVIID-SXPRBRBTSA-N O-(3-O-D-galactosyl-N-acetyl-beta-D-galactosaminyl)-L-serine Chemical compound CC(=O)N[C@H]1[C@H](OC[C@H]([NH3+])C([O-])=O)O[C@H](CO)[C@H](O)[C@@H]1OC1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 XDMCWZFLLGVIID-SXPRBRBTSA-N 0.000 description 2
- 108091034117 Oligonucleotide Proteins 0.000 description 2
- 108010038807 Oligopeptides Proteins 0.000 description 2
- 102000015636 Oligopeptides Human genes 0.000 description 2
- 208000001388 Opportunistic Infections Diseases 0.000 description 2
- 241000150452 Orthohantavirus Species 0.000 description 2
- 241001631646 Papillomaviridae Species 0.000 description 2
- 206010035148 Plague Diseases 0.000 description 2
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 description 2
- 101710094000 Programmed cell death 1 ligand 1 Proteins 0.000 description 2
- 108010072866 Prostate-Specific Antigen Proteins 0.000 description 2
- 102000007066 Prostate-Specific Antigen Human genes 0.000 description 2
- 208000003251 Pruritus Diseases 0.000 description 2
- 206010037660 Pyrexia Diseases 0.000 description 2
- 102100029986 Receptor tyrosine-protein kinase erbB-3 Human genes 0.000 description 2
- 101710100969 Receptor tyrosine-protein kinase erbB-3 Proteins 0.000 description 2
- 102100029981 Receptor tyrosine-protein kinase erbB-4 Human genes 0.000 description 2
- 101710100963 Receptor tyrosine-protein kinase erbB-4 Proteins 0.000 description 2
- 241000725643 Respiratory syncytial virus Species 0.000 description 2
- 206010038910 Retinitis Diseases 0.000 description 2
- 208000006257 Rinderpest Diseases 0.000 description 2
- 241000702670 Rotavirus Species 0.000 description 2
- 241000710799 Rubella virus Species 0.000 description 2
- 101100123851 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) HER1 gene Proteins 0.000 description 2
- 241000191940 Staphylococcus Species 0.000 description 2
- 208000007107 Stomach Ulcer Diseases 0.000 description 2
- 241000194017 Streptococcus Species 0.000 description 2
- 241000193998 Streptococcus pneumoniae Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 102100037906 T-cell surface glycoprotein CD3 zeta chain Human genes 0.000 description 2
- 208000001871 Tachycardia Diseases 0.000 description 2
- 206010043376 Tetanus Diseases 0.000 description 2
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
- 102100023935 Transmembrane glycoprotein NMB Human genes 0.000 description 2
- 206010069363 Traumatic lung injury Diseases 0.000 description 2
- 241000223104 Trypanosoma Species 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- 108010079206 V-Set Domain-Containing T-Cell Activation Inhibitor 1 Proteins 0.000 description 2
- 102100038929 V-set domain-containing T-cell activation inhibitor 1 Human genes 0.000 description 2
- 108091008605 VEGF receptors Proteins 0.000 description 2
- 206010046980 Varicella Diseases 0.000 description 2
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 2
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 2
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 2
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 2
- 108010003205 Vasoactive Intestinal Peptide Proteins 0.000 description 2
- 102400000015 Vasoactive intestinal peptide Human genes 0.000 description 2
- 241000607479 Yersinia pestis Species 0.000 description 2
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 208000007502 anemia Diseases 0.000 description 2
- 230000001130 anti-lysozyme effect Effects 0.000 description 2
- 102000025171 antigen binding proteins Human genes 0.000 description 2
- 108091000831 antigen binding proteins Proteins 0.000 description 2
- 230000000890 antigenic effect Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- 206010003549 asthenia Diseases 0.000 description 2
- CXQCLLQQYTUUKJ-ALWAHNIESA-N beta-D-GalpNAc-(1->4)-[alpha-Neup5Ac-(2->8)-alpha-Neup5Ac-(2->3)]-beta-D-Galp-(1->4)-beta-D-Glcp-(1<->1')-Cer(d18:1/18:0) Chemical compound O[C@@H]1[C@@H](O)[C@H](OC[C@H](NC(=O)CCCCCCCCCCCCCCCCC)[C@H](O)\C=C\CCCCCCCCCCCCC)O[C@H](CO)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@]2(O[C@H]([C@H](NC(C)=O)[C@@H](O)C2)[C@H](O)[C@@H](CO)O[C@]2(O[C@H]([C@H](NC(C)=O)[C@@H](O)C2)[C@H](O)[C@H](O)CO)C(O)=O)C(O)=O)[C@@H](O[C@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](CO)O1 CXQCLLQQYTUUKJ-ALWAHNIESA-N 0.000 description 2
- 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 2
- 238000001574 biopsy Methods 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000002458 cell surface marker Substances 0.000 description 2
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 238000011260 co-administration Methods 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 238000012875 competitive assay Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 230000001268 conjugating effect Effects 0.000 description 2
- 230000021615 conjugation Effects 0.000 description 2
- 239000000356 contaminant Substances 0.000 description 2
- 230000016396 cytokine production Effects 0.000 description 2
- 102000003675 cytokine receptors Human genes 0.000 description 2
- 108010057085 cytokine receptors Proteins 0.000 description 2
- 208000025729 dengue disease Diseases 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000006471 dimerization reaction Methods 0.000 description 2
- 206010013023 diphtheria Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 208000002173 dizziness Diseases 0.000 description 2
- 210000001900 endoderm Anatomy 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 201000001155 extrinsic allergic alveolitis Diseases 0.000 description 2
- 230000001605 fetal effect Effects 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- SXXHYAMKYMNIHI-UHFFFAOYSA-N fluoroimino(sulfanylidene)methane Chemical compound FN=C=S SXXHYAMKYMNIHI-UHFFFAOYSA-N 0.000 description 2
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 2
- 229940044627 gamma-interferon Drugs 0.000 description 2
- GIVLTTJNORAZON-HDBOBKCLSA-N ganglioside GM2 (18:0) Chemical compound O[C@@H]1[C@@H](O)[C@H](OC[C@H](NC(=O)CCCCCCCCCCCCCCCCC)[C@H](O)\C=C\CCCCCCCCCCCCC)O[C@H](CO)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@]2(O[C@H]([C@H](NC(C)=O)[C@@H](O)C2)[C@H](O)[C@H](O)CO)C(O)=O)[C@@H](O[C@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](CO)O1 GIVLTTJNORAZON-HDBOBKCLSA-N 0.000 description 2
- PFJKOHUKELZMLE-VEUXDRLPSA-N ganglioside GM3 Chemical compound O[C@@H]1[C@@H](O)[C@H](OC[C@@H]([C@H](O)/C=C/CCCCCCCCCCCCC)NC(=O)CCCCCCCCCCCCC\C=C/CCCCCCCC)O[C@H](CO)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@]2(O[C@H]([C@H](NC(C)=O)[C@@H](O)C2)[C@H](O)[C@H](O)CO)C(O)=O)[C@@H](O)[C@@H](CO)O1 PFJKOHUKELZMLE-VEUXDRLPSA-N 0.000 description 2
- 150000002270 gangliosides Chemical class 0.000 description 2
- 201000005917 gastric ulcer Diseases 0.000 description 2
- 238000010353 genetic engineering Methods 0.000 description 2
- 230000002489 hematologic effect Effects 0.000 description 2
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 2
- 208000005252 hepatitis A Diseases 0.000 description 2
- 208000002672 hepatitis B Diseases 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 235000020256 human milk Nutrition 0.000 description 2
- 210000004251 human milk Anatomy 0.000 description 2
- 208000022098 hypersensitivity pneumonitis Diseases 0.000 description 2
- 230000036543 hypotension Effects 0.000 description 2
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 230000036737 immune function Effects 0.000 description 2
- 208000026278 immune system disease Diseases 0.000 description 2
- 230000006058 immune tolerance Effects 0.000 description 2
- 230000003053 immunization Effects 0.000 description 2
- 238000010324 immunological assay Methods 0.000 description 2
- 238000001114 immunoprecipitation Methods 0.000 description 2
- 238000009169 immunotherapy Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 229940117681 interleukin-12 Drugs 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- VBUWHHLIZKOSMS-RIWXPGAOSA-N invicorp Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)C(C)C)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 VBUWHHLIZKOSMS-RIWXPGAOSA-N 0.000 description 2
- 201000002364 leukopenia Diseases 0.000 description 2
- 231100001022 leukopenia Toxicity 0.000 description 2
- 230000029226 lipidation Effects 0.000 description 2
- 201000005249 lung adenocarcinoma Diseases 0.000 description 2
- 231100000515 lung injury Toxicity 0.000 description 2
- 206010025135 lupus erythematosus Diseases 0.000 description 2
- 231100001023 lymphopenia Toxicity 0.000 description 2
- 235000018977 lysine Nutrition 0.000 description 2
- 201000004792 malaria Diseases 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 108010071421 milk fat globule Proteins 0.000 description 2
- 238000010369 molecular cloning Methods 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 108010059074 monomethylauristatin F Proteins 0.000 description 2
- 208000013465 muscle pain Diseases 0.000 description 2
- 238000002703 mutagenesis Methods 0.000 description 2
- 231100000350 mutagenesis Toxicity 0.000 description 2
- OHDXDNUPVVYWOV-UHFFFAOYSA-N n-methyl-1-(2-naphthalen-1-ylsulfanylphenyl)methanamine Chemical compound CNCC1=CC=CC=C1SC1=CC=CC2=CC=CC=C12 OHDXDNUPVVYWOV-UHFFFAOYSA-N 0.000 description 2
- 230000008693 nausea Effects 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 230000009826 neoplastic cell growth Effects 0.000 description 2
- 210000000440 neutrophil Anatomy 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 238000011275 oncology therapy Methods 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 229960005489 paracetamol Drugs 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 238000010647 peptide synthesis reaction Methods 0.000 description 2
- 230000004962 physiological condition Effects 0.000 description 2
- 239000013612 plasmid Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 210000002307 prostate Anatomy 0.000 description 2
- 238000000159 protein binding assay Methods 0.000 description 2
- 238000002708 random mutagenesis Methods 0.000 description 2
- 238000003259 recombinant expression Methods 0.000 description 2
- 238000010188 recombinant method Methods 0.000 description 2
- 206010039083 rhinitis Diseases 0.000 description 2
- 229960004641 rituximab Drugs 0.000 description 2
- FGDZQCVHDSGLHJ-UHFFFAOYSA-M rubidium chloride Chemical compound [Cl-].[Rb+] FGDZQCVHDSGLHJ-UHFFFAOYSA-M 0.000 description 2
- 210000003296 saliva Anatomy 0.000 description 2
- 201000000306 sarcoidosis Diseases 0.000 description 2
- SIXSYDAISGFNSX-NJFSPNSNSA-N scandium-47 Chemical compound [47Sc] SIXSYDAISGFNSX-NJFSPNSNSA-N 0.000 description 2
- 230000003248 secreting effect Effects 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 239000007790 solid phase Substances 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 230000035900 sweating Effects 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 230000006794 tachycardia Effects 0.000 description 2
- 101150047061 tag-72 gene Proteins 0.000 description 2
- 206010043554 thrombocytopenia Diseases 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 238000011830 transgenic mouse model Methods 0.000 description 2
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- 238000002255 vaccination Methods 0.000 description 2
- 229940124676 vascular endothelial growth factor receptor Drugs 0.000 description 2
- 230000024883 vasodilation Effects 0.000 description 2
- 201000002498 viral encephalitis Diseases 0.000 description 2
- 201000010044 viral meningitis Diseases 0.000 description 2
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- PNDPGZBMCMUPRI-HVTJNCQCSA-N 10043-66-0 Chemical compound [131I][131I] PNDPGZBMCMUPRI-HVTJNCQCSA-N 0.000 description 1
- MIJDSYMOBYNHOT-UHFFFAOYSA-N 2-(ethylamino)ethanol Chemical compound CCNCCO MIJDSYMOBYNHOT-UHFFFAOYSA-N 0.000 description 1
- UAIUNKRWKOVEES-UHFFFAOYSA-N 3,3',5,5'-tetramethylbenzidine Chemical compound CC1=C(N)C(C)=CC(C=2C=C(C)C(N)=C(C)C=2)=C1 UAIUNKRWKOVEES-UHFFFAOYSA-N 0.000 description 1
- 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 1
- TVZGACDUOSZQKY-LBPRGKRZSA-N 4-aminofolic acid Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 TVZGACDUOSZQKY-LBPRGKRZSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 206010066728 Acute interstitial pneumonitis Diseases 0.000 description 1
- 208000026872 Addison Disease Diseases 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010001889 Alveolitis Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 108010032595 Antibody Binding Sites Proteins 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 206010069002 Autoimmune pancreatitis Diseases 0.000 description 1
- 108010012919 B-Cell Antigen Receptors Proteins 0.000 description 1
- 102000019260 B-Cell Antigen Receptors Human genes 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 1
- 208000011691 Burkitt lymphomas Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 102000005600 Cathepsins Human genes 0.000 description 1
- 108010084457 Cathepsins Proteins 0.000 description 1
- 206010057248 Cell death Diseases 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 108010044226 Class 8 Receptor-Like Protein Tyrosine Phosphatases Proteins 0.000 description 1
- 102000006449 Class 8 Receptor-Like Protein Tyrosine Phosphatases Human genes 0.000 description 1
