HRP20110302T1 - Ca6 antigen-specifični citotoksični konjugat i postupci za njegovu uporabu - Google Patents
Ca6 antigen-specifični citotoksični konjugat i postupci za njegovu uporabu Download PDFInfo
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- HRP20110302T1 HRP20110302T1 HR20110302T HRP20110302T HRP20110302T1 HR P20110302 T1 HRP20110302 T1 HR P20110302T1 HR 20110302 T HR20110302 T HR 20110302T HR P20110302 T HRP20110302 T HR P20110302T HR P20110302 T1 HRP20110302 T1 HR P20110302T1
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- cytotoxic
- carbon atoms
- alkenyl
- substance
- cytotoxic conjugate
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- 231100000433 cytotoxic Toxicity 0.000 title claims abstract 87
- 230000001472 cytotoxic effect Effects 0.000 title claims abstract 87
- 238000000034 method Methods 0.000 title claims abstract 8
- 239000000427 antigen Substances 0.000 title 1
- 102000036639 antigens Human genes 0.000 title 1
- 108091007433 antigens Proteins 0.000 title 1
- 239000012634 fragment Substances 0.000 claims abstract 30
- 239000000203 mixture Substances 0.000 claims abstract 14
- 230000001225 therapeutic effect Effects 0.000 claims abstract 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 43
- 239000000126 substance Substances 0.000 claims 43
- 125000003342 alkenyl group Chemical group 0.000 claims 40
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 36
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 30
- -1 CC-1065 compound Chemical class 0.000 claims 24
- 125000000217 alkyl group Chemical group 0.000 claims 19
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims 19
- WKPWGQKGSOKKOO-RSFHAFMBSA-N maytansine Chemical class 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 claims 11
- 229930126263 Maytansine Natural products 0.000 claims 10
- 125000003107 substituted aryl group Chemical group 0.000 claims 8
- 229940123237 Taxane Drugs 0.000 claims 7
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 claims 7
- 206010028980 Neoplasm Diseases 0.000 claims 5
- 125000003275 alpha amino acid group Chemical group 0.000 claims 5
- 230000010261 cell growth Effects 0.000 claims 5
- 230000002401 inhibitory effect Effects 0.000 claims 5
- 125000003118 aryl group Chemical group 0.000 claims 4
- 201000011510 cancer Diseases 0.000 claims 4
- 125000000623 heterocyclic group Chemical group 0.000 claims 4
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims 4
- 102000040430 polynucleotide Human genes 0.000 claims 4
- 108091033319 polynucleotide Proteins 0.000 claims 4
- 239000002157 polynucleotide Substances 0.000 claims 4
- 239000013598 vector Substances 0.000 claims 4
- 125000000392 cycloalkenyl group Chemical group 0.000 claims 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims 3
- QWPXBEHQFHACTK-KZVYIGENSA-N (10e,12e)-86-chloro-12,14,4-trihydroxy-85,14-dimethoxy-33,2,7,10-tetramethyl-15,16-dihydro-14h-7-aza-1(6,4)-oxazina-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-6-one Chemical group CN1C(=O)CC(O)C2(C)OC2C(C)C(OC(=O)N2)CC2(O)C(OC)\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 QWPXBEHQFHACTK-KZVYIGENSA-N 0.000 claims 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims 2
- QWPXBEHQFHACTK-UHFFFAOYSA-N Maytansinol Natural products CN1C(=O)CC(O)C2(C)OC2C(C)C(OC(=O)N2)CC2(O)C(OC)C=CC=C(C)CC2=CC(OC)=C(Cl)C1=C2 QWPXBEHQFHACTK-UHFFFAOYSA-N 0.000 claims 2
- 206010033128 Ovarian cancer Diseases 0.000 claims 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims 2
- 101100054666 Streptomyces halstedii sch3 gene Proteins 0.000 claims 2
- 239000013604 expression vector Substances 0.000 claims 2
- 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 claims 1
- 206010006187 Breast cancer Diseases 0.000 claims 1
- 208000026310 Breast neoplasm Diseases 0.000 claims 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 claims 1
- 206010014759 Endometrial neoplasm Diseases 0.000 claims 1
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 claims 1
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 claims 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 claims 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 claims 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims 1
- 208000004354 Vulvar Neoplasms Diseases 0.000 claims 1
- 150000001413 amino acids Chemical class 0.000 claims 1
