DK2538976T3 - Immunkonjugater mod folatreceptor-1 og anvendelser deraf - Google Patents
Immunkonjugater mod folatreceptor-1 og anvendelser deraf Download PDFInfo
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- DK2538976T3 DK2538976T3 DK11748067.3T DK11748067T DK2538976T3 DK 2538976 T3 DK2538976 T3 DK 2538976T3 DK 11748067 T DK11748067 T DK 11748067T DK 2538976 T3 DK2538976 T3 DK 2538976T3
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- 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
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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. Immunkonjugat, der har formlen (A) - (L) - (C), hvor: (A) er et antistof eller antigenbindende fragment; (L) er en linker; og (C) er et maytansinoid eller en maytansinoid-analog, hvor linkeren (L) binder (A) til (C), hvor (A) er udvalgt fra gruppen bestående af: i) et humaniseret antistof eller antigenbindende fragment deraf, der specifikt binder en human folatreceptor-1, hvor antistoffet eller det antigenbindende fragment deraf omfatter: (a) en tungkæde-CDR1, der omfatter GYFMN (SEQ ID NO: 1); en tungkæde-CDR2, der omfatter RIHPYDGDTFYNQKFQG (SEQ ID NO: 2); og en tungkæde-CDR3, der omfatter YDGSRAMDY (SEQ ID NO: 3); og (b) en letkæde-CDR1, der omfatter KASQSVSF AGTSLMH (SEQ ID NO: 7); en letkæde-CDR2, der omfatter RASNLEA (SEQ ID NO: 8); og en letkæde-CDR3, der omfatter QQSREYPYT (SEQ ID NO: 9), ii) et humaniseret antistof eller antigenbindende fragment deraf, der specifikt binder den humane folatreceptor-1, der omfatter det variable tungkæde-domæne ifølge SEQ ID NO: 4, og det variable letkædedomæne ifølge SEQ ID NO: 10 eller SEQ ID N0:11, iii) et humaniseret antistof eller antigenbindende fragment deraf, der specifikt binder den humane folatreceptor-1, der omfatter tungkæden ifølge SEQ ID NO: 6 og letkæden ifølge SEQ ID NO: 12 eller 13, eller iv) et humaniseret antistof eller antigenbindende fragment deraf, der omfatter en tungkæde kodet for af plasmid-DNA’et, der er indleveret hos ATCC den 7. april 2010 og har ATCC deponeringsnummer PTA-10772, og en letkæde kodet for af plasmid-DNA’et, der er indleveret hos ATCC den 7. april 2010 og har ATCC deponeringsnummer PTA-10773 eller -10774.
2. Immunkonjugat ifølge krav 1, endvidere kendetegnet ved, at (L) er en linker udvalgt fra gruppen bestående af en fraspaltelig linker, en ikke-fraspaltelig linker, en hydrofil linker og en dicarboxylsyrebaseret linker.
3. Immunkonjugat ifølge krav 2, hvor linkeren er udvalgt fra gruppen bestående af /V-succinimidyl4-(2-pyridyldithio)-2-sulfobutanoat (sulfo-SPDB), /V-succinimidyl 4-(2-pyridyldithio)butanoat (SPDB), A/-succinimidyl-[(N-maleimidpropionamido)-tetraethyleneglycol]ester (NHS-PEG4-maleimid), /V-succinimidyl 4-(2-pyridyl-dithio)pentanoat (SPP), /V-succinimidyl 4-(2-pyridyldithio)-2-sulfopentanoat (sulfo-SPP), /V-succinimidyl 4-(maleimidomethyl)cyclohexancarboxylat (SMCC), /V-sulfosuccinimidyl 4-(maleimidomethyl)cyclohexancarboxylat (sulfo-SMCC) og /V-succinimidyl-4-(iodoacetyl)-aminobenzoat (SIAB).
4. Immunkonjugat ifølge et hvilket som helst af kravene 1 til 3, hvor maytansinoidet er N(2’)-deacetyl-N2’-(4-mercapto-4-methyl-1-oxopentyl)-maytansin eller N(2’)-deacetyl-N(2’)-(3-mercapto-1-oxopropyl)-maytansin.