- 241000223205 Coccidioides immitis Species 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- 108020004635 Complementary DNA Proteins 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 241000702421 Dependoparvovirus Species 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 102000016607 Diphtheria Toxin Human genes 0.000 description 1
- 108010053187 Diphtheria Toxin Proteins 0.000 description 1
- 101710181478 Envelope glycoprotein GP350 Proteins 0.000 description 1
- 102000009024 Epidermal Growth Factor Human genes 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 108700004714 Gelonium multiflorum GEL Proteins 0.000 description 1
- 101710114816 Gene 41 protein Proteins 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 102000006395 Globulins Human genes 0.000 description 1
- 108010044091 Globulins Proteins 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 208000002705 Glucose Intolerance Diseases 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 description 1
- 102100035943 HERV-H LTR-associating protein 2 Human genes 0.000 description 1
- 102100036243 HLA class II histocompatibility antigen, DQ alpha 1 chain Human genes 0.000 description 1
- 102100036241 HLA class II histocompatibility antigen, DQ beta 1 chain Human genes 0.000 description 1
- 108010086786 HLA-DQA1 antigen Proteins 0.000 description 1
- 108010067148 HLA-DQbeta antigen Proteins 0.000 description 1
- 208000031071 Hamman-Rich Syndrome Diseases 0.000 description 1
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 101100005713 Homo sapiens CD4 gene Proteins 0.000 description 1
- 101000996823 Homo sapiens Cell surface A33 antigen Proteins 0.000 description 1
- 101100334515 Homo sapiens FCGR3A gene Proteins 0.000 description 1
- 101000746367 Homo sapiens Granulocyte colony-stimulating factor Proteins 0.000 description 1
- 101000746373 Homo sapiens Granulocyte-macrophage colony-stimulating factor Proteins 0.000 description 1
- 101000946860 Homo sapiens T-cell surface glycoprotein CD3 epsilon chain Proteins 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- 238000012450 HuMAb Mouse Methods 0.000 description 1
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 description 1
- 201000009794 Idiopathic Pulmonary Fibrosis 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
- 108010009817 Immunoglobulin Constant Regions Proteins 0.000 description 1
- 102000009786 Immunoglobulin Constant Regions Human genes 0.000 description 1
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 1
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 1
- 102000018071 Immunoglobulin Fc Fragments Human genes 0.000 description 1
- 108010091135 Immunoglobulin Fc Fragments Proteins 0.000 description 1
- 206010051792 Infusion related reaction Diseases 0.000 description 1
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 description 1
- 102100026720 Interferon beta Human genes 0.000 description 1
- 108010005714 Interferon beta-1b Proteins 0.000 description 1
- 102000003814 Interleukin-10 Human genes 0.000 description 1
- 108090000174 Interleukin-10 Proteins 0.000 description 1
- 108010002386 Interleukin-3 Proteins 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
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-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
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 102000004083 Lymphotoxin-alpha Human genes 0.000 description 1
- 108090000542 Lymphotoxin-alpha Proteins 0.000 description 1
- 208000030984 MIRAGE syndrome Diseases 0.000 description 1
- 102100028123 Macrophage colony-stimulating factor 1 Human genes 0.000 description 1
- 101710127797 Macrophage colony-stimulating factor 1 Proteins 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 238000000585 Mann–Whitney U test Methods 0.000 description 1
- 101000884277 Mus musculus CD276 antigen Proteins 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 206010029240 Neuritis Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 244000061176 Nicotiana tabacum Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 238000012408 PCR amplification Methods 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 201000011152 Pemphigus Diseases 0.000 description 1
- 208000031845 Pernicious anaemia Diseases 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 1
- 101000762949 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) Exotoxin A Proteins 0.000 description 1
- 206010037423 Pulmonary oedema Diseases 0.000 description 1
- 102000006382 Ribonucleases Human genes 0.000 description 1
- 108010083644 Ribonucleases Proteins 0.000 description 1
- 108010039491 Ricin Proteins 0.000 description 1
- 238000011579 SCID mouse model Methods 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 108010029180 Sialic Acid Binding Ig-like Lectin 3 Proteins 0.000 description 1
- 102000001555 Sialic Acid Binding Ig-like Lectin 3 Human genes 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 102220499347 Synaptotagmin-like protein 5_L43A_mutation Human genes 0.000 description 1
- 108010092262 T-Cell Antigen Receptors Proteins 0.000 description 1
- 208000029052 T-cell acute lymphoblastic leukemia Diseases 0.000 description 1
- 102100035794 T-cell surface glycoprotein CD3 epsilon chain Human genes 0.000 description 1
- 101710156660 T-cell surface glycoprotein CD3 zeta chain Proteins 0.000 description 1
- 210000000662 T-lymphocyte subset Anatomy 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical class [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- GKLVYJBZJHMRIY-OUBTZVSYSA-N Technetium-99 Chemical compound [99Tc] GKLVYJBZJHMRIY-OUBTZVSYSA-N 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- 101800004564 Transforming growth factor alpha Proteins 0.000 description 1
- 102400001320 Transforming growth factor alpha Human genes 0.000 description 1
- 101800001690 Transmembrane protein gp41 Proteins 0.000 description 1
- 208000030886 Traumatic Brain injury Diseases 0.000 description 1
- 102100040247 Tumor necrosis factor Human genes 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 108010075974 Vasoactive Intestinal Peptide Receptors Chemical group 0.000 description 1
- 102000012088 Vasoactive Intestinal Peptide Receptors Human genes 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 108010003533 Viral Envelope Proteins Proteins 0.000 description 1
- 241000219094 Vitaceae Species 0.000 description 1
- 206010047642 Vitiligo Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- IEDXPSOJFSVCKU-HOKPPMCLSA-N [4-[[(2S)-5-(carbamoylamino)-2-[[(2S)-2-[6-(2,5-dioxopyrrolidin-1-yl)hexanoylamino]-3-methylbutanoyl]amino]pentanoyl]amino]phenyl]methyl N-[(2S)-1-[[(2S)-1-[[(3R,4S,5S)-1-[(2S)-2-[(1R,2R)-3-[[(1S,2R)-1-hydroxy-1-phenylpropan-2-yl]amino]-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl]-3-methoxy-5-methyl-1-oxoheptan-4-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]-N-methylcarbamate Chemical compound CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCc1ccc(NC(=O)[C@H](CCCNC(N)=O)NC(=O)[C@@H](NC(=O)CCCCCN2C(=O)CCC2=O)C(C)C)cc1)C(C)C IEDXPSOJFSVCKU-HOKPPMCLSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 201000004073 acute interstitial pneumonia Diseases 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000004520 agglutination Effects 0.000 description 1
- 150000001295 alanines Chemical group 0.000 description 1
- 229960000548 alemtuzumab Drugs 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- 229960003896 aminopterin Drugs 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000009830 antibody antigen interaction Effects 0.000 description 1
- 230000005875 antibody response Effects 0.000 description 1
- 238000011230 antibody-based therapy Methods 0.000 description 1
- 238000011319 anticancer therapy Methods 0.000 description 1
- 238000011394 anticancer treatment Methods 0.000 description 1
- 230000030741 antigen processing and presentation Effects 0.000 description 1
- 125000000613 asparagine group Chemical group N[C@@H](CC(N)=O)C(=O)* 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 208000010928 autoimmune thyroid disease Diseases 0.000 description 1
- 229940003504 avonex Drugs 0.000 description 1
- 239000008228 bacteriostatic water for injection Substances 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- 229940021459 betaseron Drugs 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 238000010256 biochemical assay Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 238000004159 blood analysis Methods 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- OZVBMTJYIDMWIL-AYFBDAFISA-N bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 description 1
- 229960002802 bromocriptine Drugs 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 230000028956 calcium-mediated signaling Effects 0.000 description 1
- 229930195731 calicheamicin Natural products 0.000 description 1
- 229940112129 campath Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000007910 cell fusion Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000007969 cellular immunity Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 230000009920 chelation Effects 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 239000013611 chromosomal DNA Substances 0.000 description 1
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 description 1
- 201000003486 coccidioidomycosis Diseases 0.000 description 1
- 230000024203 complement activation Effects 0.000 description 1
- 230000009918 complex formation Effects 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 108010018927 conglutinin Proteins 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000004940 costimulation Effects 0.000 description 1
- 230000000139 costimulatory effect Effects 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 230000009260 cross reactivity Effects 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 239000000430 cytokine receptor antagonist Substances 0.000 description 1
- 206010052015 cytokine release syndrome Diseases 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- QCUFYOBGGZSFHY-UHFFFAOYSA-N depsidomycin Chemical compound O=C1C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(NC=O)C(C)CC)C(C)OC(=O)C2CCCNN2C(=O)C(CC(C)C)NC(=O)C2CCCNN21 QCUFYOBGGZSFHY-UHFFFAOYSA-N 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 229960000520 diphenhydramine Drugs 0.000 description 1
- PCHPORCSPXIHLZ-UHFFFAOYSA-N diphenhydramine hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 PCHPORCSPXIHLZ-UHFFFAOYSA-N 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000009231 family therapy Methods 0.000 description 1
- 229960004887 ferric hydroxide Drugs 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 238000002825 functional assay Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 238000003205 genotyping method Methods 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 235000021021 grapes Nutrition 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 208000021760 high fever Diseases 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 239000012510 hollow fiber Substances 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 102000046157 human CSF2 Human genes 0.000 description 1
- 102000054366 human GPA33 Human genes 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 238000011577 humanized mouse model Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 102000027596 immune receptors Human genes 0.000 description 1
- 108091008915 immune receptors Proteins 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 238000013115 immunohistochemical detection Methods 0.000 description 1
- 238000011532 immunohistochemical staining Methods 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 238000011501 immunologic monitoring Methods 0.000 description 1
- 230000006054 immunological memory Effects 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 238000002650 immunosuppressive therapy Methods 0.000 description 1
- 229940051026 immunotoxin Drugs 0.000 description 1
- 239000002596 immunotoxin Substances 0.000 description 1
- 238000000126 in silico method Methods 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 229940055742 indium-111 Drugs 0.000 description 1
- APFVFJFRJDLVQX-AHCXROLUSA-N indium-111 Chemical compound [111In] APFVFJFRJDLVQX-AHCXROLUSA-N 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000012678 infectious agent Substances 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- IEECXTSVVFWGSE-UHFFFAOYSA-M iron(3+);oxygen(2-);hydroxide Chemical compound [OH-].[O-2].[Fe+3] IEECXTSVVFWGSE-UHFFFAOYSA-M 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 238000011005 laboratory method Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000004816 latex Substances 0.000 description 1
- 229920000126 latex Polymers 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000001638 lipofection Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000005265 lung cell Anatomy 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 230000002101 lytic effect Effects 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 210000003071 memory t lymphocyte Anatomy 0.000 description 1
- 210000002418 meninge Anatomy 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 238000001823 molecular biology technique Methods 0.000 description 1
- 238000003032 molecular docking Methods 0.000 description 1
- 230000004784 molecular pathogenesis Effects 0.000 description 1