- 230000030833 cell death Effects 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 claims 1
- 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 claims 1
- 229960000975 daunorubicin Drugs 0.000 claims 1
- 125000002228 disulfide group Chemical group 0.000 claims 1
- AMRJKAQTDDKMCE-UHFFFAOYSA-N dolastatin Chemical class CC(C)C(N(C)C)C(=O)NC(C(C)C)C(=O)N(C)C(C(C)C)C(OC)CC(=O)N1CCCC1C(OC)C(C)C(=O)NC(C=1SC=CN=1)CC1=CC=CC=C1 AMRJKAQTDDKMCE-UHFFFAOYSA-N 0.000 claims 1
- 229960004679 doxorubicin Drugs 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 230000009036 growth inhibition Effects 0.000 claims 1
- 238000000338 in vitro Methods 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 201000002528 pancreatic cancer Diseases 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 150000003573 thiols Chemical class 0.000 claims 1
- 239000011230 binding agent Substances 0.000 abstract 2
- 241001529936 Murinae Species 0.000 abstract 1
- 229940127089 cytotoxic agent Drugs 0.000 abstract 1
- 239000002254 cytotoxic agent Substances 0.000 abstract 1
- 231100000599 cytotoxic agent Toxicity 0.000 abstract 1
- 201000010099 disease Diseases 0.000 abstract 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 1
- 230000017095 negative regulation of cell growth Effects 0.000 abstract 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4748—Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
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- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
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- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
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- 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
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- 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
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
- C07K16/3076—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells against structure-related tumour-associated moieties
- C07K16/3092—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells against structure-related tumour-associated moieties against tumour-associated mucins
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
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- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
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- C—CHEMISTRY; METALLURGY
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- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
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- C07K2317/565—Complementarity determining region [CDR]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
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- C07—ORGANIC CHEMISTRY
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- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
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Abstract
Humanizirano protutijelo ili njegov fragment koji se veže za epitop, naznačeno time što sadrži barem jednu varijabilnu regiju teškog lanca najmanje 98% identičnu sekvenci aminokiselina SEQ ID NO: 10 ili 11 i barem jednu varijabilnu regiju lakog lanca najmanje 98% identičnu sekvenci aminokiselina SEQ ID NO: 8, pri čemu barem jedna spomenuta varijabilna regija teškog lanca ili njezin fragment sadrži tri uzastopne regije koje određuju komplement, sa sekvencama aminokiselina SEQ ID NOS:1, 21, odnosno 3, i pri čemu barem jedna spomenuta varijabilna regija lakog lanca ili njezin fragment sadrži tri uzastopne regije koje određuju komplement, sa sekvencama aminokiselina SEQ ID NOS: 4, 5, odnosno 6. Patent sadrži još 70 patentnih zahtjeva.
Claims (71)
1. Humanizirano protutijelo ili njegov fragment koji se veže za epitop, naznačeno time što sadrži barem jednu varijabilnu regiju teškog lanca najmanje 98% identičnu sekvenci aminokiselina SEQ ID NO: 10 ili 11 i barem jednu varijabilnu regiju lakog lanca najmanje 98% identičnu sekvenci aminokiselina SEQ ID NO: 8, pri čemu barem jedna spomenuta varijabilna regija teškog lanca ili njezin fragment sadrži tri uzastopne regije koje određuju komplement, sa sekvencama aminokiselina SEQ ID NOS:1, 21, odnosno 3, i pri čemu barem jedna spomenuta varijabilna regija lakog lanca ili njezin fragment sadrži tri uzastopne regije koje određuju komplement, sa sekvencama aminokiselina SEQ ID NOS: 4, 5, odnosno 6.