5. Immunkonjugat ifølge krav 1, der har formlen (A) - (L) - (C), hvor: (A) er et humaniseret antistof eller antigenbindende fragment deraf, der specifikt binder en human folatreceptor-1, hvor antistoffet eller det antigenbindende fragment deraf omfatter: (a) en tungkæde-CDR1, der omfatter GYFMN (SEQ ID NO: 1); en tungkæde-CDR2, der omfatter RIHPYDGDTFYNQKFQG (SEQ ID NO: 2); og en tungkæde-CDR3, der omfatter YDGSRAMDY (SEQ ID NO: 3); og (b) en letkæde-CDR1, der omfatter KASQSVSFAGTSLMH (SEQ ID NO: 7); en letkæde-CDR2, der omfatter RASNLEA (SEQ ID NO: 8); og en letkæde-CDR3, der omfatter QQSREYPYT (SEQ ID NO: 9); hvor (L) er /V-succinimidyl 4-(2-pyridyldithio)butanoat (SPDB) eller /V-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoat (sulfo-SPDB), og (C) er N(2’)-deacetyl-N2’-(4-mercapto-4-methyl-1-oxopentyl)-maytansin eller N(2’)-deacetyl-N(2’)-(3-mercapto-1-oxopropyl)-maytansin, hvor linkeren (L) binder (A) til (C).
6. Immunkonjugat ifølge krav 1 med formlen (A) - (L) - (C), hvor i) (A) er et humaniseret antistof, der omfatter det variable tungkædedomæne ifølge SEQ ID NO: 4, og det variable letkædedomæne ifølge SEQ ID NO: 10 eller SEQ ID N0:11; (L) er /V-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoat (sulfo-SPDB); og (C) er N(2’)-deacetyl-N2’-(4-mercapto-4-methyl-1-oxopentyl)-maytansin, ϋ) (A) er et humaniseret antistof, der omfatter det variable tungkædedomæne ifølge SEQ ID NO: 4, og det variable letkædedomæne ifølge SEQ ID NO: 10 eller SEQ ID N0:11; (L) er /V-succinimidyl-[(N-maleimidpropionamido)-tetraethyleneglycol]ester (NHS-PEG4-maleimid); og (C) er N(2’)-deacetyl-N2’-(4-mercapto-4-methyl-1-oxopentyl)-maytansin, iii) (A) er et humaniseret antistof, der omfatter det variable tungkædedomæne ifølge SEQ ID NO: 4, og det variable letkædedomæne ifølge SEQ ID NO: 10 eller SEQ ID N0:11; (L) er/V-succinimidyl 4-(2-pyridyldithio)butanoat (SPDB); og (C) er N(2’)-deacetyl-N2’-(4-mercapto-4-methyl-1-oxopentyl)-maytansin, iv) (A) er et humaniseret antistof, der omfatter det variable tungkædedomæne ifølge SEQ ID NO: 4, og det variable letkædedomæne ifølge SEQ ID NO: 10 eller SEQ ID N0:11; (L) er/V-succinimidyl 4-(2-pyridyldithio)-2-sulfopentanoat (sulfo-SPP); og (C) er N(2’)-deacetyl-N(2’)-(3-mercapto-1-oxopropyl)-maytansin, eller v) (A) er et humaniseret antistof, der omfatter det variable tungkædedomæne ifølge SEQ ID NO: 4, og det variable letkædedomæne ifølge SEQ ID NO: 10 eller SEQ ID NO: 11; (L) er /V-succinimidyl 4-(2-pyridyldithio)pentanoat (SPP); og (C) N(2')-deacetyl-N(2')-(3-mercapto-1-oxopropyl)-maytansin, hvor linkeren (L) binder (A) til (C), navnlig hvor (A) er et humaniseret antistof, der omfatter det variable tungkædedomæne ifølge SEQ ID N0:4, og det variable letkædedomæne ifølge SEQ ID NO: 10 eller SEQ ID N0:11; (L) er/V-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoat (sulfo-SPDB); og (C) er N(2')-deacetyl-N2'-(4-mercapto-4-methyl-1-oxopentyl)-maytansin; hvor (L) binder (A) til (C).