- 238000002625 monoclonal antibody therapy Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 230000000869 mutational effect Effects 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 208000025189 neoplasm of testis Diseases 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 235000021590 normal diet Nutrition 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 230000005305 organ development Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 201000001976 pemphigus vulgaris Diseases 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 238000003752 polymerase chain reaction Methods 0.000 description 1
- 102000054765 polymorphisms of proteins Human genes 0.000 description 1
- 208000005987 polymyositis Diseases 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 201000009104 prediabetes syndrome Diseases 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
- TVLSRXXIMLFWEO-UHFFFAOYSA-N prochloraz Chemical compound C1=CN=CN1C(=O)N(CCC)CCOC1=C(Cl)C=C(Cl)C=C1Cl TVLSRXXIMLFWEO-UHFFFAOYSA-N 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- 230000000644 propagated effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000001742 protein purification Methods 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 208000005333 pulmonary edema Diseases 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000000941 radioactive substance Substances 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229940038850 rebif Drugs 0.000 description 1
- 229940051173 recombinant immunotoxin Drugs 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000010425 regulation of immunoglobulin secretion Effects 0.000 description 1
- 230000006716 regulation of lymphocyte proliferation Effects 0.000 description 1
- 210000003289 regulatory T cell Anatomy 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 208000030925 respiratory syncytial virus infectious disease Diseases 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000011268 retreatment Methods 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- WUAPFZMCVAUBPE-IGMARMGPSA-N rhenium-186 Chemical compound [186Re] WUAPFZMCVAUBPE-IGMARMGPSA-N 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 102200000898 rs104894496 Human genes 0.000 description 1
- 102200015453 rs121912293 Human genes 0.000 description 1
- 102220223311 rs139642328 Human genes 0.000 description 1
- 102220065979 rs150401144 Human genes 0.000 description 1
- 102200077960 rs1555897088 Human genes 0.000 description 1
- 102220044897 rs587781661 Human genes 0.000 description 1
- 102200163548 rs63751094 Human genes 0.000 description 1
- 102220188005 rs886053373 Human genes 0.000 description 1
- 229940102127 rubidium chloride Drugs 0.000 description 1
- 231100000279 safety data Toxicity 0.000 description 1
- 238000009781 safety test method Methods 0.000 description 1
- 208000011581 secondary neoplasm Diseases 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000006152 selective media Substances 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 238000002333 serotherapy Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 210000004989 spleen cell Anatomy 0.000 description 1
- 210000004988 splenocyte Anatomy 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 230000008093 supporting effect Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000005737 synergistic response Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940056501 technetium 99m Drugs 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 229940126622 therapeutic monoclonal antibody Drugs 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 230000009258 tissue cross reactivity Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000816 toxic dose Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 108091007466 transmembrane glycoproteins Proteins 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000005909 tumor killing Effects 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- HFQKBOPMAOTAIR-TZSVBWBLSA-N α-d-galactosyl-(1->4)-β-d-galactosyl-(1->4)-β-d-glucosylceramide Chemical compound O[C@@H]1[C@@H](O)[C@H](OC[C@@H]([C@H](O)/C=C/CCCCCCCCCCCCC)NC(C)=O)O[C@H](CO)[C@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)[C@@H](CO)O1 HFQKBOPMAOTAIR-TZSVBWBLSA-N 0.000 description 1
Images
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
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2809—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
-
- C—CHEMISTRY; METALLURGY
- C03—GLASS; MINERAL OR SLAG WOOL
- C03C—CHEMICAL COMPOSITION OF GLASSES, GLAZES OR VITREOUS ENAMELS; SURFACE TREATMENT OF GLASS; SURFACE TREATMENT OF FIBRES OR FILAMENTS MADE FROM GLASS, MINERALS OR SLAGS; JOINING GLASS TO GLASS OR OTHER MATERIALS
- C03C17/00—Surface treatment of glass, not in the form of fibres or filaments, by coating
- C03C17/34—Surface treatment of glass, not in the form of fibres or filaments, by coating with at least two coatings having different compositions
- C03C17/36—Surface treatment of glass, not in the form of fibres or filaments, by coating with at least two coatings having different compositions at least one coating being a metal
- C03C17/38—Surface treatment of glass, not in the form of fibres or filaments, by coating with at least two coatings having different compositions at least one coating being a metal at least one coating being a coating of an organic material
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
-
- 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
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
-
- C—CHEMISTRY; METALLURGY
- C03—GLASS; MINERAL OR SLAG WOOL
- C03C—CHEMICAL COMPOSITION OF GLASSES, GLAZES OR VITREOUS ENAMELS; SURFACE TREATMENT OF GLASS; SURFACE TREATMENT OF FIBRES OR FILAMENTS MADE FROM GLASS, MINERALS OR SLAGS; JOINING GLASS TO GLASS OR OTHER MATERIALS
- C03C17/00—Surface treatment of glass, not in the form of fibres or filaments, by coating
- C03C17/34—Surface treatment of glass, not in the form of fibres or filaments, by coating with at least two coatings having different compositions
- C03C17/42—Surface treatment of glass, not in the form of fibres or filaments, by coating with at least two coatings having different compositions at least one coating of an organic material and at least one non-metal coating
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
-
- 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
- C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
-
- G—PHYSICS
- G02—OPTICS
- G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
- G02B5/00—Optical elements other than lenses
- G02B5/08—Mirrors
- G02B5/0808—Mirrors having a single reflecting layer
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01L—SEMICONDUCTOR DEVICES NOT COVERED BY CLASS H10
- H01L31/00—Semiconductor devices sensitive to infrared radiation, light, electromagnetic radiation of shorter wavelength or corpuscular radiation and specially adapted either for the conversion of the energy of such radiation into electrical energy or for the control of electrical energy by such radiation; Processes or apparatus specially adapted for the manufacture or treatment thereof or of parts thereof; Details thereof
- H01L31/04—Semiconductor devices sensitive to infrared radiation, light, electromagnetic radiation of shorter wavelength or corpuscular radiation and specially adapted either for the conversion of the energy of such radiation into electrical energy or for the control of electrical energy by such radiation; Processes or apparatus specially adapted for the manufacture or treatment thereof or of parts thereof; Details thereof adapted as photovoltaic [PV] conversion devices
- H01L31/054—Optical elements directly associated or integrated with the PV cell, e.g. light-reflecting means or light-concentrating means
- H01L31/0547—Optical elements directly associated or integrated with the PV cell, e.g. light-reflecting means or light-concentrating means comprising light concentrating means of the reflecting type, e.g. parabolic mirrors, concentrators using total internal reflection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C03—GLASS; MINERAL OR SLAG WOOL
- C03C—CHEMICAL COMPOSITION OF GLASSES, GLAZES OR VITREOUS ENAMELS; SURFACE TREATMENT OF GLASS; SURFACE TREATMENT OF FIBRES OR FILAMENTS MADE FROM GLASS, MINERALS OR SLAGS; JOINING GLASS TO GLASS OR OTHER MATERIALS
- C03C2217/00—Coatings on glass
- C03C2217/40—Coatings comprising at least one inhomogeneous layer
- C03C2217/43—Coatings comprising at least one inhomogeneous layer consisting of a dispersed phase in a continuous phase
- C03C2217/44—Coatings comprising at least one inhomogeneous layer consisting of a dispersed phase in a continuous phase characterized by the composition of the continuous phase
- C03C2217/445—Organic continuous phases
-
- C—CHEMISTRY; METALLURGY
- C03—GLASS; MINERAL OR SLAG WOOL
- C03C—CHEMICAL COMPOSITION OF GLASSES, GLAZES OR VITREOUS ENAMELS; SURFACE TREATMENT OF GLASS; SURFACE TREATMENT OF FIBRES OR FILAMENTS MADE FROM GLASS, MINERALS OR SLAGS; JOINING GLASS TO GLASS OR OTHER MATERIALS
- C03C2217/00—Coatings on glass
- C03C2217/40—Coatings comprising at least one inhomogeneous layer
- C03C2217/43—Coatings comprising at least one inhomogeneous layer consisting of a dispersed phase in a continuous phase
- C03C2217/46—Coatings comprising at least one inhomogeneous layer consisting of a dispersed phase in a continuous phase characterized by the dispersed phase
- C03C2217/465—Coatings comprising at least one inhomogeneous layer consisting of a dispersed phase in a continuous phase characterized by the dispersed phase having a specific shape
-
- C—CHEMISTRY; METALLURGY
- C03—GLASS; MINERAL OR SLAG WOOL
- C03C—CHEMICAL COMPOSITION OF GLASSES, GLAZES OR VITREOUS ENAMELS; SURFACE TREATMENT OF GLASS; SURFACE TREATMENT OF FIBRES OR FILAMENTS MADE FROM GLASS, MINERALS OR SLAGS; JOINING GLASS TO GLASS OR OTHER MATERIALS
- C03C2217/00—Coatings on glass
- C03C2217/40—Coatings comprising at least one inhomogeneous layer
- C03C2217/43—Coatings comprising at least one inhomogeneous layer consisting of a dispersed phase in a continuous phase
- C03C2217/46—Coatings comprising at least one inhomogeneous layer consisting of a dispersed phase in a continuous phase characterized by the dispersed phase
- C03C2217/47—Coatings comprising at least one inhomogeneous layer consisting of a dispersed phase in a continuous phase characterized by the dispersed phase consisting of a specific material
- C03C2217/475—Inorganic materials
- C03C2217/479—Metals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/71—Decreased effector function due to an Fc-modification
-
- 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
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02E—REDUCTION OF GREENHOUSE GAS [GHG] EMISSIONS, RELATED TO ENERGY GENERATION, TRANSMISSION OR DISTRIBUTION
- Y02E10/00—Energy generation through renewable energy sources
- Y02E10/50—Photovoltaic [PV] energy
- Y02E10/52—PV systems with concentrators
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Immunology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Physics & Mathematics (AREA)
- Diabetes (AREA)
- Oncology (AREA)
- Materials Engineering (AREA)
- General Physics & Mathematics (AREA)
- Geochemistry & Mineralogy (AREA)
- Pulmonology (AREA)
- Hematology (AREA)
- Rheumatology (AREA)
- Computer Hardware Design (AREA)
- Optics & Photonics (AREA)
- Power Engineering (AREA)
- Microelectronics & Electronic Packaging (AREA)
- Electromagnetism (AREA)
- Condensed Matter Physics & Semiconductors (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Obesity (AREA)
- Physical Education & Sports Medicine (AREA)
- Neurology (AREA)
Description
本出願は、米国特許出願第61/488,716号(2011年5月21日出願、出願中)及び第61/530,353号(2011年9月1日出願、出願中)に対する優先権を主張し、上記出願はそれぞれ参照により全体を本明細書に組み込むものとする。
本出願は、米国特許法施行規則1.821以下参照に従い、1つ又は複数の配列表を含み、これらは紙及びコンピュータ読み取り可能な媒体の両方で開示され、紙及びコンピュータ読み取り可能な開示は参照により全体を本明細書に組み込むものとする。
細胞(骨髄から誘導される)が抗体を分泌するために必要とされる。T細胞は、1つの抗原を別の抗原から識別できるように並外れた免疫特異性を示すことが極めて重要である。
している抗原提示細胞によってのみ活性化することができる。共刺激がない状態でナイーブT細胞が抗原を認識すると、T細胞がアネルギー性になる。T細胞及びB細胞が適応免疫応答を得るように活性化するために2つの信号が必要であることで、T細胞が認識できる系内の位置で抗原提示細胞上に存在し得る自己抗原に対して、応答しないようにするメカニズムを提供することができる。T細胞が抗原提示細胞と接触した結果、必要な2つの信号のうち一方しか発生しない場合、T細胞は活性化されず、適応免疫応答が生じない。
r Assembly, Ligand Recognition, and Initiation of Signaling」(Cold Spring Harb. Perspect. Biol. 2:a005140))。この複合体は特に重要である。何故なら、多数(10個)の免疫受容活性化チロシンモチーフ(ITAM)を含有するからである。
験することができる。すなわち、(i)関連する種で、すなわち候補薬品がオルソログ抗原を認識できる種で、(ii)ヒト抗原を含むトランスジェニック動物で、及び(iii)動物に存在するオルソログ抗原を結合することができる候補薬品の代用薬を使用することである。トランスジェニック動物の限界は、このテクノロジが通常は齧歯動物に限定されていることである。しかし、齧歯動物とヒトとは生理機能に重大な違いがあり、そのことは齧歯動物で取得した安全性データからヒトでの安全性を予測することを困難にすることがある。候補薬品の代用薬の限界は、実際の候補薬品と比較して物質の組成が異なり、往々にして使用される動物が、以上で説明したような限界を有する齧歯動物であることである。したがって、齧歯動物で生成された前臨床データは、候補薬品に関して予測能力が限られている。安全性試験のための選択方法は、関連する種、好ましくは下等霊長類を使用することである。当技術分野で説明されているヒトでの治療介入に適切なCD3結合分子の現在の限界は、関連する種が高等霊長類、特にカニクイザルであることである。したがって、ヒトと霊長類両方のCD3に結合可能な抗CD3抗体が非常に望ましい。このような抗体が、米国特許公開第20100150918号及びPCT特許公開WO2008/119567号で説明されている。
(I)CD3特異的VLドメインは、h-mab2 VL-1(配列ID番号:16)、h-mab2 VL-2(配列ID番号:18)、h-mab2 VL-3(配列ID番号:20)、h-mab2 VL-4(配列ID番号:22)、h-mab2 VL-5(配列ID番号:24)、h-mab2 VL-6(配列ID番号:26)、h-mab2 VL-7(配列ID番号:28)、h-mab2 VL-8(配列ID番号:30)、h-mab2 VL-9(配列ID番号:32)、及びh-mab2 VL-10(配列ID番号:34)からなる群から選択され、上記CD3特異的VHドメインは、h-mab2 VH-1(配列ID番号:36)、h-mab2 VH-2(配列ID番号:38)、h-mab2 VH-3(配列ID番号:40)、h-mab2 VH-4(配列ID番号:42)、h-mab2 VH-5(配列ID番号:44)、h-mab2 VH-6(配列ID番号:46)、h-mab2 VH-6L(配列ID番号:54)、h-mab2 VH-7(配列ID番号:48)、h-mab2 VH-8(配列ID番号:50)、h-mab2 VH-8L(配列ID番号:55)、h-mab2 VH-8 di-1(配列ID番号:56)、h-mab2 VH-8 di-2(配列ID番号:57)、h-mab2 VH-6M(配列ID番号:72)、h-mab2 VH-8M(配列ID番号:74)、h-mab2 VH-2k(配列ID番号:87)、及びh-mab2 VH-5k(配列ID番号:88)からなる群から選択されるか、又は、