2. Protutijelo ili njegov fragment koji se veže za epitop, prema zahtjevu 1, naznačeno time što varijabilna regija lakog lanca ili njezin fragment ima sekvencu aminokiselina SEQ ID NO:8.
3. Protutijelo ili njegov fragment koji se veže za epitop, prema zahtjevu 1, naznačeno time što varijabilna regija teškog lanca ili njezin fragment ima sekvencu aminokiselina SEQ ID NO:10 ili SEQ ID NO:11.
4. Polinukelotid, naznačen time što kodira protutijelo ili fragment koji se veže za epitop prema bilo kojem od zahtjeva 1 ili 2.
5. Polinukelotid, naznačen time što kodira laki ili teški lanac protutijela ili fragment koji se veže za epitop prema bilo kojem od zahtjeva 1 ili 2.
6. Vektor, naznačen time što sadrži polinukelotid prema zahtjevu 4.
7. Vektor, naznačen time što sadrži polinukelotid prema zahtjevu 5.
8. Vektor prema zahtjevu 6, naznačen time što je to vektor ekspresije koji eksprimira navedeno protutijelo ili fragment koji se veže za epitop.
9. Vektor prema zahtjevu 7, naznačen time što je to vektor ekspresije koji eksprimira navedeno protutijelo ili fragment koji se veže za epitop.
10. Citotoksični konjugat, naznačen time što obuhvaća tvar koja se veže za stanicu i citotoksičnu tvar, pri čemu ta tvar koja se veže za stanicu obuhvaća humanizirano protutijelo ili njegov fragment koji se veže za epitop prema zahtjevima 1-3.
11. Citotoksični konjugat prema zahtjevu 10, naznačen time što su tvar koja se veže za stanicu i citotoksična tvar kovalentno povezane.
12. Citotoksični konjugat prema zahtjevu 10, naznačen time što su tvar koja se veže za stanicu i citotoksična tvar kovalentno povezane preko PEG vezne skupine.
13. Citotoksični konjugat prema zahtjevu 10, naznačen time što su tvar koja se veže za stanicu i naznačen time što kovalentno povezane preko tiolne ili disulfidne funkcionalne skupine citotoksične tvari.
14. Citotoksični konjugat prema zahtjevu 10, naznačen time što se fragment protutijela odabire iz skupine koja obuhvaća Fab fragment, Fab’ fragment, F(ab’)2 fragment, Fd fragment, jednolančani Fvs (scFv) fragment, jednolančano protutijelo, disulfid-spojeni Fvs (sdFv) fragment i fragment koji sadrži ili VL ili VH domenu.
15. Citotoksični konjugat prema zahtjevu 10, naznačen time što je citotoksična tvar član izabran iz skupine koja obuhvaća derivat majtanzina, taksoidni spoj, CC-1065 spoj, derivat dolastatina, daunorubicina i doksorubicina.
16. Citotoksični konjugat prema zahtjevu 15, naznačen time što je citotoksična tvar majtanzin DM1 formule (I):
[image]
17. Citotoksični konjugat prema zahtjevu 15, naznačen time što je citotoksična tvar majtanzin DM4 formule (II):
[image]
18. Citotoksični konjugat prema zahtjevu 15, naznačen time što je citotoksična tvar majtanzin formule (III):
[image]
gdje:
Y’ predstavlja
(CR7CR8)l(CR9=CR10)pC=CqAr(CR5CR6)mDu(CR11=CR12)rC=C)sBt(CR3CR4)nCR1R2SZ,
gdje:
R1 i R2 su svaki nezavisno CH3, C2H5, linearni alkil ili alkenil s 1 do 10 atoma ugljika, razgranati ili ciklički alkil ili alkenil s 3 do 10 atoma ugljika, fenil, supstituirani fenil ili heterociklički aromatski ili heterocikloalkilni radikal, i dodatno R2 može biti H;
A, B, D su cikloalkil ili cikloalkenil s 3 -10 atoma ugljika, jednostavni ili supstituirani aril ili heterociklički aromatski ili heterocikloalkilni radikal;
R3, R4, R5, R6, R7, R8, R9, R11 i R12 su svaki nezavisno H, CH3, C2H5, linearni alkil ili alkenil s 1 do 10 atoma ugljika, razgranati ili ciklički alkil ili alkenil s 3 do 10 atoma ugljika, fenil, supstituirani fenil ili heterociklički aromatski ili heterocikloalkilni radikal;
l, m, n, o, p, q, r, s i t su svaki nezavisno 0 ili cijeli broj od 1 do 5, uz uvjet da barem dva od l, m, n, o, p, q, r, s i t nisu nikad nula; i
Z je H, SR ili -COR, pri čemu je R linearni alkil ili alkenil s 1 do 10 atoma ugljika, razgranati ili ciklički alkil ili alkenil s 3 do 10 atoma ugljika, ili jednostavni ili supstituirani aril ili heterociklički aromatski ili heterocikloalkilni radikal.
