JP2017531625A - アントラサイクリンジスルフィド中間体、抗体−薬物複合体、及び方法 - Google Patents
アントラサイクリンジスルフィド中間体、抗体−薬物複合体、及び方法 Download PDFInfo
- Publication number
- JP2017531625A JP2017531625A JP2017513785A JP2017513785A JP2017531625A JP 2017531625 A JP2017531625 A JP 2017531625A JP 2017513785 A JP2017513785 A JP 2017513785A JP 2017513785 A JP2017513785 A JP 2017513785A JP 2017531625 A JP2017531625 A JP 2017531625A
- Authority
- JP
- Japan
- Prior art keywords
- antibody
- drug
- receptor
- linker
- protein
- 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.)
- Granted
Links
- 239000000611 antibody drug conjugate Substances 0.000 title claims abstract description 131
- 229940049595 antibody-drug conjugate Drugs 0.000 title claims abstract description 131
- 238000000034 method Methods 0.000 title claims abstract description 37
- 229940045799 anthracyclines and related substance Drugs 0.000 title claims abstract description 27
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 239000000543 intermediate Substances 0.000 title claims description 51
- 239000003814 drug Substances 0.000 claims abstract description 57
- 229940079593 drug Drugs 0.000 claims abstract description 56
- -1 NPTIIb Proteins 0.000 claims description 133
- 206010028980 Neoplasm Diseases 0.000 claims description 91
- 239000000427 antigen Substances 0.000 claims description 60
- 108091007433 antigens Proteins 0.000 claims description 60
- 102000036639 antigens Human genes 0.000 claims description 60
- 108090000623 proteins and genes Proteins 0.000 claims description 56
- 201000011510 cancer Diseases 0.000 claims description 41
- 235000018417 cysteine Nutrition 0.000 claims description 41
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 40
- 102100033423 GDNF family receptor alpha-1 Human genes 0.000 claims description 36
- 101000579425 Homo sapiens Proto-oncogene tyrosine-protein kinase receptor Ret Proteins 0.000 claims description 32
- 102100028286 Proto-oncogene tyrosine-protein kinase receptor Ret Human genes 0.000 claims description 32
- 150000001875 compounds Chemical class 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 30
- 235000018102 proteins Nutrition 0.000 claims description 30
- 102000004169 proteins and genes Human genes 0.000 claims description 30
- 101000997961 Homo sapiens GDNF family receptor alpha-1 Proteins 0.000 claims description 24
- 101000628535 Homo sapiens Metalloreductase STEAP2 Proteins 0.000 claims description 24
- 108060003951 Immunoglobulin Proteins 0.000 claims description 24
- 102100034845 KiSS-1 receptor Human genes 0.000 claims description 24
- 102100026711 Metalloreductase STEAP2 Human genes 0.000 claims description 24
- 125000002947 alkylene group Chemical group 0.000 claims description 24
- 125000003118 aryl group Chemical group 0.000 claims description 24
- 102000018358 immunoglobulin Human genes 0.000 claims description 24
- 102100022430 Melanocyte protein PMEL Human genes 0.000 claims description 22
- 125000005647 linker group Chemical group 0.000 claims description 21
- 101000713169 Homo sapiens Solute carrier family 52, riboflavin transporter, member 2 Proteins 0.000 claims description 20
- 102100032129 Lymphocyte antigen 6K Human genes 0.000 claims description 20
- 102100032780 Semaphorin-5B Human genes 0.000 claims description 20
- 102100036862 Solute carrier family 52, riboflavin transporter, member 2 Human genes 0.000 claims description 20
- 101000620359 Homo sapiens Melanocyte protein PMEL Proteins 0.000 claims description 17
- 108010023729 Complement 3d Receptors Proteins 0.000 claims description 16
- 102000011412 Complement 3d Receptors Human genes 0.000 claims description 16
- 101001091205 Homo sapiens KiSS-1 receptor Proteins 0.000 claims description 16
- 101001065550 Homo sapiens Lymphocyte antigen 6K Proteins 0.000 claims description 16
- 101000623901 Homo sapiens Mucin-16 Proteins 0.000 claims description 16
- 101000853730 Homo sapiens RING finger and transmembrane domain-containing protein 2 Proteins 0.000 claims description 16
- 101000654679 Homo sapiens Semaphorin-5B Proteins 0.000 claims description 16
- 101000835745 Homo sapiens Teratocarcinoma-derived growth factor 1 Proteins 0.000 claims description 16
- 102100031036 Leucine-rich repeat-containing G-protein coupled receptor 5 Human genes 0.000 claims description 16
- 102100032131 Lymphocyte antigen 6E Human genes 0.000 claims description 16
- 102100023123 Mucin-16 Human genes 0.000 claims description 16
- 102100035928 RING finger and transmembrane domain-containing protein 2 Human genes 0.000 claims description 16
- 102100026404 Teratocarcinoma-derived growth factor 1 Human genes 0.000 claims description 16
- 125000004450 alkenylene group Chemical group 0.000 claims description 15
- 125000004419 alkynylene group Chemical group 0.000 claims description 15
- 238000011282 treatment Methods 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 102100029690 Tumor necrosis factor receptor superfamily member 13C Human genes 0.000 claims description 13
- 210000002307 prostate Anatomy 0.000 claims description 13
- 102100025218 B-cell differentiation antigen CD72 Human genes 0.000 claims description 12
- 102100024220 CD180 antigen Human genes 0.000 claims description 12
- 102100031511 Fc receptor-like protein 2 Human genes 0.000 claims description 12
- 101000980829 Homo sapiens CD180 antigen Proteins 0.000 claims description 12
- 101001063456 Homo sapiens Leucine-rich repeat-containing G-protein coupled receptor 5 Proteins 0.000 claims description 12
- 101000844504 Homo sapiens Transient receptor potential cation channel subfamily M member 4 Proteins 0.000 claims description 12
- 102100038210 Lymphocyte antigen 6 complex locus protein G6d Human genes 0.000 claims description 12
- 102100038437 Sodium-dependent phosphate transport protein 2B Human genes 0.000 claims description 12
- 229940125644 antibody drug Drugs 0.000 claims description 12
- 102000005962 receptors Human genes 0.000 claims description 12
- 108020003175 receptors Proteins 0.000 claims description 12
- 102100026159 Tomoregulin-1 Human genes 0.000 claims description 11
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 claims description 10
- 102100039094 Tyrosinase Human genes 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 230000008878 coupling Effects 0.000 claims description 10
- 238000010168 coupling process Methods 0.000 claims description 10
- 238000005859 coupling reaction Methods 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 101000934338 Homo sapiens Myeloid cell surface antigen CD33 Proteins 0.000 claims description 9
- 102000052922 Large Neutral Amino Acid-Transporter 1 Human genes 0.000 claims description 9
- 102100025243 Myeloid cell surface antigen CD33 Human genes 0.000 claims description 9
- 206010060862 Prostate cancer Diseases 0.000 claims description 9
- 102100036735 Prostate stem cell antigen Human genes 0.000 claims description 9
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 9
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 claims description 9
- 108091006232 SLC7A5 Proteins 0.000 claims description 9
- 210000003719 b-lymphocyte Anatomy 0.000 claims description 9
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 125000006850 spacer group Chemical group 0.000 claims description 9
- 102100020998 Aspartate beta-hydroxylase domain-containing protein 1 Human genes 0.000 claims description 8
- 101710129514 B-cell differentiation antigen CD72 Proteins 0.000 claims description 8
- 102100031658 C-X-C chemokine receptor type 5 Human genes 0.000 claims description 8
- 102100026094 C-type lectin domain family 12 member A Human genes 0.000 claims description 8
- 102100032768 Complement receptor type 2 Human genes 0.000 claims description 8
- 102100031517 Fc receptor-like protein 1 Human genes 0.000 claims description 8
- 101710120224 Fc receptor-like protein 1 Proteins 0.000 claims description 8
- 101000783987 Homo sapiens Aspartate beta-hydroxylase domain-containing protein 1 Proteins 0.000 claims description 8
- 101000846911 Homo sapiens Fc receptor-like protein 2 Proteins 0.000 claims description 8
- 101000958332 Homo sapiens Lymphocyte antigen 6 complex locus protein G6d Proteins 0.000 claims description 8
- 101001065568 Homo sapiens Lymphocyte antigen 6E Proteins 0.000 claims description 8
- 101000829779 Homo sapiens Probable G-protein coupled receptor 19 Proteins 0.000 claims description 8
- 101000825475 Homo sapiens Protein shisa-2 homolog Proteins 0.000 claims description 8
- 101000604039 Homo sapiens Sodium-dependent phosphate transport protein 2B Proteins 0.000 claims description 8
- 101000834948 Homo sapiens Tomoregulin-2 Proteins 0.000 claims description 8
- 101000606090 Homo sapiens Tyrosinase Proteins 0.000 claims description 8
- 108010076800 Kisspeptin-1 Receptors Proteins 0.000 claims description 8
- 108010006444 Leucine-Rich Repeat Proteins Proteins 0.000 claims description 8
- 102000003735 Mesothelin Human genes 0.000 claims description 8
- 108090000015 Mesothelin Proteins 0.000 claims description 8
- 102100037603 P2X purinoceptor 5 Human genes 0.000 claims description 8
- 102100023417 Probable G-protein coupled receptor 19 Human genes 0.000 claims description 8
- 102100022938 Protein shisa-2 homolog Human genes 0.000 claims description 8
- 102100026160 Tomoregulin-2 Human genes 0.000 claims description 8
- 102100031228 Transient receptor potential cation channel subfamily M member 4 Human genes 0.000 claims description 8
- 108060008724 Tyrosinase Proteins 0.000 claims description 8
- 239000002299 complementary DNA Substances 0.000 claims description 8
- 210000004901 leucine-rich repeat Anatomy 0.000 claims description 8
- 102100031507 Fc receptor-like protein 5 Human genes 0.000 claims description 7
- 101000846908 Homo sapiens Fc receptor-like protein 5 Proteins 0.000 claims description 7
- 230000001419 dependent effect Effects 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 102100027203 B-cell antigen receptor complex-associated protein beta chain Human genes 0.000 claims description 6
- 102100038080 B-cell receptor CD22 Human genes 0.000 claims description 6
- 101710188619 C-type lectin domain family 12 member A Proteins 0.000 claims description 6
- 102000000844 Cell Surface Receptors Human genes 0.000 claims description 6
- 108010001857 Cell Surface Receptors Proteins 0.000 claims description 6
- 101000914491 Homo sapiens B-cell antigen receptor complex-associated protein beta chain Proteins 0.000 claims description 6
- HAXFWIACAGNFHA-UHFFFAOYSA-N aldrithiol Chemical group C=1C=CC=NC=1SSC1=CC=CC=N1 HAXFWIACAGNFHA-UHFFFAOYSA-N 0.000 claims description 6
- 239000000562 conjugate Substances 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 102000035160 transmembrane proteins Human genes 0.000 claims description 6
- 108091005703 transmembrane proteins Proteins 0.000 claims description 6
- 108091008875 B cell receptors Proteins 0.000 claims description 5
- 102100025473 Carcinoembryonic antigen-related cell adhesion molecule 6 Human genes 0.000 claims description 5
- 101000914326 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 6 Proteins 0.000 claims description 5
- 108010029485 Protein Isoforms Proteins 0.000 claims description 5
- 102000001708 Protein Isoforms Human genes 0.000 claims description 5
- 230000005945 translocation Effects 0.000 claims description 5
- 102100027205 B-cell antigen receptor complex-associated protein alpha chain Human genes 0.000 claims description 4
- 108010003455 BLyS receptor Proteins 0.000 claims description 4
- 102000001893 Bone Morphogenetic Protein Receptors Human genes 0.000 claims description 4
- 108010040422 Bone Morphogenetic Protein Receptors Proteins 0.000 claims description 4
- 108010061298 CXCR5 Receptors Proteins 0.000 claims description 4
- 102100030886 Complement receptor type 1 Human genes 0.000 claims description 4
- 102100026245 E3 ubiquitin-protein ligase RNF43 Human genes 0.000 claims description 4
- 102000002045 Endothelin Human genes 0.000 claims description 4
- 108050009340 Endothelin Proteins 0.000 claims description 4
- 101710105157 GDNF family receptor alpha-1 Proteins 0.000 claims description 4
- 108090000722 Glial cell line-derived neurotrophic factor receptors Proteins 0.000 claims description 4
- 102100031546 HLA class II histocompatibility antigen, DO beta chain Human genes 0.000 claims description 4
- 102000018713 Histocompatibility Antigens Class II Human genes 0.000 claims description 4
- 108010027412 Histocompatibility Antigens Class II Proteins 0.000 claims description 4
- 101100118545 Holotrichia diomphalia EGF-like gene Proteins 0.000 claims description 4
- 101000914489 Homo sapiens B-cell antigen receptor complex-associated protein alpha chain Proteins 0.000 claims description 4
- 101000884305 Homo sapiens B-cell receptor CD22 Proteins 0.000 claims description 4
- 101000922405 Homo sapiens C-X-C chemokine receptor type 5 Proteins 0.000 claims description 4
- 101000727061 Homo sapiens Complement receptor type 1 Proteins 0.000 claims description 4
- 101000941929 Homo sapiens Complement receptor type 2 Proteins 0.000 claims description 4
- 101100119857 Homo sapiens FCRL2 gene Proteins 0.000 claims description 4
- 101000866281 Homo sapiens HLA class II histocompatibility antigen, DO beta chain Proteins 0.000 claims description 4
- 101000576802 Homo sapiens Mesothelin Proteins 0.000 claims description 4
- 101000628547 Homo sapiens Metalloreductase STEAP1 Proteins 0.000 claims description 4
- 101001024605 Homo sapiens Next to BRCA1 gene 1 protein Proteins 0.000 claims description 4
- 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 claims description 4
- 101710174256 Leucine-rich repeat-containing G-protein coupled receptor 5 Proteins 0.000 claims description 4
- 102000004086 Ligand-Gated Ion Channels Human genes 0.000 claims description 4
- 108090000543 Ligand-Gated Ion Channels Proteins 0.000 claims description 4
- 101710160635 Lymphocyte antigen 6 complex locus protein G6d Proteins 0.000 claims description 4
- 101710157879 Lymphocyte antigen 6E Proteins 0.000 claims description 4
- 101710158212 Lymphocyte antigen 6K Proteins 0.000 claims description 4
- 102000018697 Membrane Proteins Human genes 0.000 claims description 4
- 108010052285 Membrane Proteins Proteins 0.000 claims description 4
- 102100025096 Mesothelin Human genes 0.000 claims description 4
- 102100026712 Metalloreductase STEAP1 Human genes 0.000 claims description 4
- 101100182721 Mus musculus Ly6e gene Proteins 0.000 claims description 4
- 101000623899 Mus musculus Mucin-13 Proteins 0.000 claims description 4
- 101100042271 Mus musculus Sema3b gene Proteins 0.000 claims description 4
- 108010092528 Phosphate Transport Proteins Proteins 0.000 claims description 4
- 102000016462 Phosphate Transport Proteins Human genes 0.000 claims description 4
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 claims description 4
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 claims description 4
- 108010080192 Purinergic Receptors Proteins 0.000 claims description 4
- 102000014400 SH2 domains Human genes 0.000 claims description 4
- 108050003452 SH2 domains Proteins 0.000 claims description 4
- 108091058557 SILV Proteins 0.000 claims description 4
- 108091006576 SLC34A2 Proteins 0.000 claims description 4
- 102000009203 Sema domains Human genes 0.000 claims description 4
- 108050000099 Sema domains Proteins 0.000 claims description 4
- 102000014105 Semaphorin Human genes 0.000 claims description 4
- 108050003978 Semaphorin Proteins 0.000 claims description 4
- 101710199399 Semaphorin-5B Proteins 0.000 claims description 4
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 claims description 4
- 101100523267 Staphylococcus aureus qacC gene Proteins 0.000 claims description 4
- 102000003618 TRPM4 Human genes 0.000 claims description 4
- 101710098080 Teratocarcinoma-derived growth factor Proteins 0.000 claims description 4
- 108060008245 Thrombospondin Proteins 0.000 claims description 4
- 102000002938 Thrombospondin Human genes 0.000 claims description 4
- 101710175559 Tomoregulin-1 Proteins 0.000 claims description 4
- 101710178300 Tumor necrosis factor receptor superfamily member 13C Proteins 0.000 claims description 4
- 241000269368 Xenopus laevis Species 0.000 claims description 4
- 239000012190 activator Substances 0.000 claims description 4
- 230000001086 cytosolic effect Effects 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 claims description 4
- 229910052709 silver Inorganic materials 0.000 claims description 4
- 239000004332 silver Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 208000035782 susceptibility to 1 Hirschsprung disease Diseases 0.000 claims description 4
- 108010037277 thymic shared antigen-1 Proteins 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 241000124008 Mammalia Species 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- 229940127089 cytotoxic agent Drugs 0.000 claims description 2
- 101001136592 Homo sapiens Prostate stem cell antigen Proteins 0.000 claims 2
- 210000004027 cell Anatomy 0.000 description 74
- 125000003275 alpha amino acid group Chemical group 0.000 description 60
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- 241000282414 Homo sapiens Species 0.000 description 40
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 31
- 239000000243 solution Substances 0.000 description 30
- 125000001424 substituent group Chemical group 0.000 description 26
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 25
- 108091007491 NSP3 Papain-like protease domains Proteins 0.000 description 21
- 108020004414 DNA Proteins 0.000 description 18
- 238000001727 in vivo Methods 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 17
- 125000004432 carbon atom Chemical group C* 0.000 description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 16
- 241000699670 Mus sp. Species 0.000 description 16
- 235000001014 amino acid Nutrition 0.000 description 16
- 150000007523 nucleic acids Chemical class 0.000 description 16
- 108090000765 processed proteins & peptides Proteins 0.000 description 16
- 229940024606 amino acid Drugs 0.000 description 15
- 208000035475 disorder Diseases 0.000 description 15
- 102000004196 processed proteins & peptides Human genes 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 14
- 125000000623 heterocyclic group Chemical group 0.000 description 14
- 238000000338 in vitro Methods 0.000 description 14
- 102000039446 nucleic acids Human genes 0.000 description 14
- 108020004707 nucleic acids Proteins 0.000 description 14
- 229920001184 polypeptide Polymers 0.000 description 14
- 238000006467 substitution reaction Methods 0.000 description 14
- 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 13
- 230000014509 gene expression Effects 0.000 description 13
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- 239000013598 vector Substances 0.000 description 13
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 239000000872 buffer Substances 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- 229960001612 trastuzumab emtansine Drugs 0.000 description 12
- 206010006187 Breast cancer Diseases 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- 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 11
- 239000002953 phosphate buffered saline Substances 0.000 description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 10
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 10
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 10
- 150000001413 amino acids Chemical class 0.000 description 10
- 125000004429 atom Chemical group 0.000 description 10
- 230000003833 cell viability Effects 0.000 description 10
- 201000010099 disease Diseases 0.000 description 10
- 230000035772 mutation Effects 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 230000004614 tumor growth Effects 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 9
- 108091034117 Oligonucleotide Proteins 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 210000000349 chromosome Anatomy 0.000 description 9
- 230000000875 corresponding effect Effects 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 230000006870 function Effects 0.000 description 9
- SLURUCSFDHKXFR-WWMWMSKMSA-N (7s,9s)-7-[[(1s,3r,4as,9s,9ar,10as)-9-methoxy-1-methyl-3,4,4a,6,7,9,9a,10a-octahydro-1h-pyrano[1,2][1,3]oxazolo[3,4-b][1,4]oxazin-3-yl]oxy]-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione Chemical compound O=C1C2=CC=CC(OC)=C2C(=O)C(C(O)=C23)=C1C(O)=C3C[C@@](O)(C(=O)CO)C[C@@H]2O[C@H]1C[C@@H]2N3CCO[C@H](OC)[C@H]3O[C@@H]2[C@H](C)O1 SLURUCSFDHKXFR-WWMWMSKMSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- HDFGOPSGAURCEO-UHFFFAOYSA-N N-ethylmaleimide Chemical compound CCN1C(=O)C=CC1=O HDFGOPSGAURCEO-UHFFFAOYSA-N 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 125000000539 amino acid group Chemical group 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- 238000001990 intravenous administration Methods 0.000 description 8
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 230000009261 transgenic effect Effects 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 7
- 229930006000 Sucrose Natural products 0.000 description 7
- 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 7
- 238000004458 analytical method Methods 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 229960004679 doxorubicin Drugs 0.000 description 7
- 239000012634 fragment Substances 0.000 description 7
- 238000002703 mutagenesis Methods 0.000 description 7
- 231100000350 mutagenesis Toxicity 0.000 description 7
- 239000013612 plasmid Substances 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 241000894007 species Species 0.000 description 7