7. Immunkonjugat ifølge et hvilket som helst af kravene 1 til 6, der endvidere omfatter 2-6 (C), navnlig i) endvidere omfattende et andet (C), ii) endvidere omfattende et andet og et tredje (C), eller iii) endvidere omfattende et andet, et tredje og et fjerde (C), fortrinsvis endvidere omfattende 3-4 (C).
8. Immunkonjugat ifølge et hvilket som helst af kravene 1 til 6, hvor antistoffet eller det antigenbindende fragment omfatter et Fab, et Fab’, a F(ab’)2, et Fd, et enkeltkæde Fv eller scFv, et disulfidbundet Fv, et intrabody, et lgG-CH2, et minibody, et F(ab’)3, ettetrabody, et triabody, et diabody, DVD-lg, Fcab, mAb2, et (scFv)2 eller et scFv-Fc.
9. Immunkonjugat ifølge et hvilket som helst af kravene 1 til 6, hvor antistoffet eller det antigenbindende fragment binder til en human folatreceptor-1 med en Kd på 1,0 til 10 nM, fortrinsvis binder det til en human folatreceptor-1 med en Kd på 1,0 nM eller bedre, hvor bindingsaffiniteten navnlig måles ved strømningscytometri, Biacore eller radioimmunassay.
10. Farmaceutisk sammensætning omfattende immunkonjugatet ifølge et hvilket som helst af kravene 1 til 9 og en farmaceutisk acceptabel bærer, fortrinsvis hvor immunkonjugaterne har et gennemsnit på 3 til 4 (C) pr. (A), navnlig hvor immunkonjugaterne har et gennemsnit på 3,5 ± 0,5 (C) pr. (A).
11. Diagnostisk reagens omfattende immunkonjugatet ifølge et hvilket som helst af kravene 1 til 9, hvor det diagnostiske reagens endvidere omfatter en markør, hvor markøren fortrinsvis er udvalgt fra gruppen bestående af en radiomarkør, en fluorophor, en chromophor, et billeddannende middel og en metalion.
12. Immunkonjugat ifølge et hvilket som helst af kravene 1 til 9 til anvendelse i behandlingen af cancer hos en person.
13. Immunkonjugat ifølge et hvilket som helst af kravene 1 til 9 til anvendelse ifølge krav 12, hvor canceren er udvalgt fra gruppen bestående af ovariecancer, hjernecancer, brystcancer, uteruscancer, endometriecancer, pankreascancer, nyrecancer, peritonealcancer og lungecancer, hvor canceren fortrinsvis er ovariecancer, uteruscancer, endometriecancer, peritonealcancer eller en lungecancer, hvor canceren mere fortrinsvis er ovariecancer.
14. Immunkonjugat til anvendelse i behandlingen af cancer hos en person, hvor immunkonjugatet har formlen (A) - (L) - (C), hvor: (A) er et antistof eller antigenbindende fragment deraf, der specifikt binder en human folatreceptor-1, hvor antistoffet eller det antigenbindende fragment deraf omfatter det variable tungkædedomæne ifølge SEQ ID NO: 4 og det variable letkædedomæne ifølge SEQ ID NO: 10 eller SEQ ID NO: 11; (L) er linkeren N-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoat (sulfo-SPDB); og (C) er cytotoxin N(2’)-deacetyl-N2’-(4-mercapto-4-methyl-1-oxopentyl)-maytansin, hvor (L) binder (A) til (C), navnlig hvor canceren er udvalgt fra gruppen bestående af ovariecancer, hjernecancer, brystcancer, uteruscancer, endometriecancer, pankreascancer, nyrecancer, peritonealcancer og lungecancer, navnlig hvor canceren er ovariecancer, uteruscancer, endometriecancer, peritonealcancer eller en lungecancer.
15. Immunkonjugat ifølge krav 14 til anvendelse ifølge krav 14, hvor canceren er ovariecancer, uteruscancer, endometriecancer eller peritonealcancer.
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