(II)CD3特異的VLドメインは、h-mab 1 VL-1(配列ID番号:10)及びh-mab1 VL-2(配列ID番号:12)からなる群から選択され、CD3特異的VHドメインはh-mab1 VH(配列ID番号:14)である。
(A)エフェクター機能がない、又はエフェクター機能が低下した、又は
(B)抗体のFc領域がFc受容体に結合する能力が低減している
Fc領域を有する上記CD3結合分子の実施形態に関し、
エフェクター機能の低下及び結合能力の低減は、野生型Fc受容体のそれに関する。
(I).第1のポリペプチド鎖は、アミノ末端とカルボキシ末端とを含む、さらにN末端からC末端への間に、
(i)CD3特異的VLドメインを含むドメイン(A)と、
(ii)第2の免疫グロブリンの重鎖可変ドメイン(VH2)の結合領域を含むドメイン(B)と、
(iii)ドメイン(C)とを含み、
ドメイン(A)及び(B)はエピトープ結合部位を形成するために相互に会合せず、且つ、
(II)第2のポリペプチド鎖は、アミノ末端とカルボキシ末端とを含む、さらにN末端からC末端への間に、
(i)第2の免疫グロブリンの軽鎖可変ドメイン(VL2)の結合領域を含むドメイン(D)と、
(ii)CD3特異的VHドメインを含むドメイン(E)と、
(iii)ドメイン(F)とを含み、
ドメイン(D)及び(E)はエピトープ結合部位を形成するために相互に会合せず、
(1)ドメイン(A)及び(E)は、ヒトCD3と非ヒト哺乳類のCD3との両方に免疫特異的に結合可能である抗原結合ドメインを形成するために会合し、
(2)ドメイン(B)及び(D)は、第2のエピトープに免疫特異的に結合する結合部位を形成するために会合し、第2のエピトープは、ドメイン(A)及び(E)の会合から形成された抗原結合ドメインによって結合されたCD3エピトープとは異なり、
(3)ドメイン(C)及び(F)は相互に共有会合する。
本明細書で使用する「CD3結合分子」という用語は、分子の可変領域に位置する少なくとも1つの抗原認識部位(例えば抗体の抗原結合ドメイン)を通してヒトCD3と非ヒト哺乳類のCD3との両方に免疫特異的に結合可能な分子を指す。本明細書で使用する、ヒトCD3と非ヒト哺乳類のCD3との両方に免疫特異的に結合するこのような能力は、1つの抗原結合ドメインがこのようなCD3分子の両方に同時に結合する能力を指すものではなく、ヒトCD3の存在下でインキュベートされた場合に、ヒトCD3に免疫特異的に結合し、非ヒト哺乳類CD3の存在下でインキュベートされた場合に、このような非ヒト哺乳類のCD3に免疫特異的に結合するように、このような抗原結合ドメインが交差反応性を示すものである。
7-1A、A33、成体赤血球1次内胚葉I抗原、アルファ胎児タンパク質、RNA腫瘍ウイルスのエンベロープ抗原、膀胱腫瘍癌胎児性抗原、B7-H1、B7-H2、B7-H3、B7-H4、B7-H5、B7-H6、バーキットリンパ腫抗原-38.13、CA125、CD18、CD19、ヒトBリンパ腫抗原-CD20、CD22、CD33、CD44、CD52、CEA、CO17-1A、CTA-1、CTLA-4、表皮性成長因子受容体、Ep-CAM、EphA2、胎児赤血球I抗原、線維肉腫抗原、ガングリオシドGD2、ガングリオシドGD3、ガングリオシドGM2、ガングリオシドGM3、GICA19-9、gpIIIb/IIIa、gp72、HER1、HER-2/neu、HER3、HER4、高分子量黒色腫抗原、HLA-DR抗原、ヒト白血病T細胞抗原-Gp37、ヒト肺癌腫抗原L20、ヒト肺癌腫抗L6、ヒト乳脂肪球抗原、IgE、KS1/4全癌腫抗原LEA、肺腺癌F3抗原、悪性ヒト白血球抗原-APO-1、黒色腫抗原gp75、黒色腫会合抗原p97、ネオ糖タンパク質、nuC242、多型上皮ムチン抗原、前立腺特異的抗原、前立腺特異的膜抗原、前立腺酸性ホスホターゼ、SK-1抗原、TAG-72、T-抗原、腫瘍抗原CA125、腫瘍抗原MUC1、腫瘍特異的移植型の細胞表面の抗原、血管内皮成長因子、血管内皮成長因子-受容体、及びαvβ3)。あるいは、このような追加の抗原又はエピトープは、病原体(例えば、A型肝炎、B型肝炎、C型肝炎、インフルエンザ、水痘、アデノウイルス、I型単純ヘルペス(HSV-I)、II型単純ヘルペス(HSV-II)、牛疫、ライノウイルス、エコーウイルス、ロタウイルス、呼吸器系合胞体ウイルス、パピロマウイルス、パポバウイルス、サイトメガロウイルス、エキノウイルス、アルボウイルス、ハンタウイルス、コクサッキウイルス、流行性耳下腺炎ウイルス、麻疹ウイルス、風疹ウイルス、ポリオウイルス、天然痘、EBウイルス、I型ヒト免疫不全症ウイルス(HIV-I)、II型ヒト免疫不全症ウイルス(HIV-II)、ウイルス性髄膜炎、ウイルス性脳炎、デング熱、天然痘;マイコバクテリアリケッチア、マイコプラズマ、ナイセリア、肺炎球菌、ボレリアブルグドルフェリ、炭疽菌、連鎖球菌、ブドウ球菌、マイコバクテリア、破傷風、百日咳(Pertissus)、コレラ、悪疫、ジフテリア、クラミジア、及びレジオネラ;リーシュマニア、コクシジア、トリパノソーマ又はマラリア;クラミジア及びリケッチア)と会合することができる。
換えの発現、トランスジェニック動物などによる)に関して限定されるものではない。この用語は、免疫グロブリン全体、更に「抗体」の定義で上記フラグメントなどを含む。
, K.他(1993)の「Cancer Res 53:851-856」、Riechmann, L.他(1988)の「Reshaping Human Antibodies for Therapy」(Nature 332:323-327)、Verhoeyen, M.他(1988)の「Reshaping Human Antibodies: Grafting An Antilysozyme Activity」(Science 239:1534-1536)、Kettleborough, C.A.他(1991)の「Humanization Of A Mouse Monoclonal Antibody By CDR-Grafting: The Importance Of Framework Residues On Loop Conformation」(Protein Engineering 4:773-3783)、Maeda, H.他(1991)の「Construclion of Reshaped Human Antibodies With HIV-Neutralizing Activity」(Human Antibodies Hybridoma 2:124-134)、Gorman, S.D.他(1991)の「Reshaping A Therapeutic CD4 Antibody」(Proc. Natl. Acad. Sci. (U.S.A.) 88:4181-4185)、Tempest, P.R.他(1991)の「Reshaping A Human Monoclonal Antibody To Inhibit Human Respiratory Syncytial Virus Infection in vivo」(Bio/Technology 9:266-271)、Co, M.S.他(1991)の「Humanized Antibodies For Antiviral Therapy」(Proc. Natl. Acad. Sci. (U.S.A.) 88:2869-2873)、Carter, P.他(1992)の「Hummanization Of An Anti-p185her2 Antibody For Human Cancer Therapy」(Proc. Natl. Acad. Sci. (U.S.A.) 89:4285-4289)、及びCo, M.S.他(1992)の「Chimeric And Humanized Antibodies With Specificity For The CD33 Antigen」(J. Immunol. 148:1149-1154)で報告されている。
必要としない(しかし、それを含むことはできる)。通常、結合という場合、それは「免疫特異的」結合を意味するが、これは必然的ではない。
鎖として、又は会合した鎖として発生できることが理解される。
モノクローナル抗体を作成する方法が当技術分野で知られている。使用できる1つの方法は、Kohler, G.他(1975)の「Continuous Cultures Of Fused Cells Secreting Antibody Of Predefined Specificity」(Nature 256:495-497 )の方法、又はその変形である。通常、モノクローナル抗体はマウスなどの非ヒト種で発生する。一般的に、免疫化にはマウス又はラットが使用されるが、他の動物も使用することができる。抗体は、免疫原生量のヒトCD3を含有する細胞、細胞抽出物、又はタンパク質製剤でマウスを免疫化することによって産生される。免疫原は、1次細胞、培養した細胞系統、癌細胞、核酸、又は組織とすることができるが、これらに限定されない。
,567号、第5,807,715号、第5,866,692号、及び第6,331,415号を参照されたい。
. 138:4534-4538)、及びBrown他(1987)の「Tumor-Specific Genetically Engineered Murine/Human Chimeric Monoclonal Antibody」(Cancer Res. 47:3577-3583)を参照されたい)。適切なヒト抗体定常ドメインと融合する前にヒト支持フレームワーク領域(FR)に移植された齧歯動物のCDRについて説明する参考文献もある(例えば、Riechmann, L.他(1988)の「Reshaping Human Antibodies for Therapy」(Nature 332:323-327)、Verhoeyen, M.他(1988)の「Reshaping Human Antibodies: Grafting An Antilysozyme Activity」(Science 239:1534-1536)、及びJones他(1986)の「Replacing The Complementarity-Determining Regions In A Human Antibody With Those From A Mouse」(Nature 321:522-525)を参照されたい)。別の参考文献は、組み換え技術で貼り合わせた齧歯動物フレームワーク領域によって支持された齧歯動物のCDRについて説明している。例えば、欧州特許公開第519,596号を参照されたい。これらの「ヒト化」分子は、ヒト受容者におけるこれら成分の治療適用の継続時間及び有効性を制限する齧歯動物の非ヒト抗体分子に対する望ましくない免疫応答を最小化するように設計される。抗体をヒト化するために同様に使用できる他の方法が、Daugherty他(1991)の「Polymerase Chain Reaction Facilitates The Clonig, CDR-Grafting, And Rapid Expression Of A Murine Monoclonal Antibody Directed Against The CD18 Component Of Leukocyte Integrins」(Nucl. Acids Res. 19:2471-2476)及び米国特許第6,180,377号、第6,054,297号、第5,997,867号、及び第5,866,692号に開示されている。
CD3に結合するポリペプチド及びモノクローナル抗体をスクリーニングするために、幾つかの方法を使用することができる。「結合」とは、生物学的又は免疫学的に適切な特異的結合を指し、例えば非特異的標的に対して免疫グロブリンを非常に高い濃度で使用する場合に生じるような、非特異的結合を指すものではないことが理解される。一実施形態では、標準的なスクリーニング技術を使用して、CD3に結合するためにモノクローナル抗体をスクリーニングする。この方法で、抗CD3モノクローナル抗体を獲得した。本発明の好ましいハイブリドーマは、抗体mAb1及びmAb2、又はそのキメラ又はヒト化誘導体を生成するものである。しかし、CD3に結合する追加のモノクローナル抗体を識別することができる。そのために、ヒトCD3、更に霊長類のCD3に結合する区別能力
について、モノクローナル抗体をスクリーニングする。
幾つかの方法のいずれかを使用して、抗CD3抗体を特徴付けることができる。1つの方法は、それが結合するエピトープを識別することである。エピトープのマッピングが様々な供給源、例えばPepscan Systems(オランダ、レリスタット)から商業的に入手可能である。エピトープのマッピングを使用して、抗CD3抗体が結合する先の配列を判定することができる。エピトープは線状エピトープとする、すなわちアミノ酸の1本鎖に含有されるか、又は必ずしも1本鎖に含有されないアミノ酸の3次元相互作用によって形成された立体配座エピトープとすることができる。
本発明は組成物、例えば抗CD3抗体、抗CD3抗体から誘導されるポリペプチド、抗CD3抗体をコード化する配列を含むポリヌクレオチド、及び本明細書で説明するような他の薬剤を含む医薬組成物を包含する。本発明は更に、任意のCD3ペプチドアゴニスト、アンタゴニスト又は修飾因子、及び特定のCD3ペプチドアゴニスト、アンタゴニスト又は修飾因子の意図された1つ又は複数の機能を支援する追加の化学的構造の接合体を提供する。これらの接合体には、本明細書で説明する診断、スクリーニング又は精製手順に使用する任意の可溶性固体支持基質などの高分子に共有結合するCD3ペプチドアゴニスト、アンタゴニスト又は修飾因子が含まれる。適切な基質材料には、化学的に不活性で、高い多孔性を有し、ペプチドリガンドとの共有結合を形成することができる多数の官能基を有する任意の物質が含まれる。基質材料、及び基質-リガンド接合体を調製する手順の例がDean他(編集)の「AFFINITY CHROMATOGRAPHY: A PRACTICAL APPROACH」(IRL Press (1985))、Loweの「An Introduction to Affinity Chromatography」、Work他(編集)の「LABORATORY TECHNIQUES IN BIOCHEMISTRY AND MOLECULAR BIOLOGY」第7巻パートII(North-Holland(1979))、Porath他の「Biospecific Affinity Chromatography」、Neurath, H.他(編集)の「THE PROTEINS」第3版第1巻pp.95~178(1975)、及びSchott, H.の「AFFINITY CHROMATOGRAPHY」(Macel Dekker, Inc.、ニューヨーク(1984))で説明されている。
(1)正常なヒトT細胞の表面上に内因的に発現した状態のヒトCD3に特異的に結合する能力、
(2)ヒト白血病T細胞の表面上に内因的に発現した状態のヒトCD3に特異的に結合する能力、
(3)正常な非ヒトT細胞の表面上に内因的に発現した状態の非ヒトCD3(例えばカニクイザルのCD3)に特異的に結合する能力、
(4)非ヒト白血病T細胞の表面上に内因的に発現した状態の非ヒトCD3に特異的に結合する能力、
(5)CD3複合体の形成を中和する(すなわち結合を阻止又は妨害する)能力、TCR複合体の形成を中和する能力、
(6)TCR複合体による信号送出を(アンタゴニスティック又はアゴニスティックに)調節する能力、
(7)Fc受容体に結合する能力、
(8)元の抗体が優先的に結合する同じCD3エピトープに優先的に結合する能力など、既知の抗CD3抗体をCD3に優先的に結合するのを競合的に抑制する能力、
(9)生細胞の表面に露出したCD3の部分にインビトロ又はインビボで結合する能力、生癌細胞の表面に露出したCD3の部分に結合する能力、
(10)化学療法薬を癌T細胞に送出する能力、及び/又は
(11)治療薬、毒素又は検出可能なマーカをT細胞に送出する能力
のいずれか(1つ又は複数)により、更に識別され、特徴付けられる。
、又は以上で識別された宿主細胞によって産生された抗体と同一であるCDRを有しても、又は有していなくてもよい。CDR領域の判定は、十分に当技術分野の範囲内である。他の実施形態には、本明細書で識別されたように沈着、又はこのような抗体から誘導されるハイブリドーマから産生される抗体の少なくとも2個、3個、4個、5個又は6個のCDRと実質的に同種である少なくとも2個、3個、4個、5個、又は6個のCDRを有する抗体が含まれる。本発明では、結合特異性及び/又は全体的活性は一般的に保持されるが、沈着したハイブリドーマによって産生された抗体と比較して、活性の程度は変化することがある(大きくなるか、又は小さくなることがある)ことが理解される。本発明は、これらの抗体のいずれかを作成する方法も提供する。抗体の作成方法は当技術分野で知ら
れており、本明細書で説明する。
由来する。一実施形態では、可変領域は元の抗体の軽鎖に由来する。別の実施形態では、可変領域は抗体の重鎖に由来する。別の実施形態では、5個(以上)の近接アミノ酸は、抗体の相補性決定領域(CDR)に由来する。
従来の免疫機能では、抗体-抗原複合体と免疫系の細胞との相互作用は、広範囲の応答をもたらし、その範囲は抗体依存の細胞毒性、肥満細胞脱顆粒、及び食作用などのエフェクターの機能から、リンパ球増殖及び抗体分泌の調節などの免疫調節性信号まである。これらの相互作用はすべて、抗体又は免疫複合体のFcドメインが造血細胞上の特殊な細胞表面受容体と結合することによって開始する。抗体及び免疫複合体が引き金となる細胞応答の多様性は、3つのFc受容体、すなわちFcγRI(CD64)、FcγRII(CD32)、及びFcγRIII(CD16)の構造的異質性に由来する。FcγRI(CD64)、FcγRIIA(CD32A)及びFcγRIII(CD16)は活性化(すなわち免疫系を増強する)受容体であり、FcγRIIB(CD32B)は阻害性(すなわち免疫系を減衰させる)受容体である。IgG1 Fc領域のアミノ酸配列を以下に示す(配列ID番号:9、参照により明示的に本明細書に組み込むものとし、移行は「Kabat EU」と呼ばれるKabat他の「SEQUENCE OF PROTEINS OF IMMUNOLOGICAL INTEREST」第5版(Public Health Service、メリーランド州NIH(1991))に従って番号付けされている)。残基230~341はFc CH2領域である。残基342~447はFc CH3領域である。
配列ID番号:9
.他(1999)の「Recombinant human IgG Molecules Lacking Fcgamma Receptor I Binding And Monocyte Triggering Activities」(Eur. J. Immunol. 29:2613-24)、Jefferis, R.他(1996)の「Modulation of Fc(Gamma)R And Human Complement Activation By IgG3-Core Oligosaccharide Interactions」(Immunol. Lett.54:101-04)、Lund, J.他(1996)の「Multiple Interactions Of IgG With Its Core Oligosaccharide Can Modulate Recognition By Complement And Human Fc Gamma Receptor I And Influence The Synthesis Of Its Oligosaccharide Chairns」(J. Immunol. 157:4963-4969)、Hutchins他(1995)の「Improved Biodistribution, Tumor Targeting, And Reduced Immunogenicity In Mice With A Gamma 4 Variant of Campath-1H」(Proc. Natl. Acad. Sci. (U.S.A.) 92:11980-84)、Jefferis, R.他(1995)の「Recognition Sites On Human IgG For Fc Gamma Receptors: The Role Of Glycosylation」(Immunol. Lett. 44:111-17)、Lund, J.他(1995)の「Oligosaccharide-Protein Interactions In IgG Can Modulate Recognition By Fc Gamma Receptors」(FASEB J. 9:115-19)、Alegre, M.L.他(1994)の「A Non-Activating "Humanized" Anti-CD3 Monoclonal Antibody Retains Immunosuppressive Properties In Vivo」(Transplantation 57:1537-1543)、Lund他(1992)の「Multiple Binding Sites on The CH2 Domain Of IgG For Mouse Fc Gamma R11」(Mol. Immunol. 29:53-59)、Lund他(1991)の「Human Fc Gamma RI And Fc Gamma RII Interact With Distinct But Overllapping Sites On Human IgG」(J. Immunol. 147:2657-2662)、Duncan, A.R.他(1988)の「Localization of The Binding Site For The Human High-Affinity Fc Receptor On IgG」(Nature 332:563-564)、米国特許第5,624,821号、第5,885,573号、第6,194,551号、第7,276,586号、及び第7,317,091号、及びPCT特許公開WO00/42072号及びPCT特許WO99/58572号で開示されているように、当技術分野で知られている任意のFc変異体を使用することを包含する。
以上で説明したように、本発明は追加的に、二重特異的、三重特異的及び多重特異的抗体を包含する。このような抗体の特に好ましい例としては、少なくとも2つのエピトープ結合部位を形成し、少なくともその1つがCD3に特異的に結合する少なくとも2本のポリペプチド鎖を含む「DART(商標)」ダイアボディ分子が挙げられる。例示的「DART(商標)」ダイアボディ分子が、US20100174053号、US20090060910号、US20070004909号、EP2158221号、EP1868650号、WO2010080538号、WO2008157379号、及びWO2006113665号に開示されている。
(i)エピトープ(1)に特異的な第1の免疫グロブリン(VL1)の軽鎖可変ドメインの結合領域を含むドメイン(A)と、
(ii)エピトープ(2)に特異的な第2の免疫グロブリン(VH2)の重鎖可変ドメインの結合領域を含むドメイン(B)と、
(iii)ドメイン(C)とを含む。
このようなDART(商標)ダイアボディの第2のポリペプチド鎖は、
(i)エピトープ(2)に特異的な第2の免疫グロブリン(VL2)の軽鎖可変ドメインの結合領域を含むドメイン(D)と、
(ii)エピトープ(1)に特異的な第1の免疫グロブリン(VH1)の重鎖可変ドメインの結合領域を含むドメイン(E)と、
(iii)ドメイン(F)とを含む。
DART(商標)ダイアボディドメイン(A)及び(B)は、相互に会合してエピトープ結合部位を形成するものではない。同様に、DART(商標)ダイアボディドメイン(D)及び(E)は、相互に会合してエピトープ結合部位を形成するものではない。それどころか、DART(商標)ダイアボディドメイン(A)及び(E)が会合して、エピトープ(1)を結合する結合部位を形成し、上記DART(商標)ダイアボディドメイン(B)及び(D)が会合して、上記エピトープ(2)を結合する結合部位を形成する。ドメイン(C)及び(F)は相互に共有結合する。
本発明の抗CD3抗体及びその抗原結合フラグメントは、CD3の発現を伴う癌の治療、及び自己免疫疾患及び他の炎症性疾患の治療に特に有益である。
本発明の抗体及び抗原結合フラグメントは、T細胞の表面に存在するCD3に結合する。本発明の抗原結合フラグメントは、T細胞を腫瘍細胞へとリダイレクトするために、DART又はBiTE分子などの二重特異的(又は三重特異的又は多重特異的)分子の関係で使用することができる。これで、T細胞が腫瘍細胞を殺傷することができる。本発明の二重特異的(又は三重特異的又は多重特異的)分子は、ヒトCD3及び非ヒト哺乳類(例えばカニクイザル)のCDの両方に、及び第2(又は追加的)の異なる抗原又はエピトープに結合することができる。第2の抗原又はエピトープは、腫瘍細胞上に発現する腫瘍抗原であることが好ましい。このような腫瘍細胞は、癌、例えば、乳癌、前立腺癌、胃癌、肺癌、結腸癌、直腸癌、膵臓癌、肝臓癌、卵巣癌、口腔癌、咽頭癌、食道癌、喉頭癌、骨癌、皮膚癌、メラノーマ、子宮癌、精巣癌、膀胱癌、腎臓癌、脳腫瘍、グリア芽腫、甲状腺癌、リンパ腫、骨髄腫、及び白血病からの可能性がある。このような追加の抗原又はエピトープは、細胞表面腫瘍抗原又はエピトープ(17-1A、A33、成体赤血球1次内胚葉I抗原、アルファ胎児タンパク、RNA腫瘍ウイルスのエンベロープ抗原、膀胱腫瘍癌胎児性抗原、B7-H1、B7-H2、B7-H3、B7-H4、B7-H5、B7-H6、バーキットリンパ腫抗原-38.13、CA125、CD18、CD19、ヒトBリンパ腫抗原-CD20、CD22、CD33、CD44、CD52、CEA、CO17-1A、CTA-1、CTLA-4、表皮性成長因子受容体、Ep-CAM、EphA2、胎児赤血球I抗原、線維肉腫抗原、ガングリオシドGD2、ガングリオシドGD3、ガングリオシドGM2、ガングリオシドGM3、GICA19-9、gpIIIb/IIIa、gp72、HER1、HER-2/neu、HER3、HER4、高分子量黒色腫抗原、HLA-DR抗原、ヒト白血病T細胞抗原-Gp37、ヒト肺癌腫抗原L20、ヒト肺癌腫抗原L6、ヒト乳脂肪球抗原、IgE、KS1/4全癌腫抗原LEA、肺腺癌F3抗原、悪性ヒト白血球抗原-APO-1、黒色腫抗原gp75、黒色腫会合抗原p97、ネオ糖タンパク質、nuC242、多型上皮ムチン抗原、前立腺特異的抗原、前立腺特異的膜抗原、前立腺酸性ホスホターゼ、SK-1抗原、TAG-72、T-抗原、腫瘍抗原CA125、腫瘍抗原MUC1、腫瘍特異的移植型の細胞表面の抗原、血管内皮成長因子、血管内皮成長因子-受容体、及びαvβ3など)であることが好ましい。あるいは、このような追加の抗原又はエピトープは、病原体(例えば、A型肝炎、B型肝炎、C型肝炎、インフルエンザ、水痘、アデノウイルス、I型単純ヘルペス(HSV-I)、II型単純ヘルペス(HSV-II)、牛疫、ライノウイルス、エコーウイルス、ロタウイルス、呼吸器系合胞体ウイルス、パピロマウイルス、パポバウイルス、サイトメガロウイルス、エキノウイルス、アルボウイルス、ハンタウイルス、コクサッキウイルス、流行性耳下腺炎ウイルス、麻疹ウイルス、風疹ウイルス、ポリオウイルス、天然痘、EBウイルス、I型ヒト免疫不全症ウイルス(HIV-I)、II型ヒト免疫不全症ウイルス(HIV-II)、ウイルス性髄膜炎、ウイルス性脳炎、デング熱、天然痘;マイコバクテリアリケッチア、マイコプラズマ、ナイセリア、肺炎球菌、ボレリアブルグドルフェリ、炭疽菌、連鎖球菌、ブドウ球菌、マイコバクテリア、破傷風、百日咳(Pertissus)、コレラ、悪疫、ジフテリア、クラミジア、及びレジオネラ;リーシュマニア、コクシジア、トリパノソーマ又はマラリア;クラミジア及びリケッチア)と会合することができる。
本発明は、移植片拒絶、移植片対宿主疾患、望ましくない遅延型過敏反応(遅延型アレルギー反応など)、T細胞性肺疾患、及び自己免疫疾患などのT細胞性疾患又は障害の症状を治療、予防、進行遅延、及び/又は改善する方法も提供する。T細胞性肺疾患には類肉腫症、過敏性肺臓炎、急性間質肺炎、肺胞炎、肺線維症、突発性肺線維症及び炎症性肺損傷を特徴とする他の疾患が含まれる。T細胞自己免疫疾患には、多発性硬化症、神経炎、多発性筋炎、乾癬、白斑、シェーグレン症候群、慢性関節リウマチ、1型糖尿病、自己免疫膵臓炎、炎症性腸疾患(例えば、クローン病及び潰瘍性大腸炎)、小児脂肪便症、糸球体腎炎、強皮症、類肉腫症、自己免疫甲状腺疾患(例えば、橋本甲状腺炎及びブレーブス病)、重症性筋無力症、アジソン病、自己免疫ブドウ膜網膜炎、尋常性天疱瘡、原発性胆汁性肝硬変、悪性貧血、及び全身性紅斑性狼瘡、狼瘡(特に皮膚)、臓器移植の影響、移植片対宿主病(GVHD)などが含まれる。特に、本発明の方法は早期段階の患者で、自己免疫による障害を遅延させるか、又は軽減し、高レベルの機能を維持し、及び/又は他の療法の必要性を低下させるので有利である(例えば、I型糖尿病の治療又は予防で、本発明の方法は、被験者の外生インスリン投与の必要性を低下させることができる)。更に、本発明の方法は、以前は治療用抗体、及び特に抗T細胞(例えば抗CD3)抗体又は抗原結合フラグメント)の投与に伴っていたサイトカイン放出症候群の発生を減少させるか、又は発生をなくすことができるので有利である。
一態様では、本発明の実施形態は、従来の療法で治療した被験者で達成された寛解よりも長期間の臨床的寛解を達成し、維持するように治療したヒト被験者を提供する。例えば、従来の療法で自己免疫疾患の症状の3カ月の寛解を達成した場合、本発明の組成物は、最大6カ月、最大12カ月、及び場合によっては最大1年~2年、又はそれ以上の症状の完全な寛解を提供することができる。特定の自己免疫疾患では、特に自己免疫疾患の診断直後に療法を開始する場合に、再発しない完全な寛解を提供することが可能なことがある。
本発明の実施形態で使用する抗体の薬学的製剤は、所望の純度を有する本発明の組成物を、薬学分野で認識されている任意選択の薬学的に許容可能な担体、賦形剤又は安定剤を凍結乾燥製剤又は水溶液の形態で混合することによって保存、輸送及び投与用に調製される。
本発明は、本発明のヒト化抗体を充填した1つ又は複数の容器を含む薬品パック又はキットを提供する。更に、疾患の治療に有用な1つ又は複数の他の予防薬又は治療薬も薬品パック又はキットに含めることができる。本発明は、本発明の医薬組成物の1つ又は複数の成分を充填した1つ又は複数の容器を含む薬品パック又はキットも提供する。任意選択で、このような容器には、製造、薬品又は生物学的製品の使用又は販売を規制する政府当局によって規定された形態の通知書を添付することができ、この通知書は、ヒトに投与するための製造、使用又は販売の当局による認可を反映する。