- 239000005720 sucrose Substances 0.000 description 7
- 239000004215 Carbon black (E152) Substances 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- 108700020796 Oncogene Proteins 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- 239000007983 Tris buffer Substances 0.000 description 6
- 102000003425 Tyrosinase Human genes 0.000 description 6
- 210000000577 adipose tissue Anatomy 0.000 description 6
- 125000000732 arylene group Chemical group 0.000 description 6
- 230000001363 autoimmune Effects 0.000 description 6
- 238000001516 cell proliferation assay Methods 0.000 description 6
- 238000012054 celltiter-glo Methods 0.000 description 6
- 125000000107 disulfanyl group Chemical group [*]SS[H] 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 125000001072 heteroaryl group Chemical group 0.000 description 6
- 229930195733 hydrocarbon Natural products 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Chemical group C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 6
- 230000004481 post-translational protein modification Effects 0.000 description 6
- 150000003254 radicals Chemical class 0.000 description 6
- 125000006413 ring segment Chemical group 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 5
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 5
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 5
- 230000004071 biological effect Effects 0.000 description 5
- 239000006143 cell culture medium Substances 0.000 description 5
- 230000022534 cell killing Effects 0.000 description 5
- 231100000433 cytotoxic Toxicity 0.000 description 5
- 230000001472 cytotoxic effect Effects 0.000 description 5
- 231100000673 dose–response relationship Toxicity 0.000 description 5
- 239000012636 effector Substances 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 208000032839 leukemia Diseases 0.000 description 5
- 210000004962 mammalian cell Anatomy 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 238000010405 reoxidation reaction Methods 0.000 description 5
- 238000002741 site-directed mutagenesis Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 5
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 5
- 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 description 4
- DJQYYYCQOZMCRC-UHFFFAOYSA-N 2-aminopropane-1,3-dithiol Chemical group SCC(N)CS DJQYYYCQOZMCRC-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 4
- 208000026310 Breast neoplasm Diseases 0.000 description 4
- 102100020743 Dipeptidase 1 Human genes 0.000 description 4
- 102100031968 Ephrin type-B receptor 2 Human genes 0.000 description 4
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 4
- 239000004472 Lysine Substances 0.000 description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical class C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical group C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- 239000012317 TBTU Substances 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 4
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical class C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 4
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 238000012217 deletion Methods 0.000 description 4
- 230000037430 deletion Effects 0.000 description 4
- 230000001900 immune effect Effects 0.000 description 4
- 230000002998 immunogenetic effect Effects 0.000 description 4
- 238000003780 insertion Methods 0.000 description 4
- 230000037431 insertion Effects 0.000 description 4
- 210000003292 kidney cell Anatomy 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 229960002087 pertuzumab Drugs 0.000 description 4
- 238000012746 preparative thin layer chromatography Methods 0.000 description 4
- 230000009257 reactivity Effects 0.000 description 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 150000003573 thiols Chemical group 0.000 description 4
- 238000002054 transplantation Methods 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 208000023275 Autoimmune disease Diseases 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- RXYPXQSKLGGKOL-UHFFFAOYSA-N CN1CCN(C)CC1 Chemical compound CN1CCN(C)CC1 RXYPXQSKLGGKOL-UHFFFAOYSA-N 0.000 description 3
- 241000282693 Cercopithecidae Species 0.000 description 3
- 101150029707 ERBB2 gene Proteins 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 3
- 108010087819 Fc receptors Proteins 0.000 description 3
- 102000009109 Fc receptors Human genes 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- 101001064462 Homo sapiens Ephrin type-B receptor 2 Proteins 0.000 description 3
- 101000834937 Homo sapiens Tomoregulin-1 Proteins 0.000 description 3
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 3
- 206010025323 Lymphomas Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 108010067787 Proteoglycans Proteins 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 206010047115 Vasculitis Diseases 0.000 description 3
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000033115 angiogenesis Effects 0.000 description 3
- 239000012300 argon atmosphere Substances 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 3
- 238000010367 cloning Methods 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 230000021615 conjugation Effects 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin 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(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 230000004069 differentiation Effects 0.000 description 3
- 150000002019 disulfides Chemical class 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 235000019439 ethyl acetate Nutrition 0.000 description 3
- 230000013595 glycosylation Effects 0.000 description 3
- 238000006206 glycosylation reaction Methods 0.000 description 3
- 229940022353 herceptin Drugs 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000004191 hydrophobic interaction chromatography Methods 0.000 description 3
- 230000003463 hyperproliferative effect Effects 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 201000007270 liver cancer Diseases 0.000 description 3
- 210000005229 liver cell Anatomy 0.000 description 3
- 208000014018 liver neoplasm Diseases 0.000 description 3
- 238000004020 luminiscence type Methods 0.000 description 3
- 210000004698 lymphocyte Anatomy 0.000 description 3
- 230000036210 malignancy Effects 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- PXYPBZYXNPAGFW-UHFFFAOYSA-N methyl 4-[2-(4-phenylphenyl)propan-2-yloxycarbonyloxy]benzoate Chemical group C1=CC(C(=O)OC)=CC=C1OC(=O)OC(C)(C)C1=CC=C(C=2C=CC=CC=2)C=C1 PXYPBZYXNPAGFW-UHFFFAOYSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- CTMCWCONSULRHO-UHQPFXKFSA-N nemorubicin Chemical compound C1CO[C@H](OC)CN1[C@@H]1[C@H](O)[C@H](C)O[C@@H](O[C@@H]2C3=C(O)C=4C(=O)C5=C(OC)C=CC=C5C(=O)C=4C(O)=C3C[C@](O)(C2)C(=O)CO)C1 CTMCWCONSULRHO-UHQPFXKFSA-N 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 3
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 229960000575 trastuzumab Drugs 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- KEIFWROAQVVDBN-UHFFFAOYSA-N 1,2-dihydronaphthalene Chemical class C1=CC=C2C=CCCC2=C1 KEIFWROAQVVDBN-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 2
- SEKLFMRSNLFPRB-UHFFFAOYSA-N 2-(pyridin-2-yldisulfanyl)ethanamine;hydrochloride Chemical compound Cl.NCCSSC1=CC=CC=N1 SEKLFMRSNLFPRB-UHFFFAOYSA-N 0.000 description 2
- 125000004398 2-methyl-2-butyl group Chemical group CC(C)(CC)* 0.000 description 2
- 125000004918 2-methyl-2-pentyl group Chemical group CC(C)(CCC)* 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- 125000004917 3-methyl-2-butyl group Chemical group CC(C(C)*)C 0.000 description 2
- 125000004919 3-methyl-2-pentyl group Chemical group CC(C(C)*)CC 0.000 description 2
- 125000004921 3-methyl-3-pentyl group Chemical group CC(CC)(CC)* 0.000 description 2
- BHQUBONFIYNJDA-UHFFFAOYSA-N 5-nitro-1h-pyridine-2-thione Chemical compound [O-][N+](=O)C1=CC=C(S)N=C1 BHQUBONFIYNJDA-UHFFFAOYSA-N 0.000 description 2
- ROUFCTKIILEETD-UHFFFAOYSA-N 5-nitro-2-[(5-nitropyridin-2-yl)disulfanyl]pyridine Chemical compound N1=CC([N+](=O)[O-])=CC=C1SSC1=CC=C([N+]([O-])=O)C=N1 ROUFCTKIILEETD-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 208000023328 Basedow disease Diseases 0.000 description 2
- 102100032312 Brevican core protein Human genes 0.000 description 2
- 0 C*C(N(*)C(*)C(*)N(*)C(C)=O)=O Chemical compound C*C(N(*)C(*)C(*)N(*)C(C)=O)=O 0.000 description 2
- 102000002086 C-type lectin-like Human genes 0.000 description 2
- 108050009406 C-type lectin-like Proteins 0.000 description 2
- PCBZRNYXXCIELG-WYFCWLEVSA-N COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 Chemical compound COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 PCBZRNYXXCIELG-WYFCWLEVSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- 102000011727 Caspases Human genes 0.000 description 2
- 108010076667 Caspases Proteins 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 108020004705 Codon Proteins 0.000 description 2
- 241000254173 Coleoptera Species 0.000 description 2
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 241000699802 Cricetulus griseus Species 0.000 description 2
- SBJKKFFYIZUCET-JLAZNSOCSA-N Dehydro-L-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(=O)C1=O SBJKKFFYIZUCET-JLAZNSOCSA-N 0.000 description 2
- SBJKKFFYIZUCET-UHFFFAOYSA-N Dehydroascorbic acid Natural products OCC(O)C1OC(=O)C(=O)C1=O SBJKKFFYIZUCET-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- GKQLYSROISKDLL-UHFFFAOYSA-N EEDQ Chemical compound C1=CC=C2N(C(=O)OCC)C(OCC)C=CC2=C1 GKQLYSROISKDLL-UHFFFAOYSA-N 0.000 description 2
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 2
- 208000015023 Graves' disease Diseases 0.000 description 2
- 208000017891 HER2 positive breast carcinoma Diseases 0.000 description 2
- 241000238631 Hexapoda Species 0.000 description 2
- 101000869050 Homo sapiens Caveolae-associated protein 2 Proteins 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 108060001084 Luciferase Proteins 0.000 description 2
- 239000005089 Luciferase Substances 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 101100327295 Mus musculus Cd22 gene Proteins 0.000 description 2
- 241000872931 Myoporum sandwicense Species 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 2
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 description 2
- 108091028043 Nucleic acid sequence Proteins 0.000 description 2
- 108091005461 Nucleic proteins Chemical group 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 208000031845 Pernicious anaemia Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical group C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- 208000021386 Sjogren Syndrome Diseases 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- PZBFGYYEXUXCOF-UHFFFAOYSA-N TCEP Chemical compound OC(=O)CCP(CCC(O)=O)CCC(O)=O PZBFGYYEXUXCOF-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- 208000024780 Urticaria Diseases 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Chemical compound CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 2
- 241000251539 Vertebrata <Metazoa> 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
- 150000007513 acids Chemical class 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 101150115889 al gene Proteins 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 125000002393 azetidinyl group Chemical group 0.000 description 2
- 239000008228 bacteriostatic water for injection Substances 0.000 description 2
- 150000001555 benzenes Chemical class 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- 125000004452 carbocyclyl group Chemical group 0.000 description 2
- 238000003763 carbonization Methods 0.000 description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 2
- 238000012219 cassette mutagenesis Methods 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000006037 cell lysis Effects 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 229960002173 citrulline Drugs 0.000 description 2
- 230000000295 complement effect Effects 0.000 description 2
- 230000002596 correlated effect Effects 0.000 description 2
- 210000005220 cytoplasmic tail Anatomy 0.000 description 2
- 230000001085 cytostatic effect Effects 0.000 description 2
- 229960000975 daunorubicin Drugs 0.000 description 2
- 235000020960 dehydroascorbic acid Nutrition 0.000 description 2
- 239000011615 dehydroascorbic acid Substances 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 2
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 2
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical class C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 125000002228 disulfide group Chemical group 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 229930182470 glycoside Natural products 0.000 description 2
- 210000003714 granulocyte Anatomy 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 208000014951 hematologic disease Diseases 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 238000013537 high throughput screening Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229940072221 immunoglobulins Drugs 0.000 description 2
- 238000000099 in vitro assay Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 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 2
- 150000002500 ions Chemical class 0.000 description 2
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 206010025135 lupus erythematosus Diseases 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 229960005558 mertansine Drugs 0.000 description 2
- ANZJBCHSOXCCRQ-FKUXLPTCSA-N mertansine Chemical compound CO[C@@H]([C@@]1(O)C[C@H](OC(=O)N1)[C@@H](C)[C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(=O)CCS)CC(=O)N1C)\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 ANZJBCHSOXCCRQ-FKUXLPTCSA-N 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
- 238000010369 molecular cloning Methods 0.000 description 2
- 210000001616 monocyte Anatomy 0.000 description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- 201000000050 myeloid neoplasm Diseases 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229950010159 nemorubicin Drugs 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 125000001715 oxadiazolyl group Chemical group 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 description 2
- 235000011009 potassium phosphates Nutrition 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 238000001542 size-exclusion chromatography Methods 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 229940074404 sodium succinate Drugs 0.000 description 2
- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 description 2
- 125000003003 spiro group Chemical group 0.000 description 2
- 206010041823 squamous cell carcinoma Diseases 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical group O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- 210000000115 thoracic cavity Anatomy 0.000 description 2
- 206010043778 thyroiditis Diseases 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000011830 transgenic mouse model Methods 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 230000035899 viability Effects 0.000 description 2
- AIFRHYZBTHREPW-UHFFFAOYSA-N β-carboline Chemical group N1=CC=C2C3=CC=CC=C3NC2=C1 AIFRHYZBTHREPW-UHFFFAOYSA-N 0.000 description 2
- AGGWFDNPHKLBBV-YUMQZZPRSA-N (2s)-2-[[(2s)-2-amino-3-methylbutanoyl]amino]-5-(carbamoylamino)pentanoic acid Chemical compound CC(C)[C@H](N)C(=O)N[C@H](C(O)=O)CCCNC(N)=O AGGWFDNPHKLBBV-YUMQZZPRSA-N 0.000 description 1
- JHDROZPIXZYTMZ-UHFFFAOYSA-N (4-nitrophenyl) 2-(pyridin-2-yldisulfanyl)ethyl carbonate Chemical compound C1=CC([N+](=O)[O-])=CC=C1OC(=O)OCCSSC1=CC=CC=N1 JHDROZPIXZYTMZ-UHFFFAOYSA-N 0.000 description 1
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 1
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- JPRPJUMQRZTTED-UHFFFAOYSA-N 1,3-dioxolanyl Chemical group [CH]1OCCO1 JPRPJUMQRZTTED-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical group C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- HXKKHQJGJAFBHI-UHFFFAOYSA-N 1-aminopropan-2-ol Chemical compound CC(O)CN HXKKHQJGJAFBHI-UHFFFAOYSA-N 0.000 description 1
- FGYADSCZTQOAFK-UHFFFAOYSA-N 1-methylbenzimidazole Chemical compound C1=CC=C2N(C)C=NC2=C1 FGYADSCZTQOAFK-UHFFFAOYSA-N 0.000 description 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical group C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical class C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- KEQTWHPMSVAFDA-UHFFFAOYSA-N 2,3-dihydro-1h-pyrazole Chemical compound C1NNC=C1 KEQTWHPMSVAFDA-UHFFFAOYSA-N 0.000 description 1
- FFMBYMANYCDCMK-UHFFFAOYSA-N 2,5-dihydro-1h-imidazole Chemical compound C1NCN=C1 FFMBYMANYCDCMK-UHFFFAOYSA-N 0.000 description 1
- JYWKEVKEKOTYEX-UHFFFAOYSA-N 2,6-dibromo-4-chloroiminocyclohexa-2,5-dien-1-one Chemical compound ClN=C1C=C(Br)C(=O)C(Br)=C1 JYWKEVKEKOTYEX-UHFFFAOYSA-N 0.000 description 1
- PORTXTUJPQINJC-UHFFFAOYSA-N 2-(pyridin-2-yldisulfanyl)ethanol Chemical compound OCCSSC1=CC=CC=N1 PORTXTUJPQINJC-UHFFFAOYSA-N 0.000 description 1
- YVFLKEHIGMOLQI-UHFFFAOYSA-N 2-(pyridin-2-yldisulfanyl)propan-1-amine Chemical compound NCC(C)SSC1=CC=CC=N1 YVFLKEHIGMOLQI-UHFFFAOYSA-N 0.000 description 1
- QDGAVODICPCDMU-UHFFFAOYSA-N 2-amino-3-[3-[bis(2-chloroethyl)amino]phenyl]propanoic acid Chemical group OC(=O)C(N)CC1=CC=CC(N(CCCl)CCCl)=C1 QDGAVODICPCDMU-UHFFFAOYSA-N 0.000 description 1
- OGMADIBCHLQMIP-UHFFFAOYSA-N 2-aminoethanethiol;hydron;chloride Chemical compound Cl.NCCS OGMADIBCHLQMIP-UHFFFAOYSA-N 0.000 description 1
- SRSAMLMFVUJPSR-UHFFFAOYSA-N 2-carboxyethylphosphanium;chloride Chemical compound Cl.OC(=O)CCP SRSAMLMFVUJPSR-UHFFFAOYSA-N 0.000 description 1
- 125000004922 2-methyl-3-pentyl group Chemical group CC(C)C(CC)* 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 101710111653 2-methylisocitrate lyase Proteins 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 1
- HCZBCEYVAPRCDV-UHFFFAOYSA-N 2-sulfanylpropylazanium;chloride Chemical compound Cl.CC(S)CN HCZBCEYVAPRCDV-UHFFFAOYSA-N 0.000 description 1
- 125000001698 2H-pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- KIUMMUBSPKGMOY-UHFFFAOYSA-N 3,3'-Dithiobis(6-nitrobenzoic acid) Chemical compound C1=C([N+]([O-])=O)C(C(=O)O)=CC(SSC=2C=C(C(=CC=2)[N+]([O-])=O)C(O)=O)=C1 KIUMMUBSPKGMOY-UHFFFAOYSA-N 0.000 description 1
- PBVAJRFEEOIAGW-UHFFFAOYSA-N 3-[bis(2-carboxyethyl)phosphanyl]propanoic acid;hydrochloride Chemical compound Cl.OC(=O)CCP(CCC(O)=O)CCC(O)=O PBVAJRFEEOIAGW-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 description 1
- QLILRKBRWXALIE-UHFFFAOYSA-N 3-nitropyridine Chemical compound [O-][N+](=O)C1=CC=CN=C1 QLILRKBRWXALIE-UHFFFAOYSA-N 0.000 description 1
- JVQIKJMSUIMUDI-UHFFFAOYSA-N 3-pyrroline Chemical compound C1NCC=C1 JVQIKJMSUIMUDI-UHFFFAOYSA-N 0.000 description 1
- 125000004364 3-pyrrolinyl group Chemical group [H]C1=C([H])C([H])([H])N(*)C1([H])[H] 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin 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-VTZDEGQISA-N 0.000 description 1
- MCGBIXXDQFWVDW-UHFFFAOYSA-N 4,5-dihydro-1h-pyrazole Chemical compound C1CC=NN1 MCGBIXXDQFWVDW-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
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 125000004920 4-methyl-2-pentyl group Chemical group CC(CC(C)*)C 0.000 description 1
- 125000001826 4H-pyranyl group Chemical group O1C(=CCC=C1)* 0.000 description 1
- XGWFJBFNAQHLEF-UHFFFAOYSA-N 9-anthroic acid Chemical compound C1=CC=C2C(C(=O)O)=C(C=CC=C3)C3=CC2=C1 XGWFJBFNAQHLEF-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 208000026872 Addison Disease Diseases 0.000 description 1
- 208000036832 Adenocarcinoma of ovary Diseases 0.000 description 1
- OMNVYXHOSHNURL-WPRPVWTQSA-N Ala-Phe Chemical compound C[C@H](N)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 OMNVYXHOSHNURL-WPRPVWTQSA-N 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 208000032671 Allergic granulomatous angiitis Diseases 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010061424 Anal cancer Diseases 0.000 description 1
- 208000003343 Antiphospholipid Syndrome Diseases 0.000 description 1
- 208000007860 Anus Neoplasms Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 206010003827 Autoimmune hepatitis Diseases 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- 230000024704 B cell apoptotic process Effects 0.000 description 1
- 108010046304 B-Cell Activation Factor Receptor Proteins 0.000 description 1
- 101710187595 B-cell receptor CD22 Proteins 0.000 description 1
- 230000003844 B-cell-activation Effects 0.000 description 1
- 208000009137 Behcet syndrome Diseases 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 102100027052 Bone morphogenetic protein receptor type-1B Human genes 0.000 description 1
- 101710140080 Brevican core protein Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 108090000342 C-Type Lectins Proteins 0.000 description 1
- 102000003930 C-Type Lectins Human genes 0.000 description 1
- JCGPMZZOHUHICU-GDLZYMKVSA-N CC(C)(CNC([C@@](CCc1c(c(C(c2c3cccc2OC)=O)c2C3=O)O)(Cc1c2O)O)=O)SSc(nc1)ccc1[N+]([O-])=O Chemical compound CC(C)(CNC([C@@](CCc1c(c(C(c2c3cccc2OC)=O)c2C3=O)O)(Cc1c2O)O)=O)SSc(nc1)ccc1[N+]([O-])=O JCGPMZZOHUHICU-GDLZYMKVSA-N 0.000 description 1
- PCUSRTDSIWHZTQ-UHFFFAOYSA-N CC(CN)(C)SSC1=NC=CC=C1 Chemical compound CC(CN)(C)SSC1=NC=CC=C1 PCUSRTDSIWHZTQ-UHFFFAOYSA-N 0.000 description 1
- XCNWVNNDBZRDEA-NTSWFWBYSA-N C[C@@H](CCC1)O[C@H]1O Chemical compound C[C@@H](CCC1)O[C@H]1O XCNWVNNDBZRDEA-NTSWFWBYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- UJOBWOGCFQCDNV-UHFFFAOYSA-N Carbazole Natural products C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 238000003734 CellTiter-Glo Luminescent Cell Viability Assay Methods 0.000 description 1
- 102000006574 Chemokine CXCL13 Human genes 0.000 description 1
