DK1507556T3 - Calicheamicin-derivat-bærerkonjugater - Google Patents
Calicheamicin-derivat-bærerkonjugater Download PDFInfo
- Publication number
- DK1507556T3 DK1507556T3 DK03724432.4T DK03724432T DK1507556T3 DK 1507556 T3 DK1507556 T3 DK 1507556T3 DK 03724432 T DK03724432 T DK 03724432T DK 1507556 T3 DK1507556 T3 DK 1507556T3
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- DK
- Denmark
- Prior art keywords
- seq
- antibody
- prednisone
- cdr
- cyclophosphamide
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- HXCHCVDVKSCDHU-LULTVBGHSA-N calicheamicin Chemical class C1[C@H](OC)[C@@H](NCC)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@](C/3=C/CSSSC)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HXCHCVDVKSCDHU-LULTVBGHSA-N 0.000 title claims description 125
- 229930195731 calicheamicin Natural products 0.000 title claims description 102
- 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 description 230
- 238000000034 method Methods 0.000 claims description 123
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- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 claims description 118
- 229960004618 prednisone Drugs 0.000 claims description 118
- 239000000203 mixture Substances 0.000 claims description 113
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 93
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Claims (85)
1. Fremgangsmåde til fremstilling af en sammensætning omfattende monomere calicheamicinderivat/antistof-konjugater med reduceret lav konjugeret fraktion (LCF) under 10 procent, med formlen Pr(-X-S-S-W)m, hvor: Pr er et antistof, X er en hydroliserbar linker, som er i stand til at frigive calicheamicinderivatet fra konjugatet efter binding og indtrængning i målceller, W er et calicheamicin; m er den gennemsnitlige belastning for et renset konjugationsprodukt, således at det cytotoksiske medikament udgør 4-10 vægt% af konjugatet; og (-X-S-S-W)m er et calicheamicinderivat, hvilken fremgangsmåde omfatter følgende trin: (1) tilførsel af calicheamicinderivatet til antistoffet, hvor calicheamicinderivatet udgør 4,5-11 vægt% af antistoffet; (2) inkubering af calicheamicinderivatet og antistoffet i en ikke-nukleofil, proteinkompatibel, bufret opløsning med en pH i området fra omkring 8 til 9, for tilvejebringelse af en sammensætning omfattende monomer cytotoksisk medikament/bærerkonjugat, hvor opløsningen yderligere omfatter (a) ethanol, og (b) et additiv omfattende i det mindste én C6-Cie-carboxylsyre eller dets salt, valgt blandt: decanoat, 100 mM nanonoat, 20 mM undecanoat, 5 mM dodecanoat, og hvor inkuberingen udføres ved en temperatur liggende fra omkring 30°C til omkring 35°C over en tidsperiode, som ligger fra omkring 15 minutter til 24 timer; og (3) underkastning af sammensætningen fremstillet i trin (2) for en chromatografisk separationsproces for at separere monomer cytotoksisk calicheamicin-derivat/antistofkonjugater med en belastning i området 4-10 vægt% cytotoksisk medikament, og med lav konjugeret fraktion (LCF) under 10 procent, fra ikke-konjugeret antistof, calicheamicinderivat og aggregerede konjugater.
2. Fremgangsmåde ifølge krav 1, hvor antistoffet vælges fra en gruppe bestående af et monoklonalt antistof, et kimærisk antistof, et humant antistof, et humaniseret antistof, et enkeltkædeantistof, og et biologisk aktivt antistoffragment, hvor det biologisk aktive fragment er et Fab, et modificeret Fab, Fab', F(ab')2 eller Fv eller en tungkæde monomer eller dimer.
3. Fremgangsmåde ifølge krav 2, hvor det humaniserede antistof er rettet imod celleoverfladeantigenet CD22.
4. Fremgangsmåde ifølge krav 1, hvor antistoffet omfatter en let kæde variabel region omfattende SEQ ID NO: 19, og en tung kæde variabel region omfattende SEQ ID NO: 27.
5. Fremgangsmåde ifølge krav 1, hvor antistoffet omfatter en let kæde omfattende SEQ ID NO: 28 og en tung kæde omfattende SEQ ID NO: 30.
