RU2015151046A - Антитела против стеночной тейхоевой кислоты и их конъюгаты - Google Patents
Антитела против стеночной тейхоевой кислоты и их конъюгаты Download PDFInfo
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- RU2015151046A RU2015151046A RU2015151046A RU2015151046A RU2015151046A RU 2015151046 A RU2015151046 A RU 2015151046A RU 2015151046 A RU2015151046 A RU 2015151046A RU 2015151046 A RU2015151046 A RU 2015151046A RU 2015151046 A RU2015151046 A RU 2015151046A
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- Prior art keywords
- antibody
- seq
- cdr
- antibiotic
- chain
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- 239000002253 acid Substances 0.000 title claims 9
- 150000001875 compounds Chemical class 0.000 claims 9
- 108090000765 processed proteins & peptides Proteins 0.000 claims 9
- 230000003115 biocidal effect Effects 0.000 claims 7
- 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 claims 6
- 239000003242 anti bacterial agent Substances 0.000 claims 6
- 125000005647 linker group Chemical group 0.000 claims 6
- 239000012634 fragment Substances 0.000 claims 5
- YCLREGRRHGLOAK-UHFFFAOYSA-N 1-[(3-amino-2-methylphenyl)methyl]-4-(2-thiophen-2-ylethoxy)pyridin-2-one Chemical compound CC1=C(N)C=CC=C1CN1C(=O)C=C(OCCC=2SC=CC=2)C=C1 YCLREGRRHGLOAK-UHFFFAOYSA-N 0.000 claims 4
- ZFRUGZMCGCYBRC-UHFFFAOYSA-N 1h-1,8-naphthyridin-2-one Chemical compound C1=CC=NC2=NC(O)=CC=C21 ZFRUGZMCGCYBRC-UHFFFAOYSA-N 0.000 claims 4
- MPORYQCGWFQFLA-ONPDANIMSA-N 7-[(7s)-7-amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-[(1r,2s)-2-fluorocyclopropyl]-4-oxoquinoline-3-carboxylic acid;trihydrate Chemical compound O.O.O.C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1.C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 MPORYQCGWFQFLA-ONPDANIMSA-N 0.000 claims 4
- 108010013198 Daptomycin Proteins 0.000 claims 4
- YJQPYGGHQPGBLI-UHFFFAOYSA-N Novobiocin Natural products O1C(C)(C)C(OC)C(OC(N)=O)C(O)C1OC1=CC=C(C(O)=C(NC(=O)C=2C=C(CC=C(C)C)C(O)=CC=2)C(=O)O2)C2=C1C YJQPYGGHQPGBLI-UHFFFAOYSA-N 0.000 claims 4
- XEFQLINVKFYRCS-UHFFFAOYSA-N Triclosan Chemical compound OC1=CC(Cl)=CC=C1OC1=CC=C(Cl)C=C1Cl XEFQLINVKFYRCS-UHFFFAOYSA-N 0.000 claims 4
- 125000000539 amino acid group Chemical group 0.000 claims 4
- 150000001413 amino acids Chemical group 0.000 claims 4
- 229960002227 clindamycin Drugs 0.000 claims 4
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 claims 4
- DOAKLVKFURWEDJ-QCMAZARJSA-N daptomycin Chemical compound C([C@H]1C(=O)O[C@H](C)[C@@H](C(NCC(=O)N[C@@H](CCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@H](CO)C(=O)N[C@H](C(=O)N1)[C@H](C)CC(O)=O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](CC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CCCCCCCCC)C(=O)C1=CC=CC=C1N DOAKLVKFURWEDJ-QCMAZARJSA-N 0.000 claims 4
- 229960005484 daptomycin Drugs 0.000 claims 4
- 229960002950 novobiocin Drugs 0.000 claims 4
- YJQPYGGHQPGBLI-KGSXXDOSSA-N novobiocin Chemical compound O1C(C)(C)[C@H](OC)[C@@H](OC(N)=O)[C@@H](O)[C@@H]1OC1=CC=C(C(O)=C(NC(=O)C=2C=C(CC=C(C)C)C(O)=CC=2)C(=O)O2)C2=C1C YJQPYGGHQPGBLI-KGSXXDOSSA-N 0.000 claims 4
- STZYTFJPGGDRJD-NHUWBDDWSA-N retapamulin Chemical compound C([C@H]([C@@]1(C)[C@@H](C[C@@](C)(C=C)[C@@H](O)[C@@H]2C)OC(=O)CS[C@@H]3C[C@H]4CC[C@H](N4C)C3)C)C[C@]32[C@H]1C(=O)CC3 STZYTFJPGGDRJD-NHUWBDDWSA-N 0.000 claims 4
- 229960002771 retapamulin Drugs 0.000 claims 4
- 229960003177 sitafloxacin Drugs 0.000 claims 4
- 229960003500 triclosan Drugs 0.000 claims 4