- 108010008955 Chemokine CXCL13 Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 241000282552 Chlorocebus aethiops Species 0.000 description 1
- 206010008609 Cholangitis sclerosing Diseases 0.000 description 1
- 208000006344 Churg-Strauss Syndrome Diseases 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 208000015943 Coeliac disease Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- IGXWBGJHJZYPQS-SSDOTTSWSA-N D-Luciferin Chemical compound OC(=O)[C@H]1CSC(C=2SC3=CC=C(O)C=C3N=2)=N1 IGXWBGJHJZYPQS-SSDOTTSWSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical class OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 238000001712 DNA sequencing Methods 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 1
- 206010011878 Deafness Diseases 0.000 description 1
- CYCGRDQQIOGCKX-UHFFFAOYSA-N Dehydro-luciferin Natural products OC(=O)C1=CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 CYCGRDQQIOGCKX-UHFFFAOYSA-N 0.000 description 1
- 102100024746 Dihydrofolate reductase Human genes 0.000 description 1
- 208000017701 Endocrine disease Diseases 0.000 description 1
- 208000018428 Eosinophilic granulomatosis with polyangiitis Diseases 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical group OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 1
- 238000011771 FVB mouse Methods 0.000 description 1
- 108090000331 Firefly luciferases Proteins 0.000 description 1
- BJGNCJDXODQBOB-UHFFFAOYSA-N Fivefly Luciferin Natural products OC(=O)C1CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 BJGNCJDXODQBOB-UHFFFAOYSA-N 0.000 description 1
- 108010014612 Follistatin Proteins 0.000 description 1
- 102000016970 Follistatin Human genes 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- 208000016621 Hearing disease Diseases 0.000 description 1
- 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 description 1
- 102100028999 High mobility group protein HMGI-C Human genes 0.000 description 1
- 241001272567 Hominoidea Species 0.000 description 1
- 101000731086 Homo sapiens Brevican core protein Proteins 0.000 description 1
- 101000912622 Homo sapiens C-type lectin domain family 12 member A Proteins 0.000 description 1
- 101100496086 Homo sapiens CLEC12A gene Proteins 0.000 description 1
- 101000932213 Homo sapiens Dipeptidase 1 Proteins 0.000 description 1
- 101000935587 Homo sapiens Flavin reductase (NADPH) Proteins 0.000 description 1
- 101000986379 Homo sapiens High mobility group protein HMGI-C Proteins 0.000 description 1
- 101001044893 Homo sapiens Interleukin-20 receptor subunit alpha Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 208000028482 Hypothalamic disease Diseases 0.000 description 1
- 208000025282 Hypothalamo-pituitary disease Diseases 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- 102100026120 IgG receptor FcRn large subunit p51 Human genes 0.000 description 1
- 101710177940 IgG receptor FcRn large subunit p51 Proteins 0.000 description 1
- 102000018071 Immunoglobulin Fc Fragments Human genes 0.000 description 1
- 108010091135 Immunoglobulin Fc Fragments Proteins 0.000 description 1
- 102000006496 Immunoglobulin Heavy Chains Human genes 0.000 description 1
- 108010019476 Immunoglobulin Heavy Chains Proteins 0.000 description 1
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 1
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 208000027601 Inner ear disease Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102100022706 Interleukin-20 receptor subunit alpha Human genes 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- 244000017020 Ipomoea batatas Species 0.000 description 1
- 235000002678 Ipomoea batatas Nutrition 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- VHJLVAABSRFDPM-IMJSIDKUSA-N L-1,4-dithiothreitol Chemical compound SC[C@H](O)[C@@H](O)CS VHJLVAABSRFDPM-IMJSIDKUSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical group NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 description 1
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 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
- 208000017119 Labyrinth disease Diseases 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 108090001090 Lectins Proteins 0.000 description 1
- 102000004856 Lectins Human genes 0.000 description 1
- 206010024612 Lipoma Diseases 0.000 description 1
- DDWFXDSYGUXRAY-UHFFFAOYSA-N Luciferin Natural products CCc1c(C)c(CC2NC(=O)C(=C2C=C)C)[nH]c1Cc3[nH]c4C(=C5/NC(CC(=O)O)C(C)C5CC(=O)O)CC(=O)c4c3C DDWFXDSYGUXRAY-UHFFFAOYSA-N 0.000 description 1
- 208000005777 Lupus Nephritis Diseases 0.000 description 1
- 102000008072 Lymphokines Human genes 0.000 description 1
- 108010074338 Lymphokines Proteins 0.000 description 1
- 101000920534 Lysinibacillus sphaericus Gamma-D-glutamyl-L-diamino acid endopeptidase 1 Proteins 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- 208000032271 Malignant tumor of penis Diseases 0.000 description 1
- 229930126263 Maytansine Natural products 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 108010021466 Mutant Proteins Proteins 0.000 description 1
- 102000008300 Mutant Proteins Human genes 0.000 description 1
- 201000002481 Myositis Diseases 0.000 description 1
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 102400000058 Neuregulin-1 Human genes 0.000 description 1
- 108090000556 Neuregulin-1 Proteins 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- UQMUIPXTUDIUJD-SCSAIBSYSA-N O[C@H]1NCCOC1 Chemical compound O[C@H]1NCCOC1 UQMUIPXTUDIUJD-SCSAIBSYSA-N 0.000 description 1
- 108020005187 Oligonucleotide Probes Proteins 0.000 description 1
- 208000005225 Opsoclonus-Myoclonus Syndrome Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 101710160107 Outer membrane protein A Proteins 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061328 Ovarian epithelial cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical group C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 206010034277 Pemphigoid Diseases 0.000 description 1
- 201000011152 Pemphigus Diseases 0.000 description 1
- 208000002471 Penile Neoplasms Diseases 0.000 description 1
- 206010034299 Penile cancer Diseases 0.000 description 1
- 102000000447 Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase Human genes 0.000 description 1
- 108010055817 Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase Proteins 0.000 description 1
- 108010030544 Peptidyl-Lys metalloendopeptidase Proteins 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 241000276498 Pollachius virens Species 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 206010036105 Polyneuropathy Diseases 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 1
- 101710120463 Prostate stem cell antigen Proteins 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- 206010037549 Purpura Diseases 0.000 description 1
- 241001672981 Purpura Species 0.000 description 1
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Natural products C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 208000003782 Raynaud disease Diseases 0.000 description 1
- 208000012322 Raynaud phenomenon Diseases 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 208000004337 Salivary Gland Neoplasms Diseases 0.000 description 1
- 206010061934 Salivary gland cancer Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- 108010029157 Sialic Acid Binding Ig-like Lectin 2 Proteins 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 229920002253 Tannate Polymers 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 201000007023 Thrombotic Thrombocytopenic Purpura Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 208000003441 Transfusion reaction Diseases 0.000 description 1
- 108010051765 Type I Bone Morphogenetic Protein Receptors Proteins 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 244000000188 Vaccinium ovalifolium Species 0.000 description 1
- 206010047741 Vulval cancer Diseases 0.000 description 1
- 208000004354 Vulvar Neoplasms Diseases 0.000 description 1
- UNMBAGCIDCZPHX-UHFFFAOYSA-N [(2-methylpropan-2-yl)oxycarbonylamino] 2-methylpropane-1-sulfonate Chemical compound CC(C)CS(=O)(=O)ONC(=O)OC(C)(C)C UNMBAGCIDCZPHX-UHFFFAOYSA-N 0.000 description 1
- DACWQSNZECJJGG-UHFFFAOYSA-N [1,2,4]triazolo[1,5-a]pyridine Chemical compound C1=CC=CN2N=CN=C21 DACWQSNZECJJGG-UHFFFAOYSA-N 0.000 description 1
- CLQIYJQJWCUVJQ-UHFFFAOYSA-N [N+](=O)([O-])C=1C=CC(=NC=1)SSC(CN)C Chemical compound [N+](=O)([O-])C=1C=CC(=NC=1)SSC(CN)C CLQIYJQJWCUVJQ-UHFFFAOYSA-N 0.000 description 1
- RGYIRJVYVFPVTN-UHFFFAOYSA-N [N+](=O)([O-])C=1C=CC(=NC=1)SSCCO Chemical compound [N+](=O)([O-])C=1C=CC(=NC=1)SSCCO RGYIRJVYVFPVTN-UHFFFAOYSA-N 0.000 description 1
- CHKFLBOLYREYDO-SHYZEUOFSA-N [[(2s,4r,5r)-5-(4-amino-2-oxopyrimidin-1-yl)-4-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)C[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 CHKFLBOLYREYDO-SHYZEUOFSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000004520 agglutination Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 108010011559 alanylphenylalanine Proteins 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- SRHNADOZAAWYLV-XLMUYGLTSA-N alpha-L-Fucp-(1->2)-beta-D-Galp-(1->4)-[alpha-L-Fucp-(1->3)]-beta-D-GlcpNAc Chemical compound O[C@H]1[C@H](O)[C@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](O[C@H]2[C@@H]([C@@H](NC(C)=O)[C@H](O)O[C@@H]2CO)O[C@H]2[C@H]([C@H](O)[C@H](O)[C@H](C)O2)O)O[C@H](CO)[C@H](O)[C@@H]1O SRHNADOZAAWYLV-XLMUYGLTSA-N 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003302 anti-idiotype Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000011230 antibody-based therapy Methods 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 201000011165 anus cancer Diseases 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 201000005000 autoimmune gastritis Diseases 0.000 description 1
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 description 1
- 201000004339 autoimmune neuropathy Diseases 0.000 description 1
- 208000010928 autoimmune thyroid disease Diseases 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004601 benzofurazanyl group Chemical group N1=C2C(=NO1)C(=CC=C2)* 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 description 1
- GPRLTFBKWDERLU-UHFFFAOYSA-N bicyclo[2.2.2]octane Chemical compound C1CC2CCC1CC2 GPRLTFBKWDERLU-UHFFFAOYSA-N 0.000 description 1
- GNTFBMAGLFYMMZ-UHFFFAOYSA-N bicyclo[3.2.2]nonane Chemical compound C1CC2CCC1CCC2 GNTFBMAGLFYMMZ-UHFFFAOYSA-N 0.000 description 1
- 239000004305 biphenyl Chemical class 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 125000002529 biphenylenyl group Chemical class C1(=CC=CC=2C3=CC=CC=C3C12)* 0.000 description 1
- ACBQROXDOHKANW-UHFFFAOYSA-N bis(4-nitrophenyl) carbonate Chemical compound C1=CC([N+](=O)[O-])=CC=C1OC(=O)OC1=CC=C([N+]([O-])=O)C=C1 ACBQROXDOHKANW-UHFFFAOYSA-N 0.000 description 1
- 210000004952 blastocoel Anatomy 0.000 description 1
- 201000000053 blastoma Diseases 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 208000000594 bullous pemphigoid Diseases 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000005341 cation exchange Methods 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000011712 cell development Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 238000003570 cell viability assay Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 235000013477 citrulline Nutrition 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 230000004540 complement-dependent cytotoxicity Effects 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=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](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)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)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 239000012045 crude solution Substances 0.000 description 1
- 201000003278 cryoglobulinemia Diseases 0.000 description 1
- 208000004921 cutaneous lupus erythematosus Diseases 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 150000001945 cysteines Chemical class 0.000 description 1
- 229960003067 cystine Drugs 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000003831 deregulation Effects 0.000 description 1
- 201000001981 dermatomyositis Diseases 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 125000002576 diazepinyl group Chemical group N1N=C(C=CC=C1)* 0.000 description 1
- 229960005215 dichloroacetic acid Drugs 0.000 description 1
- 108020001096 dihydrofolate reductase Proteins 0.000 description 1
- 125000005057 dihydrothienyl group Chemical group S1C(CC=C1)* 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- 230000009266 disease activity Effects 0.000 description 1
- 125000005883 dithianyl group Chemical group 0.000 description 1
- 125000005411 dithiolanyl group Chemical group S1SC(CC1)* 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical group SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 201000008184 embryoma Diseases 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 210000003013 erythroid precursor cell Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- XWBDWHCCBGMXKG-UHFFFAOYSA-N ethanamine;hydron;chloride Chemical compound Cl.CCN XWBDWHCCBGMXKG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 description 1
- 125000005677 ethinylene group Chemical group [*:2]C#C[*:1] 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 125000005469 ethylenyl group Chemical group 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000013613 expression plasmid Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 125000004612 furopyridinyl group Chemical group O1C(=CC2=C1C=CC=N2)* 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000002523 gelfiltration Methods 0.000 description 1
- 239000003168 generic drug Substances 0.000 description 1
- 229940114119 gentisate Drugs 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 230000000762 glandular Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000002518 glial effect Effects 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 239000003630 growth substance Substances 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 230000010370 hearing loss Effects 0.000 description 1
- 231100000888 hearing loss Toxicity 0.000 description 1
- 208000016354 hearing loss disease Diseases 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical compound O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 102000027596 immune receptors Human genes 0.000 description 1
- 108091008915 immune receptors Proteins 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 229940127121 immunoconjugate Drugs 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 125000003392 indanyl group Chemical class C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000005835 indanylene group Chemical group 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003454 indenyl group Chemical class C1(C=CC2=CC=CC=C12)* 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 108091008042 inhibitory receptors Proteins 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000035990 intercellular signaling Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical group C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 125000000741 isoleucyl group Chemical group [H]N([H])C(C(C([H])([H])[H])C([H])([H])C([H])([H])[H])C(=O)O* 0.000 description 1
- TWBYWOBDOCUKOW-UHFFFAOYSA-M isonicotinate Chemical compound [O-]C(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-M 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical group C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000002523 lectin Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 210000001853 liver microsome Anatomy 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 201000005249 lung adenocarcinoma Diseases 0.000 description 1
- 210000005265 lung cell Anatomy 0.000 description 1
- 201000005243 lung squamous cell carcinoma Diseases 0.000 description 1
- 239000012931 lyophilized formulation Substances 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- WKPWGQKGSOKKOO-RSFHAFMBSA-N maytansine Chemical compound CO[C@@H]([C@@]1(O)C[C@](OC(=O)N1)([C@H]([C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(C)=O)CC(=O)N1C)C)[H])\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 WKPWGQKGSOKKOO-RSFHAFMBSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 125000001620 monocyclic carbocycle group Chemical group 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 231100000219 mutagenic Toxicity 0.000 description 1
- 230000003505 mutagenic effect Effects 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- KVKFRMCSXWQSNT-UHFFFAOYSA-N n,n'-dimethylethane-1,2-diamine Chemical compound CNCCNC KVKFRMCSXWQSNT-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 230000009707 neogenesis Effects 0.000 description 1
- 238000007857 nested PCR Methods 0.000 description 1
- 230000004766 neurogenesis Effects 0.000 description 1
- 208000008795 neuromyelitis optica Diseases 0.000 description 1
- 210000004967 non-hematopoietic stem cell Anatomy 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- UMRZSTCPUPJPOJ-KNVOCYPGSA-N norbornane Chemical compound C1C[C@H]2CC[C@@H]1C2 UMRZSTCPUPJPOJ-KNVOCYPGSA-N 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-M oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC([O-])=O ZQPPMHVWECSIRJ-KTKRTIGZSA-M 0.000 description 1
- 239000002751 oligonucleotide probe Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 208000013371 ovarian adenocarcinoma Diseases 0.000 description 1
- 208000011932 ovarian sarcoma Diseases 0.000 description 1
- 201000006588 ovary adenocarcinoma Diseases 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003551 oxepanyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 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
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 201000001976 pemphigus vulgaris Diseases 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 201000002628 peritoneum cancer Diseases 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- 108010011613 phagocytosis receptor Proteins 0.000 description 1
- 229960005190 phenylalanine Drugs 0.000 description 1
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 210000001778 pluripotent stem cell Anatomy 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000007824 polyneuropathy Effects 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- AFNBMGLGYSGFEZ-UHFFFAOYSA-M potassium;ethanethioate Chemical compound [K+].CC([S-])=O AFNBMGLGYSGFEZ-UHFFFAOYSA-M 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 201000000742 primary sclerosing cholangitis Diseases 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- 230000000644 propagated effect Effects 0.000 description 1
- 230000001902 propagating effect Effects 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical group C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 238000003259 recombinant expression Methods 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 208000010157 sclerosing cholangitis Diseases 0.000 description 1
- 210000000717 sertoli cell Anatomy 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- YNJCFDAODGKHAV-UHFFFAOYSA-N tert-butyl n-(2-hydroxypropyl)carbamate Chemical compound CC(O)CNC(=O)OC(C)(C)C YNJCFDAODGKHAV-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000001583 thiepanyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 125000004571 thiomorpholin-4-yl group Chemical group N1(CCSCC1)* 0.000 description 1
- 229930192474 thiophene Chemical group 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000025366 tissue development Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 230000036269 ulceration Effects 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 201000005102 vulva cancer Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/6807—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense
- A61K47/6809—Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
- A61K47/6855—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Cell Biology (AREA)
- Molecular Biology (AREA)
- Oncology (AREA)
- Biochemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本出願は、参照により全体が本明細書に組み込まれる、2014年9月12日出願の米国仮出願第62/049720号の優先権の利益を主張するものである。
本出願は、ASCII形式で電子的に提出されており、かつ参照により全体が本明細書に組み込まれる配列表を包含する。2015年9月4日に作成された前記ASCIIのコピーは、P05813−US_SL.txtという名前であり、16,012バイトのサイズである。
Ant-L-(Z)m-X I
式中、Antが、以下の構造から選択され、
式中、波線が、Lへの結合を示し、
Lが、−CH2O−、−CH2N(R)−、-N(R)-、-N(R)(C1-C12アルキレン)-、−N(R)(C2-C8アルケニレン)-、-N(R)(C2-C8アルキニレン)-、-N(R)(CH2CH2O)n-、及び以下の構造から選択されるリンカーであり、
式中、波線が、Ant及びZへの結合を示し、
Zが、-CH2C(O)-、-CH2C(O)NR(C1-C12アルキレン)-、及び以下の構造から選択される任意のスペーサーであり、
式中、波線が、L及びXへの結合を示し、
Rが、H、C1-C12アルキル、またはC6-C20アリールであり、
Z1が、-(C1-C12アルキレン)-、-(C2-C8アルケニレン)-、-(C2-C8アルキニレン)-、-O(C1-C12アルキレン)-、-O(C2-C8アルケニレン)-、-O(C2-C8アルキニレン)-、及び-(CH2CH2O)n-から選択され、
mが、0または1であり、
nが、1〜6であり、
Xが、ピリジルジスルフィドであり、この場合、ピリジルが、NO2、Cl、F、及びBrから選択される1つ以上の基で任意に置換され、
アルキレン、アルケニレン、アルキニレン、アルキル、及びアリールが、F、Cl、Br、N(CH3)2、及びOCH3から選択される1つ以上の基で任意に置換される、アントラサイクリンジスルフィド中間体を含む。
Ab-S−S-(Zm-L-D)pII:
式中、Abが、(1)〜(53)から選択される1つ以上の腫瘍関連抗原または細胞表面受容体に結合する抗体であり、
(1)BMPR1B(骨形態形成タンパク質受容体IB型)、
(2)E16(LAT1、SLC7A5)、
(3)STEAP1(前立腺6膜貫通上皮抗原)、
(4)MUC16(0772P、CA125)、
(5)MPF(MPF、MSLN、SMR、巨核球増強因子、メソテリン)、
(6)Napi2b(NAPI−3B、NPTIIb、SLC34A2、溶質担体ファミリー34(リン酸ナトリウム)、メンバー2、II型ナトリウム依存性リン酸輸送体3b)、
(7)Sema 5b(FLJ10372、KIAA1445、Mm.42015、SEMA5B、SEMAG、セマフォリン5b Hlog、セマドメイン、7回トロンボスポンジン反復(1型及び1型様)、膜貫通ドメイン(TM)及び短細胞質ドメイン、(セマフォリン)5B)、
(8)PSCA hlg(2700050C12Rik、C530008O16Rik、RIKEN cDNA 2700050C12、RIKEN cDNA 2700050C12遺伝子)、
(9)ETBR(エンドセリンB型受容体)、
(10)MSG783(RNF124、仮想タンパク質FLJ20315)、
(11)STEAP2(HGNC_8639、IPCA−1、PCANAP1、STAMP1、STEAP2、STMP、前立腺癌関連遺伝子1、前立腺癌関連タンパク質1、前立腺6膜貫通上皮抗原2、6膜貫通前立腺タンパク質)、
(12)TrpM4(BR22450、FLJ20041、TRPM4、TRPM4B、一過性受容体電位カチオンチャネル、サブファミリーM、メンバー4)、
(13)CRIPTO(CR、CR1、CRGF、CRIPTO、TDGF1、奇形癌腫由来成長因子)、
(14)CD21(CR2(補体受容体2)またはC3DR(C3d/エプスタインバーウイルス受容体)またはHs 73792)、
(15)CD79b(CD79B、CD79β、IGb(免疫グロブリン関連ベータ)、B29)、