6. Fremgangsmåde ifølge krav 1, hvor antistoffet omfatter SEQ ID NO: 1 for CDR-H1, SEQ ID NO: 2 eller SEQ ID NO: 13 eller SEQ ID NO: 15 eller SEQ ID NO: 16 eller rester 50-66 af SEQ ID NO: 23 eller rester 50-66 af SEQ ID NO: 27 for CDR-H2, SEQ ID NO: 3 for CDR-H3, SEQ ID NO: 4 for CDR-L1, SEQ ID NO: 5 for CDR-L2 og SEQ ID NO: 6 for CDR-L3.
7. Fremgangsmåde ifølge krav 6, hvor antistoffet omfatter rester 50-66 af SEQ ID NO: 27 for CDR-H2.
8. Fremgangsmåde ifølge krav 3, hvor det humaniserede anti-CD22-antistof er et CDR-podet antistof, som er et variantantistof tilvejebragt ved en affinitetsmodningsprotokol og som har forøget affinitet for humant CD22.
9. Fremgangsmåde ifølge krav 1, hvor calicheamicinet er gamma-calicheamicin eller N-acetyl-gamma-calicheamicin.
10. Fremgangsmåde ifølge krav 1 eller 9, hvor calicheamicinet er funktionaliseret med 3-mercapto-3-methyl-butanoylhydrazid.
11. Fremgangsmåde ifølge krav 1, hvor den hydrolyserbare linker er 4-(4-acetylphenoxy)butansyre (AcBut).
12. Fremgangsmåde ifølge krav 1, hvor additivet i trin (2)(b) er decanoat tilvejebragt ved en koncentration på imellem 30 til 50 mM.
13. Fremgangsmåde ifølge krav 1, hvor den chromatografiske separationsproces i trin (3) er størrelseseksklusionschromatografi (SEC).
14. Fremgangsmåde ifølge krav 1, hvor den chromatografiske separationsproces i trin (3) er HPLC, FPLC eller Sephacryl S-200-chromatografi.
15. Fremgangsmåde ifølge krav 1, hvor den chromatografiske separationsproces i trin (3) er hydrofob interaktionschromatografi (HIC).
16. Fremgangsmåde ifølge krav 15, hvor den hydrofobe interaktionschromatografi (HIC) udføres under anvendelse af Phenyl Sepharose 6 Fast Flow chromatografisk medie, Butyl Sepharose 4 Fast Flow chromatografisk medie, Octyl Sepharose 4 Fast Flow chromatografisk medie, Toyopearl Ether-650M chromatografisk medie, Macro-Prep methyl HIC medie eller Macro-Prep t-Butyl HIC medie.
17. Fremgangsmåde ifølge krav 16, hvor den hydrofobiske interaktionschromatografi (HIC) udføres under anvendelse af Butyl Sepharose 4 Fast Flow chromatografisk medie.
18. Sammensætninger omfattende monomere calicheamicinderivat/anti-CD22-antistofkonjugater med reduceret lav konjugeret fraction (LCF) under 10 procent og med formlen Pr(-X-S-S-W)m, hvor: Pr er et anti-CD22-antistof, X er en hydrolyserbar linker, som er i stand til at frigive calicheamicinet fra konjugatet efter binding og indtrængning i målceller; W er calicheamicin; m er den gennemsnitlige belastning for et renset konjugationsprodukt således, at calicheamicinet udgør 4-10 vægt% af konjugatet; og (-X-S-S-W)m er et calicheamicinderivat.
19. Sammensætning ifølge krav 18, hvor anti-CD22-antistoffet vælges fra en gruppe bestående af et monoklonalt antistof, et kimærisk antistof, et humant antistof, et humaniseret antistof, et enkeltkædeantistof, og et biologisk aktivt antistoffragment, hvor det biologisk aktive fragment er et Fab, et modificeret Fab, Fab', F(ab')2 eller Fv eller en tungkæde monomer eller dimer.
20. Sammensætning ifølge krav 18, hvor anti-CD22-antistoffet omfatter en let kæde variabel region omfattende SEQ ID NO: 19 og en tung kæde variabel region omfattende SEQ ID NO: 27.
21. Sammensætning ifølge krav 18, hvor anti-CD22-antistoffet omfatter en let kæde omfattende SEQ ID NO: 28 og en tung kæde omfattende SEQ ID NO: 30.