19. Citotoksični konjugat prema zahtjevu 18, naznačen time što R1 je H, R2 je metil i Z je H.
20. Citotoksični konjugat prema zahtjevu 18, naznačen time što su R1 i R2 metil i Z je H.
21. Citotoksični konjugat prema zahtjevu 18, naznačen time što R1 je H, R2 je metil, i Z je -SCH3.
22. Citotoksični konjugat prema zahtjevu 18, naznačen time što su R1 i R2 metil i Z je -SCH3.
23. Citotoksični konjugat prema zahtjevu 15, naznačen time što je citotoksična tvar majtanzin izabran iz skupine koja obuhvaća formule (IV-L), (IV-D) i (IV-D,L):
[image]
gdje:
Y predstavlja (CR7R8)l(CR5R6)m(CR3R4)nCR1R2SZ,
gdje:
R1 i R2 su svaki nezavisno CH3, C2H5, linearni alkil ili alkenil s 1 do 10 atoma ugljika, razgranati ili ciklički alkil ili alkenil s 3 do 10 atoma ugljika, fenil, supstituirani fenil ili heterociklički aromatski ili heterocikloalkilni radikal, i dodatno R2 može biti H;
R3, R4, R5, R6, R7 i R8 su svaki nezavisno H, CH3, C2H5, linearni alkil ili alkenil s 1 do 10 atoma ugljika, razgranati ili ciklički alkil ili alkenil s 3 do 10 atoma ugljika, fenil, supstituirani fenil ili heterociklički aromatski ili heterocikloalkilni radikal;
l, m i n su svaki nezavisno cijeli broj od 1 do 5, i dodatno n može biti 0;
Z je H, SR ili -COR, pri čemu je R linearni ili razgranati alkil ili alkenil s 1 do 10 atoma ugljika, ciklički alkil ili alkenil s 3 do 10 atoma ugljika, ili jednostavni ili supstituirani aril ili heterociklički aromatski ili heterocikloalkilni radikal; i
May predstavlja majtanzinoid koji nosi bočni lanac na C-3, C-14 hidroksimetil, C-15 hidroksi ili C-20 desmetil.
24. Citotoksični konjugat prema zahtjevu 23, naznačen time što R1 je H, R2 je metil, R5, R6, R7 i R8 su svaki H, l i m su svaki 1, n je 0 i Z je H.
25. Citotoksični konjugat prema zahtjevu 23, naznačen time što su R1 i R2 metil, R5, R6, R7 i R8 su svaki H, l i m su 1, n je 0 i Z je H.
26. Citotoksični konjugat prema zahtjevu 23, naznačen time što R1 je H, R2 je metil, R5, R6, R7 i R8 su svaki H, l i m su svaki 1, n je 0 i Z je -SCH3.
27. Citotoksični konjugat prema zahtjevu 23, naznačen time što su R1 i R2 metil, R5, R6, R7 i R8 su svaki H, l i m su 1, n je 0 i Z je - SCH3.