(16)FcRH2(IFGP4、IRTA4、SPAP1A(SH2ドメイン含有ホスファターゼアンカータンパク質1a)、SPAP1B、SPAP1C)、
(17)HER2、
(18)NCA、
(19)MDP、
(20)IL20Rα、
(21)ブレビカン、
(22)EphB2R、
(23)ASLG659、
(24)PSCA、
(25)GEDA、
(26)BAFF−R(B細胞活性化因子受容体、BLyS受容体3、BR3)、
(27)CD22(B細胞受容体CD22−Bアイソフォーム)、
(28)CD79a(CD79A、CD79α、免疫グロブリン関連アルファ)、
(29)CXCR5(バーキットリンパ腫受容体1)、
(30)HLA−DOB(MHCクラスII分子のベータサブユニット(Ia抗原))、
(31)P2X5(プリン作動性受容体P2Xリガンド開口型イオンチャネル5)、
(32)CD72(B細胞分化抗原CD72、Lyb−2)、
(33)LY64(リンパ球抗原64(RP105)、ロイシンリッチリピート(LRR)ファミリーのI型膜タンパク質)、
(34)FcRH1(Fc受容体様タンパク質1)、
(35)FcRH5(IRTA2、免疫グロブリンスーパーファミリー受容体転座関連2)、
(36)TENB2(推定膜貫通プロテオグリカン)、
(37)PMEL17(シルバーホモログ、SILV、D12S53E、PMEL17、SI、SIL)、
(38)TMEFF1(EGF様及び2つのホリスタチン様ドメイン1を有する膜貫通タンパク質、トモレグリン−1)、
(39)GDNF−Ra1(GDNFファミリー受容体アルファ1、GFRA1、GDNFR、GDNFRA、RETL1、TRNR1、RET1L、GDNFR−アルファ1、GFR−ALPHA−1)、
(40)Ly6E(リンパ球抗原6複合体、遺伝子座E、Ly67、RIG−E、SCA−2、TSA−1)、
(41)TMEM46(シサホモログ2(アフリカツメガエル)、SHISA2)、
(42)Ly6G6D(リンパ球抗原6複合体、遺伝子座G6D、Ly6−D、MEGT1)、
(43)LGR5(ロイシンリッチリピート含有Gタンパク質共役受容体5、GPR49、GPR67)、
(44)RET(RETプロト癌遺伝子、MEN2A、HSCR1、MEN2B、MTC1、PTC、CDHF12、Hs.168114、RET51、RET−ELE1)、
(45)LY6K(リンパ球抗原6複合体、遺伝子座K、LY6K、HSJ001348、FLJ35226)、
(46)GPR19(Gタンパク質共役受容体19、Mm.4787)、
(47)GPR54(KISS1受容体、KISS1R、GPR54、HOT7T175、AXOR12)、
(48)ASPHD1(アスパラギン酸ベータヒドロキシラーゼドメイン含有1、LOC253982)、
(49)チロシナーゼ(TYR、OCAIA、OCA1A、チロシナーゼ、SHEP3)、
(50)TMEM118(リングフィンガータンパク質、膜貫通2、RNFT2、FLJ14627)、
(51)GPR172A(Gタンパク質共役受容体172A、GPCR41、FLJ11856、D15Ertd747e)、
(52)CD33、及び
(53)CLL−1、
Dが、以下の構造から選択されるアントラサイクリン誘導体であり、
式中、波線が、Lへの結合を示し、
Lが、−CH2O−、−CH2N(R)−、-N(R)-、-N(R)(C1-C12アルキレン)-、−N(R)(C2-C8アルケニレン)-、-N(R)(C2-C8アルキニレン)-、-N(R)(CH2CH2O)n-、及び以下の構造から選択されるリンカーであり、
式中、波線が、D及びZへの結合を示し、
Zが、-CH2C(O)-、-CH2C(O)NR(C1-C12アルキレン)-、及び以下の構造から選択される任意のスペーサーであり、
Rが、H、C1-C12アルキル、またはC6-C20アリールであり、
Z1が、-(C1-C12アルキレン)-、-(C2-C8アルケニレン)-、-(C2-C8アルキニレン)-、及び-(CH2CH2O)n-から選択され、
mが、0または1であり、
nが、1〜6であり、
pが、1〜8の整数であり、
アルキレン、アルケニレン、アルキニレン、アルキル、及びアリールが、F、Cl、Br、N(CH3)2、NO2、及びOCH3から選択される1つ以上の基で任意に置換される、抗体−薬物複合体化合物、またはその薬学的に許容される塩である。
別途明記されない限り、本明細書で使用される以下の用語及び語句は、以下の意味を有するよう意図されている。
本発明の化合物は、システイン操作抗体を含む抗体−薬物複合体を含み、そこで野生型または親抗体の1つ以上のアミノ酸がシステインアミノ酸(THIOMAB(商標))と置き換えられる。任意の形態の抗体がそのように操作され得る、すなわち変異させられ得る。例えば、親Fab抗体断片が操作されて、システイン操作Fabを形成することができる。同様に、親モノクローナル抗体が操作されて、THIOMAB(商標)を形成することができる。単一の部位変異が、Fab抗体断片に単一の操作されたシステイン残基を生成する一方で、単一の部位変異が、IgG抗体の二量体性質により、全長THIOMAB(商標)に2つの操作されたシステイン残基を生成することに留意されたい。置き換えられた(「操作された」)システイン(Cys)残基を有する変異体は、新たに導入された操作されたシステインチオール基の反応性について評価される。チオール反応性値は、0〜1.0の範囲の相対的な数値用語であり、任意のシステイン操作抗体に対して測定することができる。本発明のシステイン操作抗体のチオール反応性値は、0.6〜1.0、0.7〜1.0、または0.8〜1.0の範囲である。
腫瘍関連抗原:
(1)BMPR1B(骨形態形成タンパク質受容体IB型、Genbank受託番号 NM_001203)
ten Dijke,P.,et al Science 264(5155):101−104(1994),Oncogene 14(11):1377−1382(1997))、WO2004063362(請求項2)、WO2003042661(請求項12)、US2003134790−A1(38〜39貢)、WO2002102235(請求項13、296貢)、WO2003055443(91〜92貢)、WO200299122(実施例2、528〜530貢)、WO2003029421(請求項6)、WO2003024392(請求項2、図112)、WO200298358(請求項1、183貢)、WO200254940(100〜101貢)、WO200259377(349〜350貢)、WO200230268(請求項27、376貢)、WO200148204(実施例、図4)
NP_001194骨形態形成タンパク質受容体、IB型/pid=NP_001194.1−
相互参照:MIM:603248、NP_001194.1、AY065994
(2)E16(LAT1、SLC7A5、Genbank受託番号 NM_003486)
Biochem. Biophys. Res.Commun. 255(2),283−288(1999),Nature 395(6699):288−291(1998)、Gaugitsch,H.W.,et al(1992)J.Biol.Chem. 267(16):11267−11273)、WO2004048938(実施例2)、WO2004032842(実施例IV)、WO2003042661(請求項12)、WO2003016475(請求項1)、WO200278524(実施例2)、WO200299074(請求項19、127〜129貢)、WO200286443(請求項27、222貢、393貢)、WO2003003906(請求項10、293貢)、WO200264798(請求項33、93〜95貢)、WO200014228(請求項5、133〜136貢)、US2003224454(図3)、WO2003025138(請求項12、150貢)、
NP_003477溶質担体ファミリー7(カチオン性アミノ酸輸送体、y+
系)、メンバー5/pid=NP_003477.3−人類
相互参照:MIM:600182、NP_003477.3、NM_015923、NM_003486_1
(3)STEAP1(前立腺6膜貫通上皮抗原、Genbank受託番号 NM_012449)
Cancer Res.61(15),5857−5860(2001),Hubert,R.S.,et al(1999)Proc. Natl. Acad. Sci. U.S.A.96(25):14523−14528)、WO2004065577(請求項6)、WO2004027049(図1L)、EP1394274(実施例11)、WO2004016225(請求項2)、WO2003042661(請求項12)、US2003157089(実施例5)、US2003185830(実施例5)、US2003064397(図2)、WO200289747(実施例5、618〜619貢)、WO2003022995(実施例9、図13A、実施例53、173貢、実施例2、図2A)、
NP_036581前立腺6膜貫通上皮抗原
相互参照:MIM:604415、NP_036581.1、NM_012449_1
(4)0772P(CA125、MUC16、Genbank受託番号 AF361486)
J.Biol.Chem.276(29):27371−27375(2001))、WO2004045553(請求項14)、WO200292836(請求項6、図12)、WO200283866(請求項15、116〜121貢)、US2003124140(実施例16)、US798959 相互参照:GI:34501467、AAK74120.3、AF361486_1
(5)MPF(MPF、MSLN、SMR、巨核球増強因子、メソテリン、Genbank受託番号 NM_005823)Yamaguchi、N.,et al Biol.Chem. 269(2),805−808(1994),Proc. Natl. Acad. Sci. U.S.A.96(20):11531−11536(1999)、Proc. Natl.Acad.Sci.U.S.A.93(1):136−140(1996)、J.Biol.Chem.270(37):21984−21990(1995))、WO2003101283(請求項14)、(WO2002102235(請求項13、287〜288貢)、WO2002101075(請求項4、308〜309貢)、WO200271928(320〜321貢)、WO9410312(52〜57貢)、相互参照:MIM:601051、NP_005814.2、NM_005823_1
(6)Napi3b(NAPI−3B、NPTIIb、SLC34A2、溶質担体ファミリー34(リン酸ナトリウム)、メンバー2、II型ナトリウム依存性リン酸輸送体3b、Genbank受託番号 NM_006424)
J.Biol.Chem.277(22):19665−19672(2002),Genomics 62(2):281−284(1999),Feild,J.A.,et al(1999)Biochem.Biophys.Res.Commun.258(3):578−582)、WO2004022778(請求項2)、EP1394274(実施例11)、WO2002102235(請求項13、326貢)、EP875569(請求項1、17〜19貢)、WO200157188(請求項20、329貢)、WO2004032842(実施例IV)、WO200175177(請求項24、139〜140貢)、
相互参照:MIM:604217、NP_006415.1、NM_006424_1
(7)Sema 5b(FLJ10372、KIAA1445、Mm.42015、SEMA5B、SEMAG、セマフォリン5b Hlog、セマドメイン、7回トロンボスポンジン反復(1型及び1型様)、膜貫通ドメイン(TM)及び短細胞質ドメイン、(セマフォリン)5B、Genbank受託番号 AB040878)
Nagase T.,et al(2000)DNA Res.7(2):143−150)、WO2004000997(請求項1)、WO2003003984(請求項1)、WO200206339(請求項1、50貢)、WO200188133(請求項1、41〜43貢、48〜58貢)、WO2003054152(請求項20)、WO2003101400(請求項11)、
受託:Q9P283、EMBL、AB040878、BAA95969.1. Genew、HGNC:10737、
(8)PSCA hlg(2700050C12Rik、C530008O16Rik、RIKEN cDNA 2700050C12、RIKEN cDNA 2700050C12遺伝子、Genbank受託番号 AY358628)、Ross et al(2002)Cancer Res.62:2546−2553、US2003129192(請求項2)、US2004044180(請求項12)、US2004044179(請求項11)、US2003096961(請求項11)、US2003232056(実施例5)、WO2003105758(請求項12)、US2003206918(実施例5)、EP1347046(請求項1)、WO2003025148(請求項20)、
相互参照:GI:37182378、AAQ88991.1、AY358628_1
(9)ETBR(エンドセリンB型受容体、Genbank受託番号 AY275463)、
Nakamuta M.,et al Biochem.Biophys.Res.Commun.177,34−39,1991、Ogawa Y.,et al Biochem.Biophys.Res.Commun.178,248−255,1991、Arai H.,et al Jpn. Circ. J.56,1303−1307,1992、Arai H.,et al J.Biol.Chem. 268,3463−3470,1993、Sakamoto A.,Yanagisawa M.,et al Biochem. Biophys. Res.Commun. 178,656−663,1991、Elshourbagy N.A.,et al J.Biol. Chem.268,3873−3879,1993、Haendler B.,et al J.Cardiovasc.Pharmacol.20,s1−S4,1992、Tsutsumi M.,et al Gene 228,43−49,1999、Strausberg R.L.,et al Proc.Natl.Acad.Sci.U.S.A.99,16899−16903,2002、Bourgeois C.,et al J.Clin.Endocrinol. Metab. 82,3116−3123,1997、Okamoto Y.,et al Biol.Chem. 272,21589−21596,1997、Verheij J.B.,et al Am. J.Med. Genet.08,223−225、2002、Hofstra R.M.W.,et al Eur. J.Hum. Genet. 5,180−185,1997、Puffenberger E.G.,et al Cell 79,1257−1266,1994、Attie T.,et al,Hum. Mol.Genet.4,2407−2409,1995、Auricchio A.,et al Hum.Mol.Genet.5:351−354,1996、Amiel J.,et al Hum.Mol.Genet.5,355−357,1996、Hofstra R.M.W.,et al Nat.Genet.12,445−447,1996、Svensson P.J.,et al Hum.Genet. 103,145−148,1998、Fuchs S.,et al Mol. Med. 7,115−124,2001、Pingault V.,et al(2002)Hum. Genet. 111,198−206、WO2004045516(請求項1)、WO2004048938(実施例2)、WO2004040000(請求項151)、WO2003087768(請求項1)、WO2003016475(請求項1)、WO2003016475(請求項1)、WO200261087(図1)、WO2003016494(図6)、WO2003025138(請求項12、144貢)、WO200198351(請求項1、124〜125貢)、EP522868(請求項8、図2)、WO200177172(請求項1、297〜299貢)、US2003109676、US6518404(図3)、US5773223(請求項1a、第31〜34欄)、WO2004001004
(10)MSG783(RNF124、仮想タンパク質FLJ20315、Genbank受託番号 NM_017763)、
WO2003104275(請求項1)、WO2004046342(実施例2)、WO2003042661(請求項12)、WO2003083074(請求項14、61貢)、WO2003018621(請求項1)、WO2003024392(請求項2、図93)、WO200166689(実施例6)、
相互参照:LocusID:54894、NP_060233.2、NM_017763_1
(11) STEAP2(HGNC_8639、IPCA−1、PCANAP1、STAMP1、STEAP2、STMP、前立腺癌関連遺伝子1、前立腺癌関連タンパク質1、前立腺6膜貫通上皮抗原2、6膜貫通前立腺タンパク質、Genbank受託番号 AF455138)
Lab.Invest.82(11):1573−1582(2002))、WO2003087306、US2003064397(請求項1、図1)、WO200272596(請求項13、54〜55貢)、WO200172962(請求項1、図4B)、WO2003104270(請求項11)、WO2003104270(請求項16)、US2004005598(請求項22)、WO2003042661(請求項12)、US2003060612(請求項12、図10)、WO200226822(請求項23、図2)、WO200216429(請求項12、図10)、
相互参照:GI:22655488、AAN04080.1、AF455138_1
(12)TrpM4(BR22450、FLJ20041、TRPM4、TRPM4B、一過性受容体電位カチオンチャネル、サブファミリーM、メンバー4、Genbank受託番号 NM_017636)
Xu,X.Z.,et al Proc.Natl.Acad.Sci.U.S.A.98(19):10692−10697(2001),Cell 109(3):397−407(2002),J.Biol.Chem.278(33):30813−30820(2003))、US2003143557(請求項4)、WO200040614(請求項14、100〜103貢)、WO200210382(請求項1、図9A)、WO2003042661(請求項12)、WO200230268(請求項27、391貢)、US2003219806(請求項4)、WO200162794(請求項14、図1A〜D)、
相互参照:MIM:606936、NP_060106.2、NM_017636_1
(13)CRIPTO(CR、CR1、CRGF、CRIPTO、TDGF1、奇形癌腫由来成長因子、Genbank受託番号 NP_003203またはNM_003212)
Ciccodicola,A.,et al EMBO J.8(7):1987−1991(1989),Am. J.Hum. Genet. 49(3):555−565(1991))、US2003224411(請求項1)、WO2003083041(実施例1)、WO2003034984(請求項12)、WO200288170(請求項2、52〜53貢)、WO2003024392(請求項2、図58)、WO200216413(請求項1、94〜95貢、105貢)、WO200222808(請求項2、図1)、US5854399(実施例2、第17〜18欄)、US5792616(図2)、
相互参照:MIM:187395、NP_003203.1、NM_003212_1
(14)CD21(CR2(補体受容体2)またはC3DR(C3d/エプスタインバーウイルス受容体)またはHs.73792、Genbank受託番号 M26004)
Fujisaku et al(1989)J.Biol.Chem.264(4):2118−2125)、Weis J.J.,et al J.Exp.Med.167,1047−1066,1988、Moore M.,et al Proc.Natl. Acad.Sci.U.S.A.84,9194−9198,1987、Barel M.,et al Mol.Immunol.35,1025−1031,1998、Weis J.J.,et al Proc.Natl.Acad.Sci.U.S.A.83,5639−5643,1986、Sinha S.K.,et al(1993)J.Immunol. 150,5311−5320、WO2004045520(実施例4)、US2004005538(実施例1)、WO2003062401(請求項9)、WO2004045520(実施例4)、WO9102536(図9.1〜9.9)、WO2004020595(請求項1)、
受託:P20023、Q13866、Q14212、EMBL、M26004、AAA35786.1.
(15)CD79b(CD79B、CD79β、IGb(免疫グロブリン関連ベータ)、B29、Genbank受託番号 NM_000626または11038674)
Proc. Natl.Acad.Sci.U.S.A.(2003)100(7):4126−4131,Blood(2002)100(9):3068−3076,Muller et al (1992)Eur.J.Immunol.22(6):1621−1625)、WO2004016225(請求項2、図140)、WO2003087768、US2004101874(請求項1、102貢)、WO2003062401(請求項9)、WO200278524(実施例2)、US2002150573(請求項5、15貢)、US5644033、WO2003048202(請求項1、306及び309貢)、WO99/558658、US6534482(請求項13、図17A/B)、WO200055351(請求項11、1145〜1146貢)、
相互参照:MIM:147245、NP_000617.1、NM_000626_1
(16)FcRH2(IFGP4、IRTA4、SPAP1A(SH2ドメイン含有ホスファターゼアンカータンパク質1a)、SPAP1B、SPAP1C、Genbank受託番号 NM_030764、AY358130)
Genome Res.13(10):2265−2270(2003),Immunogenetics 54(2):87−95(2002),Blood 99(8):2662−2669(2002),Proc.Natl.Acad.Sci.U.S.A.98(17):9772−9777(2001),Xu,M.J.,et al(2001)Biochem.Biophys.Res.Commun. 280(3):768−775、WO2004016225(請求項2)、WO2003077836、WO200138490(請求項5、図18D−1〜18D−2)、WO2003097803(請求項12)、WO2003089624(請求項25)、
相互参照:MIM:606509、NP_110391.2、NM_030764_1
(17)HER2(ErbB2、Genbank受託番号 M11730)
Coussens L.,et al Science(1985)230(4730):1132−1139)、Yamamoto T.,et al Nature 319,230−234,1986、Semba K.,et al Proc.Natl.Acad.Sci.U.S.A.82,6497−6501,1985、Swiercz J.M.,et al J.Cell Biol.165,869−880,2004、Kuhns J.J.,et al J.Biol.Chem. 274,36422−36427,1999、Cho H.−S.,et al Nature 421,756−760,2003、Ehsani A.,et al(1993)Genomics 15,426−429、WO2004048938(実施例2)、WO2004027049(図1I)、WO2004009622、WO2003081210、WO2003089904(請求項9)、WO2003016475(請求項1)、US2003118592、WO2003008537(請求項1)、WO2003055439(請求項29、図1A〜B)、WO2003025228(請求項37、図5C)、WO200222636(実施例13、95〜107貢)、WO200212341(請求項68、図7)、WO200213847(71〜74貢)、WO200214503(114〜117貢)、WO200153463(請求項2、41〜46貢)、WO200141787(15貢)、WO200044899(請求項52、図7)、WO200020579(請求項3、図2)、US5869445(請求項3、第31〜38欄)、WO9630514(請求項2、56〜61貢)、EP1439393(請求項7)、WO2004043361(請求項7)、WO2004022709、WO200100244(実施例3、図4)、
受託:P04626、EMBL、M11767、AAA35808.1. EMBL、M11761、AAA35808.1.
(18)NCA(CEACAM6、Genbank受託番号 M18728)、
Barnett T.,et al Genomics 3,59−66,1988、Tawaragi Y.,et al Biochem.Biophys.Res.Commun.150,89−96,1988、Strausberg R.L.,et al Proc.Natl.Acad.Sci.U.S.A.99:16899−16903,2002、WO2004063709、EP1439393(請求項7)、WO2004044178(実施例4)、WO2004031238、WO2003042661(請求項12)、WO200278524(実施例2)、WO200286443(請求項27、427貢)、WO200260317(請求項2)、
受託:P40199、Q14920、EMBL、M29541、AAA59915.1.MBL、M18728
(19)MDP(DPEP1、Genbank受託番号 BC017023)
Proc.Natl.Acad.Sci.U.S.A.99(26):16899−16903(2002))、WO2003016475(請求項1)、WO200264798(請求項33、85〜87貢)、JP05003790(図6〜8)、WO9946284(図9)、
相互参照:MIM:179780、AAH17023.1、BC017023_1
(20)IL20Rα(IL20Ra、ZCYTOR7、Genbank受託番号 AF184971)、
Clark H.F.,et al Genome Res.13,2265−2270,2003、Mungall A.J.,et al Nature 425,805−811,2003、Blumberg H.,et al Cell 104,9−19,2001、Dumoutier L.,et al J.Immunol.167,3545−3549,2001、Parrish−Novak J.,et al J.Biol.Chem.277,47517−47523,2002、Pletnev S.,et al(2003)Biochemistry 42:12617−12624、Sheikh F.,et al(2004)J.Immunol. 172,2006−2010、EP1394274(実施例11)、US2004005320(実施例5)、WO2003029262(74〜75貢)、WO2003002717(請求項2、63貢)、WO200222153(45〜47貢)、US2002042366(20〜21貢)、WO200146261(57〜59貢)、WO200146232(63〜65貢)、WO9837193(請求項1、55〜59貢)、
受託:Q9UHF4、Q6UWA9、Q96SH8、EMBL、AF184971、AAF01320.1.
(21)ブレビカン(BCAN、BEHAB、Genbank受託番号 AF229053)
Gary S.C.,et al Gene 256,139−147,2000、Clark H.F.,et al Genome Res.13,2265−2270,2003、Strausberg R.L.,et al Proc.Natl.Acad.Sci.U.S.A.99,16899−16903,2002、US2003186372(請求項11)、US2003186373(請求項11)、US2003119131(請求項1、図52)、US2003119122(請求項1、図52)、US2003119126(請求項1)、US2003119121(請求項1、図52)、US2003119129(請求項1)、US2003119130(請求項1)、US2003119128(請求項1、図52)、US2003119125(請求項1)、WO2003016475(請求項1)、WO200202634(請求項1)、
(22)EphB2R(DRT、ERK、Hek5、EPHT3、Tyro5、Genbank受託番号 NM_004442)
Chan,J.and Watt,V.M.,Oncogene 6(6),1057−1061(1991)Oncogene 10(5):897−905(1995),Annu. Rev.Neurosci. 21:309−345(1998),Int.Rev.Cytol.196:177−244(2000))、WO2003042661(請求項12)、WO200053216(請求項1、41貢)、WO2004065576(請求項1)、WO2004020583(請求項9)、WO2003004529(128〜132貢)、WO200053216(請求項1、42貢)、
相互参照:MIM:600997、NP_004433.2、NM_004442_1
(23)ASLG659(B7h、Genbank受託番号 AX092328)
US20040101899(請求項2)、WO2003104399(請求項11)、WO2004000221(図3)、US2003165504(請求項1)、US2003124140(実施例2)、US2003065143(図60)、WO2002102235(請求項13、299貢)、US2003091580(実施例2)、WO200210187(請求項6、図10)、WO200194641(請求項12、図7b)、WO200202624(請求項13、図1A〜1B)、US2002034749(請求項54、45〜46貢)、WO200206317(実施例2、320〜321貢、請求項34、321〜322貢)、WO200271928(468〜469貢)、WO200202587(実施例1、図1)、WO200140269(実施例3、190〜192貢)、WO200036107(実施例2、205〜207貢)、WO2004053079(請求項12)、WO2003004989(請求項1)、WO200271928(233〜234貢、452〜453貢)、WO0116318、
(24)PSCA(前立腺幹細胞抗原前駆体、Genbank受託番号 AJ297436)
Reiter R.E.,et al Proc.Natl.Acad. Sci. U.S.A.95,1735−1740,1998、Gu Z.,et al Oncogene 19,1288−1296,2000、Biochem.Biophys. Res.Commun. (2000)275(3):783−788、WO2004022709、EP1394274(実施例11)、US2004018553(請求項17)、WO2003008537(請求項1)、WO200281646(請求項1、164貢)、WO2003003906(請求項10、288貢)、WO200140309(実施例1、図17)、US2001055751(実施例1、図1b)、WO200032752(請求項18、図1)、WO9851805(請求項17、97貢)、WO9851824(請求項10、94貢)、WO9840403(請求項2、図1B)、
受託:O43653、EMBL、AF043498、AAC39607.1.
(25)GEDA(Genbank受託番号 AY260763)、
AAP14954脂肪腫HMGIC融合パートナー様タンパク質/pid=AAP14954.1−人類
種:人類(ヒト)
WO2003054152(請求項20)、WO2003000842(請求項1)、WO2003023013(実施例3、請求項20)、US2003194704(請求項45)、
相互参照:GI:30102449、AAP14954.1、AY260763_1
(26)BAFF−R(B細胞活性化因子受容体、BLyS受容体3、BR3、Genbank受託番号 AF116456)、BAFF受容体/pid=NP_443177.1−人類
Thompson,J.S.,et al Science 293(5537),2108−2111(2001)、WO2004058309、WO2004011611、WO2003045422(実施例、32〜33貢)、WO2003014294(請求項35、図6B)、WO2003035846(請求項70、615〜616貢)、WO200294852(第136〜137欄)、WO200238766(請求項3、133貢)、WO200224909(実施例3、図3)、
相互参照:MIM:606269、NP_443177.1、NM_052945_1、AF132600
(27)CD22(B細胞受容体CD22−Bアイソフォーム、BL−CAM、Lyb−8、Lyb8、SIGLEC−2、FLJ22814、Genbank受託番号 AK026467)、
Wilson et al(1991)J.Exp. Med. 173:137−146、WO2003072036(請求項1、図1)、
相互参照:MIM:107266、NP_001762.1、NM_001771_1
(28)CD79a(CD79A、CD79α、免疫グロブリン関連アルファ、Igベータ(CD79B)と共有的に相互作用し、Ig M分子を有する表面上に複合体を形成し、B細胞分化に関与するシグナルを伝達するB細胞特異的タンパク質)、pI:4.84、MW:25028 TM:2[P]遺伝子染色体:19q13.2、Genbank受託番号 NP_001774.10)
WO2003088808、US20030228319、WO2003062401(請求項9)、US2002150573(請求項4、13〜14貢)、WO9958658(請求項13、図16)、WO9207574(図1)、US5644033、Ha et al(1992)J.Immunol.148(5):1526−1531、Mueller et al(1992)Eur.J.Biochem.22:1621−1625、Hashimoto et al(1994)Immunogenetics 40(4):287−295、Preud’homme et al(1992)Clin.Exp.Immunol.90(1):141−146、Yu et al(1992)J.Immunol.148(2)633−637、Sakaguchi et al(1988)EMBO J.7(11):3457−3464
(29)CXCR5(バーキットリンパ腫受容体1、CXCL13ケモカインによって活性化され、リンパ球移動及び体液性防御において機能し、HIV−2感染、ならびに恐らくAIDS、リンパ腫、骨髄腫、及び白血病の発症に関与するGタンパク質共役受容体)、372aa、pI:8.54 MW:41959 TM:7[P]遺伝子染色体:11q23.3、Genbank受託番号 NP_001707.1)
WO2004040000、WO2004015426、US2003105292(実施例2)、US6555339(実施例2)、WO200261087(図1)、WO200157188(請求項20、269貢)、WO200172830(12〜13貢)、WO200022129(実施例1、152〜153貢、実施例2、254〜256貢)、WO9928468(請求項1、38貢)、US5440021(実施例2、第49〜52欄)、WO9428931(56〜58貢)、WO9217497(請求項7、図5)、Dobner et al(1992)Eur. J.Immunol.22:2795−2799、Barella et al(1995)Biochem.J.309:773−779、
(30)HLA−DOB(ペプチドに結合してそれらをCD4+Tリンパ球に提示するMHCクラスII分子のベータサブユニット(Ia抗原))、273aa、pI:6.56 MW:30820 TM:1[P]遺伝子染色体:6p21.3、Genbank受託番号 NP_002111.1)
Tonnelle et al(1985)EMBO J.4(11):2839−2847、Jonsson et al(1989)Immunogenetics 29(6):411−413、Beck et al(1992)J.Mol.Biol.228:433−441、Strausberg et al(2002)Proc.Natl. Acad. Sci USA 99:16899−16903、Servenius et al(1987)J.Biol. Chem. 262:8759−8766、Beck et al(1996)J.Mol. Biol. 255:1−13、Naruse et al(2002)Tissue Antigens 59:512−519、WO9958658(請求項13、図15)、US6153408(第35〜38欄)、US5976551(第168〜170欄)、US6011146(第145〜146欄)、Kasahara et al(1989)Immunogenetics 30(1):66−68、Larhammar et al(1985)J.Biol.Chem.260(26):14111−14119
(31)P2X5(プリン作動性受容体P2Xリガンド開口型イオンチャネル5、細胞外ATPによって開口されたイオンチャネル、シナプス伝達及び神経新生に関与している可能性があり、欠損は特発性排尿筋不安定の病態生理学に寄与し得る)、422aa)、pI:7.63、MW:47206 TM:1[P]遺伝子染色体:17p13.3、Genbank受託番号 NP_002552.2)
Le et al(1997)FEBS Lett. 418(1−2):195−199、WO2004047749、WO2003072035(請求項10)、Touchman et al(2000)Genome Res.10:165−173、WO200222660(請求項20)、WO2003093444(請求項1)、WO2003087768(請求項1)、WO2003029277(82貢)
(32)CD72(B細胞分化抗原CD72、Lyb−2)PROTEIN SEQUENCE Full maeaity...tafrfpd(1..359、359aa)、pI:8.66、MW:40225 TM:1[P]遺伝子染色体:9p13.3、Genbank受託番号 NP_001773.1)
WO2004042346(請求項65)、WO2003026493(51〜52貢、57〜58貢)、WO200075655(105〜106貢)、Von Hoegen et al(1990)J.Immunol.144(12):4870−4877、Strausberg et al(2002)Proc.Natl.Acad.Sci USA 99:16899−16903
(33)LY64(リンパ球抗原64(RP105)、ロイシンリッチリピート(LRR)ファミリーのI型膜タンパク質、B細胞活性化及びアポトーシスを調節し、機能喪失は全身性紅斑性狼瘡を有する患者における疾患活動性の増加に関連している)、661aa、pI:6.20、MW:74147 TM:1[P]遺伝子染色体:5q12、Genbank受託番号 NP_005573.1)
US2002193567、WO9707198(請求項11、39〜42貢)、Miura et al(1996)Genomics 38(3):299−304、Miura et al(1998)Blood 92:2815−2822、WO2003083047、WO9744452(請求項8、57〜61貢)、WO200012130(24〜26貢)
(34)FcRH1(Fc受容体様タンパク質1、C2型Ig様及びITAMドメインを含有する免疫グロブリンFcドメインの推定受容体、Bリンパ球分化に関与する可能性がある)、429aa、pI:5.28、MW:46925 TM:1[P]遺伝子染色体:1q21−1q22、Genbank受託番号 NP_443170.1)
WO2003077836、WO200138490(請求項6、図18E−1〜18−E−2)、Davis et al(2001)Proc.Natl.Acad.Sci USA 98(17):9772−9777、WO2003089624(請求項8)、EP1347046(請求項1)、WO2003089624(請求項7)
(35)IRTA2(免疫グロブリンスーパーファミリー受容体転座関連2、B細胞発生及びリンパ腫新生に関与する可能性のある推定免疫受容体、転座による遺伝子の調節解除がいくつかのB細胞悪性腫瘍で生じる)、977aa、pI:6.88 MW:106468 TM:1[P]遺伝子染色体:1q21、Genbank受託番号 ヒト:AF343662、AF343663、AF343664、AF343665、AF369794、AF397453、AK090423、AK090475、AL834187、AY358085、マウス:AK089756、AY158090、AY506558、NP_112571.1
WO2003024392(請求項2、図97)、Nakayama et al(2000)Biochem.Biophys.Res.Commun.277(1):124−127、WO2003077836、WO200138490(請求項3、図18B−1〜18B−2)
(36)TENB2(TMEFF2、トモレグリン、TPEF、HPP1、TR、推定膜貫通プロテオグリカン、成長因子及びホリスタチンのEGF/ヘレグリンファミリーに関連)、374aa、NCBI受託:AAD55776、AAF91397、AAG49451、NCBI RefSeq、NP_057276、NCBI遺伝子:23671、OMIM:605734、SwissProt Q9UIK5、Genbank受託番号 AF179274、AY358907、CAF85723、CQ782436
WO2004074320(配列番号810)、JP2004113151(配列番号2、4、8)、WO2003042661(配列番号580)、WO2003009814(配列番号411)、EP1295944(69〜70貢)、WO200230268(329貢)、WO200190304(配列番号2706)、US2004249130、US2004022727、WO2004063355、US2004197325、US2003232350、US2004005563、US2003124579、Horie et al(2000)Genomics 67:146−152、Uchida et al(1999)Biochem.Biophys.Res.Commun.266:593−602、Liang et al(2000)Cancer Res.60:4907−12、Glynne−Jones et al(2001)Int J Cancer.Oct 15;94(2):178−84
(37)PMEL17(シルバーホモログ、SILV、D12S53E、PMEL17、SI、SIL)、ME20、gp100)BC001414、BT007202、M32295、M77348、NM_006928、McGlinchey,R.P. et al(2009)Proc.Natl.Acad.Sci.U.S.A.106(33),13731−13736、Kummer,M.P.et al(2009)J.Biol.Chem.284(4),2296−2306
(38)TMEFF1(EGF様及び2つのホリスタチン様ドメイン1を有する膜貫通タンパク質、トモレグリン−1)、H7365、C9orf2、C9ORF2、U19878、X83961、NM_080655、NM_003692、Harms,P.W.(2003)Genes Dev.17(21),2624−2629、Gery,S.et al(2003)Oncogene 22(18):2723−2727
(39)GDNF−Ra1(GDNFファミリー受容体アルファ1、GFRA1、GDNFR、GDNFRA、RETL1、TRNR1、RET1L、GDNFR−アルファ1、GFR−ALPHA−1)、U95847、BC014962、NM_145793 NM_005264、Kim,M.H. et al(2009)Mol. Cell.Biol.29(8),2264−2277、Treanor,J.J.et al(1996)Nature 382(6586):80−83
(40)Ly6E(リンパ球抗原6複合体、遺伝子座E、Ly67、RIG−E、SCA−2、TSA−1)、NP_002337.1、NM_002346.2、de Nooij−van Dalen,A.G. et al(2003)Int.J.Cancer 103(6),768−774、Zammit,D.J.et al(2002)Mol.Cell.Biol.22(3):946−952
(41)TMEM46(シサホモログ2(アフリカツメガエル)、SHISA2)、NP_001007539.1、NM_001007538.1、Furushima,K.et al(2007)Dev.Biol.306(2),480−492、Clark,H.F.et al(2003)Genome Res.13(10):2265−2270
(42)Ly6G6D(リンパ球抗原6複合体、遺伝子座G6D、Ly6−D、MEGT1)、NP_067079.2、NM_021246.2、Mallya,M. et al(2002)Genomics 80(1):113−123、Ribas,G. et al(1999)J.Immunol.163(1):278−287
(43)LGR5(ロイシンリッチリピート含有Gタンパク質共役受容体5、GPR49、GPR67)、NP_003658.1、NM_003667.2、Salanti,G.et al(2009)Am.J.Epidemiol.170(5):537−545、Yamamoto,Y.et al(2003)Hepatology 37(3):528−533
(44)RET(RETプロト癌遺伝子、MEN2A、HSCR1、MEN2B、MTC1、PTC、CDHF12、Hs.168114、RET51、RET−ELE1)、NP_066124.1、NM_020975.4、Tsukamoto,H.et al(2009)Cancer Sci. 100(10):1895−1901、Narita,N.et al(2009)Oncogene 28(34):3058−3068
(45)LY6K(リンパ球抗原6複合体、遺伝子座K、LY6K、HSJ001348、FLJ35226)、NP_059997.3、NM_017527.3、Ishikawa,N.et al(2007)Cancer Res. 67(24):11601−11611、de Nooij−van Dalen,A.G.et al(2003)Int. J.Cancer 103(6):768−774
(46)GPR19(Gタンパク質共役受容体19、Mm.4787)、NP_006134.1、NM_006143.2、Montpetit,A.and Sinnett,D.(1999)Hum.Genet.105(1−2):162−164、O’Dowd,B.F.et al(1996)FEBS Lett.394(3):325−329
(47)GPR54(KISS1受容体、KISS1R、GPR54、HOT7T175、AXOR12)、NP_115940.2、NM_032551.4、Navenot,J.M.et al(2009)Mol.Pharmacol.75(6):1300−1306、Hata,K.et al(2009)Anticancer Res.29(2):617−623、
(48)ASPHD1(アスパラギン酸ベータヒドロキシラーゼドメイン含有1、LOC253982)、NP_859069.2、NM_181718.3、Gerhard,D.S.et al(2004)Genome Res.14(10B):2121−2127
(49)チロシナーゼ(TYR、OCAIA、OCA1A、チロシナーゼ、SHEP3)、NP_000363.1、NM_000372.4、Bishop,D.T.et al(2009)Nat.Genet.41(8):920−925、Nan,H.et al(2009)Int.J.Cancer 125(4):909−917、
(50)TMEM118(リングフィンガータンパク質、膜貫通2、RNFT2、FLJ14627)、NP_001103373.1、NM_001109903.1、Clark,H.F.et al(2003)Genome Res.13(10):2265−2270、Scherer,S.E.et al(2006)Nature 440(7082):346−351
(51)GPR172A(Gタンパク質共役受容体172A、GPCR41、FLJ11856、D15Ertd747e)、NP_078807.1、NM_024531.3、Ericsson,T.A.et al(2003)Proc.Natl.Acad.Sci.U.S.A.100(11):6759−6764、Takeda,S.et al(2002)FEBS Lett. 520(1−3):97−101.