本明細書で開示した方法によって作成されるCD3に対する抗体は、細胞表面から放出された後に血液中で循環する癌細胞の有無、又はそのレベルの識別にも使用することができる(例えば可溶性CD3)。このように循環する抗原は、本明細書で教示する方法により検出される能力を保持する無傷のCD3抗原、又はそのフラグメントであってもよい。このような検出は、例えば当技術分野で一般的に使用される標準的な方法を使用するFACS分析によって実行することができる。
び急性白血病性肺障害が含まれる。
ヒト及びカニクイザル両方のCD3へのmAb1結合
mAb1がヒトCD3に結合する能力を判定するために、捕捉ELISAを実施した。プレートを1μg/mLの可溶性カニクイザルCD3(「sCD3」)でコーティングし、様々な濃度のmAb1抗体のキメラ変異体(ch-mAb1)(mAb1の様々な配列及びヒト抗体の定常領域を含有する)と、ヒト化変異体(h-mAb1)と、キメラmAb1抗体の軽鎖及びmAb1のヒト化変異体の重鎖で構成された抗体とが存在する状態でインキュベートした。その実験結果を図1Aに示す。実験は、mAb1が哺乳類の非ヒト種のCD3に結合する能力を示す。更に、キメラmAb1抗体の結合を、ヒト化変異体mAb1 LC-2及びmAb1の重鎖で構成された抗体の結合と比較した。その実験結果を図1Bに示す。実験は、mAb1がヒトCD3に結合する能力を示す。したがって、図1A及び図1Bにより、ヒト化mAb1がヒトCD3と非ヒト哺乳類のCD3との両方に結合できたことが明らかになる。ヒト化mAbは、sCD3及びキメラmAb1のそれと同様のhCD3に対する結合を示した。
mAb1のヒト化
mAb1のヒト化誘導体を調製した。このヒト化誘導体のアミノ酸配列及びコード化ポリヌクレオチド配列を以下に示す。CDRを太字体及び下線で示す。
mAb2のヒト化
mAb2のヒト化誘導体を調製した。これらのヒト化誘導体のアミノ酸配列及びコード化ポリヌクレオチド配列を以下に示す。CDRを太字体及び下線で示す。
ヒト及びカニクイザル両方のCD3へのmAb2結合
以上で説明したように、mAb2抗体は元々、ヒトCD3への結合能力に基づいて分離されていた。mAb2が非ヒトCD3に結合する能力を判定するために、捕捉ELISAを実施した。プレートを1μg/mLのCD3(ヒト又はカニクイザル)でコーティングし、様々な濃度のmAb2抗体のキメラ変異体(ch-mAb2)(mAb2の可変配列及びヒト抗体の定常領域を含有する)が存在する状態でインキュベートした。対照標準として、ヒト化mAb2抗体の軽鎖及びキメラ抗体の重鎖で構成された抗体でもプレートをインキュベートした。この実験結果を図2A及び図2Bに示し、それは、キメラmAb2変異体がヒトCD3及びカニクイザルCD3に同等の結合を示したことを明らかにする。
キメラ及びヒト化mAb2軽鎖及び重鎖の変異体の結合特徴の分析
キメラ及びヒト化mAb2が非ヒトCD3に結合する能力を判定するために、捕捉ELISAを実施した。プレートを1μg/mLのCD3の細胞外ドメイン(可溶性CD3)(ヒト又はカニクイザル)でコーティングし、様々な濃度の抗体が存在する状態でインキュベートした。この実験結果を図8A及び図8Bに示し、これはmAb2及びそのヒト化変異体が、可溶性ヒトCD3及び可溶性カニクイザルCD3に同等の結合を示したことを明らかにする。
ヒト及びカニクイザルCD3に対するmAb2の結合の定量化
mAb2とヒト又はカニクイザルCD3の間の結合程度を測定するために、BIACORE(商標)分析を実施した。BIACORE(商標)分析は、解離定数kdを測定する。抗体とその標的との結合親和性(KD)は、KD=kd/kaによる会合(会合定数、ka)及び解離(解離定数、kd)の動力学的定数の関数である。BIACORE(商標)分析は、表面プラズモン共鳴を使用して、これらの動力学的パラメータを直接測定する。抗EK抗体を使用して抗CD3抗体mAb2(6.3~100nM)を支持体に固定化し、可溶性ヒトCD3(shCD3)又は可溶性カニクイザルCD3(scCD3)が存在する状態でインキュベートした。解離の時間経過を測定し、データの二価フィットを実施した。BIACORE(商標)分析の結果を図9A~図9Dに示す。動力学的データを表3に要約する。
h-mAb2のCDRを含有するDART(商標)ダイアボディの二重特異的結合データ
ヒト化mAb2(h-mAb2)のCDRを使用して、Her2/neu(DART(商標)ダイアボディ「Her2-h-mAb2」)に、又はCD19(DART(商標)ダイアボディ「CD19-h-mAb2」)に、又は表皮性成長因子受容体(EGFR)(DART(商標)ダイアボディ「ERBITUX(商標)-h-mAb2」)に結合可能な抗CD3第1のエピトープ結合部位及び第2のエピトープ結合部位を有するDART(商標)の系列を産生した。
Her2-h-mAb2のDART(商標)ダイアボディのhXR32VL-Her-2VH-Eコイルのアミノ酸配列(hXR32VL配列とHer2VH配列の間、及びHer2VH配列とEコイル配列の間のリンカーには下線を付した)(配列ID番号:58)
CD19-h-mAb2のDART(商標)ダイアボディのCD19VL-hXR32VH-Eコイルのアミノ酸配列(CD19VL配列とhVR32VH配列の間、及びhXR32VH配列とEコイル配列の間のリンカーには下線を付した)(配列ID番号:60)
ERBITUX(商標)-h-mAb2のDART(商標)ダイアボディのhXR32VL-EGFRVH-Eコイルのアミノ酸配列(hXR32VL配列とEGFRVH配列の間、及びEGFRVH配列とEコイル配列の間のリンカーには下線を付した)(配列ID番号:62)
B7-H3-1-h-mAb2のDART(商標)ダイアボディのhBRCA69DVL-hXR32VH-Eコイルのアミノ酸配列(hBRCA69DVL配列とhXR32VH配列の間、及びhXR32VH配列とEコイル配列の間のリンカーには下線を付した)(配列ID番号:64)
B7-H3-2-h-mAb2のDART(商標)ダイアボディのhBRCA84DVL-hXR32VH-Eコイルのアミノ酸配列(hBRCA84DVL配列とhXR32VH配列の間、及びhXR32VH配列とEコイル配列の間のリンカーには下線を付した)(配列ID番号:66)
HER2/neu及びCD3に特異的な二重親和性再標的決定試薬(DART(商標))ダイアボディが強力なリダイレクトされたT細胞殺傷を仲介する
HER2/neu及びCD3に特異的な二重親和性再標的決定試薬(DART(商標))ダイアボディを調製した。このようなDART(商標)ダイアボディは、T細胞を(このようなT細胞をCD3結合DART(商標)ダイアボディのCD3結合部分に結合することによって)腫瘍細胞の位置に(このような癌細胞をDART(商標)ダイアボディのHER2/neu結合部分に結合することによって)局在化する能力を有する。これで、局在化したT細胞は、本明細書で「リダイレクトされた」殺傷と呼ばれるプロセスで、腫瘍細胞の殺傷を仲介することができる。
自己免疫疾患の患者の抗TCRモノクローナル抗体療法
患者:1型糖尿病の患者を40人、参加するように以下の基準に従って募集した。すなわち、年齢は7歳と20歳の間、米国糖尿病学会の基準による診断の6週間以内、及び抗GAD65、抗ICA512及び/又は抗インスリン自己抗体の存在が確認されている。患者は、調査の経過中、その掛かり付けの医師の治療を受け続ける。
B7H3及びCD3に特異的な二重親和性再標的決定試薬(DART(商標))ダイアボディが強力なリダイレクトされたT細胞殺傷を仲介する
B7H3及びCD3に特異的な二重親和性再標的決定試薬(DART(商標))ダイアボディを調製した。B7H3は、腫瘍細胞系統で免疫組織学的に検出したものである(Chapoval, A.他(2001)の「B7-H3: A Costimulatory Molecule For T Cell Activation and IFN- γ Production」(Nature Immunol. 2:269-274)、Saatian, B.他(2004)の「Expression Of Genes For B7-H3 And Other T Cell Ligands B Nasal Epithelial Cells During Differentiation And Activation」(Amer. J. Physiol. Lung Cell. Mol. Physiol. 287:L217-L225)、Castriconi他(2004)の「Identification Of 4Ig-B7-H3 As A Neuroblastoma-Associated Molecule That Exerts A Protective Role From An NK Cell-Mediated Lysis」(Proc. Natl. Acad. Sci. (U.S.A.) 101(34):12640-12645))、Sun, M.他(2002)の「Characterization of Mouse and Human B7-H3 Genes」(J. Immunol. 168:6294-6297))。幾つかの別個の研究が、ヒト悪性腫瘍細胞はB7-H3タンパク質の発現に顕著な増加を示し、この発現増加は疾患重症度の上昇を伴ったことを示し(Zang, X.他(2007)の「The B7 Family And Cancer Therapy: Costimulation And Coinhibition」(Clin. Cancer Res. 13:5271-5279))、腫瘍が免疫回避経路としてB7-H3を利用していると示唆している(Hofmeyer, K.他(2008)の「The Contrasting Role Of B7-H3」(Proc. Natl. Acad. Sci. (U.S.A.) 105(30):10277-10278))。
4420-h-mAb2 DART(商標)ダイアボディの4420VL-hXR32VH-Eコイルのアミノ酸配列(4420VL配列とhXR32VH配列の間、及びhXR32VH配列とEコイル配列の間のリンカーには下線を付した)(配列ID番号:68)
A33及びCD3に特異的な二重親和性再標的決定試薬(DART(商標))ダイアボディが強力なリダイレクトされたT細胞殺傷を仲介する
A33抗原及びCD3に特異的な二重親和性再標的決定試薬(DART(商標))ダイアボディ(「A33-h-mAb2」DART(商標)ダイアボディ)を調製した。A33は、正常なヒトの結腸及び小腸の上皮に発現し、ヒト結腸癌の95%を超える膜抗原である(Heath, J.K.他(1997)の「The human A33 Antigen Is A Transmembrane Glycoprotein And A Novel Member Of The Immunoglobulin Superfamily」(Proc. Natl. Acad. Sci. (USA)94:469-474))。
A33-h-mAb2 DART(商標)ダイアボディのRECA47VL-hXR32VH-Kコイルのアミノ酸配列(RECA47VL配列とhXR32VH配列の間、及びhXR32VH配列とKコイル配列の間のリンカーには下線を付した)(配列ID番号:70)
CD3に特異的な二重親和性再標的決定試薬(DART(商標))ダイアボディが、他のヒト特異的CD3ダイアボディと同等のリダイレクトされたT細胞仲介殺傷を引き起こす
本発明のCD3特異的二重親和性再標的決定試薬(DART(商標))ダイアボディを更に判定するために、上記CD19-h-mAb2 DART(商標)ダイアボディがリダイレクトされたT細胞仲介殺傷を引き起こす能力を、Moore, P.A.他(2011)の(「Application Of Dual Affinity Retargeting Molecules To Achieve Optimal Redirected T-Cell Killing Of B-Cell Lymphoma」(Blood 117(17):4542-4551))のCD19×CD3 DARTダイアボディと比較した。CD19-h-mAb2 DART(商標)ダイアボディは、ヒトCD3に、及び非ヒトCD3に特異性を示し、Moore, P.A.他(2011)のCD19×CD3 DARTダイアボディはヒトCD3にのみ特異性を示す。
CD3に特異的なカニクイザル交差反応性二重親和性再標的決定試薬(DART(商標))ダイアボディによるリダイレクトされた細胞溶解
上記CD19-h-mAb2 DART(商標)ダイアボディが、ヒト又はカニクイザルの存在する状態でリダイレクトされたT細胞仲介殺傷を引き起こす能力を調査した。
二重親和性再標的決定試薬(DART(商標))ダイアボディは標的細胞の結合を必要とする
観察された本発明のCD3 DART(商標)ダイアボディにより仲介されたリダイレクトされた殺傷が特異的であったことを実証するために、標的細胞が存在する状態及び存在しない状態で殺傷程度を測定した。
ヒト化カニクイザル/ヒト交差反応性DART(商標)ダイアボディによるリダイレクトされた殺傷
本発明のDART(商標)ダイアボディがリダイレクトされた殺傷を仲介する能力を更に実証するために、A498腎臓癌標的細胞又はA431類表皮細胞癌細胞(Lee, C.M.他(2010)の「The Distribution of The Therapeutic Monoclonal Antibodies Cetuximab And Trastuzumab Within Solid Tumors」(BMC Cancer 10:255; pages 1-11)、Bryant, J.A.他(2004)の「EGF Actives Intracellular And Intercellular Calcium Signaling By Distinct Pathways In Tumor Cells」(Cancer Biol. Ther. 3(12):1243-1249))、及びPMBCエフェクター細胞(E:T=30:1)の存在する状態で様々なDART(商標)ダイアボディにより仲介されるリダイレクトされた殺傷の程度を測定した。
Claims (23)
- 抗体の抗原結合フラグメントを含むCD3結合分子であって、前記抗原結合フラグメントが抗体CD3特異的VLドメイン及び抗体CD3特異的VHドメインを含み、前記CD3特異的VLドメイン及び前記CD3特異的VHドメインが、ヒトCD3のエピトープ及び非ヒト哺乳類のCD3のエピトープの両方に免疫特異的に結合可能な抗原結合ドメインを形成し、
(I)前記CD3特異的VLドメインが、配列ID番号:5にある3つの相補性決定領域(CDR)を含み、
(II)前記CD3特異的VHドメインが、配列ID番号:7にある3つの相補性決定領域(CDR)を含み、D65Gのアミノ酸置換を含むように修飾され、
その番号がKabatの番号付け方式に従っている、
CD3結合分子。 - 前記CD3特異的VLドメインが、h-mab2 VL-4(配列ID番号:22)、h-mab2 VL-6(配列ID番号:26)、h-mab2 VL-7(配列ID番号:28)、h-mab2 VL-8(配列ID番号:30)、h-mab2 VL-9(配列ID番号:32)、及びh-mab2 VL-10(配列ID番号:34)からなる群から選択される、請求項1に記載のCD3結合分子。
- 前記CD3特異的VHドメインが、前記アミノ置換を含むことにより、h-mab2 VH-1(配列ID番号:36)、h-mab2 VH-2(配列ID番号:38)、h-mab2 VH-3(配列ID番号:40)、h-mab2 VH-4(配列ID番号:42)、h-mab2 VH-5(配列ID番号:44)、h-mab2 VH-6(配列ID番号:46)、h-mab2 VH-7(配列ID番号:48)、及びh-mab2 VH-8(配列ID番号:50)のアミノ酸とは異なるアミノ酸配列を含む、請求項1又は2に記載のCD3結合分子。
- 前記CD3結合分子が抗体である、請求項1~3のいずれか1項に記載のCD3結合分子。
- 前記抗体が、
(A)Fc領域を欠損しているか、又は
(B)Fc領域を含んでいるが、
(i)エフェクター機能を欠損しているか、
(ii)エフェクター機能が低下しているか、若しくは
(iii)前記抗体の前記Fc領域がFc受容体に結合する能力が低減しており、
前記エフェクター機能の欠損、前記エフェクター機能の低下、及び前記結合する能力の低減が、野生型Fc受容体に対してものである、請求項4に記載のCD3結合分子。 - 前記CD3結合分子が、第1のポリペプチド鎖及び第2のポリペプチド鎖を含むCD3結合ダイアボディであり、前記鎖が相互に共有結合し、
(I)前記第1のポリペプチド鎖が、アミノ(N-)末端とカルボキシ(C-)末端とを含み、さらにN末端からC末端への間に、
(i)前記CD3特異的VLドメインを含むドメイン(A)と、
(ii)第2の免疫グロブリンの重鎖可変ドメイン(VH2)の結合領域を含むドメイン(B)と、
(iii)ドメイン(C)とを含み、
前記ドメイン(A)及び(B)が相互に会合してエピトープ結合部位を形成することなく、
且つ、
(II)前記第2のポリペプチド鎖が、アミノ(N-)末端とカルボキシ(C-)末端とを含み、さらにN末端からC末端への間に
(i)前記第2の免疫グロブリンの軽鎖可変ドメイン(VL2)の結合領域を含むドメイン(D)と、
(ii)前記CD3特異的VHドメインを含むドメイン(E)と、
(iii)ドメイン(F)とを含み、
前記ドメイン(D)及び(E)が相互に会合してエピトープ結合部位を形成することなく、
さらに、
(1)前記ドメイン(A)及び(E)が会合して、ヒトCD3と非ヒト哺乳類のCD3との両方に免疫特異的に結合可能な前記抗原結合ドメインを形成し、
(2)前記ドメイン(B)及び(D)が会合して、第2のエピトープに免疫特異的に結合する結合部位を形成し、前記第2のエピトープが、前記ドメイン(A)及び(E)の前記会合から形成された前記抗原結合ドメインと結合する前記CD3エピトープとは異なり、
(3)前記ドメイン(C)及び(F)が相互に共有会合する、請求項1~3のいずれか1項に記載のCD3結合分子。 - 前記第2のエピトープが、CD3のエピトープではない、請求項6に記載のCD3結合分子。
- 前記第2のエピトープが、前記ドメイン(A)及び(E)の前記会合から形成された前記抗原結合ドメインと結合する前記CD3エピトープとは異なるCD3のエピトープである、請求項6に記載のCD3結合分子。
- ヒト化抗体である、請求項1に記載のCD3結合分子。
- (i)CD3及び(ii)(a)腫瘍抗原、又は(ii)(b)細胞表面の抗原、受容体若しくは受容体リガンドの両方に免疫特異的に結合可能である、請求項1~3及び6~9のいずれか1項に記載のCD3結合分子。
- 前記CD3結合分子が、CD3及び腫瘍細胞上に発現した腫瘍抗原に免疫特異的に結合可能であり、前記腫瘍細胞は、乳癌、前立腺癌、胃癌、肺癌、結腸癌、直腸癌、膵臓癌、肝臓癌、卵巣癌、口腔癌、咽頭癌、食道癌、喉頭癌、骨癌、皮膚癌、黒色腫、子宮癌、精巣癌、膀胱癌、腎臓癌、脳腫瘍、グリア芽腫、甲状腺癌、リンパ腫、骨髄腫、及び白血病からなる群から選択される癌からの腫瘍細胞である、請求項10に記載のCD3結合分子。
- 前記CD3結合分子が、CD3に、及び細胞表面の抗原、受容体又は受容体リガンドに免疫特異的に結合可能であり、前記細胞表面の抗原、受容体又は受容体リガンドがHER2/neu、B7-H3、CD20、PSMA、IGF-1R、EGFR、A33、CD19又はEp-CAMである、請求項10に記載のCD3結合分子。
- 前記CD3結合分子が、CD3に、及び細胞表面の抗原、受容体又は受容体リガンドに免疫特異的に結合可能であり、前記細胞表面の抗原、受容体又は受容体リガンドが、T細胞とB細胞の会合に関与する分子であり、前記T細胞とB細胞の会合に関与する分子が、CD19、CD20、CD22、CD23、CD27、CD32B、CD38、CD40、CD79a、CD79b、CD80、CD86、LFA-1、LFA-3及びCFA-1からなる群から選択される、請求項10に記載のCD3結合分子。
- (A)前記ドメイン(B)が、配列ID番号:65の119~238位のアミノ酸残基を含み、且つ
(B)前記ドメイン(D)が、配列ID番号:64の1~107位のアミノ酸残基を含む、請求項6~8のいずれか1項に記載のCD3結合分子。 - (A)前記ドメイン(B)が、配列ID番号:67の119~240位のアミノ酸残基を含み、且つ
(B)前記ドメイン(D)が、配列ID番号:66の1~107位のアミノ酸残基を含む、請求項6~8のいずれか1項に記載のCD3結合分子。 - 前記CD3特異的VLドメインが、h-mab2 VL-6(配列ID番号:26)である、請求項6~15のいずれか1項に記載のCD3結合分子。
- 前記CD3結合分子が、Fcドメイン又はその一部を含む、請求項1~16のいずれか1項に記載のCD3結合分子。
- (A)前記第1のポリペプチド鎖がさらにEコイル配列を含むとともに、前記第2のポリペプチド鎖がさらにKコイル配列を含み、又は
(B)前記第1のポリペプチド鎖がさらにKコイル配列を含むとともに、前記第2のポリペプチド鎖がさらにEコイル配列を含み、
前記Eコイル配列が、配列ID番号:62の244~271位のアミノ酸残基であり、前記Kコイル配列が、配列ID番号:63の247~274位のアミノ酸残基である、請求項6~8及び14~17のいずれか1項に記載のCD3結合分子。 - 前記CD3結合分子が、Fcドメイン又はその一部を含む、請求項18に記載のCD3結合分子。
- 請求項1~19のいずれか1項に記載の前記CD3結合分子、及び薬学的に許容可能な担体、賦形剤又は希釈剤を含む医薬組成物。
- 癌又は自己免疫若しくは炎症性疾患の治療のための医薬の製造における、請求項1~19のいずれか1項に記載の前記CD3結合分子又は請求項20に記載の前記医薬組成物の使用。
- 前記自己免疫又は炎症性疾患が、I型インスリン依存性糖尿病、リウマチ性関節炎、全身性エリテマトーデス、多発性硬化症、炎症性腸疾患、重症筋無力症、小児脂肪便症、シェーグレン症候群、グレーブス病、クローン病、自己免疫肝炎、乾癬、乾癬性関節炎、喘息、アレルギー性鼻炎、臓器移植の影響、又は移植片対宿主病(GVHD)からなる群から選択される、請求項21に記載の使用。
- 前記自己免疫又は炎症性疾患が、I型インスリン依存性糖尿病である、請求項22の記載の使用。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2021159475A JP2022001580A (ja) | 2011-05-21 | 2021-09-29 | ヒト及び非ヒトcd3に結合可能なcd3結合分子 |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161488716P | 2011-05-21 | 2011-05-21 | |
US61/488,716 | 2011-05-21 | ||
US201161530353P | 2011-09-01 | 2011-09-01 | |
US61/530,353 | 2011-09-01 | ||
JP2017089423A JP6496349B2 (ja) | 2011-05-21 | 2017-04-28 | ヒト及び非ヒトcd3に結合可能なcd3結合分子 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017089423A Division JP6496349B2 (ja) | 2011-05-21 | 2017-04-28 | ヒト及び非ヒトcd3に結合可能なcd3結合分子 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2021159475A Division JP2022001580A (ja) | 2011-05-21 | 2021-09-29 | ヒト及び非ヒトcd3に結合可能なcd3結合分子 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2019142866A JP2019142866A (ja) | 2019-08-29 |
JP7302990B2 true JP7302990B2 (ja) | 2023-07-04 |
Family
ID=47217980
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2014512882A Active JP6141831B2 (ja) | 2011-05-21 | 2012-05-16 | ヒト及び非ヒトcd3に結合可能なcd3結合分子 |
JP2017089423A Expired - Fee Related JP6496349B2 (ja) | 2011-05-21 | 2017-04-28 | ヒト及び非ヒトcd3に結合可能なcd3結合分子 |
JP2019043220A Active JP7302990B2 (ja) | 2011-05-21 | 2019-03-08 | ヒト及び非ヒトcd3に結合可能なcd3結合分子 |
JP2021159475A Pending JP2022001580A (ja) | 2011-05-21 | 2021-09-29 | ヒト及び非ヒトcd3に結合可能なcd3結合分子 |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2014512882A Active JP6141831B2 (ja) | 2011-05-21 | 2012-05-16 | ヒト及び非ヒトcd3に結合可能なcd3結合分子 |
JP2017089423A Expired - Fee Related JP6496349B2 (ja) | 2011-05-21 | 2017-04-28 | ヒト及び非ヒトcd3に結合可能なcd3結合分子 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2021159475A Pending JP2022001580A (ja) | 2011-05-21 | 2021-09-29 | ヒト及び非ヒトcd3に結合可能なcd3結合分子 |
Country Status (32)
Country | Link |
---|---|
US (4) | US9587021B2 (ja) |
EP (2) | EP2714733B1 (ja) |
JP (4) | JP6141831B2 (ja) |
KR (2) | KR102060389B1 (ja) |
CN (3) | CN107722124A (ja) |
AU (3) | AU2012259161B2 (ja) |
BR (2) | BR112013029893A2 (ja) |
CA (1) | CA2836857C (ja) |
CL (3) | CL2013003329A1 (ja) |
CO (1) | CO6970560A2 (ja) |
CY (1) | CY1122020T1 (ja) |
DK (1) | DK2714733T3 (ja) |
EA (1) | EA033677B1 (ja) |
EC (1) | ECSP13013101A (ja) |
ES (1) | ES2732213T3 (ja) |
HR (1) | HRP20190756T1 (ja) |
HU (1) | HUE044209T2 (ja) |
IL (3) | IL229575B (ja) |
LT (1) | LT2714733T (ja) |
MA (1) | MA35174B1 (ja) |
ME (1) | ME03440B (ja) |
MX (1) | MX369220B (ja) |
MY (1) | MY173899A (ja) |
NZ (1) | NZ703939A (ja) |
PL (1) | PL2714733T3 (ja) |
PT (1) | PT2714733T (ja) |
RS (1) | RS58765B1 (ja) |
SG (3) | SG10201703425RA (ja) |
SI (1) | SI2714733T1 (ja) |
UA (3) | UA115122C2 (ja) |
WO (1) | WO2012162067A2 (ja) |
ZA (1) | ZA201308602B (ja) |
Families Citing this family (191)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9963510B2 (en) | 2005-04-15 | 2018-05-08 | Macrogenics, Inc. | Covalent diabodies and uses thereof |
US9096651B2 (en) | 2007-09-26 | 2015-08-04 | Chugai Seiyaku Kabushiki Kaisha | Method of modifying isoelectric point of antibody via amino acid substitution in CDR |
NZ588507A (en) | 2008-04-11 | 2012-11-30 | Chugai Pharmaceutical Co Ltd | Antigen-binding molecule capable of binding to two or more antigen molecules repeatedly |
US9493578B2 (en) | 2009-09-02 | 2016-11-15 | Xencor, Inc. | Compositions and methods for simultaneous bivalent and monovalent co-engagement of antigens |
CN103052649B (zh) | 2010-07-29 | 2015-12-16 | Xencor公司 | 具有修改的等电点的抗体 |
CN107973851A (zh) | 2010-11-30 | 2018-05-01 | 中外制药株式会社 | 与多分子的抗原重复结合的抗原结合分子 |