28. Citotoksični konjugat prema zahtjevu 23, naznačen time što je citotoksična tvar predstavljena formulom (IV-L).
29. Citotoksični konjugat prema zahtjevu 15, naznačen time što je citotoksična tvar majtanzin formule (V):
[image]
gdje:
Y predstavlja (CR7R8)l(CR5R6)m(CR3R4)nCR1R2SZ,
gdje:
R1 i R2 su svaki nezavisno CH3, C2H5, linearni alkil ili alkenil s 1 do 10 atoma ugljika, razgranati ili ciklički alkil ili alkenil s 3 do 10 atoma ugljika, fenil, supstituirani fenil ili heterociklički aromatski ili heterocikloalkilni radikal, i dodatno R2 može biti H;
R3, R4, R5, R6, R7 i R8 su svaki nezavisno H, CH3, C2H5, linearni alkil ili alkenil s 1 do 10 atoma ugljika, razgranati ili ciklički alkil ili alkenil s 3 do 10 atoma ugljika, fenil, supstituirani fenil ili heterociklički aromatski ili heterocikloalkilni radikal;
l, m i n su svaki nezavisno cijeli broj od 1 do 5, i dodatno n može biti 0; i
Z je H, SR ili -COR, pri čemu je R linearni alkil ili alkenil s 1 do 10 atoma ugljika, razgranati ili ciklički alkil ili alkenil s 3 do 10 atoma ugljika, ili jednostavni ili supstituirani aril ili heterociklički aromatski ili heterocikloalkilni radikal.
30. Citotoksični konjugat prema zahtjevu 29, naznačen time što R1 je H, R2 je metil, R5, R6, R7 i R8 su svaki H; l i m su svaki 1, n je 0 i Z je H.
31. Citotoksični konjugat prema zahtjevu 29, naznačen time što su R1 i R2 metil, R5, R6, R7 i R8 su svaki H, l i m su 1, n je 0 i Z je H.
32. Citotoksični konjugat prema zahtjevu 29, naznačen time što R1 je H, R2 je metil, R5, R6, R7 i R8 su svaki H, l i m su svaki 1, n je 0 i Z je -SCH3.
33. Citotoksični konjugat prema zahtjevu 29, naznačen time što su R1 i R2 metil, R5, R6, R7 i R8 su svaki H, l i m su 1, n je 0 i Z je - SCH3.
34. Citotoksični konjugat prema zahtjevu 15, naznačen time što je citotoksična tvar majtanzin izabran iz skupine koja obuhvaća formule (VI-L), (VI-D) i (VI-D,L):
[image]
gdje:
Y2 predstavlja (CR7R8)l(CR5R6)m(CR5R6)(CR3R4)nCR1R2SZ2,
gdje:
R1 i R2 su svaki nezavisno CH3, C2H5, linearni alkil ili alkenil s 1 do 10 atoma ugljika, razgranati ili ciklički alkil ili alkenil s 3 do 10 atoma ugljika, fenil, supstituirani fenil ili heterociklički aromatski ili heterocikloalkilni radikal, i dodatno R2 može biti H;
R3, R4, R5, R6, R7 i R8 su svaki nezavisno H, CH3, C2H5, linearni ciklički alkil ili alkenil s 1 do 10 atoma ugljika, razgranati ili ciklički alkil ili alkenil s 3 do 10 atoma ugljika, fenil, supstituirani fenil ili heterociklički aromatski ili heterocikloalkilni radikal;
l, m i n su svaki nezavisno cijeli broj od 1 do 5, i dodatno n može biti 0;
Z2 je SR ili -COR, pri čemu je R linearni alkil ili alkenil s 1 do 10 atoma ugljika, razgranati ili ciklički alkil ili alkenil s 3 do 10 atoma ugljika, ili jednostavni ili supstituirani aril ili heterociklički aromatski ili heterocikloalkilni radikal; i
May je majtanzinoid.