(52)シアル酸結合免疫グロブリン様レクチンファミリーのメンバーであるCD33は、67kDaグリコシル化膜貫通タンパク質である。CD33は、関与する骨髄単核細胞及び赤血球前駆細胞に加えて、大半の脊髄細胞及び単球白血病細胞上で発現する。これは、最も初期の多能性幹細胞、成熟顆粒球、リンパ球細胞、または非造血細胞上では見られない(Sabbath et al.,(1985)J.Clin.Invest.75:756−56、Andrews et al.,(1986)Blood 68:1030−5).CD33は、その細胞質尾部上に2つのチロシン残基を含有し、それらの各々の後に、多くの阻害受容体に見られる免疫受容体チロシンベースの阻害モチーフ(ITIM)と同様の疎水性残基が続く。
(53)CLL−1(CLEC12A、MICL、及びDCAL2)は、C型レクチン/C型レクチン様ドメイン(CTL/CTLD)スーパーファミリーのメンバーをコードする。このファミリーのメンバーは、共通のタンパク質折り畳みを共有し、細胞接着、細胞間シグナル伝達、糖タンパク質代謝回転等の種々の機能を有し、炎症及び免疫応答に関与する。この遺伝子によってコードされたタンパク質は、顆粒球及び単球機能の負の調節因子である。この遺伝子のいくつかの選択的にスプライスされた転写物変異形について説明されているが、これらの変異形のうちのいくつかの全長性質は決定されていない。この遺伝子は、染色体12p13上のナチュラルキラー遺伝子複合体領域における他のCTL/CTLDスーパーファミリーメンバーに密接に連結している(Drickamer K(1999)Curr.Opin.Struct.Biol.9(5):585−90、van Rhenen A,et al.,(2007)Blood 110(7):2659−66、Chen CH,et al. (2006)Blood 107(4):1459−67、Marshall AS,et al.(2006)Eur.J.Immunol.36(8):2159−69、Bakker AB,et al(2005)Cancer Res.64(22):8443−50、Marshall AS,et al(2004)J.Biol.Chem.279(15):14792−802)。CLL−1は、(カルシウムまたは糖のいずれかに結合することは予測されない)単一のC型レクチン様ドメイン、ストーク領域、膜貫通ドメイン、及びITIMモチーフを含有する短い細胞質尾部を含むII型膜貫通受容体であると示されている。
表3のADCの抗CD22抗体は、US8226945によると、3つの軽鎖超可変領域(HVR−L1、HVR−L2、及びHVR−L3)ならびに3つの重鎖超可変領域(HVR−H1、HVR−H2、及びHVR−H3)を含む。
ある特定の実施形態では、表3のADCは、抗HER2抗体を含む。本発明の一実施形態では、本発明のADCの抗HER2抗体は、ヒト化抗HER2抗体、例えば、参照により本明細書に具体的に組み込まれるUS5821337の表3に記載のhuMAb4D5−1、huMAb4D5−2、huMAb4D5−3、huMAb4D5−4、huMAb4D5−5、huMAb4D5−6、huMAb4D5−7、及びhuMAb4D5−8を含む。それらの抗体は、HER2に結合するマウス抗体(4D5)の相補性決定領域を有するヒトフレームワーク領域を含有する。ヒト化抗体huMAb4D5−8は、HERCEPTIN(登録商標)という商標名で市販されているトラスツズマブとも称される。本発明の別の実施形態では、本発明のADCの抗HER2抗体は、ヒト化抗HER2抗体、例えば、US7862817に記載のヒト化2C4を含む。例示のヒト化2C4抗体は、PERJETA(登録商標)という商標名で市販されているペルツズマブである。
表2のADCの抗CD33抗体15G15.33は、3つの軽鎖超可変領域(HVR−L1、HVR−L2、及びHVR−L3)ならびに3つの重鎖超可変領域(HVR−H1、HVR−H2、及びHVR−H3)を含む。
EIVLTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGVNSV
SGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPWTFGQGTKVEIK
(配列番号13)
QVQLVQSGAEVKKPGSSVKVSCKASGGIFSNHAISWVRQAPGQGLEWMGGIIPIFGTANY
AQKFQGRVTITADESTSTAFMELSSLRSEDTAVYYCAREWADVFDIWGQGTMVTVSS
(配列番号14)
抗CD33抗体9C3及び他の実施形態
9C3 VL
DIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKRLIYAASSLQSGVPSRF
SGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPWTFGQGTKLEIK
(配列番号21)
9C3 VH
EVQLVESGGALIQPGGSLRLSCVASGFTISGNYMSWVRQAPGKGLEWVSLIYSGDSTYYADS
VKGRFNISRDISKNTVYLQMNSLRVEDTAVYYCVRDGYYVSDMVVWGKGTTVTVSS
(配列番号22)
9C3.2 VL
DIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKRLIYAASSLQSGVPSRF
SGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPWTFGQGTKLEIK
(配列番号23)
9C3.2 VH
EVQLVESGGALIQPGGSLRLSCVASGFTISGNYMSWVRQAPGKGLEWVSLIYSGDSTYYADS
VKGRFTISRDISKNTVYLQMNSLRVEDTAVYYCVRDGYYVSDMVVWGKGTTVTVSS
(配列番号24)
9C3.3 VL
DIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKRLIYAASSLQSGVPSRF
SGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPWTFGQGTKLEIK
(配列番号25)
9C3.3 VH
EVQLVESGGALIQPGGSLRLSCVASGFTISGNYMSWVRQAPGKGLEWVSLIYSGDSTYYADS
VKGRFSISRDISKNTVYLQMNSLRVEDTAVYYCVRDGYYVSDMVVWGKGTTVTVSS
(配列番号26)
9C3.4 VL
DIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKRLIYAASSLQSGVPSRF
SGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPWTFGQGTKLEIK
(配列番号27)
9C3.4 VH
EVQLVESGGALIQPGGSLRLSCVASGFTISGNYMSWVRQAPGKGLEWVSLIYSGDSTYYADS
VKGRFAISRDISKNTVYLQMNSLRVEDTAVYYCVRDGYYVSDMVVWGKGTTVTVSS
(配列番号28)
本発明の抗体−薬物複合体化合物は、ケトン基にてジスルフィド基で誘導体化されたPNU−15682部分から成るアントラサイクリンジスルフィド中間体を含む。
Ant-L-(Z)m-X I
式中、Antが、以下の構造から選択され、
式中、波線が、Lへの結合を示し、
Lが、−CH2O−、−CH2N(R)−、-N(R)-、-N(R)(C1-C12アルキレン)-、−N(R)(C2-C8アルケニレン)-、-N(R)(C2-C8アルキニレン)-、-N(R)(CH2CH2O)n-、及び以下の構造から選択されるリンカーであり、
式中、波線が、Ant及びZへの結合を示し、
Zが、-CH2C(O)-、-CH2C(O)NR(C1-C12アルキレン)-、及び以下の構造から選択される任意のスペーサーであり、
式中、波線が、L及びXへの結合を示し、
Rが、H、C1-C12アルキル、またはC6-C20アリールであり、
Z1が、-(C1-C12アルキレン)-、-(C2-C8アルケニレン)-、-(C2-C8アルキニレン)-、-O(C1-C12アルキレン)-、-O(C2-C8アルケニレン)-、-O(C2-C8アルキニレン)-、及び-(CH2CH2O)n-から選択され、
mが、0または1であり、
nが、1〜6であり、
Xが、ピリジルジスルフィドであり、この場合、ピリジルが、NO2、Cl、F、CN、及びBrから選択される1つ以上の基で任意に置換され、
アルキレン、アルケニレン、アルキニレン、アルキル、及びアリールが、F、Cl、Br、N(CH3)2、NO2、及びOCH3から選択される1つ以上の基で任意に置換される。
本発明の抗体−薬物複合体(ADC)化合物は、強力なアントラサイクリン薬物部分に連結された腫瘍関連抗原に特異的な抗体を含み、癌を含むいくつかの過剰増殖性障害に対して有効な治療活性を有するものを含む。薬物部分の生物学的活性は、抗体への複合によって調節される。本発明のADCは、有効用量のアントラサイクリン薬物、または毒素を腫瘍細胞または部位に選択的に送達し、それにより、治療指数(「治療濃度域」)を増加させながら、より高い選択性、すなわち、より低い効果的用量が達成され得る。例示の実施形態では、ADC化合物は、リンカーによってアントラサイクリン薬物部分に複合される、すなわち共有結合されるシステイン操作抗体を含む。
Ab-S−S-(Zm-L-D)pII
またはその薬学的に許容される塩を有し、
式中、Abが、(1)〜(53)から選択される1つ以上の腫瘍関連抗原または細胞表面受容体に結合する抗体であり、
(1)BMPR1B(骨形態形成タンパク質受容体IB型)、
(2)E16(LAT1、SLC7A5)、
(3)STEAP1(前立腺6膜貫通上皮抗原)、
(4)MUC16(0772P、CA125)、
(5)MPF(MPF、MSLN、SMR、巨核球増強因子、メソテリン)、
(6)Napi2b(NAPI−3B、NPTIIb、SLC34A2、溶質担体ファミリー34(リン酸ナトリウム)、メンバー2、II型ナトリウム依存性リン酸輸送体3b)、
(7)Sema 5b(FLJ10372、KIAA1445、Mm.42015、SEMA5B、SEMAG、セマフォリン5b Hlog、セマドメイン、7回トロンボスポンジン反復(1型及び1型様)、膜貫通ドメイン(TM)及び短細胞質ドメイン、(セマフォリン)5B)、
(8)PSCA hlg(2700050C12Rik、C530008O16Rik、RIKEN cDNA 2700050C12、RIKEN cDNA 2700050C12遺伝子)、
(9)ETBR(エンドセリンB型受容体)、
(10)MSG783(RNF124、仮想タンパク質FLJ20315)、
(11)STEAP2(HGNC_8639、IPCA−1、PCANAP1、STAMP1、STEAP2、STMP、前立腺癌関連遺伝子1、前立腺癌関連タンパク質1、前立腺6膜貫通上皮抗原2、6膜貫通前立腺タンパク質)、
(12)TrpM4(BR22450、FLJ20041、TRPM4、TRPM4B、一過性受容体電位カチオンチャネル、サブファミリーM、メンバー4)、
(13)CRIPTO(CR、CR1、CRGF、CRIPTO、TDGF1、奇形癌腫由来成長因子)、
(14)CD21(CR2(補体受容体2)またはC3DR(C3d/エプスタインバーウイルス受容体)またはHs 73792)、
(15)CD79b(CD79B、CD79β、IGb(免疫グロブリン関連ベータ)、B29)、
(16)FcRH2(IFGP4、IRTA4、SPAP1A(SH2ドメイン含有ホスファターゼアンカータンパク質1a)、SPAP1B、SPAP1C)、
(17)HER2、
(18)NCA、
(19)MDP、
(20)IL20Rα、
(21)ブレビカン、
(22)EphB2R、
(23)ASLG659、
(24)PSCA、
(25)GEDA、
(26)BAFF−R(B細胞活性化因子受容体、BLyS受容体3、BR3)、
(27)CD22(B細胞受容体CD22−Bアイソフォーム)、
(28)CD79a(CD79A、CD79α、免疫グロブリン関連アルファ)、
(29)CXCR5(バーキットリンパ腫受容体1)、
(30)HLA−DOB(MHCクラスII分子のベータサブユニット(Ia抗原))、
(31)P2X5(プリン作動性受容体P2Xリガンド開口型イオンチャネル5)、
(32)CD72(B細胞分化抗原CD72、Lyb−2)、
(33)LY64(リンパ球抗原64(RP105)、ロイシンリッチリピート(LRR)ファミリーのI型膜タンパク質)、
(34)FcRH1(Fc受容体様タンパク質1)、
(35)FcRH5(IRTA2、免疫グロブリンスーパーファミリー受容体転座関連2)、
(36)TENB2(推定膜貫通プロテオグリカン)、
(37)PMEL17(シルバーホモログ、SILV、D12S53E、PMEL17、SI、SIL)、
(38)TMEFF1(EGF様及び2つのホリスタチン様ドメイン1を有する膜貫通タンパク質、トモレグリン−1)、
(39)GDNF−Ra1(GDNFファミリー受容体アルファ1、GFRA1、GDNFR、GDNFRA、RETL1、TRNR1、RET1L、GDNFR−アルファ1、GFR−ALPHA−1)、
(40)Ly6E(リンパ球抗原6複合体、遺伝子座E、Ly67、RIG−E、SCA−2、TSA−1)、
(41)TMEM46(シサホモログ2(アフリカツメガエル)、SHISA2)、
(42)Ly6G6D(リンパ球抗原6複合体、遺伝子座G6D、Ly6−D、MEGT1)、
(43)LGR5(ロイシンリッチリピート含有Gタンパク質共役受容体5、GPR49、GPR67)、
(44)RET(RETプロト癌遺伝子、MEN2A、HSCR1、MEN2B、MTC1、PTC、CDHF12、Hs.168114、RET51、RET−ELE1)、
(45)LY6K(リンパ球抗原6複合体、遺伝子座K、LY6K、HSJ001348、FLJ35226)、
(46)GPR19(Gタンパク質共役受容体19、Mm.4787)、
(47)GPR54(KISS1受容体、KISS1R、GPR54、HOT7T175、AXOR12)、
(48)ASPHD1(アスパラギン酸ベータヒドロキシラーゼドメイン含有1、LOC253982)、
(49)チロシナーゼ(TYR、OCAIA、OCA1A、チロシナーゼ、SHEP3)、
(50)TMEM118(リングフィンガータンパク質、膜貫通2、RNFT2、FLJ14627)、
(51)GPR172A(Gタンパク質共役受容体172A、GPCR41、FLJ11856、D15Ertd747e)、
(52)CD33、及び
(53)CLL−1、
Dが、以下の構造から選択されるアントラサイクリン誘導体であり、
式中、波線が、Lへの結合を示し、
Lが、−CH2O−、−CH2N(R)−、-N(R)-、-N(R)(C1-C12アルキレン)-、−N(R)(C2-C8アルケニレン)-、-N(R)(C2-C8アルキニレン)-、-N(R)(CH2CH2O)n-、及び以下の構造から選択されるリンカーであり、
式中、波線が、D及びZへの結合を示し、
Zが、-CH2C(O)-、-CH2C(O)NR(C1-C12アルキレン)-、及び以下の構造から選択される任意のスペーサーであり、
Rが、H、C1-C12アルキル、またはC6-C20アリールであり、
Z1が、-(C1-C12アルキレン)-、-(C2-C8アルケニレン)-、-(C2-C8アルキニレン)-、及び-(CH2CH2O)n-から選択され、
mが、0または1であり、
nが、1〜6であり、
pが、1〜8の整数である。
表2:抗体−薬物複合体(ADC)
DAR=平均薬物/抗体比
A118C(EU番号付け)=A121C(連続番号付け)=A114C(Kabat番号付け)
野生型(「WT」)、システイン操作変異体抗体(「thio」)、軽鎖(「LC」)、重鎖(「HC」)、6−マレイミドカプロイル(「MC」)、マレイミドプロパノイル(「MP」)、バリン−シトルリン(「val−cit」または「vc」)、アラニン−フェニルアラニン(「ala−phe」)、p−アミノベンジル(「PAB」)、及びp−アミノベンジルオキシカルボニル(「PABC」)
表3:切断不可能、非ジスルフィド、コンパレータADC
一般に、抗体−薬物複合体(ADC)の細胞毒性または細胞増殖抑制活性は、受容体タンパク質、例えば、HER2を有する哺乳類細胞を、細胞培養培地中のADCの抗体に曝すことと、その細胞を約6時間〜約5日間培養することと、細胞生存率を測定することとによって測定される。細胞ベースのインビトロアッセイを使用して、本発明のADCの生存率(増殖)、細胞毒性、及びアポトーシス誘発(カスパーゼ活性化)を測定した。
本発明の抗体−薬物複合体(ADC)のインビボ有効性は、マウスにおける腫瘍異種移植片研究(実施例22)によって測定され得る。抗体−薬物複合体(ADC)のインビボ有効性を、マウスにおける腫瘍成長阻害(実施例21)によって測定した。本発明のADCは、腫瘍成長の阻害において驚くべき予想外の効力を示した。ADCの有効性を腫瘍細胞の標的抗原発現と相関させた。
本発明の治療用抗体−薬物複合体(ADC)の医薬製剤は、典型的には、非経口投与、すなわち、ボーラス、静脈内、腫瘍内注入のために、薬学的に許容される非経口ビヒクルとともに注入可能な単位剤形で調製される。所望の純度を有する抗体−薬物複合体(ADC)は、凍結乾燥製剤または水溶液の形態で、薬学的に許容される希釈剤、担体、賦形剤、または安定剤と任意に混合される(Remington’s Pharmaceutical Sciences(1980)16th edition,Osol,A.Ed.)。
本発明の抗体−薬物複合体(ADC)を使用して、例えば腫瘍抗原の過剰発現を特徴とする様々な疾患または障害を治療することができることが企図される。例示の状態または過剰増殖性障害としては、良性または悪性固形腫瘍ならびに白血病及びリンパ性悪性疾患等の血液学的障害が挙げられる。他には、神経障害、グリア障害、星状障害、視床下部障害、腺障害、マクロファージ障害、上皮障害、間質障害、胞胚腔障害、炎症性障害、血管新生障害、及び自己免疫等の免疫学的障害が挙げられる。
本発明の別の実施形態では、上述の障害の治療に有用な材料を含有する製品または「キット」が提供される。この製品は、容器及び容器上のラベルまたは容器に関連する添付文書を含む。好適な容器としては、例えば、ボトル、バイアル、シリンジ、ブリスターパック等が挙げられる。これらの容器は、ガラスまたはプラスチック等の様々な材料から形成され得る。この容器は、状態の治療に有効な抗体−薬物複合体(ADC)組成物を保持し、滅菌アクセスポートを有し得る(例えば、この容器は、静脈注射用溶液バッグまたは皮下注射針によって貫通可能なストッパーを有するバイアルであり得る)。この組成物中の少なくとも1つの活性薬剤は、ADCである。ラベルまたは添付文書は、この組成物が癌等の選定された状態を治療するために使用されることを示す。あるいは、またはさらに、この製品は、注射用静菌水(BWFI)、リン酸緩衝生理食塩水、リンガー溶液、及びデキストロース溶液等の薬学的に許容される緩衝液を含む第2の(または第3の)容器をさらに含み得る。それは、他の緩衝液、希釈剤、フィルター、針、及びシリンジ等の商業的視点及び使用者の視点から望ましい他の材料をさらに含み得る。
LD−51:(2S,4S)−4−[[(1S,3R,4aS,9S,9aR,10aS)−9−メトキシ−1−メチル−3,4,4a,6,7,9,9a,10a−オクタヒドロ−1H−ピラノ[1,2]オキサゾロ[3,4−b][1,4]オキサジン−3−イル]オキシ]−2,5,12−トリヒドロキシ−7−メトキシ−6,11−ジオキソ−N−[2−(2−ピリジルジスルファニル)エチル]−3,4−ジヒドロ−1H−テトラセン−2−カルボキサミドの合成
LD−52:2−(2−ピリジルジスルファニル)エチルN−[2−[[2−[(2S,4S)−4−[[(1S,3R,4aS,9S,9aR,10aS)−9−メトキシ−1−メチル−3,4,4a,6,7,9,9a,10a−オクタヒドロ−1H−ピラノ[1,2]オキサゾロ[3,4−b][1,4]オキサジン−3−イル]オキシ]−2,5,12−トリヒドロキシ−7−メトキシ−6,11−ジオキソ−3,4−ジヒドロ−1H−テトラセン−2−イル]−2−オキソ−エトキシ]カルボニル−メチル−アミノ]エチル]−N−メチル−カルバメートの合成
LD−53:[2−メチル−2−(2−ピリジルジスルファニル)プロピル]N−[2−[[2−[(2S,4S)−4−[[(1S,3R,4aS,9S,9aR,10aS)−9−メトキシ−1−メチル−3,4,4a,6,7,9,9a,10a−オクタヒドロ−1H−ピラノ[1,2]オキサゾロ[3,4−b][1,4]オキサジン−3−イル]オキシ]−2,5,12−トリヒドロキシ−7−メトキシ−6,11−ジオキソ−3,4−ジヒドロ−1H−テトラセン−2−イル]−2−オキソ−エトキシ]カルボニル−メチル−アミノ]エチル]−N−メチル−カルバメートの合成
LD−54:(2S,4S)−4−[[(1S,3R,4aS,9S,9aR,10aS)−9−メトキシ−1−メチル−3,4,4a,6,7,9,9a,10a−オクタヒドロ−1H−ピラノ[1,2]オキサゾロ[3,4−b][1,4]オキサジン−3−イル]オキシ]−2,5,12−トリヒドロキシ−7−メトキシ−N−[2−メチル−2−(2−ピリジルジスルファニル)プロピル]−6,11−ジオキソ−3,4−ジヒドロ−1H−テトラセン−2−カルボキサミドの合成
LD−55:(2S,4S)−4−[[(1S,3R,4aS,9S,9aR,10aS)−9−メトキシ−1−メチル−3,4,4a,6,7,9,9a,10a−オクタヒドロ−1H−ピラノ[1,2]オキサゾロ[3,4−b][1,4]オキサジン−3−イル]オキシ]−2,5,12−トリヒドロキシ−7−メトキシ−N−[2−メチル−2−[(5−ニトロ−2−ピリジル)ジスルファニル]プロピル]−6,11−ジオキソ−3,4−ジヒドロ−1H−テトラセン−2−カルボキサミドの合成
LD−56:2−(2−ピリジルジスルファニル)プロピルN−メチル−N−[2−[メチル−[2−オキソ−2−[2,5,12−トリヒドロキシ−7−メトキシ−4−[(9−メトキシ−1−メチル−3,4,4a,6,7,9,9a,10a−オクタヒドロ−1H−ピラノ[1,2]オキサゾロ[3,4−b][1,4]オキサジン−3−イル)オキシ]−6,11−ジオキソ−3,4−ジヒドロ−1H−テトラセン−2−イル]エトキシ]カルボニル−アミノ]エチル]カルバメートの合成
LD−57:(2S,4S)−4−[[(1S,3R,4aS,9S,9aR,10aS)−9−メトキシ−1−メチル−3,4,4a,6,7,9,9a,10a−オクタヒドロ−1H−ピラノ[1,2]オキサゾロ[3,4−b][1,4]オキサジン−3−イル]オキシ]−2,5,12−トリヒドロキシ−7−メトキシ−N−[2−[(5−ニトロ−2−ピリジル)ジスルファニル]エチル]−6,11−ジオキソ−3,4−ジヒドロ−1H−テトラセン−2−カルボキサミドの合成
LD−58:2−[(5−ニトロ−2−ピリジル)ジスルファニル]エチルN−[2−[[2−[(2S,4S)−4−[[(1S,3R,4aS,9S,9aR,10aS)−9−メトキシ−1−メチル−3,4,4a,6,7,9,9a,10a−オクタヒドロ−1H−ピラノ[1,2]オキサゾロ[3,4−b][1,4]オキサジン−3−イル]オキシ]−2,5,12−トリヒドロキシ−7−メトキシ−6,11−ジオキソ−3,4−ジヒドロ−1H−テトラセン−2−イル]−2−オキソ−エトキシ]カルボニル−メチル−アミノ]エチル]−N−メチル−カルバメートの合成
LD−59:2,5,12−トリヒドロキシ−7−メトキシ−4−[(9−メトキシ−1−メチル−3,4,4a,6,7,9,9a,10a−オクタヒドロ−1H−ピラノ[1,2]オキサゾロ[3,4−b][1,4]オキサジン−3−イル)オキシ]−N−[2−[(5−ニトロ−2−ピリジル)ジスルファニル]プロピル]−6,11−ジオキソ−3,4−ジヒドロ−1H−テトラセン−2−カルボキサミドの合成
LD−60:[2−オキソ−2−[2,5,12−トリヒドロキシ−7−メトキシ−4−[(9−メトキシ−1−メチル−3,4,4a,6,7,9,9a,10a−オクタヒドロ−1H−ピラノ[1,2]オキサゾロ[3,4−b][1,4]オキサジン−3−イル)オキシ]−6,11−ジオキソ−3,4−ジヒドロ−1H−テトラセン−2−イル]エチル]N−メチル−N−[2−[メチル−[2−[(5−ニトロ−2−ピリジル)ジスルファニル]プロポキシカルボニル]アミノ]エチル]カルバメートの合成
LD−61:2,5,12−トリヒドロキシ−7−メトキシ−4−[(9−メトキシ−1−メチル−3,4,4a,6,7,9,9a,10a−オクタヒドロ−1H−ピラノ[1,2]オキサゾロ[3,4−b][1,4]オキサジン−3−イル)オキシ]−6,11−ジオキソ−N−[2−(2−ピリジルジスルファニル)プロピル]−3,4−ジヒドロ−1H−テトラセン−2−カルボキサミドの合成
LD−62:(2S,4S)−2,5,12−トリヒドロキシ−7−メトキシ−4−(((1S,3R,4aS,9S,9aR,10aS)−9−メトキシ−1−メチルオクタヒドロ−1H−ピラノ[4’,3’:4,5]オキサゾロ[2,3−c][1,4]オキサジン−3−イル)オキシ)−N−((R)−2−((5−ニトロピリジン−2−イル)ジスルファニル)プロピル)−6,11−ジオキソ−1,2,3,4,6,11−ヘキサヒドロテトラセン−2−カルボキサミドの合成
LD−63:(2S,4S)−2,5,12−トリヒドロキシ−7−メトキシ−4−(((1S,3R,4aS,9S,9aR,10aS)−9−メトキシ−1−メチルオクタヒドロ−1H−ピラノ[4’,3’:4,5]オキサゾロ[2,3−c][1,4]オキサジン−3−イル)オキシ)−N−((S)−2−((5−ニトロピリジン−2−イル)ジスルファニル)プロピル)−6,11−ジオキソ−1,2,3,4,6,11−ヘキサヒドロテトラセン−2−カルボキサミドの合成
ある特定の条件下で、システイン操作抗体を、2mM EDTAを有する50mMトリス(pH7.5)中で、DTT(クレランド試薬、ジチオスレイトール)またはTCEP(トリス(2−カルボキシエチル)ホスフィン塩酸塩、Getz et al(1999)Anal.Biochem.Vol 273:73−80;Soltec Ventures,Beverly,MA)等の還元剤で、37℃で3時間または室温で一晩処置することにより、表1の中間体等の本発明のリンカー−薬物中間体との複合に対して反応させることができる。CHO細胞中で発現した全長システイン操作モノクローナル抗体(THIOMAB(商標))(Gomez et al(2010)Biotechnology and Bioeng.105(4):748−760、Gomez et al(2010)Biotechnol.Prog.26:1438−1445)を、例えば、約50倍過剰のDTTで、室温で一晩還元して、新たに導入されたシステイン残基と培養培地中に存在するシステインとの間に生じ得るジスルフィド結合を還元した。還元されたTHIOMAB(商標)を希釈し、10mM酢酸ナトリウム(pH5)中のHiTrap Sカラム上に装填し、0.3M塩化ナトリウムを含有するPBSで溶出した。あるいは、この抗体を、20分の1の体積の10%酢酸を添加することにより酸性化し、10mMコハク酸塩(pH5)で希釈し、そのカラム上に装填し、その後、10カラム体積のコハク酸緩衝液で洗浄した。このカラムを50mMトリス(pH7.5)、2mM EDTAで溶出した。
実施例2の還元及び再酸化手順後、システイン操作抗体(THIOMAB(商標))をPBS(リン酸緩衝生理食塩水)緩衝液中に溶解し、氷上で冷やす。表1のLD−51〜LD−61を含むが、これらに限定されない、チオール反応性ピリジルジスルフィド基を有する過剰の約1.5モル〜20当量のリンカー−薬物中間体をDMSO中に溶解し、アセトニトリル及び水中に希釈し、PBS中の冷やした還元された再酸化抗体に添加する。典型的には、このリンカー−薬物を、50mMトリス(pH8)中約20mMの濃度のDMSOストックからその抗体に添加し、反応混合物のLC−MS分析によって決定されるように反応が完了するまで約1〜約24時間監視する。反応が完了すると、過剰のマレイミドを添加して反応停止処理し、いずれの反応していない抗体チオール基もキャップする。複合混合物を、HiTrap SP FFカラム上に装填し、それを通して溶出して、過剰の薬物−リンカー中間体及び他の不純物を除去することができる。反応混合物を遠心限外濾過により濃縮し、システイン操作抗体薬物複合体をPBS中G25樹脂での溶出により精製して脱塩し、滅菌条件下で0.2μmのフィルターを通して濾過し、保管用に凍結させた。
以下のプロトコルを用いた細胞増殖アッセイ(CELLTITER GLO(商標)発光細胞生存率アッセイ、Promega Corp.Technical Bulletin TB288、Mendoza et al(2002)Cancer Res.62:5485−5488)により、ADCの有効性を測定した。
1.約104細胞(SKBR−3、BT474、MCF7、またはMDA−MB−468)を有する一定分量の100mLの細胞培養培地を不透明壁付き96ウェルプレートの各ウェル中に堆積させた。
2.培地を含有する細胞なしの対照ウェルを調製した。
3.ADCを実験ウェルに添加し、3〜5日間インキュベートした。
4.これらのプレートを約30分間室温に平衡化した。
5.各ウェル中に存在する細胞培養培地の体積に等しい体積のCELLTITER GLO(商標)試薬を添加した。
6.これらの内容物を軌道振盪器上で2分間混合して、細胞溶解を誘導した。
7.このプレートを室温で10分間インキュベートして、発光シグナルを安定させた。
8.発光を記録し、RLU=相対発光単位でグラフに報告した。
データを標準偏差エラーバーで各複製物セットの発光の平均としてプロットする。このプロトコルは、CELLTITER GLO(商標)発光細胞の修飾である。
培地:SK−BR−3を50/50/10%FBS/グルタミン中で成長させ、250μg/mLのG−418 OVCAR−3をRPMI/20%FBS/グルタミン中で成長させる。
0日目の単回処置前に、腫瘍を構築し、体積150〜200mm3(キャリパーを使用して測定)に成長させた。式:V(mm3)=0.5A×B2(式中、A及びBは、それぞれ、長い直径及び短い直径である)に従ってキャリパーを使用して腫瘍体積を測定した。腫瘍体積が3000mm3に到達する前に、または腫瘍が切迫した潰瘍形成の兆候を示したときに、マウスを安楽死させた。各実験群(1群当たり10匹のマウス)から収集したデータを平均+SEとして表した。
Claims (26)
- 式Iのリンカー−薬物中間体であって、
Ant-L-(Z)m-X I
式中、Antが、以下の構造から選択され、
式中、波線が、Lへの結合を示し、
Lが、−CH2O−、−CH2N(R)−、-N(R)-、-N(R)(C1-C12アルキレン)-、−N(R)(C2-C8アルケニレン)-、-N(R)(C2-C8アルキニレン)-、-N(R)(CH2CH2O)n-、及び以下の構造から選択されるリンカーであり、
式中、波線が、Ant及びZへの結合を示し、
Zが、-CH2C(O)-、-CH2C(O)NR(C1-C12アルキレン)-、及び以下の構造から選択される任意のスペーサーであり、
式中、波線が、L及びXへの結合を示し、
Rが、H、C1-C12アルキル、またはC6-C20アリールであり、
Z1が、-(C1-C12アルキレン)-、-(C2-C8アルケニレン)-、-(C2-C8アルキニレン)-、-O(C1-C12アルキレン)-、-O(C2-C8アルケニレン)-、-O(C2-C8アルキニレン)-、及び-(CH2CH2O)n-から選択され、
mが、0または1であり、
nが、1〜6であり、
Xが、ピリジルジスルフィドであり、この場合、ピリジルが、NO2、Cl、F、CN、及びBrから選択される1つ以上の基で置換されていてもよく、
アルキレン、アルケニレン、アルキニレン、アルキル、及びアリールが、F、Cl、Br、N(CH3)2、及びOCH3から選択される1つ以上の基で置換されていてもよい、前記リンカー−薬物中間体。 - Lが−CH2O−である、請求項1に記載のリンカー−薬物中間体。
- Lが−N(R)−または-N(R)(C1-C12アルキレン)-である、請求項1に記載のリンカー−薬物中間体。
- Z1が-(C1-C12アルキレン)-または-O(C1-C12アルキレン)-である、請求項1に記載のリンカー−薬物中間体。
- Z1が-O(C1-C12アルキレン)-である、請求項5に記載のリンカー−薬物中間体。
- RがHまたはC1-C12アルキルである、請求項5に記載のリンカー−薬物中間体。
- R1がNO2であり、nが1である、請求項9に記載のリンカー−薬物中間体。
- ジスルフィド、リンカーL、及び任意のスペーサーZによって1つ以上のアントラサイクリン誘導体薬物部分Dに共有結合される抗体を含む抗体−薬物複合体化合物であって、式II:
Ab−S−S−(Zm−L−D)p II
を有し、
式中、Abが、(1)〜(53)から選択される1つ以上の腫瘍関連抗原または細胞表面受容体に結合する抗体であり、