- 108010053950 Teicoplanin Proteins 0.000 claims 3
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 claims 3
- 229960000723 ampicillin Drugs 0.000 claims 3
- 229960004099 azithromycin Drugs 0.000 claims 3
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 claims 3
- DDTDNCYHLGRFBM-YZEKDTGTSA-N chembl2367892 Chemical compound CC(=O)N[C@H]1[C@@H](O)[C@H](O)[C@H](CO)O[C@H]1O[C@@H]([C@H]1C(N[C@@H](C2=CC(O)=CC(O[C@@H]3[C@H]([C@H](O)[C@H](O)[C@@H](CO)O3)O)=C2C=2C(O)=CC=C(C=2)[C@@H](NC(=O)[C@@H]2NC(=O)[C@@H]3C=4C=C(O)C=C(C=4)OC=4C(O)=CC=C(C=4)[C@@H](N)C(=O)N[C@H](CC=4C=C(Cl)C(O5)=CC=4)C(=O)N3)C(=O)N1)C(O)=O)=O)C(C=C1Cl)=CC=C1OC1=C(O[C@H]3[C@H]([C@@H](O)[C@H](O)[C@H](CO)O3)NC(C)=O)C5=CC2=C1 DDTDNCYHLGRFBM-YZEKDTGTSA-N 0.000 claims 3
- 229960004679 doxorubicin Drugs 0.000 claims 3
- PZFAZQUREQIODZ-LJQANCHMSA-N dvf0pr037d Chemical compound C1CCOC(C=N2)=C1C=C2CNC(CC1)CCN1C[C@H]1N2C(=O)C=NC(C=CC3=O)=C2N3C1 PZFAZQUREQIODZ-LJQANCHMSA-N 0.000 claims 3
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims 3
- 229960005277 gemcitabine Drugs 0.000 claims 3
- 238000000034 method Methods 0.000 claims 3
- 108020004707 nucleic acids Proteins 0.000 claims 3
- 150000007523 nucleic acids Chemical class 0.000 claims 3
- 102000039446 nucleic acids Human genes 0.000 claims 3
- BTTNOGHPGJANSW-IBGZPJMESA-N radezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(C=2C=CC(CNCC=3NN=NC=3)=CC=2)C(F)=C1 BTTNOGHPGJANSW-IBGZPJMESA-N 0.000 claims 3
- 229950009965 radezolid Drugs 0.000 claims 3
- 125000006850 spacer group Chemical group 0.000 claims 3
- 229960001608 teicoplanin Drugs 0.000 claims 3
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 claims 2
- 208000035143 Bacterial infection Diseases 0.000 claims 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims 2
- 241000191967 Staphylococcus aureus Species 0.000 claims 2
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 claims 2
- 108010059993 Vancomycin Proteins 0.000 claims 2
- 125000000217 alkyl group Chemical group 0.000 claims 2
- 208000022362 bacterial infectious disease Diseases 0.000 claims 2
- 229960002173 citrulline Drugs 0.000 claims 2
- 235000018417 cysteine Nutrition 0.000 claims 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims 2
- AVAACINZEOAHHE-VFZPANTDSA-N doripenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](CNS(N)(=O)=O)C1 AVAACINZEOAHHE-VFZPANTDSA-N 0.000 claims 2
- 229960000895 doripenem Drugs 0.000 claims 2
- 239000003937 drug carrier Substances 0.000 claims 2
- 238000010353 genetic engineering Methods 0.000 claims 2
- -1 glidant Substances 0.000 claims 2
- 229960002182 imipenem Drugs 0.000 claims 2
- ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 claims 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 claims 2
- 229960003165 vancomycin Drugs 0.000 claims 2
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 claims 2
- 125000006832 (C1-C10) alkylene group Chemical group 0.000 claims 1
- JUIKUQOUMZUFQT-UHFFFAOYSA-N 2-bromoacetamide Chemical compound NC(=O)CBr JUIKUQOUMZUFQT-UHFFFAOYSA-N 0.000 claims 1
- 239000004475 Arginine Substances 0.000 claims 1
- 239000004471 Glycine Substances 0.000 claims 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims 1
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- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 claims 1
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- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims 1