AU2012245260B2 (en) | 2011-04-22 | 2016-09-08 | Aptevo Research And Development Llc | Prostate-specific membrane antigen binding proteins and related compositions and methods |
JP6141831B2 (ja) * | 2011-05-21 | 2017-06-07 | マクロジェニクス,インコーポレーテッド | ヒト及び非ヒトcd3に結合可能なcd3結合分子 |
BR112014004168A2 (pt) | 2011-08-23 | 2017-12-12 | Roche Glycart Ag | anticorpo biespecífico, composição farmacêutica, uso do anticorpo biespecífico, célula hospedeira procariótica ou eucariótica, método de produção de anticorpo e invenção |
US10851178B2 (en) | 2011-10-10 | 2020-12-01 | Xencor, Inc. | Heterodimeric human IgG1 polypeptides with isoelectric point modifications |
EP2847223B1 (en) | 2012-05-07 | 2019-03-27 | Trustees of Dartmouth College | Anti-b7-h6 antibody, fusion proteins, and methods of using the same |
JP6628966B2 (ja) | 2012-06-14 | 2020-01-15 | 中外製薬株式会社 | 改変されたFc領域を含む抗原結合分子 |
EP2869845B1 (en) * | 2012-07-06 | 2019-08-28 | Genmab B.V. | Dimeric protein with triple mutations |
CN104704004B (zh) | 2012-10-08 | 2019-12-31 | 罗切格利卡特公司 | 包含两个Fab片段的无Fc的抗体及使用方法 |
SI2943511T1 (sl) | 2013-01-14 | 2020-01-31 | Xencor, Inc. | Novi heterodimerni proteini |
US10131710B2 (en) | 2013-01-14 | 2018-11-20 | Xencor, Inc. | Optimized antibody variable regions |
US9701759B2 (en) | 2013-01-14 | 2017-07-11 | Xencor, Inc. | Heterodimeric proteins |
US9605084B2 (en) | 2013-03-15 | 2017-03-28 | Xencor, Inc. | Heterodimeric proteins |
US10968276B2 (en) | 2013-03-12 | 2021-04-06 | Xencor, Inc. | Optimized anti-CD3 variable regions |
US10487155B2 (en) | 2013-01-14 | 2019-11-26 | Xencor, Inc. | Heterodimeric proteins |
US11053316B2 (en) | 2013-01-14 | 2021-07-06 | Xencor, Inc. | Optimized antibody variable regions |
WO2014113510A1 (en) | 2013-01-15 | 2014-07-24 | Xencor, Inc. | Rapid clearance of antigen complexes using novel antibodies |
EP2953972B1 (en) | 2013-02-05 | 2020-07-08 | EngMab Sàrl | Method for the selection of antibodies against bcma |
GB201302447D0 (en) | 2013-02-12 | 2013-03-27 | Oxford Biotherapeutics Ltd | Therapeutic and diagnostic target |
PL2961771T3 (pl) | 2013-02-26 | 2020-06-01 | Roche Glycart Ag | Dwuswoiste cząsteczki wiążące antygen swoisty dla CD3 i CEA aktywujące limfocyty T |
BR112015017800A2 (pt) | 2013-02-26 | 2017-11-21 | Roche Glycart Ag | moléculas de ligação ao antígeno biespecífica ativadora de célula t, polinucleotídeo, polipeptídeo, vetor, célula hospedeira, método de produção da molécula de ligação ao antígeno biespecífica ativadora de célula t, composição farmacêutica e uso da molécula de ligação ao antígeno biespecífica ativadora de célula t |
US9487587B2 (en) * | 2013-03-05 | 2016-11-08 | Macrogenics, Inc. | Bispecific molecules that are immunoreactive with immune effector cells of a companion animal that express an activating receptor and cells that express B7-H3 and uses thereof |
ES2882183T3 (es) | 2013-03-14 | 2021-12-01 | Univ Duke | Moléculas biespecíficas que son inmunorreactivas con células efectoras inmunitarias que expresan un receptor activador |
US20160017058A1 (en) | 2013-03-14 | 2016-01-21 | The California Institute For Biomedical Research | Bispecific antibodies and uses thereof |
US10519242B2 (en) | 2013-03-15 | 2019-12-31 | Xencor, Inc. | Targeting regulatory T cells with heterodimeric proteins |
DK2970486T3 (en) | 2013-03-15 | 2018-08-06 | Xencor Inc | MODULATION OF T-CELLS WITH BISPECIFIC ANTIBODIES AND FC-FUSIONS |
US10858417B2 (en) | 2013-03-15 | 2020-12-08 | Xencor, Inc. | Heterodimeric proteins |
US10106624B2 (en) | 2013-03-15 | 2018-10-23 | Xencor, Inc. | Heterodimeric proteins |
KR102531517B1 (ko) * | 2013-07-05 | 2023-05-12 | 젠맵 에이/에스 | 인간화 또는 키메라 cd3 항체 |
ES2912932T3 (es) | 2013-07-25 | 2022-05-30 | Cytomx Therapeutics Inc | Anticuerpos multiespecíficos, anticuerpos activables multiespecíficos y procedimientos de uso de los mismos |
US11384149B2 (en) | 2013-08-09 | 2022-07-12 | Macrogenics, Inc. | Bi-specific monovalent Fc diabodies that are capable of binding CD32B and CD79b and uses thereof |
UA116479C2 (uk) | 2013-08-09 | 2018-03-26 | Макродженікс, Інк. | БІСПЕЦИФІЧНЕ МОНОВАЛЕНТНЕ Fc-ДІАТІЛО, ЯКЕ ОДНОЧАСНО ЗВ'ЯЗУЄ CD32B I CD79b, ТА ЙОГО ЗАСТОСУВАННЯ |
EP2840091A1 (en) * | 2013-08-23 | 2015-02-25 | MacroGenics, Inc. | Bi-specific diabodies that are capable of binding gpA33 and CD3 and uses thereof |
EP2839842A1 (en) * | 2013-08-23 | 2015-02-25 | MacroGenics, Inc. | Bi-specific monovalent diabodies that are capable of binding CD123 and CD3 and uses thereof |
JPWO2015068847A1 (ja) | 2013-11-11 | 2017-03-09 | 中外製薬株式会社 | 改変された抗体可変領域を含む抗原結合分子 |
EP3083689B1 (en) * | 2013-12-17 | 2020-05-27 | Genentech, Inc. | Anti-cd3 antibodies and methods of use |
SG10202008629XA (en) | 2014-03-28 | 2020-10-29 | Xencor Inc | Bispecific antibodies that bind to cd38 and cd3 |
EP3763739A1 (en) * | 2014-05-28 | 2021-01-13 | F. Hoffmann-La Roche AG | Antibodies binding to human and cynomolgus cd3 epsilon |
EP3954703A3 (en) | 2014-05-29 | 2022-05-18 | MacroGenics, Inc. | Tri-specific binding molecules and methods of use thereof |
SG11201609707WA (en) | 2014-07-01 | 2017-01-27 | Pfizer | Bispecific heterodimeric diabodies and uses thereof |
US9212225B1 (en) | 2014-07-01 | 2015-12-15 | Amphivena Therapeutics, Inc. | Bispecific CD33 and CD3 binding proteins |
BR112017001579A2 (pt) | 2014-07-25 | 2017-11-21 | Cytomx Therapeutics Inc | anticorpos anti-cd3, anticorpos anti-cd3 ativáveis, anticorpos anti-cd3 multiespecíficos, anticorpos anti-cd3 ativáveis multiespecíficos e métodos de uso dos mesmos |
MA50584A (fr) | 2014-08-04 | 2020-09-16 | Hoffmann La Roche | Molécules bispécifiques de liaison à l'antigène activant des lymphocytes t |
EP2982693A1 (en) | 2014-08-07 | 2016-02-10 | Affimed Therapeutics AG | CD3 binding domain |
WO2016019969A1 (en) | 2014-08-08 | 2016-02-11 | Ludwig-Maximilians-Universität München | Subcutaneously administered bispecific antibodies for use in the treatment of cancer |
AR101846A1 (es) | 2014-09-12 | 2017-01-18 | Genentech Inc | Anticuerpos anti-cll-1 e inmunoconjugados |
EP3197917B1 (en) * | 2014-09-26 | 2022-10-12 | MacroGenics, Inc. | Bi-specific monovalent diabodies that are capable of binding cd19 and cd3, and uses thereof |
JP6932639B2 (ja) * | 2014-09-29 | 2021-09-08 | デューク ユニバーシティ | Hiv‐1エンベロープ標的化アームを備える二重特異性分子 |
JP7125248B2 (ja) | 2014-11-11 | 2022-08-24 | 中外製薬株式会社 | 改変された抗体可変領域を含む抗原結合分子のライブラリ |
PL3221355T3 (pl) | 2014-11-20 | 2021-03-08 | F. Hoffmann-La Roche Ag | Terapia skojarzona składająca się z dwuswoistych aktywujących limfocyty T cząsteczek wiążących antygen CD3 i receptor folianowy 1 (FolR1) oraz antagonistów wiązania osi PD-1 |
NZ732144A (en) | 2014-11-26 | 2020-04-24 | Xencor Inc | Heterodimeric antibodies that bind cd3 and tumor antigens |
AU2015353416C1 (en) | 2014-11-26 | 2022-01-27 | Xencor, Inc. | Heterodimeric antibodies that bind CD3 and CD38 |
US10259887B2 (en) | 2014-11-26 | 2019-04-16 | Xencor, Inc. | Heterodimeric antibodies that bind CD3 and tumor antigens |
LT3227336T (lt) | 2014-12-05 | 2019-09-25 | F. Hoffmann-La Roche Ag | Anti-cd79b antikūnai ir jų naudojimo būdai |
WO2016089610A1 (en) * | 2014-12-06 | 2016-06-09 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Bispecific antibody for cancer immunotherapy |
AR103162A1 (es) | 2014-12-19 | 2017-04-19 | Chugai Pharmaceutical Co Ltd | Anticuerpos anti-c5 y métodos para su uso |
EP3237449A2 (en) | 2014-12-22 | 2017-11-01 | Xencor, Inc. | Trispecific antibodies |
AU2016205967B2 (en) * | 2015-01-08 | 2021-11-11 | Genmab A/S | Bispecific antibodies against CD3 and CD20 |
NZ734803A (en) | 2015-01-23 | 2023-03-31 | Sanofi Sa | Anti-cd3 antibodies, anti-cd123 antibodies and bispecific antibodies specifically binding to cd3 and/or cd123 |
WO2016141387A1 (en) | 2015-03-05 | 2016-09-09 | Xencor, Inc. | Modulation of t cells with bispecific antibodies and fc fusions |
US10344077B2 (en) | 2015-03-19 | 2019-07-09 | Duke University | HIV-1 neutralizing antibodies and uses thereof (V3 antibodies) |
AU2016232693B2 (en) | 2015-03-19 | 2021-08-12 | Duke University | HIV-1 neutralizing antibodies and uses thereof |
US11071783B2 (en) | 2015-03-19 | 2021-07-27 | Duke University | HIV-1 neutralizing antibodies and uses thereof |
US10450368B2 (en) | 2015-03-19 | 2019-10-22 | Duke University | HIV-1 neutralizing antibodies and uses thereof (CD4bs antibodies) |
CN107709363A (zh) * | 2015-05-01 | 2018-02-16 | 基因泰克公司 | 掩蔽抗cd3抗体和使用方法 |
EP3291836A4 (en) * | 2015-05-06 | 2018-11-14 | Janssen Biotech, Inc. | Prostate specific membrane antigen (psma) bispecific binding agents and uses thereof |
JP2018516248A (ja) | 2015-05-29 | 2018-06-21 | アンフィヴェナ セラピューティクス,インク. | 二重特異性のcd33およびcd3結合タンパク質を使用する方法 |
TWI773646B (zh) | 2015-06-08 | 2022-08-11 | 美商宏觀基因股份有限公司 | 結合lag-3的分子和其使用方法 |
WO2016204966A1 (en) | 2015-06-16 | 2016-12-22 | Genentech, Inc. | Anti-cd3 antibodies and methods of use |
JP6996983B2 (ja) | 2015-06-16 | 2022-02-21 | ジェネンテック, インコーポレイテッド | 抗cll-1抗体及び使用方法 |
SI3310814T1 (sl) | 2015-06-16 | 2023-11-30 | F. Hoffmann - La Roche Ag | HUMANIZIRANA IN AFINITETNO DOZORELA PROTITELESA PROTI FcRH5 IN METODE ZA NJIHOVO UPORABO |
WO2017009442A1 (en) | 2015-07-15 | 2017-01-19 | Genmab A/S | Humanized or chimeric cd3 antibodies |
UA127372C2 (uk) | 2015-07-30 | 2023-08-02 | Макродженікс, Інк. | Моноспецифічне pd-1-сполучне моноклональне антитіло |
EA201890443A1 (ru) * | 2015-08-17 | 2018-09-28 | Макродженикс, Инк. | Биспецифичные моновалентные диатела, способные связывать b7-h3 и cd3, и их применение |
KR20180053322A (ko) * | 2015-09-21 | 2018-05-21 | 압테보 리서치 앤드 디벨롭먼트 엘엘씨 | Cd3 결합 폴리펩타이드 |
AR106188A1 (es) | 2015-10-01 | 2017-12-20 | Hoffmann La Roche | Anticuerpos anti-cd19 humano humanizados y métodos de utilización |
CA2990755A1 (en) | 2015-10-02 | 2017-04-06 | F. Hoffman-La Roche Ag | Bispecific anti-ceaxcd3 t cell activating antigen binding molecules |
WO2017079272A2 (en) * | 2015-11-03 | 2017-05-11 | Ambrx, Inc. | Anti-cd3-folate conjugates and their uses |
TW201720458A (zh) * | 2015-12-04 | 2017-06-16 | 宏觀基因股份有限公司 | 能夠結合cd19 和cd3 的雙特異性單價雙抗體以及其用途 |
CN108699136B (zh) | 2015-12-07 | 2022-03-18 | Xencor股份有限公司 | 结合cd3和psma的异二聚抗体 |
IL257696B1 (en) | 2015-12-09 | 2024-07-01 | Hoffmann La Roche | Antibody against CD20 type II to reduce the formation of antibodies against drugs |
TW202208440A (zh) | 2015-12-14 | 2022-03-01 | 美商宏觀基因股份有限公司 | 對於pd-1和ctla-4具有免疫反應性的雙特異性分子及其使用方法 |
US10596257B2 (en) | 2016-01-08 | 2020-03-24 | Hoffmann-La Roche Inc. | Methods of treating CEA-positive cancers using PD-1 axis binding antagonists and anti-CEA/anti-CD3 bispecific antibodies |
EP3405493A1 (en) | 2016-01-22 | 2018-11-28 | Janssen Biotech, Inc. | Anti-ror1 antibodies, ror1 x cd3 bispecific antibodies, and methods of using the same |
US20230192844A1 (en) * | 2016-02-04 | 2023-06-22 | The Scripps Research Institute | Humanized anti-cd3 antibodies, conjugates and uses thereof |
UY37127A (es) | 2016-02-17 | 2017-08-31 | Macrogenics Inc | Moléculas de unión a ror1, y métodos de uso de las mismas |
WO2017156178A1 (en) * | 2016-03-08 | 2017-09-14 | Maverick Therapeutics, Inc. | Inducible binding proteins and methods of use |
RS64266B1 (sr) | 2016-03-22 | 2023-07-31 | Hoffmann La Roche | Bispecifični molekul koji aktivira t ćeliju koji se aktivira proteazom |
KR102514317B1 (ko) | 2016-04-15 | 2023-03-27 | 마크로제닉스, 인크. | 신규 b7-h3-결합 분자, 그것의 항체 약물 콘쥬게이트 및 그것의 사용 방법 |
WO2017210443A1 (en) * | 2016-06-01 | 2017-12-07 | Xencor, Inc. | Bispecific antibodies that bind cd123 and cd3 |
TW201902512A (zh) | 2016-06-02 | 2019-01-16 | 瑞士商赫孚孟拉羅股份公司 | 治療方法 |
EP3252078A1 (en) | 2016-06-02 | 2017-12-06 | F. Hoffmann-La Roche AG | Type ii anti-cd20 antibody and anti-cd20/cd3 bispecific antibody for treatment of cancer |
EP3463464A4 (en) * | 2016-06-07 | 2020-07-01 | MacroGenics, Inc. | COMBINATION THERAPY |
KR20230054508A (ko) | 2016-06-14 | 2023-04-24 | 젠코어 인코포레이티드 | 이중특이적 체크포인트 억제제 항체 |
MX2018016364A (es) | 2016-06-20 | 2019-11-28 | Kymab Ltd | Anticuerpos anti-pd-l1. |
CA3029209A1 (en) * | 2016-06-21 | 2017-12-28 | Teneobio, Inc. | Cd3 binding antibodies |
CN116063545A (zh) | 2016-06-28 | 2023-05-05 | Xencor股份有限公司 | 结合生长抑素受体2的异源二聚抗体 |
US10793632B2 (en) | 2016-08-30 | 2020-10-06 | Xencor, Inc. | Bispecific immunomodulatory antibodies that bind costimulatory and checkpoint receptors |
CN109843926B (zh) | 2016-09-30 | 2023-01-20 | 豪夫迈·罗氏有限公司 | 针对cd3的双特异性抗体 |
JP7273453B2 (ja) | 2016-10-14 | 2023-05-15 | ゼンコア インコーポレイテッド | IL-15/IL-15RアルファFc融合タンパク質およびPD-1抗体の断片を含む二重特異性ヘテロ二量体融合タンパク質 |
WO2018093821A1 (en) | 2016-11-15 | 2018-05-24 | Genentech, Inc. | Dosing for treatment with anti-cd20/anti-cd3 bispecific antibodies |
CA3045296A1 (en) | 2016-12-07 | 2018-06-14 | Progenity, Inc. | Gastrointestinal tract detection methods, devices and systems |
CA3048174A1 (en) * | 2016-12-22 | 2018-06-28 | Daiichi Sankyo Company, Limited | Anti-cd3 antibody and molecules comprising the antibody |
IL267589B1 (en) | 2016-12-23 | 2024-07-01 | Macrogenics Inc | ADAM9 binding molecules and methods of their use |
MX2019009967A (es) | 2017-02-24 | 2019-12-02 | Macrogenics Inc | Moleculas de union biespecificas que son capaces de unirse a cd137 y a antigenos tumorales, y usos de las mismas. |
EP4108183A1 (en) | 2017-03-30 | 2022-12-28 | Biora Therapeutics, Inc. | Treatment of a disease of the gastrointestinal tract with an immune modulatory agent released using an ingestible device |
AU2018250641A1 (en) | 2017-04-11 | 2019-10-31 | Inhibrx Biosciences, Inc. | Multispecific polypeptide constructs having constrained CD3 binding and methods of using the same |