(1)BMPR1B(骨形態形成タンパク質受容体IB型)、
(2)E16(LAT1、SLC7A5)、
(3)STEAP1(前立腺6膜貫通上皮抗原)、
(4)MUC16(0772P、CA125)、
(5)MPF(MPF、MSLN、SMR、巨核球増強因子、メソテリン)、
(6)Napi2b(NAPI−3B、NPTIIb、SLC34A2、溶質担体ファミリー34(リン酸ナトリウム)、メンバー2、II型ナトリウム依存性リン酸輸送体3b)、
(7)Sema 5b(FLJ10372、KIAA1445、Mm.42015、SEMA5B、SEMAG、セマフォリン5b Hlog、セマドメイン、7回トロンボスポンジン反復(1型及び1型様)、膜貫通ドメイン(TM)及び短細胞質ドメイン、(セマフォリン)5B)、
(8)PSCA hlg(2700050C12Rik、C530008O16Rik、RIKEN cDNA 2700050C12、RIKEN cDNA 2700050C12遺伝子)、
(9)ETBR(エンドセリンB型受容体)、
(10)MSG783(RNF124、仮想タンパク質FLJ20315)、
(11)STEAP2(HGNC_8639、IPCA−1、PCANAP1、STAMP1、STEAP2、STMP、前立腺癌関連遺伝子1、前立腺癌関連タンパク質1、前立腺6膜貫通上皮抗原2、6膜貫通前立腺タンパク質)、
(12)TrpM4(BR22450、FLJ20041、TRPM4、TRPM4B、一過性受容体電位カチオンチャネル、サブファミリーM、メンバー4)、
(13)CRIPTO(CR、CR1、CRGF、CRIPTO、TDGF1、奇形癌腫由来成長因子)、
(14)CD21(CR2(補体受容体2)またはC3DR(C3d/エプスタインバーウイルス受容体)またはHs 73792)、
(15)CD79b(CD79B、CD79β、IGb(免疫グロブリン関連ベータ)、B29)、
(16)FcRH2(IFGP4、IRTA4、SPAP1A(SH2ドメイン含有ホスファターゼアンカータンパク質1a)、SPAP1B、SPAP1C)、
(17)HER2、
(18)NCA、
(19)MDP、
(20)IL20Rα、
(21)ブレビカン、
(22)EphB2R、
(23)ASLG659、
(24)PSCA、
(25)GEDA、
(26)BAFF−R(B細胞活性化因子受容体、BLyS受容体3、BR3)、
(27)CD22(B細胞受容体CD22−Bアイソフォーム)、
(28)CD79a(CD79A、CD79α、免疫グロブリン関連アルファ)、
(29)CXCR5(バーキットリンパ腫受容体1)、
(30)HLA−DOB(MHCクラスII分子のベータサブユニット(Ia抗原))、
(31)P2X5(プリン作動性受容体P2Xリガンド開口型イオンチャネル5)、
(32)CD72(B細胞分化抗原CD72、Lyb−2)、
(33)LY64(リンパ球抗原64(RP105)、ロイシンリッチリピート(LRR)ファミリーのI型膜タンパク質)、
(34)FcRH1(Fc受容体様タンパク質1)、
(35)FcRH5(IRTA2、免疫グロブリンスーパーファミリー受容体転座関連2)、
(36)TENB2(推定膜貫通プロテオグリカン)、
(37)PMEL17(シルバーホモログ、SILV、D12S53E、PMEL17、SI、SIL)、
(38)TMEFF1(EGF様及び2つのホリスタチン様ドメイン1を有する膜貫通タンパク質、トモレグリン−1)、
(39)GDNF−Ra1(GDNFファミリー受容体アルファ1、GFRA1、GDNFR、GDNFRA、RETL1、TRNR1、RET1L、GDNFR−アルファ1、GFR−ALPHA−1)、
(40)Ly6E(リンパ球抗原6複合体、遺伝子座E、Ly67、RIG−E、SCA−2、TSA−1)、
(41)TMEM46(シサホモログ2(アフリカツメガエル)、SHISA2)、
(42)Ly6G6D(リンパ球抗原6複合体、遺伝子座G6D、Ly6−D、MEGT1)、
(43)LGR5(ロイシンリッチリピート含有Gタンパク質共役受容体5、GPR49、GPR67)、
(44)RET(RETプロト癌遺伝子、MEN2A、HSCR1、MEN2B、MTC1、PTC、CDHF12、Hs.168114、RET51、RET−ELE1)、
(45)LY6K(リンパ球抗原6複合体、遺伝子座K、LY6K、HSJ001348、FLJ35226)、
(46)GPR19(Gタンパク質共役受容体19、Mm.4787)、
(47)GPR54(KISS1受容体、KISS1R、GPR54、HOT7T175、AXOR12)、
(48)ASPHD1(アスパラギン酸ベータヒドロキシラーゼドメイン含有1、LOC253982)、
(49)チロシナーゼ(TYR、OCAIA、OCA1A、チロシナーゼ、SHEP3)、
(50)TMEM118(リングフィンガータンパク質、膜貫通2、RNFT2、FLJ14627)、
(51)GPR172A(Gタンパク質共役受容体172A、GPCR41、FLJ11856、D15Ertd747e)、
(52)CD33、及び
(53)CLL−1、
Dが、以下の構造から選択されるアントラサイクリン誘導体であり、
式中、波線が、Lへの結合を示し、
Lが、−CH2O−、−CH2N(R)−、-N(R)-、-N(R)(C1-C12アルキレン)-、−N(R)(C2-C8アルケニレン)-、-N(R)(C2-C8アルキニレン)-、-N(R)(CH2CH2O)n-、及び以下の構造から選択されるリンカーであり、
式中、波線が、D及びZへの結合を示し、
Zが、-CH2C(O)-、-CH2C(O)NR(C1-C12アルキレン)-、及び以下の構造から選択される任意のスペーサーであり、
Rが、H、C1-C12アルキル、またはC6-C20アリールであり、
Z1が、-(C1-C12アルキレン)-、-(C2-C8アルケニレン)-、-(C2-C8アルキニレン)-、及び-(CH2CH2O)n-から選択され、
mが、0または1であり、
nが、1〜6であり、
pが、1〜8の整数であり、
アルキレン、アルケニレン、アルキニレン、アルキル、及びアリールが、F、Cl、Br、N(CH3)2、NO2、及びOCH3から選択される1つ以上の基で任意に置換される、前記化合物、またはその薬学的に許容される塩。 - Lが-NH(C1-C12アルキレン)-であり、mが0である、請求項13に記載の抗体−薬物複合体化合物。
- アルキレンが、-CH2CH2-、-CH2CH2CH2-、-CH(CH3)CH2-、及び-C(CH3)2CH2-から選択される、請求項14に記載の抗体−薬物複合体化合物。
- Abがシステイン操作抗体である、請求項13に記載の抗体−薬物複合体化合物。
- 前記システイン操作抗体が、HC A118C、LC K149C、HC A140C、LC V205C、及びLC S121Cから選択される変異体である、請求項16に記載の抗体−薬物複合体化合物。
- Abが、抗HER2 4D5、抗CD22、抗CD33、抗Napi3b、抗HER2 7C2、及び抗CLL−1から選択される、請求項13に記載の抗体−薬物複合体化合物。
- pが、1、2、3、または4である、請求項13に記載の抗体−薬物複合体化合物。
- 前記抗体−薬物複合体化合物の混合物を含み、前記抗体−薬物複合体化合物混合物中の1抗体当たりの平均薬物負荷が約2〜約5である、請求項13に記載の抗体−薬物複合体化合物。
- 請求項13〜20のいずれか一項に記載の抗体−薬物複合体化合物と、薬学的に許容される希釈剤、担体、または賦形剤と、を含む、薬学的組成物。
- 患者に請求項21に記載の薬学的組成物を投与することを含む、癌の治療方法。
- 前記患者に、前記抗体−薬物複合体との併用で、化学療法剤が投与される、請求項22に記載の方法。
- 哺乳動物における癌の治療に使用するための、請求項13〜20のいずれか一項に記載の抗体−薬物複合体化合物。
- 抗体を請求項1に記載の式Iのリンカー−薬物中間体と反応させることを含む、請求項13に記載の抗体−薬物複合体化合物の作製方法。
- 請求項21に記載の薬学的組成物と、容器と、前記薬学的組成物を使用して癌を治療することができることを示す添付文書またはラベルと、を含む、製品。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201462049720P | 2014-09-12 | 2014-09-12 | |
US62/049,720 | 2014-09-12 | ||
PCT/US2015/049728 WO2016040825A1 (en) | 2014-09-12 | 2015-09-11 | Anthracycline disulfide intermediates, antibody-drug conjugates and methods |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2017531625A true JP2017531625A (ja) | 2017-10-26 |
JP6622293B2 JP6622293B2 (ja) | 2019-12-18 |
Family
ID=54197102
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017513785A Active JP6622293B2 (ja) | 2014-09-12 | 2015-09-11 | アントラサイクリンジスルフィド中間体、抗体−薬物複合体、及び方法 |
Country Status (5)
Country | Link |
---|---|
US (2) | US10149913B2 (ja) |
EP (1) | EP3191134B1 (ja) |
JP (1) | JP6622293B2 (ja) |
CN (1) | CN106714844B (ja) |
WO (1) | WO2016040825A1 (ja) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3191134B1 (en) | 2014-09-12 | 2019-11-20 | Genentech, Inc. | Anthracycline disulfide intermediates, antibody-drug conjugates and methods |
DE102015205136A1 (de) | 2015-03-20 | 2016-09-22 | Volkswagen Aktiengesellschaft | Verfahren zum Enteisen eines Wärmeübertragers einer Klimatisierungseinrichtung eines Kraftfahrzeugs |
MA43354A (fr) | 2015-10-16 | 2018-08-22 | Genentech Inc | Conjugués médicamenteux à pont disulfure encombré |
EP3522933B1 (en) * | 2016-10-05 | 2021-12-15 | F. Hoffmann-La Roche AG | Methods for preparing antibody drug conjugates |
EP3659307A4 (en) * | 2017-07-28 | 2021-09-22 | Yale University | ANTI-CANCER MEDICINAL PRODUCTS AND THEIR MANUFACTURING AND USE PROCEDURES |
CN107446050A (zh) | 2017-08-11 | 2017-12-08 | 百奥泰生物科技(广州)有限公司 | Trop2阳性疾病治疗的化合物及方法 |
CN111542344A (zh) | 2017-10-23 | 2020-08-14 | 马布林克生物科学公司 | 包含单分子量聚肌氨酸的配体-药物-缀合物 |
US20220088204A1 (en) * | 2019-01-25 | 2022-03-24 | Yale University | Anticancer drugs and methods of making and using same |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH01246295A (ja) * | 1988-02-11 | 1989-10-02 | Bristol Myers Co | 新規なリンカーを有するアントラサイクリン・イムノコンジュゲート及びその製造方法 |
JPH05201726A (ja) * | 1991-10-03 | 1993-08-10 | Hashimoto Kasei Kk | フッ素系エッチング剤からフッ化カルシウムを回収する方法 |
JP2003531821A (ja) * | 1999-12-29 | 2003-10-28 | イムノージェン インコーポレーテッド | 改変型ドキソルビシンおよびダウノルビシンを含む細胞傷害性薬剤ならびにその治療上の使用 |
WO2009099741A1 (en) * | 2008-02-01 | 2009-08-13 | Genentech, Inc. | Nemorubicin metabolite and analog reagents, antibody-drug conjugates and methods |
JP2011528360A (ja) * | 2008-07-15 | 2011-11-17 | ジェネンテック, インコーポレイテッド | アントラサイクリン誘導体コンジュゲート、その調製方法及び抗腫瘍化合物としてのその用途 |
Family Cites Families (261)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US798959A (en) | 1904-12-19 | 1905-09-05 | George W Goss | Corn-husker. |
US4464529A (en) | 1982-07-20 | 1984-08-07 | Sri International | Analogues of morpholinyl daunorubicin and morpholinyl doxorubicin |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
JPS6098584A (ja) | 1983-11-02 | 1985-06-01 | Canon Inc | カメラ―体形vtr |
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 |
GB2172594B (en) | 1985-03-22 | 1988-06-08 | Erba Farmitalia | New morpholino derivatives of daunorubicin and doxorubicin |
US5583024A (en) | 1985-12-02 | 1996-12-10 | The Regents Of The University Of California | Recombinant expression of Coleoptera luciferase |
CA2016584C (en) * | 1989-05-17 | 1999-06-29 | Robert S. Greenfield | Anthracycline conjugates having a novel linker and methods for their production |
AU6355090A (en) | 1989-08-23 | 1991-04-03 | Scripps Clinic And Research Foundation | Compositions and methods for detection and treatment of epstein-barr virus infection and immune disorders |
US5959177A (en) | 1989-10-27 | 1999-09-28 | The Scripps Research Institute | Transgenic plants expressing assembled secretory antibodies |
US5304687A (en) | 1989-12-19 | 1994-04-19 | Farmitalia Carlo Erba S.R.L. | Morpholinyl derivatives of doxorubicin and process for their preparation |
US5256643A (en) | 1990-05-29 | 1993-10-26 | The Government Of The United States | Human cripto protein |
AU9016591A (en) | 1990-10-25 | 1992-05-26 | Tanox Biosystems, Inc. | Glycoproteins associated with membrane-bound immunoglobulins as antibody targets on B cells |
DE69231223T3 (de) | 1991-03-29 | 2008-01-17 | Genentech, Inc., South San Francisco | Menschliche pf4a rezeptoren und ihre verwendung |
US5440021A (en) | 1991-03-29 | 1995-08-08 | Chuntharapai; Anan | Antibodies to human IL-8 type B receptor |
US5543503A (en) | 1991-03-29 | 1996-08-06 | Genentech Inc. | Antibodies to human IL-8 type A receptor |
ATE255131T1 (de) | 1991-06-14 | 2003-12-15 | Genentech Inc | Humanisierter heregulin antikörper |
JP3050424B2 (ja) | 1991-07-12 | 2000-06-12 | 塩野義製薬株式会社 | ヒトエンドセリンリセプター |
US5264557A (en) | 1991-08-23 | 1993-11-23 | The United States Of America As Represented By The Department Of Health And Human Services | Polypeptide of a human cripto-related gene, CR-3 |
CA2116774C (en) | 1991-09-19 | 2003-11-11 | Paul J. Carter | Expression in e. coli antibody fragments having at least a cysteine present as a free thiol. use for the production of bifunctional f(ab') 2 antibodies |
US6011146A (en) | 1991-11-15 | 2000-01-04 | Institut Pasteur | Altered major histocompatibility complex (MHC) determinant and methods of using the determinant |
US6153408A (en) | 1991-11-15 | 2000-11-28 | Institut Pasteur And Institut National De La Sante Et De La Recherche Medicale | Altered major histocompatibility complex (MHC) determinant and methods of using the determinant |
IL107366A (en) | 1992-10-23 | 2003-03-12 | Chugai Pharmaceutical Co Ltd | Genes coding for megakaryocyte potentiator |
US5644033A (en) | 1992-12-22 | 1997-07-01 | Health Research, Inc. | Monoclonal antibodies that define a unique antigen of human B cell antigen receptor complex and methods of using same for diagnosis and treatment |
US5801005A (en) | 1993-03-17 | 1998-09-01 | University Of Washington | Immune reactivity to HER-2/neu protein for diagnosis of malignancies in which the HER-2/neu oncogene is associated |
US5869445A (en) | 1993-03-17 | 1999-02-09 | University Of Washington | Methods for eliciting or enhancing reactivity to HER-2/neu protein |
US5773223A (en) | 1993-09-02 | 1998-06-30 | Chiron Corporation | Endothelin B1, (ETB1) receptor polypeptide and its encoding nucleic acid methods, and uses thereof |
US5750370A (en) | 1995-06-06 | 1998-05-12 | Human Genome Sciences, Inc. | Nucleic acid encoding human endothlein-bombesin receptor and method of producing the receptor |
US5789199A (en) | 1994-11-03 | 1998-08-04 | Genentech, Inc. | Process for bacterial production of polypeptides |
US5840523A (en) | 1995-03-01 | 1998-11-24 | Genetech, Inc. | Methods and compositions for secretion of heterologous polypeptides |
JPH08336393A (ja) | 1995-04-13 | 1996-12-24 | Mitsubishi Chem Corp | 光学活性なγ−置換−β−ヒドロキシ酪酸エステルの製造法 |
US5707829A (en) | 1995-08-11 | 1998-01-13 | Genetics Institute, Inc. | DNA sequences and secreted proteins encoded thereby |
US20020193567A1 (en) | 1995-08-11 | 2002-12-19 | Genetics Institute, Inc. | Secreted proteins and polynucleotides encoding them |
JP3646191B2 (ja) | 1996-03-19 | 2005-05-11 | 大塚製薬株式会社 | ヒト遺伝子 |
WO1997044452A1 (en) | 1996-05-17 | 1997-11-27 | Schering Corporation | Human b-cell antigens, related reagents |
GB2315067B (en) | 1996-07-11 | 2000-02-16 | Pharmacia Spa | Morpholinyl anthracycline derivatives |
US5945511A (en) | 1997-02-20 | 1999-08-31 | Zymogenetics, Inc. | Class II cytokine receptor |
US20030185830A1 (en) | 1997-02-25 | 2003-10-02 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of prostate cancer |
US7033827B2 (en) | 1997-02-25 | 2006-04-25 | Corixa Corporation | Prostate-specific polynucleotide compositions |
US6261791B1 (en) | 1997-03-10 | 2001-07-17 | The Regents Of The University Of California | Method for diagnosing cancer using specific PSCA antibodies |
EP1514876B1 (en) | 1997-03-10 | 2013-05-08 | The Regents of The University of California | Antibody against prostate stem cell antigen (PSCA) |
US6541212B2 (en) | 1997-03-10 | 2003-04-01 | The Regents Of The University Of California | Methods for detecting prostate stem cell antigen protein |
US6555339B1 (en) | 1997-04-14 | 2003-04-29 | Arena Pharmaceuticals, Inc. | Non-endogenous, constitutively activated human protein-coupled receptors |
US6319688B1 (en) | 1997-04-28 | 2001-11-20 | Smithkline Beecham Corporation | Polynucleotide encoding human sodium dependent phosphate transporter (IPT-1) |
WO1998051805A1 (en) | 1997-05-15 | 1998-11-19 | Abbott Laboratories | Reagents and methods useful for detecting diseases of the prostate |
WO1998051824A1 (en) | 1997-05-15 | 1998-11-19 | Abbott Laboratories | Reagents and methods useful for detecting disease of the urinary tract |
US6040498A (en) | 1998-08-11 | 2000-03-21 | North Caroline State University | Genetically engineered duckweed |
US6602677B1 (en) | 1997-09-19 | 2003-08-05 | Promega Corporation | Thermostable luciferases and methods of production |
US20030060612A1 (en) | 1997-10-28 | 2003-03-27 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
US20020034749A1 (en) | 1997-11-18 | 2002-03-21 | Billing-Medel Patricia A. | Reagents and methods useful for detecting diseases of the breast |
US6110695A (en) | 1997-12-02 | 2000-08-29 | The Regents Of The University Of California | Modulating the interaction of the chemokine, B Lymphocyte Hemoattractant, and its Receptor, BLR1 |
WO2004031238A2 (en) | 2002-10-03 | 2004-04-15 | Mcgill Univeristy | Antibodies and cyclic peptides which bind cea (carcinoembryonic antigen) and their use as cancer therapeutics |
WO1999046284A2 (en) | 1998-03-13 | 1999-09-16 | The Burnham Institute | Molecules that home to various selected organs or tissues |
ATE518956T1 (de) | 1998-05-13 | 2011-08-15 | Epimmune Inc | Expressionsvektoren zur stimulierung einer immunantwort und verfahren zu deren verwendung |
US20030064397A1 (en) | 1998-05-22 | 2003-04-03 | Incyte Genomics, Inc. | Transmembrane protein differentially expressed in prostate and lung tumors |
US20020187472A1 (en) | 2001-03-09 | 2002-12-12 | Preeti Lal | Steap-related protein |
WO2000012130A1 (en) | 1998-08-27 | 2000-03-09 | Smithkline Beecham Corporation | Rp105 agonists and antagonists |
JP4689781B2 (ja) | 1998-09-03 | 2011-05-25 | 独立行政法人科学技術振興機構 | アミノ酸輸送蛋白及びその遺伝子 |
AU5963699A (en) | 1998-10-02 | 2000-04-26 | Mcmaster University | Spliced form of (erb)b-2/neu oncogene |
US6858710B2 (en) | 1998-12-17 | 2005-02-22 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of ovarian cancer |
US6962980B2 (en) | 1999-09-24 | 2005-11-08 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of ovarian cancer |
US6468546B1 (en) | 1998-12-17 | 2002-10-22 | Corixa Corporation | Compositions and methods for therapy and diagnosis of ovarian cancer |
US20020119158A1 (en) | 1998-12-17 | 2002-08-29 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of ovarian cancer |
US20030091580A1 (en) | 2001-06-18 | 2003-05-15 | Mitcham Jennifer L. | Compositions and methods for the therapy and diagnosis of ovarian cancer |
JP2002536966A (ja) | 1998-12-30 | 2002-11-05 | ベス・イスラエル・ディーコニス・メディカル・センター・インコーポレーテッド | カルシウムチャネルファミリーの特徴付け |
US20030190669A1 (en) | 1998-12-30 | 2003-10-09 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