- 239000004472 Lysine Substances 0.000 claims 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 claims 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 claims 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims 1
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 claims 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims 1
- 235000004279 alanine Nutrition 0.000 claims 1
- HAXFWIACAGNFHA-UHFFFAOYSA-N aldrithiol Chemical compound C=1C=CC=NC=1SSC1=CC=CC=N1 HAXFWIACAGNFHA-UHFFFAOYSA-N 0.000 claims 1
- 150000001412 amines Chemical group 0.000 claims 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims 1
- FNXLCIKXHOPCKH-UHFFFAOYSA-N bromamine Chemical compound BrN FNXLCIKXHOPCKH-UHFFFAOYSA-N 0.000 claims 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- 235000013477 citrulline Nutrition 0.000 claims 1
- 230000001268 conjugating effect Effects 0.000 claims 1
- 238000012258 culturing Methods 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 125000000524 functional group Chemical group 0.000 claims 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 230000003834 intracellular effect Effects 0.000 claims 1
- PGLTVOMIXTUURA-UHFFFAOYSA-N iodoacetamide Chemical compound NC(=O)CI PGLTVOMIXTUURA-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 229960003085 meticillin Drugs 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims 1
- 150000003573 thiols Chemical class 0.000 claims 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 1
- 239000004474 valine Substances 0.000 claims 1
- 0 CC(C)([C@@]1*=C)S[C@@](C2NC(Cc3ccccc3)=O)N1C2=O Chemical compound CC(C)([C@@]1*=C)S[C@@](C2NC(Cc3ccccc3)=O)N1C2=O 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/12—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria
- C07K16/1267—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-positive bacteria
- C07K16/1271—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-positive bacteria from Micrococcaceae (F), e.g. Staphylococcus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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- A—HUMAN NECESSITIES
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Claims (135)
1. Изолированное анти-WTA (стеночная тейхоевая кислота) моноклональное антитело, содержащее легкую (L) цепь и тяжелую (Н) цепь, причем L цепь, содержащая CDR L1, CDR L2 и CDR L3 и Н цепь, содержащая CDR H1, CDR Н2 и CDR Н3, в которых CDR L1, CDR L2 и CDR L3 и CDR H1, CDR Н2 и CDR Н3 содержат аминокислотные последовательности CDR, каждого из антител 4461 (SEQ ID NO. 1-6), 4624 (SEQ ID NO. 7-12), 4399 (SEQ ID NO. 13-18) и 6267 (SEQ ID NO. 19-24), соответственно, как показано в таблицах 6А и 6В.
2. Изолированное анти-WTA моноклональное антитело, содержащее вариабельную область тяжелой цепи (VH), в котором VH содержит последовательность, идентичную по меньшей мере на 95% по длине области VH, выбранной из VH последовательности SEQ ID No. 26, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32 из антител 4461, 4624, 4399 и 6267, соответственно.
3. Антитело по п. 2, дополнительно содержащее вариабельную область L-цепи (VL), в которой VL содержит последовательность, идентичную по меньшей мере на 95% по длине области VL, выбранной из VL последовательности SEQ ID NO. 25, SEQ ID NO. 27, SEQ ID No. 29, SEQ ID NO. 31 антител 4461, 4624, 4399 и 6267. соответственно.
4. Антитело по п. 3, в котором антитело содержит:
(i) VL SEQ ID NO. 25 и VH SEQ ID NO. 26;
(ii) VL SEQ ID NO. 27 и VH SEQ ID NO. 28;
(iii) VL SEQ ID NO. 29 и VH SEQ ID NO. 30; или
(iv) VL SEQ ID NO. 31 и VH SEQ ID NO. 32.