35. Citotoksični konjugat prema zahtjevu 15, naznačen time što je citotoksična tvar majtanzin formule (VII):
[image]
gdje:
Y2’ predstavlja
(CR7R8)l(CR9=CR10)p(C=C)qAr(CR5R6)mDu(CR11=CR12)r(C=C)sBt(CR3R4)nCR1R2SZ2,
gdje:
R1 i R2 su svaki nezavisno CH3, C2H5, linearni ili razgranati alkil ili alkenil s 1 do 10 atoma ugljika, ciklički alkil ili alkenil s 3 do 10 atoma ugljika, fenil, supstituirani fenil ili heterociklički aromatski ili heterocikloalkilni radikal, i dodatno R2 može biti H;
A, B i D su svaki nezavisno cikloalkil ili cikloalkenil s 3 do 10 atoma ugljika, jednostavni ili supstituirani aril ili heterociklički aromatski ili heterocikloalkilni radikal;
R3, R4, R5, R6, R7, R8, R9, R11 i R12 su svaki nezavisno H, CH3, C2H5, linearni alkil ili alkenil s 1 do 10 atoma ugljika, razgranati ili ciklički alkil ili alkenil s 3 do 10 atoma ugljika, fenil, supstituirani fenil ili heterociklički aromatski ili heterocikloalkilni radikal;
l, m, n, o, p, q, r, s i t su svaki nezavisno 0 ili cijeli broj od 1 do 5, uz uvjet da barem dva od l, m, n, o, p, q, r, s i t nisu nikad nula; i
Z2 je SR ili -COR, pri čemu je R linearni alkil ili alkenil s 1 do 10 atoma ugljika, razgranati ili ciklički alkil ili alkenil s 3 do 10 atoma ugljika, ili jednostavni ili supstituirani aril ili heterociklički aromatski ili heterocikloalkilni radikal.
36. Citotoksični konjugat prema zahtjevu 35, naznačen time što R1 je H i R2 je metil.
37. Citotoksični konjugat prema zahtjevu 15, naznačen time što je citotoksična tvar majtanzin formule (VIII):
[image]
gdje:
Y1’ predstavlja
(CR7CR8)l(CR9=CR10)p(C=C)qAr(CR5 CR6)mDu(CR11=CR12)r(C=C)sBt(CR3CR4)nCR1R2S-,
gdje:
A, B i D su svaki nezavisno cikloalkil ili cikloalkenil s 3 do 10 atoma ugljika, jednostavni ili supstituirani aril ili heterociklički aromatski ili heterocikloalkilni radikal;
R3, R4, R5, R6, R7, R8, R9, R11 i R12 su svaki nezavisno H, CH3, C2H5, linearni alkil ili alkenil s 1 do 10 atoma ugljika, razgranati ili ciklički alkil ili alkenil s 3 do 10 atoma ugljika, fenil, supstituirani fenil ili heterociklički aromatski ili heterocikloalkilni radikal; i
l, m, n, o, p, q, r, s i t su svaki nezavisno 0 ili cijeli broj od 1 do 5, uz uvjet da barem dva od l, m, n, o, p, q, r, s i t nisu nikad nula.
38. Citotoksični konjugat prema zahtjevu 37, naznačen time što R1 je H i R2 je metil.
39. Citotoksični konjugat prema zahtjevu 37, naznačen time što su R1 i R2 metil.
40. Citotoksični konjugat prema zahtjevu 15, naznačen time što je citotoksična tvar majtanzin izabran iz skupine koja obuhvaća formule (IX-L), (IX-D) i (IX-D,L):
[image]
gdje:
Y1 predstavlja (CR7R8)l(CR5R6)m(CR3R4)nCR1R2S-,
gdje:
R1 i R2 su svaki nezavisno CH3, C2H5, linearni alkil ili alkenil s 1 do 10 atoma ugljika, razgranati ili ciklički alkil ili alkenil s 3 do 10 atoma ugljika, fenil, supstituirani fenil ili heterociklički aromatski ili heterocikloalkilni radikal, i dodatno R2 može biti H;
R3, R4, R5, R6, R7 i R8 su svaki nezavisno H, CH3, C2H5, linearni alkil ili alkenil s 1 do 10 atoma ugljika, razgranati ili ciklički alkil ili alkenil s 3 do 10 atoma ugljika, fenil, supstituirani fenil ili heterociklički aromatski ili heterocikloalkilni radikal;
l, m i n su svaki nezavisno cijeli broj od 1 do 5, i dodatno n može biti 0; i
May predstavlja majtanzinol koji nosi bočni lanac na C-3, C-14 hidroksimetil, C-15 hidroksi ili C-20 desmetil.