KR100766653B1 (ko) | 1999-01-29 | 2007-10-15 | 코릭사 코포레이션 | HER-2/neu 융합단백질 |
GB9905124D0 (en) | 1999-03-05 | 1999-04-28 | Smithkline Beecham Biolog | Novel compounds |
AU3395900A (en) | 1999-03-12 | 2000-10-04 | Human Genome Sciences, Inc. | Human lung cancer associated gene sequences and polypeptides |
US7312303B2 (en) | 1999-05-11 | 2007-12-25 | Genentech, Inc. | Anti-PRO4980 antibodies |
AU4952600A (en) | 1999-06-03 | 2000-12-28 | Takeda Chemical Industries Ltd. | Screening method with the use of cd100 |
EP2283867B1 (en) | 1999-06-25 | 2014-05-21 | ImmunoGen, Inc. | Methods of treatment using anti-ERBB antibody-maytansinoid conjugates |
US6949245B1 (en) | 1999-06-25 | 2005-09-27 | Genentech, Inc. | Humanized anti-ErbB2 antibodies and treatment with anti-ErbB2 antibodies |
US20030119113A1 (en) | 1999-07-20 | 2003-06-26 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US7297770B2 (en) | 1999-08-10 | 2007-11-20 | Genentech, Inc. | PRO6496 polypeptides |
US7294696B2 (en) | 1999-08-17 | 2007-11-13 | Genentech Inc. | PRO7168 polypeptides |
AU7573000A (en) | 1999-09-01 | 2001-03-26 | Genentech Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US20030232056A1 (en) | 1999-09-10 | 2003-12-18 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of ovarian cancer |
US20030206918A1 (en) | 1999-09-10 | 2003-11-06 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of ovarian cancer |
US20030129192A1 (en) | 1999-09-10 | 2003-07-10 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of ovarian cancer |
US7125978B1 (en) | 1999-10-04 | 2006-10-24 | Medicago Inc. | Promoter for regulating expression of foreign genes |
CA2385347C (en) | 1999-10-04 | 2009-12-15 | Medicago Inc. | Method for regulating transcription of foreign genes |
ES2309012T3 (es) | 1999-10-29 | 2008-12-16 | Genentech, Inc. | Composiciones del anticuerpo anti-psca y a sus procedimientos contra celulas cancerigenas que expresen psca. |
ES2586850T3 (es) | 1999-11-29 | 2016-10-19 | The Trustees Of Columbia University In The City Of New York | Aislamiento de cinco genes novedosos que codifican nuevos melanomas de tipo receptor de Fc implicados en la patogénesis del linfoma/melanoma |
CA2392510A1 (en) | 1999-11-30 | 2001-06-07 | Corixa Corporation | Compositions and methods for therapy and diagnosis of breast cancer |
JP2003530083A (ja) | 1999-12-10 | 2003-10-14 | エピミューン インコーポレイテッド | ペプチドおよび核酸組成物を使用する、HER2/neuに対する細胞性免疫応答の誘導 |
NZ502058A (en) | 1999-12-23 | 2003-11-28 | Ovita Ltd | Isolated mutated nucleic acid molecule for regulation of ovulation rate |
EP1743648B1 (en) | 1999-12-23 | 2010-03-03 | ZymoGenetics, Inc. | Method for treating inflammation |
US6610286B2 (en) | 1999-12-23 | 2003-08-26 | Zymogenetics, Inc. | Method for treating inflammation using soluble receptors to interleukin-20 |
DE60045139D1 (de) | 1999-12-23 | 2010-12-02 | Zymogenetics Inc | Löslicher Interleukin-20-Rezeptor |
CA2921260A1 (en) | 1999-12-24 | 2001-06-28 | Genentech, Inc. | Methods and compositions for prolonging elimination half-times of bioactive compounds |
US7297333B2 (en) | 2000-01-20 | 2007-11-20 | Genentech, Inc. | Anti-PRO10268 antibodies |
US20030224379A1 (en) | 2000-01-21 | 2003-12-04 | Tang Y. Tom | Novel nucleic acids and polypeptides |
US20020039573A1 (en) | 2000-01-21 | 2002-04-04 | Cheever Martin A. | Compounds and methods for prevention and treatment of HER-2/neu associated malignancies |
AU2001243142A1 (en) | 2000-02-03 | 2001-08-14 | Hyseq, Inc. | Novel nucleic acids and polypeptides |
US20020142377A1 (en) | 2000-02-22 | 2002-10-03 | Glucksmann Maria Alexandra | 18607, a novel human calcium channel |
US20030219806A1 (en) | 2000-02-22 | 2003-11-27 | Millennium Pharmaceuticals, Inc. | Novel 18607, 15603, 69318, 12303, 48000, 52920, 5433, 38554, 57301, 58324, 55063, 52991, 59914, 59921 and 33751 molecules and uses therefor |
US20040005561A1 (en) | 2000-03-01 | 2004-01-08 | Corixa Corporation | Compositions and methods for the detection, diagnosis and therapy of hematological malignancies |
US20040002068A1 (en) | 2000-03-01 | 2004-01-01 | Corixa Corporation | Compositions and methods for the detection, diagnosis and therapy of hematological malignancies |
CA2402293A1 (en) | 2000-03-07 | 2001-09-13 | Hyseq, Inc. | Novel nucleic acids and polypeptides |
JP2004521602A (ja) | 2000-03-24 | 2004-07-22 | ファハリ サッチオグリュ | 前立腺特異的または精巣特異的な新規の核酸分子、ポリペプチド、ならびに診断法および治療法 |
AU2001250412A1 (en) | 2000-03-31 | 2001-10-08 | Ipf Pharmaceuticals Gmbh | Diagnostic and medicament for analysing the cell surface proteome of tumour and inflammatory cells and for treating tumorous and inflammatory diseases, preferably using specific chemokine receptor analysis and the chemokine receptor-ligand interaction |
WO2001075177A2 (en) | 2000-04-03 | 2001-10-11 | The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Tumor markers in ovarian cancer |
IL152136A0 (en) | 2000-04-07 | 2003-05-29 | Arena Pharm Inc | Non-endogenous, constitutively activated known g protein-coupled receptors |
US20030119115A1 (en) | 2000-05-17 | 2003-06-26 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
WO2001088133A2 (en) | 2000-05-18 | 2001-11-22 | Lexicon Genetics Incorporated | Human semaphorin homologs and polynucleotides encoding the same |
AU2001274888A1 (en) | 2000-05-19 | 2001-12-03 | Human Genome Sciences, Inc. | Nucleic acids, proteins, and antibodies |
AU2001275437A1 (en) | 2000-06-09 | 2001-12-17 | Idec Pharmaceuticals Corporation | Gene targets and ligands that bind thereto for treatment and diagnosis of ovarian carcinomas |
AU2001268471A1 (en) | 2000-06-16 | 2002-01-02 | Incyte Genomics, Inc. | G-protein coupled receptors |
WO2002002587A1 (en) | 2000-06-30 | 2002-01-10 | Human Genome Sciences, Inc. | B7-like polynucleotides, polypeptides, and antibodies |
EP1383892A2 (en) | 2000-06-30 | 2004-01-28 | Incyte Genomics, Inc. | Human extracellular matrix and cell adhesion polypeptides |
EP1294885A2 (en) | 2000-06-30 | 2003-03-26 | Amgen, Inc. | B7-like molecules and uses thereof |
AU2002214531A1 (en) | 2000-07-03 | 2002-01-30 | Curagen Corporation | Proteins and nucleic acids encoding same |
US20040044179A1 (en) | 2000-07-25 | 2004-03-04 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
WO2002010187A1 (en) | 2000-07-27 | 2002-02-07 | Mayo Foundation For Medical Education And Research | B7-h3 and b7-h4, novel immunoregulatory molecules |
DE60134178D1 (de) | 2000-07-28 | 2008-07-03 | Ulrich Wissenbach | Trp8 krebsmarker |
US7229623B1 (en) | 2000-08-03 | 2007-06-12 | Corixa Corporation | Her-2/neu fusion proteins |
WO2002013847A2 (en) | 2000-08-14 | 2002-02-21 | Corixa Corporation | Methods for diagnosis and therapy of hematological and virus-associated malignancies |
BR0113235A (pt) | 2000-08-14 | 2004-06-08 | Corixa Corp | Composições e métodos para a terapia e a diagnose de malignidades associadas com her-2/neu |
JP2004520806A (ja) | 2000-08-24 | 2004-07-15 | ジェネンテック・インコーポレーテッド | 腫瘍の診断と治療のための組成物と方法 |
GB0020953D0 (en) | 2000-08-24 | 2000-10-11 | Smithkline Beecham Biolog | Vaccine |
WO2002022660A2 (en) | 2000-09-11 | 2002-03-21 | Hyseq, Inc. | Novel nucleic acids and polypeptides |
US6613567B1 (en) | 2000-09-15 | 2003-09-02 | Isis Pharmaceuticals, Inc. | Antisense inhibition of Her-2 expression |
US20060073551A1 (en) | 2000-09-15 | 2006-04-06 | Genentech, Inc. | Pro4487 polypeptides |
US7855269B2 (en) | 2000-09-15 | 2010-12-21 | Zymogenetics, Inc. | Method for treating inflammation |
UA83458C2 (uk) | 2000-09-18 | 2008-07-25 | Байоджен Айдек Ма Інк. | Виділений поліпептид baff-r (рецептор фактора активації в-клітин сімейства tnf) |
CA2422814A1 (en) | 2000-09-18 | 2002-03-21 | Biogen, Inc. | Cripto mutant and uses thereof |
EP1474528A4 (en) | 2000-10-13 | 2006-06-14 | Protein Design Labs Inc | METHODS FOR DIAGNOSING PROSTATE CANCER, COMPOSITIONS AND METHODS FOR SCREENING PROSTATE CANCER MODULATORS |
ES2329012T3 (es) | 2000-11-07 | 2009-11-20 | Zymogenetics, Inc. | Receptor del factor de necrosis tumoral humano. |
US20020150573A1 (en) | 2000-11-10 | 2002-10-17 | The Rockefeller University | Anti-Igalpha-Igbeta antibody for lymphoma therapy |
WO2002061087A2 (en) | 2000-12-19 | 2002-08-08 | Lifespan Biosciences, Inc. | Antigenic peptides, such as for g protein-coupled receptors (gpcrs), antibodies thereto, and systems for identifying such antigenic peptides |
AU2002243495A1 (en) | 2001-01-12 | 2002-07-24 | University Of Medicine And Dentistry Of New Jersey | Bone morphogenetic protein-2 in the treatment and diagnosis of cancer |
US20030119126A1 (en) | 2001-01-16 | 2003-06-26 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US20030119125A1 (en) | 2001-01-16 | 2003-06-26 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US7754208B2 (en) | 2001-01-17 | 2010-07-13 | Trubion Pharmaceuticals, Inc. | Binding domain-immunoglobulin fusion proteins |
CA2440703A1 (en) | 2001-01-24 | 2002-08-01 | Protein Design Labs, Inc. | Methods of diagnosis of breast cancer, compositions and methods of screening for modulators of breast cancer |
AU2002251841A1 (en) | 2001-01-30 | 2002-08-12 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of pancreatic cancer |
WO2002064798A1 (en) | 2001-02-12 | 2002-08-22 | Bionomics Limited | Dna sequences differentially expressed in tumour cell lines |
WO2002071928A2 (en) | 2001-03-14 | 2002-09-19 | Millennium Pharmaceuticals, Inc. | Nucleic acid molecules and proteins for the identification, assessment, prevention, and therapy of ovarian cancer |
EP1243276A1 (en) | 2001-03-23 | 2002-09-25 | Franciscus Marinus Hendrikus De Groot | Elongated and multiple spacers containing activatible prodrugs |
AU2002311787A1 (en) | 2001-03-28 | 2002-10-15 | Zycos Inc. | Translational profiling |
WO2003008537A2 (en) | 2001-04-06 | 2003-01-30 | Mannkind Corporation | Epitope sequences |
US6820011B2 (en) | 2001-04-11 | 2004-11-16 | The Regents Of The University Of Colorado | Three-dimensional structure of complement receptor type 2 and uses thereof |
WO2002083866A2 (en) | 2001-04-17 | 2002-10-24 | The Board Of Trustees Of The University Of Arkansas | Repeat sequences of the ca125 gene and their use for diagnostic and therapeutic interventions |
JP2005527180A (ja) | 2001-04-18 | 2005-09-15 | プロテイン デザイン ラブス, インコーポレイテッド | 肺がんの診断方法、肺がんの修飾因子の組成及びスクリーニングの方法 |
WO2003083041A2 (en) | 2002-03-22 | 2003-10-09 | Biogen, Inc. | Cripto-specific antibodies |
KR100592357B1 (ko) | 2001-04-26 | 2006-06-22 | 바이오겐 아이덱 엠에이 인코포레이티드 | 크립토 차단 항체 및 그 용도 |
EP1515982A4 (en) | 2001-05-09 | 2005-10-26 | Corixa Corp | METHODS AND COMPOSITIONS FOR THE THERAPY AND DIAGNOSIS OF PROSTATE CANCER |
US20030078399A1 (en) | 2001-05-11 | 2003-04-24 | Sloan-Kettering Institute For Cancer Research | Nucleic acid sequence encoding ovarian antigen, CA125, and uses thereof |
KR100976743B1 (ko) | 2001-05-24 | 2010-08-19 | 지모제넥틱스, 인코포레이티드 | Taci-면역글로불린 융합 단백질 |
US7157558B2 (en) | 2001-06-01 | 2007-01-02 | Genentech, Inc. | Polypeptide encoded by a polynucleotide overexpresses in tumors |
WO2003000842A2 (en) | 2001-06-04 | 2003-01-03 | Curagen Corporation | Novel proteins and nucleic acids encoding same |
AU2002314901A1 (en) | 2001-06-04 | 2002-12-16 | Eos Biotechnology, Inc. | Methods of diagnosis and treatment of androgen-dependent prostate cancer, prostate cancer undergoing androgen-withdrawal, and androgen-independent prostate cancer |
WO2002099060A2 (en) | 2001-06-05 | 2002-12-12 | Exelixis, Inc. | Dgks as modifiers of the p53 pathway and methods of use |
JP2005501528A (ja) | 2001-06-05 | 2005-01-20 | エクセリクシス・インコーポレイテッド | p53経路のモディファイヤーとしてのGFATsおよび使用方法 |
US7235358B2 (en) | 2001-06-08 | 2007-06-26 | Expression Diagnostics, Inc. | Methods and compositions for diagnosing and monitoring transplant rejection |
US7125663B2 (en) | 2001-06-13 | 2006-10-24 | Millenium Pharmaceuticals, Inc. | Genes, compositions, kits and methods for identification, assessment, prevention, and therapy of cervical cancer |
US7189507B2 (en) | 2001-06-18 | 2007-03-13 | Pdl Biopharma, Inc. | Methods of diagnosis of ovarian cancer, compositions and methods of screening for modulators of ovarian cancer |
CA2451465A1 (en) | 2001-06-18 | 2002-12-27 | Eos Biotechnology Inc. | Methods of diagnosis of ovarian cancer, compositions and methods of screening for modulators of ovarian cancer |
AU2002322280A1 (en) | 2001-06-21 | 2003-01-21 | Millennium Pharmaceuticals, Inc. | Compositions, kits, and methods for identification, assessment, prevention, and therapy of breast cancer |
US20030108958A1 (en) | 2001-06-28 | 2003-06-12 | Rene De Waal Malefyt | Biological activity of AK155 |
AU2002314433A1 (en) | 2001-07-02 | 2003-01-21 | Licentia Ltd. | Ephrin-tie receptor materials and methods |
US20040076955A1 (en) | 2001-07-03 | 2004-04-22 | Eos Biotechnology, Inc. | Methods of diagnosis of bladder cancer, compositions and methods of screening for modulators of bladder cancer |
WO2003003984A2 (en) | 2001-07-05 | 2003-01-16 | Curagen Corporation | Novel proteins and nucleic acids encoding same |
WO2003055439A2 (en) | 2001-07-18 | 2003-07-10 | The Regents Of The University Of California | Her2/neu target antigen and use of same to stimulate an immune response |
AU2002337657A1 (en) | 2001-07-25 | 2003-02-17 | Millennium Pharmaceuticals, Inc. | Novel genes, compositions, kits, and methods for identification, assessment, prevention, and therapy of prostate cancer |
BR0211614A (pt) | 2001-08-03 | 2006-10-31 | Genentech Inc | polipeptìdeo tacis e br3 e empregos dos mesmos |
US20070015145A1 (en) | 2001-08-14 | 2007-01-18 | Clifford Woolf | Nucleic acid and amino acid sequences involved in pain |
US20030092013A1 (en) | 2001-08-16 | 2003-05-15 | Vitivity, Inc. | Diagnosis and treatment of vascular disease |
WO2003018621A2 (en) | 2001-08-23 | 2003-03-06 | Oxford Biomedica (Uk) Limited | Genes |
US6902930B2 (en) | 2001-08-29 | 2005-06-07 | Vanderbilt University | Human Mob-5 (IL-24) receptors and uses thereof |
US20030124579A1 (en) | 2001-09-05 | 2003-07-03 | Eos Biotechnology, Inc. | Methods of diagnosis of ovarian cancer, compositions and methods of screening for modulators of ovarian cancer |
JP2005505271A (ja) | 2001-09-06 | 2005-02-24 | アジェンシス, インコーポレイテッド | 癌の処置および検出において有用なsteap−1と名称が与えられる核酸および対応するタンパク質 |
AU2002330039A1 (en) | 2001-09-17 | 2003-04-01 | Eos Biotechnology, Inc. | Methods of diagnosis of cancer compositions and methods of screening for modulators of cancer |
US20050004017A1 (en) | 2001-09-18 | 2005-01-06 | Yuval Reiss | Methods and compositions for treating hcap associated diseases |
NZ531674A (en) | 2001-09-18 | 2009-03-31 | Genentech Inc | Compositions and methods for the diagnosis and treatment of tumor |
CA2460621A1 (en) | 2001-09-19 | 2003-03-27 | Nuvelo, Inc. | Novel nucleic acids and polypeptides |