5. Антитело по любому из пп. 1-4, где антитело связывается с WTA альфа.
6. Изолированное анти-WTA моноклональное антитело, содержащее легкую цепь и Н цепь, причем L-цепь, содержащая CDR L1, CDR L2 и CDR L3 и Н-цепь, содержащая CDR H1, CDR Н2 и CDR Н3, в которых CDR L1, CDR L2 и CDR L3 и CDR H1, CDR Н2 и CDR Н3 содержат аминокислотные последовательности соответствующие CDR, каждого из антител, показанных на Фиг. 14 (SEQ ID NO. 33-110).
7. Изолированное анти-WTA моноклональное антитело, содержащее вариабельную область L-цепи (VL), в котором VL содержит последовательность, идентичную по меньшей мере на 95% по длине области VL, выбранной из VL последовательности, соответствующей каждому из антител 6078, 6263, 4450, 6297, 6239, 6232, 6259, 6292, 4462, 6265, 6253, 4497 и 4487, соответственно, как показано на Фиг. 17А-1, 17А-2, 17А-3 по нумерации Kabat 1-107.
8. Антитело по п. 7, дополнительно содержащее вариабельную область тяжелой цепи (VH), в котором VH содержит последовательность, идентичную по меньшей мере на 95% по длине области VH, выбранной из последовательностей VH, соответствующей каждому из антител 6078, 6263, 4450, 6297, 6239, 6232, 6259, 6292, 4462, 6265, 6253, 4497 и 4487, соответственно, как показано на Фиг. 17В-1 - 17В-6 по нумерации Kabat 1-113.
9. Антитело по п. 8, в котором VH содержит последовательность SEQ ID NO. 112 и VL содержит SEQ ID NO. 111.
10. Антитело по п. 7, в котором легкая цепь содержит последовательность SEQ ID NO. 115, и Н-цепь, имеющую цистеин, введенный методами генетической инженерии, содержит SEQ ID NO. 116.
11. Антитело по п. 7, в котором легкая цепь содержит последовательность SEQ ID NO. 115 и Н-цепь, имеющую цистеин, введенный методами генетической инженерии, содержит SEQ ID NO. 117, где X представляет собой М, I или V.
12. Антитело по п. 7, в котором L-цепь содержит последовательность SEQ ID NO. 121 и Н-цепь содержит последовательность SEQ ID NO. 124.
13. Изолированное анти-WTA моноклональное антитело, содержащее последовательность L-цепи SEQ ID NO. 123 и последовательность Н-цепи SEQ ID NO. 157 или SEQ ID NO. 124.
14. Антитело по п. 6, где антитело связывается с WTA бета.
15. Антитело, которое связывается с тем же эпитопом, что любое антитело по любому из пп. 1-14.
16. Композиция, содержащая антитело по любому из пп. 1-15, и фармацевтически приемлемый носитель.
17. Нуклеиновая кислота, кодирующая антитело по любому из пп. 1-15.
18. Клетка-хозяин, содержащая нуклеиновую кислоту по п. 17.
19. Способ получения антитела по любому из пп. 1-14, включающий культивирование клетки-хозяина по п. 18 в условиях, подходящих для экспрессии нуклеиновой кислоты; и выделение антител, продуцируемых клеткой.
20. Соединение конъюгата антитело-антибиотик, содержащее антитело против стеночной тейхоевой кислоты (WTA) по любому из пп. 1-15, ковалентно присоединенное посредством пептидного линкера к фрагменту антибиотика, выбранного из клиндамицина, новобиоцина, ретапамулина, даптомицина, GSK-2140944, CG-400549, ситафлоксацина, тейкопланина, триклозана, нафтиридона, радезолида, доксорубицина, ампициллина, ванкомицина, имипенема, дорипенема, гемцитабина, далбавацина и азитромицина.
21. Соединение конъюгата антитело-антибиотик по п. 20, в котором антитело содержит: i) CDR L-цепи и Н-цепи последовательностей SEQ ID NO 99-104 или CDR L-цепи и Н-цепи последовательностей SEQ ID NO. 33-38; или ii) VL последовательностей SEQ ID NO. 119 или SEQ ID NO. 123, спаренные с VH последовательностей SEQ ID NO. 120 или SEQ ID NO. 156; или iii) VL последовательности SEQ ID NO. 111, спаренная с VH последовательности SEQ ID NO. 112.