22. Sammensætning ifølge krav 18, hvor antistoffet omfatter en tung kæde, hvor det variable domæne omfatter en CDR med SEQ ID NO: 1 for CDR-H1, SEQ ID NO: 2 eller SEQ ID NO: 13 eller SEQ ID NO: 15 eller SEQ ID NO: 16 eller rester 50-66 af SEQ ID NO: 23 eller rester 50-66 af SEQ ID NO: 27 for CDR-H2, og SEQ ID NO: 3 for CDR-H3, og omfatter en let kæde, hvor det variable domæne omfatter en CDR med SEQ ID NO: 4 for CDR-L1, SEQ ID NO: 5 for CDR-L2 og SEQ ID NO: 6 for CDR-L3.
23. Sammensætning ifølge krav 18, hvor anti-CD22-antistoffet omfatter SEQ ID NO: 1 for CDR-H1, SEQ ID NO: 2 eller SEQ ID NO: 13 eller SEQ ID NO: 15 eller SEQ ID NO: 16 eller rester 50-66 af SEQ ID NO: 23 eller rester 50-66 af SEQ ID NO: 27 for CDR-H2, SEQ ID NO: 3 for CDR-H3, SEQ ID NO: 4 for CDR-L1, SEQ ID NO: 5 for CDR-L2 og SEQ ID NO: 6 for CDR-L3.
24. Sammensætning ifølge krav 23, hvor anti-CD22-antistoffet omfatter rester 50-66 af SEQ ID NO: 27forCDR-H2.
25. Sammensætning ifølge krav 19. hvor det humaniserede anti-CD22-antistof er et CDR-podet anti-CD22-antistof.
26. Sammensætning ifølge krav 19, hvor det humaniserede CD22-antistof er et CDR-podet antistof, som er et variantantistof tilvejebragt ved en affinitetsmodningsprotokol og har en forøget affinitet for humant CD22.
27. Sammensætning ifølge krav 18, hvor anti-CD22-antistoffet omfatter et variabelt domæne omfattende humane acceptorrammeregioner og ikke-humane donor-CDR'er.
28. Sammensætning ifølge krav 27, hvor de humane acceptorrammeregioner i det variable domæne af den tunge kæde i antistoffet er baserede på SEQ ID NO: 21 og 22 og omfatter donorrester ved positionerne 1,28, 48, 72 og 97 i SEQ ID NO: 8.
29. Sammensætning ifølge krav 28, hvor anti-CD22-antistoffet yderligere omfatter donorrester ved positionerne 68 og 70 i SEQ ID NO: 8.
30. Sammensætning ifølge krav 27, hvor anti-CD22-antistoffet omfatter et variabelt domæne af den lette kæde omfattende en human acceptorrammeregion baseret på SEQ ID NO: 17 og 18 og yderligere omfatter donorrester ved positionerne 2, 4, 42, 43, 50 og 65 i SEQ ID NO: 7.
31. Sammensætning ifølge krav 30, hvor anti-CD22-antistoffet yderligere omfatter en donorrest ved position 3 i SEQ ID NO: 7.
32. Sammensætning ifølge krav 18, hvor anti-CD22-antistoffet omfatter en let kæde variabel region omfatttende SEQ ID NO: 7 og en tung kæde variabel region omfattende SEQ ID NO: 8.
33. Sammensætning ifølge krav 19, hvor anti-CD22-antistoffet omfatter et hybridt CDR omfattende en trunkeret donor-CDR-sekvens, hvori den manglende del af donor-CDR er erstattet af en afvigende sekvens og danner en funktionel CDR.
34. Sammensætning ifølge krav 18, hvor calicheamicinet er gamma-calicheamicin eller N-acetyl-gamma-calicheamicin.
35. Sammensætning ifølge krav 18 eller 34, hvor calicheamiciner erfunktionaliseret med 3- mercapto-3-methylbutanoylhydrazid.
36. Sammensætning ifølge krav 18 eller 35, hvor den hydrolyserbare linker omfatter 4- (4-acetylphenoxy)butansyre (AcBut).
37. Medikament omfattende en terapeutisk effektiv dosis af sammensætningen ifølge krav 18 til anvendelse ved behandling af en proliferativ forstyrrelse, som eksprimerer CD22.
38. Medikament til anvendelse ifølge krav 37, hvor den terapeutisk effektive dosis af sammensætningen kan indgives subkutant, intraperitonealt, intravenøst, intraarterielt, intramedullært, intrathekalt, transdermalt, transkutant, intranasalt, topisk, enteralt, intravaginalt, sublingualt eller rektalt.
39. Medikament til anvendelse ifølge krav 37, hvor den terapeutisk effektive dosis af sammensætningen indgives intravenøst.
40. Medikament til anvendelse ifølge krav 37, hvor den proliferative forstyrrelse er cancer.
41. Medikament til anvendelse ifølge krav 40, hvor canceren er B-celle malignitet.
42. Medikament til anvendelse ifølge krav 41, hvor B-celle maligniteten er leukæmi.
43. Medikament til anvendelse ifølge krav 42, hvor leukæmien eksprimerer celleoverfladeantigenet CD22.
44. Medikament til anvendelse ifølge krav 41, hvor B-celle maligniteten er lymphom.
45. Medikament til anvendelse ifølge krav 44, hvor lymphomet eksprimerer celleoverfladeantigenet CD22.
46. Medikament til anvendelse ifølge krav 41, hvor B-celle maligniteten vælges fra gruppen bestående af en Non-Hodgkin's lymphom, akut lymphocytisk leukæmi og kronisk lymphocytisk leukæmi.
47. Medikament til anvendelse ifølge krav 40, hvor canceren er et carcinom.
48. Medikament til anvendelse ifølge krav 40, hvor canceren er et sarcom.
49. Medikament til anvendelse ifølge krav 40, hvor calicheamicinet i calicheamicinderivatet er gamma-calicheamicin eller N-acetylcalicheamicin.
50. Medikament til anvendelse ifølge krav 40, hvor sammensætningen kan indgives med ét eller flere bioaktive midler.
51. Medikament til anvendelse ifølge krav 50, hvor det ene eller flere bioaktive midler vælges fra en gruppe bestående af antistoffer, vækstfaktorer, hormoner, cytokiner, antihormoner, xanthiner, interleukiner, interferoner, og cytotoksiske lægemidler.
52. Medikament til anvendelse ifølge krav 51, hvor det bioaktive middel er et antistof.
53. Medikament til anvendelse ifølge krav 52, hvor antistoffet er rettet imod et celleoverfladeantigen eksprimeret på B-cellemaligniteter.
54. Medikament til anvendelse ifølge krav 53, hvor det antistof, som er rettet imod celleoverfladeantigener eksprimeret på B-cellemaligniteter, vælges fra en gruppe bestående af anti-CD19-, anti-CD20- og anti-CD33-antistoffer.
55. Medikament til anvendelse ifølge krav 54, hvor anti-CD20-antistoffet er rituximab.
56. Medikament til anvendelse ifølge krav 51, hvor cytokinerne eller vækstfaktorerne vælges fra gruppen bestående af interleukin 2 (IL-2), TNF, CSF, GM-CSF, og G-CSF.
57. Medikament til anvendelse ifølge krav 51, hvor hormonet er et steroidhormon og vælges blandt østrogener, androgener, progestiner og corticosteroider.
58. Medikament til anvendelse ifølge krav 51, hvor det cytotoksiske lægemiddel vælges fra gruppen bestående af doxorubicin, daunorubicin, idarubicin, aclarubicin, zorubicin, mitoxantron, epirubicin, carubicin, nogalamycin, menogaril, pitarubicin, valrubicin, cytarabin, gemcitabin, trifluridin, ancitabin, enocitabin, azacitidin, doxifluridin, pentostatin, broxuridin, capecitabin, cladribin, decitabin, floxuridin, fludarabin, gougerotin, puromycin, tegafur, tiazofurin, adriamycin, cisplatin, carboplatin, cyclophosphamid, dacarbazin, vinblastin, vineristin, mitoxantron, bleomycin, mechlorethamin, prednison, procarbazin, methotrexat, flurouraciler, etoposid, taxol, taxol analoger, og mitomycin.
59. Medikament til anvendelse ifølge krav 51, hvor sammensætningen kan indgives sammen med én eller flere kombinationer af cytotoksiske lægemidler, som en del af et behandlingsskema, hvor kombinationen af cytotoksiske lægemidler vælges blandt: A. CHOPP (cyclophosphamid, doxorubicin, vineristin, prednison, og procarbazin); B. CHOP (cyclophosphamid, doxorubicin, vineristin, og prednison); C. COP (cyclophosphamid, vineristin, og prednison); D. CAP-BOP (cyclophosphamid, doxorubicin, procarbazin, bleomycin, vineristin, og prednison); E. m-BACOD (methotrexat, bleomycin, doxorubicin, cyclophosphamid, vineristin, dexamethason, og leueovorin; F. ProMACE-MOPP (prednison, methotrexat, doxorubicin, cyclophosphamid, etoposid, leueovorin, mechloethamin, vineristin, prednison, og procarbazin); G. ProMACE-CytaBOM (prednison, methotrexat, doxorubicin, cyclophosphamid, etoposid, leueovorin, cytarabin, bleomycin, og vineristin); H. MACOP-B (methotrexat, doxorubicin, cyclophosphamid, vineristin, prednison, bleomycin, og leueovorin); I. MOPP (mechloethamin, vineristin, prednison, og procarbazin); J. ABVD (adriamycin/doxorubicin, bleomycin, vinblastin, og daearbazin); K. MOPP (mechloethamin, vineristin, prednison, og procarbazin) alternerende med ABV (adriamycin/doxorubicin, bleomycin, og vinblastin); L. MOPP (mechloethamin, vineristin, prednison, og procarbazin) alternerende med ABVD(adriamycin/doxorubicin, bleomycin, vinblastin, og daearbazin); M. ChIVPP (chlorambucil, vinblastin, procarbazin, og prednison); N. IMVP-16 (ifosfamid, methotrexat, og etoposid); O. MIME (methyl-gag, ifosfamid, methotrexat, og etoposid); P. DHAP (dexamethason, høj-dosis cytarabin, og cisplatin); Q. ESHAP (etoposid, methylpredisolon, høj-dosis cytarabin, og cisplatin); R. CEPP(B) (cyclophosphamid, etoposid, procarbazin, prednison, og bleomycin); S. CAMP (lomustin, mitoxantron, cytarabin, og prednison); T. CVP-1 (cyclophosphamid, vineristin, og prednison); U. ESHOP (etoposid, methylpredisolon, høj-dosis cytarabin, vineristin og cisplatin); V. EPOCH (etoposid, vineristin, og doxorubicin i 96 timer med bolusdosis af cyclophosphamid og oral prednison); W. ICE (ifosfamid, cyclophosphamid, og etoposid); X. CHOP-B (cyclophosphamid, doxorubicin, vineristin, prednison, og bleomycin); og Y. P/DOCE (epirubicin eller doxorubicin, vineristin, cyclophosphamid, og prednison).
60. Medikament til anvendelse ifølge krav 51, hvor sammensætningen kan indgives før indgivelse af én eller flere kombinationer af cytotoksiske lægemidler som en del af et behandlingsskema, hvor kombinationen af cytotoksiske lægemidler vælges blandt: A. CHOPP (cyclophosphamid, doxorubicin, vineristin, prednison, og procarbazin); B. CHOP (cyclophosphamid, doxorubicin, vineristin, og prednison); C. COP (cyclophosphamid, vineristin, og prednison); D. CAP-BOP (cyclophosphamid, doxorubicin, procarbazin, bleomycin, vineristin, og prednison); E. m-BACOD (methotrexat, bleomycin, doxorubicin, cyclophosphamid, vineristin, dexamethason, og leueovorin; F. ProMACE-MOPP (prednison, methotrexat, doxorubicin, cyclophosphamid, etoposid, leueovorin, mechloethamin, vineristin, prednison, og procarbazin); G. ProMACE-CytaBOM (prednison, methotrexat, doxorubicin, cyclophosphamid, etoposid, leueovorin, cytarabin, bleomycin, og vineristin); H. MACOP-B (methotrexat, doxorubicin, cyclophosphamid, vineristin, prednison, bleomycin, og leueovorin); I. MOPP (mechloethamin, vineristin, prednison, og procarbazin); J. ABVD (adriamycin/doxorubicin, bleomycin, vinblastin, og daearbazin); K. MOPP (mechloethamin, vineristin, prednison, og procarbazin) alternerende med ABV (adriamycin/doxorubicin, bleomycin, og vinblastin); L. MOPP (mechloethamin, vineristin, prednison, og procarbazin) alternerende med ABVD(adriamycin/doxorubicin, bleomycin, vinblastin, og daearbazin); M. ChIVPP (chlorambucil, vinblastin, procarbazin, og prednison); N. IMVP-16 (ifosfamid, methotrexat, og etoposid); O. MIME (methyl-gag, ifosfamid, methotrexat, og etoposid); P. DHAP (dexamethason, høj-dosis cytarabin, og cisplatin); Q. ESHAP (etoposid, methylpredisolon, høj-dosis cytarabin, og cisplatin); R. CEPP(B) (cyclophosphamid, etoposid, procarbazin, prednison, og bleomycin); S. CAMP (lomustin, mitoxantron, cytarabin, og prednison); T. CVP-1 (cyclophosphamid, vineristin, og prednison); U. ESHOP (etoposid, methylpredisolon, høj-dosis cytarabin, vineristin og cisplatin); V. EPOCH (etoposid, vineristin, og doxorubicin i 96 timer med bolusdosis af cyclophosphamid og oral prednison); W. ICE (ifosfamid, cyclophosphamid, og etoposid); X. CHOP-B (cyclophosphamid, doxorubicin, vineristin, prednison, og bleomycin); og Y. P/DOCE (epirubicin eller doxorubicin, vineristin, cyclophosphamid, og prednison).
61. Medikament til anvendelse ifølge krav 51, hvor sammensætningen kan indgives efterfølgende indgivelse af én eller flere kombinationer af cytotoksiske midler som en del af et behandlingsskema, hvor kombinationen af bioaktive midler vælges blandt: A. CHOPP (cyclophosphamid, doxorubicin, vincristin, prednison, og procarbazin); B. CHOP (cyclophosphamid, doxorubicin, vincristin, og prednison); C. COP (cyclophosphamid, vincristin, og prednison); D. CAP-BOP (cyclophosphamid, doxorubicin, procarbazin, bleomycin, vincristin, og prednison); E. m-BACOD (methotrexat, bleomycin, doxorubicin, cyclophosphamid, vincristin, dexamethason, og leucovorin; F. ProMACE-MOPP (prednison, methotrexat, doxorubicin, cyclophosphamid, etoposid, leucovorin, mechloethamin, vincristin, prednison, og procarbazin); G. ProMACE-CytaBOM (prednison, methotrexat, doxorubicin, cyclophosphamid, etoposid, leucovorin, cytarabin, bleomycin, og vincristin); H. MACOP-B (methotrexat, doxorubicin, cyclophosphamid, vincristin, prednison, bleomycin, og leucovorin); I. MOPP (mechloethamin, vincristin, prednison, og procarbazin); J. ABVD (adriamycin/doxorubicin, bleomycin, vinblastin, og dacarbazin); K. MOPP (mechloethamin, vincristin, prednison, og procarbazin) alternerende med ABV (adriamycin/doxorubicin, bleomycin, og vinblastin); L. MOPP (mechloethamin, vincristin, prednison, og procarbazin) alternerende med ABVD (adriamycin/doxorubicin, bleomycin, vinblastin, og dacarbazin); M. ChIVPP (chlorambucil, vinblastin, procarbazin, og prednison); N. IMVP-16 (ifosfamid, methotrexat, og etoposid); O. MIME (methyl-gag, ifosfamid, methotrexat, og etoposid); P. DHAP (dexamethason, høj-dosis cytarabin, og cisplatin); Q. ESHAP (etoposid, methylpredisolon, høj-dosis cytarabin, og cisplatin); R. CEPP(B) (cyclophosphamid, etoposid, procarbazin, prednison, og bleomycin); S. CAMP (lomustin, mitoxantron, cytarabin, og prednison); T. CVP-1 (cyclophosphamid, vincristin, og prednison); U. ESHOP (etoposid, methylpredisolon, høj-dosis cytarabin, vincristin og cisplatin); V. EPOCH (etoposid, vincristin, og doxorubicin i 96 timer med bolusdosis af cyclophosphamid og oral prednison); W. ICE (ifosfamid, cyclophosphamid, og etoposid); X. CHOP-B (cyclophosphamid, doxorubicin, vincristin, prednison, og bleomycin); og Y. P/DOCE (epirubicin eller doxorubicin, vincristin, cyclophosphamid, og prednison).
62. Medikament til anvendelse ifølge krav 51, hvor sammensætningen kan indgives sammen med et antistof rettet imod et celleoverfladeantigen på B-cellemaligniteter, og eventuelt omfattende én eller flere kombinationer af cytotoksiske midler som en del af et behandlingsskema, hvor kombinationen af cytotoksiske midler er valgt blandt: A. CHOPP (cyclophosphamid, doxorubicin, vineristin, prednison, og procarbazin); B. CHOP (cyclophosphamid, doxorubicin, vineristin, og prednison); C. COP (cyclophosphamid, vineristin, og prednison); D. CAP-BOP (cyclophosphamid, doxorubicin, procarbazin, bleomycin, vineristin, og prednison); E. m-BACOD (methotrexat, bleomycin, doxorubicin, cyclophosphamid, vineristin, dexamethason, og leueovorin; F. ProMACE-MOPP (prednison, methotrexat, doxorubicin, cyclophosphamid, etoposid, leueovorin, mechloethamin, vineristin, prednison, og procarbazin); G. ProMACE-CytaBOM (prednison, methotrexat, doxorubicin, cyclophosphamid, etoposid, leueovorin, cytarabin, bleomycin, og vineristin); H. MACOP-B (methotrexat, doxorubicin, cyclophosphamid, vineristin, prednison, bleomycin, og leueovorin); I. MOPP (mechloethamin, vineristin, prednison, og procarbazin); J. ABVD (adriamycin/doxorubicin, bleomycin, vinblastin, og daearbazin); K. MOPP (mechloethamin, vineristin, prednison, og procarbazin) alternerende med ABV (adriamycin/doxorubicin, bleomycin, og vinblastin); L. MOPP (mechloethamin, vineristin, prednison, og procarbazin) alternerende med ABVD (adriamycin/doxorubicin, bleomycin, vinblastin, og daearbazin); M. ChIVPP (chlorambucil, vinblastin, procarbazin, og prednison); N. IMVP-16 (ifosfamid, methotrexat, og etoposid); O. MIME (methyl-gag, ifosfamid, methotrexat, og etoposid); P. DHAP (dexamethason, høj-dosis cytarabin, og cisplatin); Q. ESHAP (etoposid, methylpredisolon, høj-dosis cytarabin, og cisplatin); R. CEPP(B) (cyclophosphamid, etoposid, procarbazin, prednison, og bleomycin); S. CAMP (lomustin, mitoxantron, cytarabin, og prednison); T. CVP-1 (cyclophosphamid, vineristin, og prednison); U. ESHOP (etoposid, methylpredisolon, høj-dosis cytarabin, vineristin og cisplatin); V. EPOCH (etoposid, vineristin, og doxorubicin i 96 timer med bolusdosis af cyclophosphamid og oral prednison); W. ICE (ifosfamid, cyclophosphamid, og etoposid); X. CHOP-B (cyclophosphamid, doxorubicin, vineristin, prednison, og bleomycin); og Y. P/DOCE (epirubicin eller doxorubicin, vineristin, cyclophosphamid, og prednison).
63. Medikament til anvendelse ifølge krav 62, hvor antistoffet, som er rettet imod celleoverfladeantigener eksprimeret på B-cellemaligniteter, er valgt fra en gruppe bestående af anti-CD19-, anti-CD20- og anti-CD33-antistoffer.
64. Medikament til anvendelse ifølge krav 63, hvor anti-CD20-antistoffet er rituximab.
65. Medikament til anvendelse ifølge krav 37, hvor anti-CD22-antistoffet omfatter en let kæde variabel region omfattende SEQ ID NO: 19 og en tung kæde variabel region omfattende SEQ ID NO: 27.
66. Medikament til anvendelse ifølge krav 37, hvor anti-CD20-antistoffet er et humaniseret antistof og omfatter en let kæde med en sekvens angivet i SEQ ID NO: 28.