41. Citotoksični konjugat prema zahtjevu 40, naznačen time što R1 je H i R2 je metil ili su R1 i R2 metil.
42. Citotoksični konjugat prema zahtjevu 40, naznačen time što R1 je H, R2 je metil, R5, R6, R7 i R8 su svaki H; I i m su svaki 1; n je 0.
43. Citotoksični konjugat prema zahtjevu 40, naznačen time što su R1 i R2 metil; R5, R6, R7 i R8 su svaki H; I i m su svaki 1; n je 0.
44. Citotoksični konjugat prema zahtjevu 41, naznačen time što je majtanzinoid predstavljen formulom (IX-L).
45. Citotoksični konjugat prema zahtjevu 42, naznačen time što je majtanzinoid predstavljen formulom (IX-L).
46. Citotoksični konjugat prema zahtjevu 43, naznačen time što je majtanzinoid predstavljen formulom (IX-L).
47. Citotoksični konjugat prema zahtjevu 15, naznačen time što je citotoksična tvar majtanzin formule (X):
[image]
gdje:
Y1 predstavlja (CR7R8)l(CR5R6)m(CR3R4)nCR1R2S-,
gdje:
R1 i R2 su svaki nezavisno CH3, C2H5, linearni alkil ili alkenil s 1 do 10 atoma ugljika, razgranati ili ciklički alkil ili alkenil s 3 do 10 atoma ugljika, fenil, supstituirani fenil ili heterociklički aromatski ili heterocikloalkilni radikal, i dodatno R2 može biti H;
R3, R4, R5, R6, R7 i R8 su svaki nezavisno H, CH3, C2H5, linearni alkil ili alkenil s 1 do 10 atoma ugljika, razgranati ili ciklički alkil ili alkenil s 3 do 10 atoma ugljika, fenil, supstituirani fenil ili heterociklički aromatski ili heterocikloalkilni radikal;
l, m i n su svaki nezavisno cijeli broj od 1 do 5, i dodatno n može biti 0; i
May predstavlja majtanzinol koji nosi bočni lanac na C-3, C-14 hidroksimetil, C-15 hidroksi ili C-20 desmetil.
48. Citotoksični konjugat prema zahtjevu 47, naznačen time što R1 je H, R2 je metil, R5, R6, R7 i R8 su svaki H; I i m su svaki 1; n je 0.
49. Citotoksični konjugat prema zahtjevu 47, naznačen time što su R1 i R2 metil; R5, R6, R7 i R8 su svaki H; I i m su 1; n je 0.
50. Citotoksični konjugat prema zahtjevu 10, naznačen time što je citotoksična tvar DM1 ili DM4.
51. Citotoksični konjugat prema zahtjevu 15, naznačen time što je citotoksična tvar taksan formule (XI):
[image]
52. In vitro postupak inhibicije rasta stanica koje eksprimiraju CA6 glikotop, naznačen time što obuhvaća dovođenje tih stanica koje eksprimiraju CA6 glikotop u kontakt sa citotoksičnim konjugatom prema zahtjevu 10.
53. Postupak inhibicije rasta stanica koje eksprimiraju CA6 glikotop, prema zahtjevu 52, naznačen time što citotoksični konjugat sadrži humaniziranu verziju mišjeg protutijela DS6 ili njegov fragment koji se veže za epitop kao tvar koja se veže za stanicu te DM1 ili DM4 kao citotoksičnu tvar.
54. Postupak inhibicije rasta stanica koje eksprimiraju CA6 glikotop, prema zahtjevu 52, naznačen time što citotoksični konjugat sadrži humaniziranu verziju mišjeg protutijela DS6 ili njegov fragment koji se veže za epitop kao tvar koja se veže za stanicu te taksan kao citotoksičnu tvar.
55. Postupak inhibicije rasta stanica koje eksprimiraju CA6 glikotop, prema zahtjevu 52, naznačen time što takva inhibicija rasta kao posljedicu izaziva smrt stanice.
56. Postupak inhibicije rasta stanica koje eksprimiraju CA6 glikotop, prema zahtjevu 52, naznačen time što se taj postupak provodi ex vivo.
57. Smjesa za liječenje, naznačena time što sadrži citotoksični konjugat prema zahtjevu 10 i farmaceutski prihvatljivi nosač ili pomoćnu tvar.
58. Smjesa za liječenje prema zahtjevu 57, naznačena time što citotoksični konjugat obuhvaća humaniziranu verziju mišjeg protutijela DS6 ili njegov fragment koji se veže za epitop kao tvar koja se veže za stanicu te DM1 ili DM4 kao citotoksičnu tvar.
59. Smjesa za liječenje prema zahtjevu 57, naznačena time što citotoksični konjugat obuhvaća humaniziranu verziju mišjeg protutijela DS6 ili njegov fragment koji se veže za epitop kao tvar koja se veže za stanicu te taksan kao citotoksičnu tvar.
60. Uporaba terapijske smjese prema zahtjevu 57, naznačena time što se radi o uporabi za proizvodnju lijeka za liječenje raka.
61. Smjesa za liječenje prema zahtjevu 57, naznačena time što se koristi za liječenje raka.
62. Uporaba ili smjesa prema zahtjevima 60 i 61, naznačena time što citotoksični konjugat citotoksični konjugat obuhvaća humaniziranu verziju mišjeg protutijela DS6 ili njegov fragment koji se veže za epitop kao tvar koja se veže za stanicu te DM1 ili DM4 kao citotoksičnu tvar.
63. Uporaba ili smjesa prema zahtjevima 60 i 61, naznačena time što citotoksični konjugat obuhvaća humaniziranu verziju mišjeg protutijela DS6 ili njegov fragment koji se veže za epitop kao tvar koja se veže za stanicu te taksan kao citotoksičnu tvar.
64. Uporaba ili smjesa prema zahtjevima 60 i 61, naznačena time što je rak takav da se CA6 glikotop eksprimira ili prekomjerno eksprimira.
65. Uporaba ili smjesa prema zahtjevima 60 i 61, naznačena time što se radi o raku izabranom iz skupine koja obuhvaća serozni karcinom jajnika, endometriodni karcinom jajnika, neoplazme cerviksa maternice, neoplazme endometrija, neoplazme vulve, rak dojke, tumor gušterače i tumor urotelijuma.
66. Kit, naznačen time što sadrži citotoksični konjugat prema zahtjevu 10, a dalje još sadrži:
a) odjeljak koji sadrži citotoksični konjugat.
67. Kit prema zahtjevu 66, naznačen time što citotoksični konjugat obuhvaća humaniziranu verziju mišjeg protutijela DS6 ili njegov fragment koji se veže za epitop kao tvar koja se veže za stanicu te taksan kao citotoksičnu tvar.
68. Kit prema zahtjevu 66, naznačen time što citotoksični konjugat obuhvaća humaniziranu verziju mišjeg protutijela DS6 ili njegov fragment koji se veže za epitop kao tvar koja se veže za stanicu te taksan kao citotoksičnu tvar.
69. Kit, naznačen time što sadrži smjesu za liječenje prema zahtjevu 57, a dalje još sadrži:
a) odjeljak koji sadrži smjesu za liječenje.
70. Kit prema zahtjevu 69, naznačen time što citotoksični konjugat iz smjese za liječenje obuhvaća humaniziranu verziju mišjeg protutijela DS6 ili njegov fragment koji se veže za epitop kao tvar koja se veže za stanicu te DM1 ili DM4 kao citotoksičnu tvar.
71. Kit prema zahtjevu 69, naznačen time što citotoksični konjugat iz smjese za liječenje obuhvaća humaniziranu verziju mišjeg protutijela DS6 ili njegov fragment koji se veže za epitop kao tvar koja se veže za stanicu te taksan kao citotoksičnu tvar.
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