22. Соединение конъюгата антитело-антибиотик по п. 20, в котором антитело против стеночной тейхоевой кислоты (WTA) связывается с Staphylococcus aureus.
23. Соединение конъюгата антитело-антибиотик по п. 20, в котором антитело против стеночной тейхоевой кислоты (WTA) связывается с метициллин-устойчивыми Staphylococcus aureus (MRSA).
24. Конъюгат антитело-антибиотик по п.20, в котором фрагмент антибиотика представляет собой четвертичный амин, присоединенный к пептидному линкеру.
25. Конъюгат антитело-антибиотик по п. 20, имеющий формулу:
Ab-(L-abx)p
в которой:
Ab представляет собой антитело против стеночной тейхоевой кислоты;
L представляет собой пептидный линкер, имеющий формулу:
-Str-Pep-Y-
в которой Str представляет собой растяжимый участок; Pep представляет собой пептид из от двух до двенадцати аминокислотных остатков, и Y представляет собой спейсерный участок;
abx представляет собой фрагмент антибиотика; а
p представляет собой целое число от 1 до 8.
26. Соединение конъюгата антитело-антибиотик по п. 20, в котором пептидный линкер имеет формулу:
-Str-Pep-Y-
в которой Str представляет собой растяжимый участок, ковалентно присоединенный к антителу против стеночной тейхоевой кислоты (WTA); Pep представляет собой пептид из от двух до двенадцати аминокислотных остатков, и Y представляет собой спейсерный участок, ковалентно присоединенный к антибиотику.
27. Конъюгат антитело-антибиотик по п. 26, в котором Str имеет формулу:
в которой R6 выбираются из группы, состоящей из С1-С10-алкилен, -С3-C8 карбоцикло, -O-(С1-С8 алкил)-, -арилен-, C1-С10 алкилен-арилен-, -арилен-C1-С10 алкилен, C1-С10 алкилен-(С3-C8 карбоцикло)-, -(С3-С8 карбоцикло)-C1-С10-алкилен, С3-C8 гетероцикло-, -C1-С10 алкилен(С3-С8 гетероцикло)-, -(С3-C8 гетероцикло)-C1-С10-алкилен, -(СН2СН2О)r-, и -(СН2СН2О)r-СН2-; и r представляет собой целое число в диапазоне от 1 до 10.
28. Конъюгат антитело-антибиотик по п. 27, где R6 представляет собой -(СН2)5-
29. Конъюгат антитело-антибиотик по п. 26, где Pep содержит от двух до двенадцати аминокислотных остатков, независимо выбранных из глицина, аланина, фенилаланина, лизина, аргинина, валина и цитруллина.
30. Конъюгат антитело-антибиотик по п. 29, где Pep представляет собой валин-цитруллин.
31. Конъюгат антитело-антибиотик по п. 26, где Y содержит пара-аминобензил или пара-аминобензилоксикарбонил.
32. Конъюгат антитело-антибиотик по п. 20, имеющий формулу:
в которой АА1 и АА2 независимо выбираются из боковых цепей аминокислоты.
33. Конъюгат антитело-антибиотик по п. 32, в котором боковую цепь аминокислоты независимо выбирается из Н, -СН3, -СН2(С6Н5), -CH2CH2CH2CH2NH2, -CH2CH2CH2NHC(NH)NH2, -СНСН(СН3)СН3 и -CH2CH2CH2NHC(O)NH2.
34. Конъюгат антитело-антибиотик по п. 32, имеющий формулу:
35. Конъюгат антитело-антибиотик по п. 32, имеющий формулу:
36. Конъюгат антитело-антибиотик по п. 35, имеющий формулу:
37. Конъюгат антитело-антибиотик по п. 35, имеющий формулу:
38. Конъюгат антитело-антибиотик по п. 35, имеющий формулу:
39. Конъюгат антитело-антибиотик по п. 35, имеющий формулу:
40. Конъюгат антитело-антибиотик по п. 35, имеющий формулу:
41. Конъюгат антитело-антибиотик по п. 35, имеющий формулу:
в которой R7 независимо выбирается из Н и С1-С12 алкила.