US20030077644A1 (en) | 2001-09-28 | 2003-04-24 | Bing Yang | Diagnosis and treatment of diseases caused by mutations in CD72 |
WO2003029421A2 (en) | 2001-10-03 | 2003-04-10 | Origene Technologies, Inc. | Regulated breast cancer genes |
WO2003029277A2 (en) | 2001-10-03 | 2003-04-10 | Rigel Pharmaceuticals, Inc. | Modulators of lymphocyte activation and migration |
US20050123925A1 (en) | 2002-11-15 | 2005-06-09 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
US20040241703A1 (en) | 2002-08-19 | 2004-12-02 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
AU2002351505B2 (en) | 2001-10-19 | 2008-04-03 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of inflammatory bowel disorders |
AU2002356858A1 (en) | 2001-10-24 | 2003-05-06 | National Jewish Medical And Research Center | Structure of tall-1 and its cognate receptor |
RU2336902C2 (ru) | 2001-10-31 | 2008-10-27 | Алькон, Инк. | Морфогенные белки кости (вмр), рецепторы вмр и связывающие вмр белки и их применение для диагностики и лечения глаукомы |
WO2003042661A2 (en) | 2001-11-13 | 2003-05-22 | Protein Design Labs, Inc. | Methods of diagnosis of cancer, compositions and methods of screening for modulators of cancer |
US20030232350A1 (en) | 2001-11-13 | 2003-12-18 | Eos Biotechnology, Inc. | Methods of diagnosis of cancer, compositions and methods of screening for modulators of cancer |
AU2002339691A1 (en) | 2001-11-29 | 2003-06-10 | Genset | Agonists and antagonists of prolixin for the treatment of metabolic disorders |
WO2003048202A2 (en) | 2001-12-03 | 2003-06-12 | Asahi Kasei Pharma Corporation | Nf-kappab activating genes |
EP1504099A4 (en) | 2001-12-10 | 2006-05-10 | Nuvelo Inc | NEW NUCLEIC ACIDS AND POLYPEPTIDES |
US20030134790A1 (en) | 2002-01-11 | 2003-07-17 | University Of Medicine And Dentistry Of New Jersey | Bone Morphogenetic Protein-2 And Bone Morphogenetic Protein-4 In The Treatment And Diagnosis Of Cancer |
US7452675B2 (en) | 2002-01-25 | 2008-11-18 | The Queen's Medical Center | Methods of screening for TRPM4b modulators |
KR20040094705A (ko) | 2002-02-21 | 2004-11-10 | 듀크 유니버시티 | 자가면역질환에 대한 시약 및 치료 방법 |
CA2476518A1 (en) | 2002-02-22 | 2003-09-04 | Genentech, Inc. | Compositions and methods for the treatment of immune related diseases |
WO2003074674A2 (en) | 2002-03-01 | 2003-09-12 | Exelixis, Inc. | MSRAs AS MODIFIERS OF THE p53 PATHWAY AND METHODS OF USE |
WO2003101400A2 (en) | 2002-06-04 | 2003-12-11 | Avalon Pharmaceuticals, Inc. | Cancer-linked gene as target for chemotherapy |
WO2003104399A2 (en) | 2002-06-07 | 2003-12-18 | Avalon Pharmaceuticals, Inc | Cancer-linked gene as target for chemotherapy |
EP2258712A3 (en) | 2002-03-15 | 2011-05-04 | Multicell Immunotherapeutics, Inc. | Compositions and Methods to Initiate or Enhance Antibody and Major-histocompatibility Class I or Class II-restricted T Cell Responses by Using Immunomodulatory, Non-coding RNA Motifs |
WO2004000997A2 (en) | 2002-03-19 | 2003-12-31 | Curagen Corporation | Therapeutic polypeptides, nucleic acids encoding same, and methods of use |
JP2005534286A (ja) | 2002-03-21 | 2005-11-17 | サネシス ファーマシューティカルズ, インコーポレイテッド | キナーゼインヒビターの同定 |
US7193069B2 (en) | 2002-03-22 | 2007-03-20 | Research Association For Biotechnology | Full-length cDNA |
CA2480404A1 (en) | 2002-03-25 | 2003-10-30 | Uab Research Foundation | Fc receptor homolog, reagents, and uses thereof |
WO2003083074A2 (en) | 2002-03-28 | 2003-10-09 | Idec Pharmaceuticals Corporation | Novel gene targets and ligands that bind thereto for treatment and diagnosis of colon carcinomas |
US20030194704A1 (en) | 2002-04-03 | 2003-10-16 | Penn Sharron Gaynor | Human genome-derived single exon nucleic acid probes useful for gene expression analysis two |
MXPA04009728A (es) | 2002-04-05 | 2005-06-08 | Agenysys Inc | Acido nucleico y proteina correspondiente titulada 98p4b6 en el tratamiento y deteccion del cancer. |
US20040101874A1 (en) | 2002-04-12 | 2004-05-27 | Mitokor Inc. | Targets for therapeutic intervention identified in the mitochondrial proteome |
MXPA04010092A (es) | 2002-04-16 | 2004-12-13 | Genentech Inc | Composiciones y metodos para el diagnostico y tratamiento de tumores. |
US20030224467A1 (en) | 2002-04-17 | 2003-12-04 | Osborne C. Kent | AIB1 as a prognostic marker and predictor of resistance to endocrine therapy |
AU2003228869A1 (en) | 2002-05-03 | 2003-11-17 | Incyte Corporation | Transporters and ion channels |
CA2485983A1 (en) | 2002-05-15 | 2003-11-27 | Avalon Pharmaceuticals | Cancer-linked gene as target for chemotherapy |
US20030224454A1 (en) | 2002-05-30 | 2003-12-04 | Ryseck Rolf Peter | Human solute carrier family 7, member 11 (hSLC7A11) |
AU2003240495A1 (en) | 2002-06-04 | 2003-12-19 | Incyte Corporation | Diagnostics markers for lung cancer |
WO2003104275A2 (en) | 2002-06-06 | 2003-12-18 | Oncotherapy Science, Inc. | Genes and polypeptides relating to human colon cancers |
WO2003104270A2 (en) | 2002-06-06 | 2003-12-18 | Ingenium Pharmaceuticals Ag | Dudulin 2 genes, expression products, non-human animal model: uses in human hematological disease |
WO2003105758A2 (en) | 2002-06-12 | 2003-12-24 | Avalon Pharmaceuticals, Inc. | Cancer-linked gene as target for chemotherapy |
AU2003247576A1 (en) | 2002-06-18 | 2003-12-31 | Archemix Corp. | Aptamer-toxin molecules and methods for using same |
US20040249130A1 (en) | 2002-06-18 | 2004-12-09 | Martin Stanton | Aptamer-toxin molecules and methods for using same |
WO2004000221A2 (en) | 2002-06-20 | 2003-12-31 | The Regents Of The University Of California | Compositions and methods for modulating lymphocyte activity |
US20060275287A1 (en) | 2002-06-21 | 2006-12-07 | Brad St Croix | Scroll compressor |
AU2003281515A1 (en) | 2002-07-19 | 2004-02-09 | Cellzome Ag | Protein complexes of cellular networks underlying the development of cancer and other diseases |
CA2492447A1 (en) | 2002-07-25 | 2004-02-05 | Genentech, Inc. | Taci antibodies and uses thereof |
JP2004121218A (ja) | 2002-08-06 | 2004-04-22 | Jenokkusu Soyaku Kenkyusho:Kk | 気管支喘息または慢性閉塞性肺疾患の検査方法 |
WO2004015426A1 (en) | 2002-08-06 | 2004-02-19 | Bayer Healthcare Ag | Diagnostics and therapeutics for diseases associated with human cxc chemokine receptor 5(cxcr5) |
EP1572957A4 (en) | 2002-08-27 | 2007-10-10 | Bristol Myers Squibb Pharma Co | IDENTIFICATION OF POLYNUCLEOTIDES FOR PREDICTING THE ACTIVITY OF COMPOUNDS INTERACTING WITH AND / OR MODULATING TYROSINE KINASE PROTEINS AND / OR TYROSINE KINASE PROTEIN PATHWAYS IN MAMMARY CELLS |
WO2004020595A2 (en) | 2002-08-29 | 2004-03-11 | Five Prime Therapeutics, Inc. | Novel human polypeptides encoded by polynucleotides |
AU2002951346A0 (en) | 2002-09-05 | 2002-09-26 | Garvan Institute Of Medical Research | Diagnosis of ovarian cancer |
EP1545610A4 (en) | 2002-09-06 | 2006-11-08 | Mannkind Corp | EPITOPE SEQUENCES |
CA2498264A1 (en) | 2002-09-09 | 2004-05-13 | Nura, Inc. | G protein coupled receptors and uses thereof |
JP2004113151A (ja) | 2002-09-27 | 2004-04-15 | Sankyo Co Ltd | 癌遺伝子及びその用途 |
JP2006501849A (ja) | 2002-10-04 | 2006-01-19 | ヴァン アンデル リサーチ インスティチュート | 腎腫瘍の分子サブ分類および新規診断マーカーの発見 |
NZ538996A (en) | 2002-10-31 | 2008-04-30 | Genentech Inc | Methods and compositions for increasing antibody production |
EP1581169A4 (en) | 2002-11-08 | 2008-09-17 | Genentech Inc | COMPOSITIONS AND METHODS FOR TREATING DISEASES RELATED TO NATURAL K CELLS |
EP1578940A4 (en) | 2002-11-13 | 2007-12-12 | Genentech Inc | METHOD AND COMPOSITIONS FOR DYSPLASED DIAGNOSIS |
AU2003298650B2 (en) | 2002-11-15 | 2010-03-11 | Musc Foundation For Research Development | Complement receptor 2 targeted complement modulators |
EP1578372A4 (en) | 2002-11-15 | 2007-10-17 | Univ Arkansas | CA125 GENE AND ITS USE IN DIAGNOSTIC AND THERAPEUTIC INTERVENTIONS |
WO2004046342A2 (en) | 2002-11-20 | 2004-06-03 | Biogen Idec Inc. | Novel gene targets and ligands that bind thereto for treatment and diagnosis of carcinomas |
EP1624753B1 (en) | 2002-11-21 | 2012-01-25 | The University of Utah Research Foundation | Purinergic modulation of smell |
US20040253606A1 (en) | 2002-11-26 | 2004-12-16 | Protein Design Labs, Inc. | Methods of detecting soft tissue sarcoma, compositions and methods of screening for soft tissue sarcoma modulators |
AU2003302774A1 (en) | 2002-12-06 | 2004-06-30 | Diadexus, Inc. | Compositions, splice variants and methods relating to ovarian specific genes and proteins |
US20040157278A1 (en) | 2002-12-13 | 2004-08-12 | Bayer Corporation | Detection methods using TIMP 1 |
US7276372B2 (en) | 2002-12-20 | 2007-10-02 | Pdl Biopharma, Inc. | Antibodies against GPR64 and uses thereof |
US20050249671A9 (en) | 2002-12-23 | 2005-11-10 | David Parmelee | Neutrokine-alpha conjugate, neutrokine-alpha complex, and uses thereof |
CA2512536A1 (en) | 2003-01-08 | 2004-07-29 | Bristol-Myers Squibb Company | Biomarkers and methods for determining sensitivity to epidermal growth factor receptor modulators |
US20050227301A1 (en) | 2003-01-10 | 2005-10-13 | Polgen | Cell cycle progression proteins |
WO2004063355A2 (en) | 2003-01-10 | 2004-07-29 | Protein Design Labs, Inc. | Novel methods of diagnosis of metastatic cancer, compositions and methods of screening for modulators of matastatic cancer |
US20040171823A1 (en) | 2003-01-14 | 2004-09-02 | Nadler Steven G. | Polynucleotides and polypeptides associated with the NF-kappaB pathway |
WO2004065576A2 (en) | 2003-01-15 | 2004-08-05 | Millennium Pharmaceuticals, Inc. | Methods and compositions for the treatment of urological disorder using differential expressed polypeptides |
EP1585768A2 (en) | 2003-01-23 | 2005-10-19 | Genentech, Inc. | Methods for producing humanized antibodies and improving yield of antibodies or antigen binding fragments in cell culture |
US20040202666A1 (en) * | 2003-01-24 | 2004-10-14 | Immunomedics, Inc. | Anti-cancer anthracycline drug-antibody conjugates |
US20060228710A1 (en) | 2003-02-14 | 2006-10-12 | Morris David W | Novel therapeutic targets in cancer |
US20030224411A1 (en) | 2003-03-13 | 2003-12-04 | Stanton Lawrence W. | Genes that are up- or down-regulated during differentiation of human embryonic stem cells |
CA2519289A1 (en) | 2003-03-18 | 2004-09-30 | Antonino Suarato | Nemorubicin as radiosensitizer in combination with radiation therapy against tumors |
WO2004082689A1 (en) | 2003-03-18 | 2004-09-30 | Pharmacia Italia Spa | Combined therapy comprising nemorubicin and a cyclooxygenase-2-inhibitor |
BRPI0516284A (pt) | 2004-09-23 | 2008-09-02 | Genentech Inc | anticorpo construìdo com cisteìna, método de selecionar anticorpos, compostos conjugados de droga-anticorpo, composição farmacêutica, método para matar ou inibir a proliferação de células de tumor, métodos de inibir a proliferação celular e o crescimento de células de tumor, artigo manufaturado e método para produzir um composto |
US20070060534A1 (en) | 2005-06-30 | 2007-03-15 | Threshold Pharmaceuticals, Inc. | Anthracycline analogs |
SG10201501103RA (en) | 2006-05-30 | 2015-04-29 | Genentech Inc | Antibodies And Immunoconjugates And Uses Therefor |
JP5290276B2 (ja) | 2007-05-08 | 2013-09-18 | ジェネンテック, インコーポレイテッド | システイン改変抗muc16抗体および抗体−薬物結合体 |
CA2695532A1 (en) | 2007-08-20 | 2009-02-26 | Enzon Pharmaceuticals, Inc. | Polymeric linkers containing pyridyl disulfide moieties |
WO2009052249A1 (en) | 2007-10-19 | 2009-04-23 | Genentech, Inc. | Cysteine engineered anti-tenb2 antibodies and antibody drug conjugates |
JP6008864B2 (ja) | 2010-12-02 | 2016-10-19 | ナーヴィアノ メディカル サイエンシズ エス.アール.エル. | モルホリニルアントラサイクリン誘導体の調製方法 |
EP3191134B1 (en) | 2014-09-12 | 2019-11-20 | Genentech, Inc. | Anthracycline disulfide intermediates, antibody-drug conjugates and methods |
-
2015
- 2015-09-11 EP EP15770738.1A patent/EP3191134B1/en active Active
- 2015-09-11 WO PCT/US2015/049728 patent/WO2016040825A1/en active Application Filing
- 2015-09-11 CN CN201580049204.7A patent/CN106714844B/zh active Active
- 2015-09-11 US US14/851,206 patent/US10149913B2/en active Active
- 2015-09-11 JP JP2017513785A patent/JP6622293B2/ja active Active
-
2018
- 2018-11-01 US US16/178,328 patent/US11090322B2/en active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH01246295A (ja) * | 1988-02-11 | 1989-10-02 | Bristol Myers Co | 新規なリンカーを有するアントラサイクリン・イムノコンジュゲート及びその製造方法 |
JPH05201726A (ja) * | 1991-10-03 | 1993-08-10 | Hashimoto Kasei Kk | フッ素系エッチング剤からフッ化カルシウムを回収する方法 |
JP2003531821A (ja) * | 1999-12-29 | 2003-10-28 | イムノージェン インコーポレーテッド | 改変型ドキソルビシンおよびダウノルビシンを含む細胞傷害性薬剤ならびにその治療上の使用 |
WO2009099741A1 (en) * | 2008-02-01 | 2009-08-13 | Genentech, Inc. | Nemorubicin metabolite and analog reagents, antibody-drug conjugates and methods |
JP2011528360A (ja) * | 2008-07-15 | 2011-11-17 | ジェネンテック, インコーポレイテッド | アントラサイクリン誘導体コンジュゲート、その調製方法及び抗腫瘍化合物としてのその用途 |
Non-Patent Citations (1)
Title |
---|
WILLNER D ET AL: "(6-MALEIMIDOCAPROYL)HYDRAZONE OF DOXORUBICIN - A NEW DERIVATIVE FOR THE PREPARATION OF IMMUNOCONJUGA", BIOCONJUGATE CHEMISTRY, vol. 4(6), JPN6019023826, 1993, US, pages 521 - 527, ISSN: 0004062323 * |
Also Published As
Publication number | Publication date |
---|---|
US10149913B2 (en) | 2018-12-11 |
CN106714844A (zh) | 2017-05-24 |
US20160074528A1 (en) | 2016-03-17 |
WO2016040825A1 (en) | 2016-03-17 |
US20190054102A1 (en) | 2019-02-21 |
JP6622293B2 (ja) | 2019-12-18 |
EP3191134A1 (en) | 2017-07-19 |
US11090322B2 (en) | 2021-08-17 |
CN106714844B (zh) | 2022-08-05 |
EP3191134B1 (en) | 2019-11-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11090322B2 (en) | Anthracycline disulfide intermediates, antibody-drug conjugates and methods | |
US10442836B2 (en) | 1-(chloromethyl)-2,3-dihydro-1H-benzo[E]indole dimer antibody-drug conjugate compounds, and methods of use and treatment | |
US10544215B2 (en) | 1-(Chloromethyl)-2,3-dihydro-1H-benzo[e]indole dimer antibody-drug conjugate compounds, and methods of use and treatment | |
US9999681B2 (en) | Peptidomimetic compounds and antibody-drug conjugates thereof | |
AU2015358532C1 (en) | Quaternary amine compounds and antibody-drug conjugates thereof | |
KR102337414B1 (ko) | 펩타이드 모방체 화합물 및 이의 항체-약물 컨쥬게이트 | |
JP7093767B2 (ja) | ピロロベンゾジアゼピンプロドラッグ及びその抗体コンジュゲート | |
JP7043425B2 (ja) | シルベストロール抗体-薬物コンジュゲート及び使用方法 | |
WO2017064675A1 (en) | Hindered disulfide drug conjugates |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20180910 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20190618 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20190702 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20191002 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20191023 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20191121 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6622293 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |