HRP20170281T1 - Imunokonjugati folatnog receptora 1 i njihove uporabe - Google Patents

Imunokonjugati folatnog receptora 1 i njihove uporabe Download PDF

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Publication number
HRP20170281T1
HRP20170281T1 HRP20170281TT HRP20170281T HRP20170281T1 HR P20170281 T1 HRP20170281 T1 HR P20170281T1 HR P20170281T T HRP20170281T T HR P20170281TT HR P20170281 T HRP20170281 T HR P20170281T HR P20170281 T1 HRP20170281 T1 HR P20170281T1
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HR
Croatia
Prior art keywords
seq
cancer
immunoconjugate
succinimidyl
variable domain
Prior art date
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HRP20170281TT
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English (en)
Inventor
Olga Ab
Daniel Tavares
Lingyun Rui
Gillian Payne
Viktor S. Goldmakher
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Immunogen, Inc.
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Publication date
Application filed by Immunogen, Inc. filed Critical Immunogen, Inc.
Publication of HRP20170281T1 publication Critical patent/HRP20170281T1/hr

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    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
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Claims (15)

1. Imunokonjugat formule (A) – (L) – (C), pri čemu je: (A) protutijelo ili antigen vezujući fragment; (L) je vezni dio; i (C) je majtanzinoid ili analog majtanzinoida. gdje navedeni vezni dio (L) povezuje (A) za (C), gdje je (A) odabran iz grupe koja se sastoji od: i) humaniziranog protutijela ili njegovog antigen vezujućeg fragmenta koji se specifično veže za humani folatni receptor 1, pri čemu protutijelo ili njegov antigen vezujući fragment obuhvaća: (a) teški lanac CDR1 koji obuhvaća GYFMN (SEQ ID NO:1); teški lanac CDR2 koji obuhvaća RIHPYDGDTFYNQKFQG (SEQ ID NO:2); i teški lanac CDR3 koji obuhvaća YDGSRAMDY (SEQ ID NO:3); i (b) laki lanac CDR1 koji obuhvaća KASQSVSF AGTSLMH (SEQ ID NO:7); laki lanac CDR2 koji obuhvaća RASNLEA (SEQ ID NO:8); i laki lanac CDR3 koji obuhvaća QQSREYPYT (SEQ ID NO:9), ii) humaniziranog protutijela ili njegovog antigen vezujućeg fragmenta koji se specifično veže za humani folatni receptor 1 obuhvaća varijabilnu domenu teškog lanca sa SEQ ID NO:4 i varijabilnu domenu lakog lanca sa SEQ ID NO:10 ili SEQ ID NO:11, iii) humaniziranog protutijela ili njegovog antigen vezujućeg fragmenta koji se specifično veže za humani folatni receptor 1 obuhvaća teški lanac sa SEQ ID NO:6 i laki lanac sa SEQ ID NO:12 ili 13, ili iv) humaniziranog protutijela ili njegovog antigen vezujućeg fragmenta koji obuhvaća teški lanac kodiran plazmidnom DNA pohranjenom kod ATCC 7. travnja 2010. godine i ma ATCC broj PTA-10772 i laki lanac kodiran plazmidnom DNA pohranjenom kod ATCC 7. travnja 2010. godine i ma ATCC broj PTA-10773 ili 10774.
2. Imunokonjugat iz patentnog zahtjeva 1, nadalje karakteriziran na način da je (L) vezni dio odabran iz grupe koja se sastoji od veznog dijela koji se može pocijepati, veznog dijela koji se ne može pocijepati, hidrofilnog veznog dijela i veznog dijela na bazi dikarboksilne kiseline.
3. Imunokonjugat iz patentnog zahtjeva 2, pri čemu je vezni dio odabran iz grupe koja se sastoji od N-sukcinimidil 4-(2-piridilditio)-2-sulfobutanoat (sulfo-SPDB), N-sukcinimidil 4-(2-piridilditio)butanoat (SPDB), N-sukcinimidil-[(N-maleimidopropionamido)-tetraetilenglikol] ester (NHS-PEG4-maleimid), N-sukcinimidil 4-(2-piridilditio)pentanoat (SPP), N-sukcinimidil 4-(2-piridilditio)-2-sulfopentanoat (sulfo-SPP), N-sukcinimidil 4-(maleimidometil) cikloheksankarboksilat (SMCC), N-sulfosukcinimidil 4-(maleimidometil) cikloheksankarboksilat (sulfo-SMCC) i N-sukcinimidil 4-(jodoacetil)-aminobenzoat (SIAB).
4. Imunokonjugat iz bilo kojeg od patentnih zahtjeva 1 do 3, pri čemu je navedeni majtanzinoid N(2’)-deacetil-N2’-(4-merkapto-4-metil-1-oksopentil)-majtanzin ili N(2’)-deacetil-N2’-(3-merkapto-1-oksopropil)-majtanzin.
5. Imunokonjugat iz patentnog zahtjeva 1, koji ima formulu (A) – (L) – (C), pri čemu je: (A)humanizirano protutijelo ili njegov antigen vezujući fragment koji se specifično veže za humani folatni receptor 1, pri čemu protutijelo ili njegov antigen vezujući fragment obuhvaća: (a) teški lanac CDR1 koji obuhvaća GYFMN (SEQ ID NO:1); teški lanac CDR2 koji obuhvaća RIHPYDGDTFYNQKFQG (SEQ ID NO:2); i teški lanac CDR3 koji obuhvaća YDGSRAMDY (SEQ ID NO:3); i (b) laki lanac CDR1 koji obuhvaća KASQSVSFAGTSLMH (SEQ ID NO:7); laki lanac CDR2 koji obuhvaća RASNLEA (SEQ ID NO:8); i laki lanac CDR3 koji obuhvaća QQSREYPYT (SEQ ID NO:9); pri čemu je (L) N-sukcinimidil 4-(2-piridilditio)butanoat (SPDB) ili N-sukcinimidil 4-(2-piridilditio)-2-sulfobutanoat (sulfo-SPDB), i (C) N(2’)-deacetil-N2’-(4-merkapto-4-metil-1-oksopentil)-majtanzin ili N(2’)-deacetil-N2’-(3-merkapto-1-oksopropil)-majtanzin, pri čemu navedeni vezni dio (L) povezuje (A) za (C).
6. Imunokonjugat iz patentnog zahtjeva 1, koji ima formulu (A) – (L) – (C), pri čemu je: i) (A)humanizirano protutijelo koje obuhvaća varijabilnu domenu teškog lanca sa SEQ ID NO:4 i varijabilnu domenu lakog lanca sa SEQ ID NO:10 ili SEQ ID NO:11; (L)je N-sukcinimidil 4-(2-piridilditio)-2-sulfobutanoat (sulfo-SPDB); i (C)je N(2’)-deacetil-N2’-(4-merkapto-4-metil-1-oksopentil)-majtanzin, ii) (A)humanizirano protutijelo koje obuhvaća varijabilnu domenu teškog lanca sa SEQ ID NO:4 i varijabilnu domenu lakog lanca sa SEQ ID NO:10 ili SEQ ID NO:11; (L)je N-sukcinimidil-[(N-maleimidopropionamido)-tetraetilenglikol] ester (NHS-PEG4-maleimid); i (C)je N(2’)-deacetil-N2’-(4-merkapto-4-metil-1-oksopentil)-majtanzin, iii) (A)humanizirano protutijelo koje obuhvaća varijabilnu domenu teškog lanca sa SEQ ID NO:4 i varijabilnu domenu lakog lanca sa SEQ ID NO:10 ili SEQ ID NO:11; (L)je N-sukcinimidil 4-(2-piridilditio)butanoat (SPDB); i (C)je N(2’)-deacetil-N2’-(4-merkapto-4-metil-1-oksopentil)-majtanzin, iv) (A)humanizirano protutijelo koje obuhvaća varijabilnu domenu teškog lanca sa SEQ ID NO:4 i varijabilnu domenu lakog lanca sa SEQ ID NO:10 ili SEQ ID NO:11; (L)je N-sukcinimidil 4-(2-piridilditio)-2-sulfobutanoat (sulfo-SPDB); i (C)je N(2’)-deacetil-N2’-(3-merkapto-1-oksopropil)-majtanzin, ili v) (A)humanizirano protutijelo koje obuhvaća varijabilnu domenu teškog lanca sa SEQ ID NO:4 i varijabilnu domenu lakog lanca sa SEQ ID NO:10 ili SEQ ID NO:11; (L)je N-sukcinimidil 4-(2-piridilditio)butanoat (SPDB); i (C)je N(2’)-deacetil-N2’-(3-merkapto-1-oksopropil)-majtanzin, pri čemu navedeni vezni dio (L) povezuje (A) za (C), posebno kada je (A)humanizirano protutijelo koje obuhvaća varijabilnu domenu teškog lanca sa SEQ ID NO:4 i varijabilnu domenu lakog lanca sa SEQ ID NO:10 ili SEQ ID NO:11; (L)je N- sukcinimidil 4-(2- piridilditio)-2-sulfobutanoat (sulfo-SPDB); i (C)je N(2’)-deacetil-N2’-(4-merkapto-4-metil-1-oksopentil)-majtanzin; pri čemu navedeni vezni dio (L) povezuje (A) za (C).
7. Imunokonjugat iz bilo kojeg od patentnih zahtjeva 1 do 6 nadalje obuhvaća 2-6 (C), a posebno i) nadalje obuhvaća drugi (C), ii) nadalje obuhvaća drugi i treći (C), ili iii) nadalje obuhvaća drugi, treći i četvrti (C), poželjno nadalje obuhvaća 3-4 (C).
8. Imunokonjugat iz bilo kojeg od patentnih zahtjeva 1 do 6 pri čemu navedeno protutijelo ili antigen vezujući fragment sadrži Fab, Fab’, F(ab’)2, Fd, jednolančani Fv ili scFV, disulfidno povezani Fv, intratijelo, IgG-CH2, minitijelo, F(ab’)3, tetratijelo, triatijelo, dijatijelo, DVD-Ig, Fcab, mAb2, (scFv)2, ili scFv-Fc.
9. Imunokonjugat iz bilo kojeg od patentnih zahtjeva 1 do 6 pri čemu se navedeno protutijelo ili antigen vezujući fragment veže za humani folatni receptor 1 s Kd od 1.0 do 10 nM, poželjno se veže za humani folatni receptor 1 s Kd od 1.0 ili boljom, posebno kada je afinitet vezanja mjeren protočnom citometrijom, Biacoreom ili radioimunoodređivanjem.
10. Farmaceutski sastav obuhvaća imunokunjugat iz bilo kojeg od patentnih zahtjeva 1 do 9 i farmaceutski prihvatljivi nosač, gdje imunokonjugati poželjno imaju prosječno 3 do 4 (C) po (A), posebno gdje imunokonjugati imaju prosječno 3.5 ± 0.5 (C) po (A).
11. Dijagnostički reagens obuhvaća imunokonjugat iz bilo kojeg od patentnih zahtjeva 1 do 9, pri čemu navedeni dijagnostički reagens nadalje obuhvaća obilježivač, poželjno gdje je obilježivač odabran iz grupe koja se sastoji od radioobilježivača, fluorofora, kromofora, agensa za slikovne tehnike i iona metala.
12. Imunokonjugat iz bilo kojeg od patentnih zahtjeva 1 do 9 za uporabu u liječenju raka kod subjekta.
13. Imunokonjugat iz bilo kojeg od patentnih zahtjeva 1 do 9 za uporabu u skladu s patentnim zahtjevom 12, pri čemu je navedeni rak odabran iz grupe koja se sastoji od raka jajnika, raka mozga, raka maternice, raka endometrija, raka gušterače, raka bubrega, raka peritoneja i raka pluća, posebno gdje je rak rak jajnika, rak maternice, rak endometrija, rak peritoneja ili rak pluća, još posebnije kada je rak rak jajnika.
14. Imunokonjugat za uporabu u liječenju raka u subjekta, pri čemu imunokonjugat ima formulu (A) – (L) – (C), pri čemu je: (A) protutijelo ili njegov antigen vezujući fragment koji se specifično veže za humani folatni receptor 1, pri čemu protutijelo ili njegov antigen vezujući fragment obuhvaća varijabilnu domenu teškog lanca sa SEQ ID NO:4 i varijabilnu domenu lakog lanca sa SEQ ID NO:10 ili SEQ ID NO:11; (L)je vezni dio N-sukcinimidil 4-(2-piridilditio)-2-sulfobutanoat (sulfo-SPDB); i (C)je citotoksin N(2’)-deacetil-N2’-(4-merkapto-4-metil-1-oksopentil)-majtanzin, pri čemu vezni dio (L) povezuje (A) za (C), posebno kada je navedeni rak odabran iz grupe koja se sastoji od raka jajnika, raka mozga, raka maternice, raka endometrija, raka gušterače, raka bubrega, raka peritoneja i raka pluća, posebno gdje je rak rak jajnika, rak maternice, rak endometrija, rak peritoneja ili rak pluća.
15. Imunokonjugat iz patentnog zahtjeva 14 za uporabu iz patentnog zahtjeva 14, pri čemu je rak rak jajnika, rak maternice, rak endometrija ili rak peritoneja.
HRP20170281TT 2010-02-24 2017-02-21 Imunokonjugati folatnog receptora 1 i njihove uporabe HRP20170281T1 (hr)

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