BR112019017241A2 (pt) | 2017-04-13 | 2020-04-14 | Agenus Inc | anticorpos anti-cd137 e métodos de uso dos mesmos |
DK3618863T3 (da) | 2017-05-01 | 2023-08-21 | Agenus Inc | Anti-tigit-antistoffer og fremgangsmåder til anvendelse deraf |
EP3635000A4 (en) | 2017-05-16 | 2021-04-14 | The Johns Hopkins University | MANABODIES AND METHODS OF USE |
EP3409322A1 (en) | 2017-06-01 | 2018-12-05 | F. Hoffmann-La Roche AG | Treatment method |
JP2020529832A (ja) | 2017-06-30 | 2020-10-15 | ゼンコア インコーポレイテッド | IL−15/IL−15Rαおよび抗原結合ドメインを含む標的化ヘテロダイマーFc融合タンパク質 |
US11472880B2 (en) | 2017-08-14 | 2022-10-18 | Morphosys Ag | Humanized antibodies for CD3 |
WO2019045856A1 (en) * | 2017-08-28 | 2019-03-07 | Systimmune, Inc. | ANTI-CD ANTIBODIES AND METHODS OF MAKING AND USING THEM |
AU2018328291B2 (en) | 2017-09-08 | 2022-10-27 | Takeda Pharmaceutical Company Limited | Constrained conditionally activated binding proteins |
EP3694885A1 (en) | 2017-10-14 | 2020-08-19 | CytomX Therapeutics, Inc. | Antibodies, activatable antibodies, bispecific antibodies, and bispecific activatable antibodies and methods of use thereof |
KR101973060B1 (ko) * | 2017-10-20 | 2019-04-26 | 주식회사 녹십자 | 항-cd3 항체 및 이를 포함하는 암 치료용 약학적 조성물 |
US10981992B2 (en) | 2017-11-08 | 2021-04-20 | Xencor, Inc. | Bispecific immunomodulatory antibodies that bind costimulatory and checkpoint receptors |
KR20200085828A (ko) | 2017-11-08 | 2020-07-15 | 젠코어 인코포레이티드 | 신규의 항-pd-1 서열을 사용한 이중특이적 및 단일특이적 항체 |
JP7357616B2 (ja) | 2017-12-05 | 2023-10-06 | 中外製薬株式会社 | Cd3およびcd137に結合する改変された抗体可変領域を含む抗原結合分子 |
AU2018385409A1 (en) | 2017-12-12 | 2020-07-02 | Macrogenics Inc. | Bispecific CD 16-binding molecules and their use in the treatment of disease |
US11319355B2 (en) | 2017-12-19 | 2022-05-03 | Xencor, Inc. | Engineered IL-2 Fc fusion proteins |
CN109939232A (zh) * | 2017-12-21 | 2019-06-28 | 张曼 | 关于cd3×b7h3双特异性抗体定向杀伤膀胱癌细胞pumc-91的应用 |
AR115360A1 (es) | 2018-02-08 | 2021-01-13 | Genentech Inc | Moléculas de unión al antígeno y métodos de uso |
BR112020016485A2 (pt) * | 2018-02-15 | 2020-12-15 | Macrogenics, Inc. | Molécula de ligação, composição farmacêutica e método para o tratamento de uma doença |
CN110305217B (zh) * | 2018-03-27 | 2022-03-29 | 广州爱思迈生物医药科技有限公司 | 双特异性抗体及其应用 |
US10982006B2 (en) | 2018-04-04 | 2021-04-20 | Xencor, Inc. | Heterodimeric antibodies that bind fibroblast activation protein |
EP3781599A1 (en) | 2018-04-18 | 2021-02-24 | Xencor, Inc. | Pd-1 targeted heterodimeric fusion proteins containing il-15/il-15ra fc-fusion proteins and pd-1 antigen binding domains and uses thereof |
JP2021520829A (ja) | 2018-04-18 | 2021-08-26 | ゼンコア インコーポレイテッド | IL−15/IL−15RA Fc融合タンパク質およびTIM−3抗原結合ドメインを含む、TIM−3標的化ヘテロ二量体融合タンパク質 |
CR20200568A (es) | 2018-05-24 | 2021-02-26 | Janssen Biotech Inc | Antcuerpos anti-cd3 y usos de estos |
CN112513081A (zh) * | 2018-06-14 | 2021-03-16 | 生物蛋白有限公司 | 多重特异性抗体构建体 |
WO2019246317A1 (en) | 2018-06-20 | 2019-12-26 | Progenity, Inc. | Treatment of a disease or condition in a tissue originating from the endoderm |
WO2019246312A1 (en) | 2018-06-20 | 2019-12-26 | Progenity, Inc. | Treatment of a disease of the gastrointestinal tract with an immunomodulator |
WO2020047389A1 (en) | 2018-08-31 | 2020-03-05 | Regeneron Pharmaceuticals, Inc. | Dosing strategy that mitigates cytokine release syndrome for cd3/c20 bispecific antibodies |
US11358999B2 (en) | 2018-10-03 | 2022-06-14 | Xencor, Inc. | IL-12 heterodimeric Fc-fusion proteins |
WO2020076970A1 (en) * | 2018-10-11 | 2020-04-16 | Inhibrx, Inc. | B7h3 single domain antibodies and therapeutic compositions thereof |
AU2019373663A1 (en) * | 2018-10-31 | 2021-04-08 | Tiziana Life Sciences Plc | Composition and methods of treating inflammatory and autoimmune diseases |
US20220249814A1 (en) | 2018-11-19 | 2022-08-11 | Progenity, Inc. | Methods and devices for treating a disease with biotherapeutics |
JP2022511813A (ja) * | 2018-12-04 | 2022-02-01 | ノバルティス アーゲー | Cd3に対する結合分子及びその使用 |
CA3131036A1 (en) * | 2019-02-22 | 2020-08-27 | Wuhan Yzy Biopharma Co., Ltd. | Cd3 antigen-binding fragment and application thereof |
WO2020180726A1 (en) | 2019-03-01 | 2020-09-10 | Xencor, Inc. | Heterodimeric antibodies that bind enpp3 and cd3 |
EP3934762A1 (en) | 2019-03-05 | 2022-01-12 | Takeda Pharmaceutical Company Limited | Constrained conditionally activated binding proteins |
JP7137696B2 (ja) | 2019-05-14 | 2022-09-14 | プロヴェンション・バイオ・インコーポレイテッド | 1型糖尿病を予防するための方法および組成物 |
CA3141909A1 (en) * | 2019-06-07 | 2020-12-10 | Adimab, Llc | High affinity anti-cd3 antibodies, and methods for their generation and use |
CN111454357B (zh) * | 2019-08-14 | 2022-03-15 | 康诺亚生物医药科技(成都)有限公司 | 一种含有抗体的肿瘤治疗剂的开发和应用 |
TW202122420A (zh) | 2019-08-30 | 2021-06-16 | 美商艾吉納斯公司 | 抗cd96抗體及其使用方法 |
TW202128756A (zh) * | 2019-10-02 | 2021-08-01 | 德商百靈佳殷格翰國際股份有限公司 | 用於癌症治療之多重專一性結合蛋白 |
PE20221511A1 (es) | 2019-12-13 | 2022-10-04 | Genentech Inc | Anticuerpos anti-ly6g6d y metodos de uso |
CN115666704A (zh) | 2019-12-13 | 2023-01-31 | 比奥拉治疗股份有限公司 | 用于将治疗剂递送至胃肠道的可摄取装置 |
BR112022013725A2 (pt) | 2020-01-13 | 2022-10-11 | Aptevo Res & Development Llc | Formulações para agentes terapêuticos proteicos |
AU2021207632A1 (en) | 2020-01-13 | 2022-07-07 | Aptevo Research And Development Llc | Methods and compositions for preventing adsorption of therapeutic proteins to drug delivery system components |
JP7085666B2 (ja) | 2020-03-31 | 2022-06-16 | 中外製薬株式会社 | Dll3標的多重特異性抗原結合分子およびその使用 |
WO2021224913A1 (en) | 2020-05-04 | 2021-11-11 | Immunorizon Ltd. | Precursor tri-specific antibody constructs and methods of use thereof |
US11919956B2 (en) | 2020-05-14 | 2024-03-05 | Xencor, Inc. | Heterodimeric antibodies that bind prostate specific membrane antigen (PSMA) and CD3 |
AU2021287998A1 (en) | 2020-06-11 | 2023-02-02 | Benaroya Research Institute At Virginia Mason | Methods and compositions for preventing type 1 diabetes |
US11780920B2 (en) | 2020-06-19 | 2023-10-10 | Hoffmann-La Roche Inc. | Antibodies binding to CD3 and CD19 |
KR20230166150A (ko) | 2020-08-19 | 2023-12-06 | 젠코어 인코포레이티드 | 항-cd28 조성물 |
US20230357440A1 (en) | 2020-09-10 | 2023-11-09 | Genmab A/S | Bispecific antibody against cd3 and cd20 in combination therapy for treating follicular lymphoma |
EP4210746A1 (en) | 2020-09-10 | 2023-07-19 | Genmab A/S | Bispecific antibodies against cd3 and cd20 for treating chronic lymphocytic leukemia |
EP4210742A1 (en) | 2020-09-10 | 2023-07-19 | Genmab A/S | Bispecific antibody against cd3 and cd20 in combination therapy for treating follicular lymphoma |
BR112023004296A2 (pt) | 2020-09-10 | 2023-04-04 | Genmab As | Método para tratar linfoma de célula b grande difusa em um indivíduo humano |
IL301085A (en) | 2020-09-10 | 2023-05-01 | Genmab As | A bispecific antibody against CD3 and CD20 in combination therapy for the treatment of diffuse large B-cell lymphoma |
US20220267450A1 (en) | 2020-10-14 | 2022-08-25 | Viridian Therapeutics, Inc. | Compositions and methods for treatment of thyroid eye disease |
CN114573703A (zh) * | 2020-12-02 | 2022-06-03 | 康诺亚生物医药科技(成都)有限公司 | 一种t细胞衔接器治疗剂的开发和应用 |
KR20230156079A (ko) | 2021-03-09 | 2023-11-13 | 젠코어 인코포레이티드 | Cd3과 cldn6에 결합하는 이종이량체 항체 |
WO2022192586A1 (en) | 2021-03-10 | 2022-09-15 | Xencor, Inc. | Heterodimeric antibodies that bind cd3 and gpc3 |
MX2023012699A (es) | 2021-04-30 | 2023-11-21 | Hoffmann La Roche | Dosificacion para el tratamiento con anticuerpo biespecifico anti-cd20/anti-cd3. |
CN117321078A (zh) | 2021-04-30 | 2023-12-29 | 豪夫迈·罗氏有限公司 | 针对用抗cd20/抗cd3双特异性抗体和抗cd79b抗体药物缀合物进行组合治疗的给药 |
KR20240024819A (ko) | 2021-05-21 | 2024-02-26 | 압테보 리서치 앤드 디벨롭먼트 엘엘씨 | 단백질 치료제의 투약 요법 |
CN118435674A (zh) | 2022-01-07 | 2024-08-02 | 株式会社电装 | 终端、基站以及通信方法 |
WO2023133595A2 (en) | 2022-01-10 | 2023-07-13 | Sana Biotechnology, Inc. | Methods of ex vivo dosing and administration of lipid particles or viral vectors and related systems and uses |
WO2023150518A1 (en) | 2022-02-01 | 2023-08-10 | Sana Biotechnology, Inc. | Cd3-targeted lentiviral vectors and uses thereof |
AU2023238766A1 (en) | 2022-03-23 | 2024-07-25 | F. Hoffmann-La Roche Ag | Combination treatment of an anti-cd20/anti-cd3 bispecific antibody and chemotherapy |
WO2023193015A1 (en) | 2022-04-01 | 2023-10-05 | Sana Biotechnology, Inc. | Cytokine receptor agonist and viral vector combination therapies |
TW202406571A (zh) | 2022-04-13 | 2024-02-16 | 美商建南德克公司 | 莫蘇妥珠單抗之醫藥組成物及其使用方法 |
TW202404637A (zh) | 2022-04-13 | 2024-02-01 | 瑞士商赫孚孟拉羅股份公司 | 抗cd20/抗cd3雙特異性抗體之醫藥組成物及使用方法 |
AU2023275531A1 (en) * | 2022-05-24 | 2024-07-18 | Provention Bio, Inc. | Methods and compositions for preventing or delaying type 1 diabetes |
CN117603351A (zh) * | 2022-08-22 | 2024-02-27 | 英脉德医疗科技(广东)有限公司 | 肿瘤微环境特异激活的Her2-CD3双特异性抗体 |
WO2024044655A1 (en) | 2022-08-24 | 2024-02-29 | Sana Biotechnology, Inc. | Delivery of heterologous proteins |
WO2024047114A1 (en) | 2022-08-31 | 2024-03-07 | Universität Zürich | Adenoviral-based in situ delivery of bispecific t cell engagers |
WO2024088987A1 (en) | 2022-10-26 | 2024-05-02 | F. Hoffmann-La Roche Ag | Combination therapy for the treatment of cancer |
WO2024102948A1 (en) | 2022-11-11 | 2024-05-16 | Celgene Corporation | Fc receptor-homolog 5 (fcrh5) specific binding molecules and bispecific t-cell engaging antibodies including same and related methods |
WO2024119157A1 (en) | 2022-12-02 | 2024-06-06 | Sana Biotechnology, Inc. | Lipid particles with cofusogens and methods of producing and using the same |
CN116239700B (zh) * | 2022-12-20 | 2024-06-21 | 浙江大学 | 一种肿瘤双靶向的三特异性t细胞衔接器及其应用 |
CN116063526A (zh) * | 2022-12-31 | 2023-05-05 | 合肥天港免疫药物有限公司 | 抗pdl1的抗体及其用途 |
CN116284448B (zh) * | 2023-02-14 | 2024-06-21 | 浙江大学 | 一种超抗原参与的三功能t细胞衔接器及其应用 |
Family Cites Families (90)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3862925A (en) | 1973-07-05 | 1975-01-28 | American Home Prod | Preparation of somatotropin release inhibiting factor and intermediates therefor |
US3842067A (en) | 1973-07-27 | 1974-10-15 | American Home Prod | Synthesis of(des-asn5)-srif and intermediates |
JPS5726506B2 (ja) | 1974-03-08 | 1982-06-04 | ||
US4105603A (en) | 1977-03-28 | 1978-08-08 | The Salk Institute For Biological Studies | Peptides which effect release of hormones |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US5807715A (en) | 1984-08-27 | 1998-09-15 | The Board Of Trustees Of The Leland Stanford Junior University | Methods and transformed mammalian lymphocyte cells for producing functional antigen-binding protein including chimeric immunoglobulin |
IL85035A0 (en) | 1987-01-08 | 1988-06-30 | Int Genetic Eng | Polynucleotide molecule,a chimeric antibody with specificity for human b cell surface antigen,a process for the preparation and methods utilizing the same |
AU600575B2 (en) | 1987-03-18 | 1990-08-16 | Sb2, Inc. | Altered antibodies |
WO1988009344A1 (en) | 1987-05-21 | 1988-12-01 | Creative Biomolecules, Inc. | Targeted multifunctional proteins |
US5208020A (en) | 1989-10-25 | 1993-05-04 | Immunogen Inc. | Cytotoxic agents comprising maytansinoids and their therapeutic use |
US5427908A (en) | 1990-05-01 | 1995-06-27 | Affymax Technologies N.V. | Recombinant library screening methods |
EP0519596B1 (en) | 1991-05-17 | 2005-02-23 | Merck & Co. Inc. | A method for reducing the immunogenicity of antibody variable domains |
WO1994004679A1 (en) | 1991-06-14 | 1994-03-03 | Genentech, Inc. | Method for making humanized antibodies |
GB9115364D0 (en) | 1991-07-16 | 1991-08-28 | Wellcome Found | Antibody |
AU669124B2 (en) | 1991-09-18 | 1996-05-30 | Kyowa Hakko Kirin Co., Ltd. | Process for producing humanized chimera antibody |
ES2136092T3 (es) | 1991-09-23 | 1999-11-16 | Medical Res Council | Procedimientos para la produccion de anticuerpos humanizados. |
US5733743A (en) | 1992-03-24 | 1998-03-31 | Cambridge Antibody Technology Limited | Methods for producing members of specific binding pairs |
GB9206422D0 (en) | 1992-03-24 | 1992-05-06 | Bolt Sarah L | Antibody preparation |
US6129914A (en) * | 1992-03-27 | 2000-10-10 | Protein Design Labs, Inc. | Bispecific antibody effective to treat B-cell lymphoma and cell line |
US7381803B1 (en) | 1992-03-27 | 2008-06-03 | Pdl Biopharma, Inc. | Humanized antibodies against CD3 |
DK0656789T3 (da) | 1992-08-21 | 1998-08-24 | Genentech Inc | Fremgangsmåde til behandling af en LFA-1-medieretforstyrrelse. |
US5736137A (en) | 1992-11-13 | 1998-04-07 | Idec Pharmaceuticals Corporation | Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma |
US6491916B1 (en) | 1994-06-01 | 2002-12-10 | Tolerance Therapeutics, Inc. | Methods and materials for modulation of the immunosuppresive activity and toxicity of monoclonal antibodies |
US20030108548A1 (en) | 1993-06-01 | 2003-06-12 | Bluestone Jeffrey A. | Methods and materials for modulation of the immunosuppressive activity and toxicity of monoclonal antibodies |
US5885573A (en) | 1993-06-01 | 1999-03-23 | Arch Development Corporation | Methods and materials for modulation of the immunosuppressive activity and toxicity of monoclonal antibodies |
US6180377B1 (en) | 1993-06-16 | 2001-01-30 | Celltech Therapeutics Limited | Humanized antibodies |
EP0759944B1 (en) | 1994-05-13 | 2001-08-16 | Biovation Limited | Target cell binding chimaeric peptides |
US6265150B1 (en) | 1995-06-07 | 2001-07-24 | Becton Dickinson & Company | Phage antibodies |
US5834597A (en) * | 1996-05-20 | 1998-11-10 | Protein Design Labs, Inc. | Mutated nonactivating IgG2 domains and anti CD3 antibodies incorporating the same |