42. Фармацевтическая композиция, содержащая соединение конъюгат антитело-антибиотик по п. 20, и фармацевтически приемлемый носитель, скользящее вещество, разбавитель или вспомогательное вещество.
43. Способ лечения бактериальной инфекции, включающий введение пациенту терапевтически эффективного количества соединения конъюгата антитело-антибиотик, содержащего антитело против стеночной тейхоевой кислоты (WTA), ковалентно присоединенное с помощью пептидного линкера к антибиотику, выбранного из клиндамицина, новобиоцина, ретапамулина, даптомицина, GSK-2140944, CG-400549, ситафлоксацина, тейкопланина, триклозана, нафтиридона, радезолида, доксорубицина, ампициллина, ванкомицина, имипенема, дорипенема, гемцитабина, далбавацина и азитромицина.
44. Способ получения соединения конъюгата антитело-антибиотик по п. 20, включающий конъюгацию антитела против стеночной тейхоевой кислоты (WTA) с фрагментом антибиотика, выбранного из клиндамицина, новобиоцина, ретапамулина, даптомицина, GSK-2140944, CG-400549, ситафлоксацина, тейкопланина, триклозана, нафтиридона, радезолида, доксорубицина, ампициллина, ванкомицина, имипенема, дорипенема, гемцитабина, далбавацина и азитромицина.
45. Набор для лечения бактериальной инфекции, включающий:
a) фармацевтическую композицию по п. 42; и
b) инструкции по применению.
46. Промежуточное соединение антибиотик-линкер, выбранное из:
X-L-abx
где:
abx представляет собой фрагмент антибиотика, выбранного из клиндамицина, новобиоцина, ретапамулина, даптомицина, GSK-2140944, CG-400549, ситафлоксацина, тейкопланина, триклозана, нафтиридона, радезолида, доксорубицина, ампициллина, ванкомицина, имипенема, дорипенема, гемцитабина, далбавацина и азитромицина;
L представляет собой пептидный линкер, ковалентно присоединенный к abx и X, и имеющий формулу:
-Str-Pep-Y-
в которой Str представляет собой растяжимый участок; Pep представляет собой пептид из от двух до двенадцати аминокислотных остатков, и Y представляет собой спейсерный участок; и
X представляет собой реакционноспособную функциональную группу, выбранную из малеимида, тиола, амино, бромида, бромацетамида, йодацетамида, п-толуолсульфоната, иодида, гидроксила, карбоксила, пиридилдисульфида и N-гидроксисукцинимида.
47. Промежуточное соединение антибиотик-линкер по п. 46, в котором X представляет собой
48. Промежуточное соединение антибиотик-линкер по п. 46, выбранное из:
49. Антитело любому из пп. 1-15, в котором антитело представляет собой F(ab) или F(ab')2.
50. Антитело по п. 49, где антитело представляет собой F(ab')2.
51. Соединение конъюгата антитело-антибиотик по любому из пп. 20-41, касающихся соединения конъюгата антитело-антибиотик, в котором антитело представляет собой F(ab) или F(ab')2.
52. Способ уничтожения внутриклеточных Staph aureus в клетках-хозяевах пациента, инфицированного Staph aureus, без уничтожения клетки-хозяева, включающий введение соединения конъюгата анти-WTA-антибиотик.
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RU2731055C2 (ru) * | 2014-12-03 | 2020-08-28 | Дженентек, Инк. | Конъюгаты антитела к staphylococcus aureus с рифамицином и их применение |
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CN105358574A (zh) | 2016-02-24 |
JP2016532433A (ja) | 2016-10-20 |
JP2019141054A (ja) | 2019-08-29 |
EP3004161B1 (en) | 2019-10-02 |
EP3004161A1 (en) | 2016-04-13 |
RU2687044C2 (ru) | 2019-05-06 |
MX2015016354A (es) | 2016-07-20 |
US20150366985A1 (en) | 2015-12-24 |
MX369758B (es) | 2019-11-20 |
CN105358574B (zh) | 2020-10-16 |
WO2014193722A1 (en) | 2014-12-04 |
US20180085470A1 (en) | 2018-03-29 |
US20160074529A1 (en) | 2016-03-17 |
US9895450B2 (en) | 2018-02-20 |
US9884126B2 (en) | 2018-02-06 |
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