67. Medikament til anvendelse ifølge krav 37, hvor anti-CD22-antistoffet er et humaniseret antistof og omfatter en tung kæde med en sekvens angivet i SEQ ID NO: 30.
68. Medikament til anvendelse ifølge krav 37, hvor anti-CD22-antistoffet omfatter en let kæde omfattende SEQ ID NO: 28 og en tung kæde omfattende SEQ ID NO: 30.
69. Medikament til anvendelse ifølge krav 37, hvor anti-CD22-antistoffet omfatter en tung kæde hvor det variable domæne omfatter et CDR med i det mindste én af sekvenserne angivet i SEQ ID NO: 1 for CDR-H1, SEQ ID NO: 2 eller SEQ ID NO: 13 eller SEQ ID NO: 15 ellerSEQ ID NO: 16 eller rester 50-66 af SEQ ID NO: 23 eller rester 50-66 af SEQ ID NO: 27 for CDR-H2, eller SEQ ID NO: 3 for CDR-H3, og omfatter en let kæde, hvor det variable domæne omfatter et CDR med i det mindste én af sekvenserne angivet i SEQ ID NO: 4 for CDR-L1, SEQ ID NO: 5for CDR-L2 ellerSEQ ID NO: 6 for CDR-L3.
70. Medikament til anvendelse ifølge krav 37, hvor anti-CD22-antistoffet omfatter SEQ ID NO: 1 for CDR-H1, SEQ ID NO: 2 eller SEQ ID NO: 13 eller SEQ ID NO: 15 eller SEQ ID NO: 16 eller rester 50-66 af SEQ ID NO: 23 eller rester 50-66 af SEQ ID NO: 27 for CDR-H2, SEQ ID NO: 3 for CDR-H3, SEQ ID NO: 4 for CDR-L1, SEQ ID NO: 5 for CDR-L2, og SEQ ID NO: 6 for CDR-L3.
71. Medikament til anvendelse ifølge krav 70, hvor anti-CD22-antistoffet omfatter rester 50-66 af SEQ ID NO: 27.
72. Medikament ifølge krav 18 med ét eller flere bioaktive midler til anvendelse ved behandling af aggressive lymphomer.
73. Medikament til anvendelse ifølge krav 72, hvor det monomere calicheamicin-derivat/anti-CD22-antistofkonjugat er CMC-544.
74. Fremgangsmåde ifølge krav 1, hvor antistoffet omfatter en CDR-H2-sekvens omfattende en aminosyrerest ved Kabat-position 55, som er en anden end asparagin.
75. Fremgangsmåde ifølge krav 74, hvor aminosyren ved Kabat-position 55 er glutamin.
76. Fremgangsmåde ifølge krav 1, hvor antistoffet omfatter en sekvens af CDR-H2 omfattende en aminosyrerest ved Kabat-position 57, som er en anden end threonin.
77. Fremgangsmåde ifølge krav 76, hvor aminosyren ved Kabat-position 57 er alanin eller valin.
78. Fremgangsmåde ifølge krav 1, hvor antistoffet omfatter en sekvens af CDR-H2 omfattende en aminosyrerest ved Kabat-position 60, som er en anden end lysin.
79. Fremgangsmåde ifølge krav 78, hvor aminosyreresten er arginin.
80. Sammensætning ifølge krav 18, hvor antistoffet omfatter en CDR-H2-sekvens omfattende en aminosyrerest ved Kabat-position 55, som er en anden end asparagin.
81. Sammensætning ifølge krav 80, hvor aminosyren ved Kabat-position 55 er glutamin.
82. Sammensætning ifølge krav 18, hvor antistoffet omfatter en sekvens af CDR-H2, som omfatter en aminosyrerest ved Kabat-position 57, som er en anden end threonin.
83. Sammensætning ifølge krav 82, hvor aminosyren ved Kabat-position 57 er alanin eller valin.
84. Sammensætning ifølge krav 18, hvor antistoffet omfatter en sekvens af CDR-H2, som omfatter en aminosyrerest ved Kabat-position 60, som er en anden end lysin.
85. Sammensætning ifølge krav 84, hvor aminosyreresten er arginin.
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