US6194551B1 (en) | 1998-04-02 | 2001-02-27 | Genentech, Inc. | Polypeptide variants |
DE69909459T2 (de) | 1998-04-21 | 2004-05-27 | Micromet Ag | Cd19xcd3 spezifische polypeptide und deren verwendung |
GB9809951D0 (en) | 1998-05-08 | 1998-07-08 | Univ Cambridge Tech | Binding molecules |
US20030187196A1 (en) | 1998-12-30 | 2003-10-02 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
CA2359067C (en) | 1999-01-15 | 2017-03-14 | Genentech, Inc. | Polypeptide variants with altered effector function |
US6737056B1 (en) | 1999-01-15 | 2004-05-18 | Genentech, Inc. | Polypeptide variants with altered effector function |
US7183387B1 (en) | 1999-01-15 | 2007-02-27 | Genentech, Inc. | Polypeptide variants with altered effector function |
EP1242401B1 (en) | 1999-11-24 | 2006-12-27 | Immunogen, Inc. | Cytotoxic agents comprising taxanes and their therapeutic use |
US6333410B1 (en) | 2000-08-18 | 2001-12-25 | Immunogen, Inc. | Process for the preparation and purification of thiol-containing maytansinoids |
US6441163B1 (en) | 2001-05-31 | 2002-08-27 | Immunogen, Inc. | Methods for preparation of cytotoxic conjugates of maytansinoids and cell binding agents |
US7151164B2 (en) | 2002-02-14 | 2006-12-19 | Immunomedics, Inc. | Anti-CD20 antibodies and fusion proteins thereof and methods of use |
CA2463931A1 (en) | 2001-10-16 | 2003-04-24 | The Government Of The United States Of America, Represented By The Secre Tary, Department Of Health And Human Services | Broadly cross-reactive neutralizing antibodies against human immunodeficiency virus selected by env-cd4-co-receptor complexes |
US7317091B2 (en) | 2002-03-01 | 2008-01-08 | Xencor, Inc. | Optimized Fc variants |
US6596757B1 (en) | 2002-05-14 | 2003-07-22 | Immunogen Inc. | Cytotoxic agents comprising polyethylene glycol-containing taxanes and their therapeutic use |
ATE483472T1 (de) | 2002-05-30 | 2010-10-15 | Macrogenics Inc | Cd16a bindungsproteine und verwendung zur behandlung von immunkrankheiten |
AU2003262650B2 (en) | 2002-08-14 | 2009-10-29 | Macrogenics, Inc. | FcgammaRIIB-specific antibodies and methods of use thereof |
DK3284753T3 (da) | 2002-10-17 | 2021-07-05 | Genmab As | Humane monoklonale antistoffer mod cd20 til anvendelse i behandlingen af multipel sclerose |
AU2003304145A1 (en) | 2002-10-18 | 2004-12-13 | Macrogenics, Inc. | Methods and compositions for vaccination comprising nucleic acid and/or polypeptide sequences of the genus borrelia |
HUE035898T2 (en) | 2002-12-16 | 2018-05-28 | Genentech Inc | Immunoglobulin variants and their applications |
US7960512B2 (en) | 2003-01-09 | 2011-06-14 | Macrogenics, Inc. | Identification and engineering of antibodies with variant Fc regions and methods of using same |
EP1587540B1 (en) | 2003-01-09 | 2021-09-15 | MacroGenics, Inc. | IDENTIFICATION AND ENGINEERING OF ANTIBODIES WITH VARIANT Fc REGIONS AND METHODS OF USING SAME |
CN1802388B (zh) | 2003-05-09 | 2011-01-05 | 杜克大学 | Cd20特异抗体及使用它们的方法 |
US7276497B2 (en) | 2003-05-20 | 2007-10-02 | Immunogen Inc. | Cytotoxic agents comprising new maytansinoids |
WO2004106383A1 (en) | 2003-05-31 | 2004-12-09 | Micromet Ag | Pharmaceutical composition comprising a bispecific antibody for epcam |
US7635472B2 (en) | 2003-05-31 | 2009-12-22 | Micromet Ag | Pharmaceutical compositions comprising bispecific anti-cd3, anti-cd19 antibody constructs for the treatment of b-cell related disorders |
US20050176028A1 (en) * | 2003-10-16 | 2005-08-11 | Robert Hofmeister | Deimmunized binding molecules to CD3 |
ES2393674T3 (es) | 2003-11-14 | 2012-12-27 | Brigham And Women's Hospital, Inc. | Métodos para modular la inmunidad |
US7235641B2 (en) | 2003-12-22 | 2007-06-26 | Micromet Ag | Bispecific antibodies |
CA2563314A1 (en) | 2004-04-16 | 2005-12-08 | Macrogenics, Inc. | Fcyriib-specific antibodies and methods of use thereof |
JP2007536246A (ja) | 2004-05-05 | 2007-12-13 | ジェネンテック・インコーポレーテッド | 自己免疫疾患の予防法 |
US7521542B2 (en) | 2004-05-10 | 2009-04-21 | Macrogenics, Inc. | Humanized FcγRIIB-specific antibodies and methods of use thereof |
SG10201606980VA (en) | 2004-06-03 | 2016-10-28 | Novimmune Sa | Anti-cd3 antibodies and methods of use thereof |
MXPA06014067A (es) | 2004-06-04 | 2007-02-15 | Genentech Inc | Metodo para tratar lupus. |
JP4463645B2 (ja) | 2004-08-27 | 2010-05-19 | 日本メクトロン株式会社 | プリント基板およびその検査方法 |
AU2005335714B2 (en) | 2004-11-10 | 2012-07-26 | Macrogenics, Inc. | Engineering Fc antibody regions to confer effector function |
US9963510B2 (en) | 2005-04-15 | 2018-05-08 | Macrogenics, Inc. | Covalent diabodies and uses thereof |
US9284375B2 (en) | 2005-04-15 | 2016-03-15 | Macrogenics, Inc. | Covalent diabodies and uses thereof |
EP3479844B1 (en) | 2005-04-15 | 2023-11-22 | MacroGenics, Inc. | Covalent diabodies and uses thereof |
EP1904105A4 (en) | 2005-07-11 | 2010-02-17 | Macrogenics Inc | METHOD FOR THE TREATMENT OF AUTOIMMUNE DISEASES WITH IMMUNOSUPPRESSIVE MONOCLONAL ANTIBODIES WITH REDUCED TOXICITY |
ES2579602T3 (es) | 2005-08-10 | 2016-08-12 | Macrogenics, Inc. | Identificación y modificación de anticuerpos con regiones Fc variantes y métodos de uso de estos |
UA92505C2 (ru) | 2005-09-12 | 2010-11-10 | Новиммюн С.А. | Композиции на основе антитела против cd3 |
DK1940881T3 (en) * | 2005-10-11 | 2017-02-20 | Amgen Res (Munich) Gmbh | COMPOSITIONS WITH ARTICLE CROSS-SPECIFIC ANTIBODIES AND APPLICATIONS THEREOF |
AU2007226752A1 (en) | 2006-03-10 | 2007-09-20 | Macrogenics, Inc. | Identification and engineering of antibodies with variant heavy chains and methods of using same |
WO2007117600A2 (en) | 2006-04-07 | 2007-10-18 | Macrogenics, Inc. | Combination therapy for treating autoimmune diseases |
ES2489646T3 (es) | 2006-05-26 | 2014-09-02 | Macrogenics, Inc. | Anticuerpos humanizados específicos a Fc gamma RIIB y sus métodos de uso |
SG10201504662WA (en) | 2006-06-14 | 2015-07-30 | Macrogenics Inc | Methods For The Treatment Of Autoimmune Disorders Using Immunosuppressive Monoclonal Antibodies With Reduced Toxicity |
EP2032159B1 (en) | 2006-06-26 | 2015-01-07 | MacroGenics, Inc. | Combination of fcgammariib antibodies and cd20-specific antibodies and methods of use thereof |
BRPI0721062A2 (pt) | 2006-12-21 | 2019-09-24 | Macrogenics Inc | métodos para prevenir ou retardar o início e para prevenir a progressão de diabete autoimune latente, métodos para tratamento de diabete autoimune latente em adultos e para tratar ou prevenir diabete de tipo 1 de início na idade adulta ou para melhorar seus sintomas em um paciente sofrendo do mesmo, e, método para prevenir ou retardar requisição de insulina em um paciente. |
WO2008091908A2 (en) | 2007-01-22 | 2008-07-31 | Raven Biotechnologies | Human cancer stem cells |
JP2010524435A (ja) * | 2007-04-03 | 2010-07-22 | マイクロメット アーゲー | 種間特異的二重特異性バインダー |
WO2008119565A2 (en) | 2007-04-03 | 2008-10-09 | Micromet Ag | Cross-species-specific binding domain |
WO2008119566A2 (en) | 2007-04-03 | 2008-10-09 | Micromet Ag | Cross-species-specific bispecific binders |
RS53008B2 (sr) | 2007-04-03 | 2022-12-30 | Amgen Res Munich Gmbh | Interspecijski specifičan cd3-epsilon vezujući domen |
CN107226864A (zh) | 2007-06-21 | 2017-10-03 | 宏观基因有限公司 | 共价双抗体及其用途 |
US20100260668A1 (en) | 2008-04-29 | 2010-10-14 | Abbott Laboratories | Dual Variable Domain Immunoglobulins and Uses Thereof |
EP2328934A4 (en) | 2008-08-26 | 2013-04-03 | Macrogenics Inc | T cell Receptor Antibodies and Method of Use |
KR101901458B1 (ko) | 2008-10-10 | 2018-09-21 | 압테보 리서치 앤드 디벨롭먼트 엘엘씨 | Tcr 복합체 면역치료제 |
ES2732191T3 (es) | 2008-12-19 | 2019-11-21 | Macrogenics Inc | Diacuerpos covalentes y usos de los mismos |
TWI653333B (zh) * | 2010-04-01 | 2019-03-11 | 安進研究(慕尼黑)有限責任公司 | 跨物種專一性之PSMAxCD3雙專一性單鏈抗體 |
JP6141831B2 (ja) * | 2011-05-21 | 2017-06-07 | マクロジェニクス,インコーポレーテッド | ヒト及び非ヒトcd3に結合可能なcd3結合分子 |
JP6926834B2 (ja) * | 2017-08-30 | 2021-08-25 | いすゞ自動車株式会社 | ステアリング装置 |
-
2012
- 2012-05-16 JP JP2014512882A patent/JP6141831B2/ja active Active
- 2012-05-16 KR KR1020137032801A patent/KR102060389B1/ko active IP Right Grant
- 2012-05-16 UA UAA201314983A patent/UA115122C2/uk unknown
- 2012-05-16 DK DK12790075.1T patent/DK2714733T3/da active
- 2012-05-16 SI SI201231589T patent/SI2714733T1/sl unknown
- 2012-05-16 CN CN201711015483.2A patent/CN107722124A/zh active Pending
- 2012-05-16 HU HUE12790075 patent/HUE044209T2/hu unknown
- 2012-05-16 EA EA201391735A patent/EA033677B1/ru not_active IP Right Cessation
- 2012-05-16 UA UAA201704655A patent/UA117072C2/uk unknown
- 2012-05-16 CA CA2836857A patent/CA2836857C/en active Active
- 2012-05-16 PT PT12790075T patent/PT2714733T/pt unknown
- 2012-05-16 SG SG10201703425RA patent/SG10201703425RA/en unknown
- 2012-05-16 BR BR112013029893A patent/BR112013029893A2/pt not_active Application Discontinuation
- 2012-05-16 MX MX2013013584A patent/MX369220B/es active IP Right Grant
- 2012-05-16 LT LTEP12790075.1T patent/LT2714733T/lt unknown
- 2012-05-16 KR KR1020197025452A patent/KR20190105112A/ko not_active Application Discontinuation
- 2012-05-16 CN CN201280036088.1A patent/CN103703024B/zh active Active
- 2012-05-16 ES ES12790075T patent/ES2732213T3/es active Active
- 2012-05-16 RS RS20190504A patent/RS58765B1/sr unknown
- 2012-05-16 CN CN201711009708.3A patent/CN107827985A/zh active Pending
- 2012-05-16 ME MEP-2019-122A patent/ME03440B/me unknown
- 2012-05-16 NZ NZ703939A patent/NZ703939A/en not_active IP Right Cessation
- 2012-05-16 US US14/118,523 patent/US9587021B2/en active Active
- 2012-05-16 BR BR122016016837A patent/BR122016016837A2/pt not_active Application Discontinuation
- 2012-05-16 UA UAA201609304A patent/UA115402C2/uk unknown
- 2012-05-16 SG SG10201509588TA patent/SG10201509588TA/en unknown
- 2012-05-16 MY MYPI2013004195A patent/MY173899A/en unknown
- 2012-05-16 SG SG2013085980A patent/SG195072A1/en unknown
- 2012-05-16 AU AU2012259161A patent/AU2012259161B2/en active Active
- 2012-05-16 EP EP12790075.1A patent/EP2714733B1/en active Active
- 2012-05-16 PL PL12790075T patent/PL2714733T3/pl unknown
- 2012-05-16 WO PCT/US2012/038219 patent/WO2012162067A2/en active Application Filing
- 2012-05-16 EP EP18215748.7A patent/EP3492494A1/en active Pending
-
2013
- 2013-11-18 ZA ZA2013/08602A patent/ZA201308602B/en unknown
- 2013-11-20 CL CL2013003329A patent/CL2013003329A1/es unknown
- 2013-11-21 IL IL229575A patent/IL229575B/en active IP Right Grant
- 2013-12-10 MA MA36550A patent/MA35174B1/fr unknown
- 2013-12-20 CO CO13297917A patent/CO6970560A2/es unknown
- 2013-12-20 EC ECSP13013101 patent/ECSP13013101A/es unknown
-
2016
- 2016-05-24 CL CL2016001254A patent/CL2016001254A1/es unknown
-
2017
- 2017-01-24 US US15/414,303 patent/US10150812B2/en active Active
- 2017-04-28 JP JP2017089423A patent/JP6496349B2/ja not_active Expired - Fee Related
- 2017-07-03 AU AU2017204545A patent/AU2017204545B2/en not_active Ceased
-
2018
- 2018-05-07 IL IL259187A patent/IL259187B/en not_active IP Right Cessation
- 2018-10-23 US US16/168,559 patent/US11111299B2/en active Active
-
2019
- 2019-01-10 AU AU2019200159A patent/AU2019200159B2/en active Active
- 2019-01-17 IL IL264293A patent/IL264293B/en active IP Right Grant
- 2019-03-08 JP JP2019043220A patent/JP7302990B2/ja active Active
- 2019-04-23 CY CY20191100442T patent/CY1122020T1/el unknown
- 2019-04-23 HR HRP20190756TT patent/HRP20190756T1/hr unknown
-
2020
- 2020-03-30 CL CL2020000830A patent/CL2020000830A1/es unknown
-
2021
- 2021-08-04 US US17/393,682 patent/US12049501B2/en active Active
- 2021-09-29 JP JP2021159475A patent/JP2022001580A/ja active Pending
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7302990B2 (ja) | ヒト及び非ヒトcd3に結合可能なcd3結合分子 | |
DK2699590T3 (en) | ENDOGLIN POLYPEPTIDES AND APPLICATIONS THEREOF | |
US11332532B2 (en) | Bispecific antibodies which bind PD-L1 and GITR | |
KR20190086477A (ko) | 다발성 골수종 치료를 위한 bcma 및 cd3에 대응하는 이중 특이적 항체 및 면역학적 약물의 복합용도 | |
JP2019513777A (ja) | 免疫療法薬を標的とする多重特異性抗原結合構築物 | |
KR20170128234A (ko) | Ror1에 특이적인 항체 및 키메라 항원 수용체 | |
TW202210521A (zh) | 對cd19具專一性之抗體及嵌合抗原受體 | |
CN111787949A (zh) | 变体cd3-结合结构域及其在用于治疗疾病的组合疗法中的用途 | |
KR20220148209A (ko) | 항cd137 작제물 및 그 용도 | |
NZ618021B2 (en) | Cd3-binding molecules capable of binding to human and non-human cd3 | |
EA045070B1 (ru) | Cd3-связывающие молекулы, способные связаться с cd3 человека и cd3, не являющимся человеческим |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20190325 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20200529 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200826 |
|
RD02 | Notification of acceptance of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7422 Effective date: 20200826 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20210112 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20210601 |
|
C60 | Trial request (containing other claim documents, opposition documents) |
Free format text: JAPANESE INTERMEDIATE CODE: C60 Effective date: 20210929 |
|
C22 | Notice of designation (change) of administrative judge |
Free format text: JAPANESE INTERMEDIATE CODE: C22 Effective date: 20220825 |
|
C13 | Notice of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: C13 Effective date: 20221104 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230120 |
|
C23 | Notice of termination of proceedings |
Free format text: JAPANESE INTERMEDIATE CODE: C23 Effective date: 20230428 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20230622 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7302990 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |