US5034514A
Expired / Lapsed
US
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Novel cross-linking agents
Assignee: Novartis Vaccines and Diagnostics Inc
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Filing: 1988-10-12
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Granted: 1991-07-23
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Expires: 2008-10-12
Abstract
Abstract Bifunctional chemicals useful for linking aldehyde containing moieties to moieties containing functionalities which are or can be reactive with sulfhydryl are claimed and have the formula: L--S--(CH.sub.2).sub.n1 --CONH--SPACER--NH--X wherein L is a leaving group selected from --H or --S--Ar, wherein Ar represents optionally substituted phenyl or pyridyl; n 1 =2-4; X is selected from: --CO--Y--CONHNH 2 , a hydrazide; ##STR1## a hydrazine; ##STR2## a hydrazine; --CO--Y--NH--CONHNH 2 , a semicarbazide; and --CO--Z--NH--CSNHNH 2 , a thiosemicarbazide; wherein Y is alkylene or oxaalkylene and Z is alkylene or a polypeptide residue briding the N-terminal amino group and C-terminal carboxy group thereof; the SPACER is oxaalkylene or oxaalkylene substituted with hydroxyl and specifically includes residues having formulas selected from a) --(CH 2 ) n2 --O--(CH 2 ) n2 --O--(CH 2 ) n2 -- wherein each n2 is independently 2-4 and b) ##STR3## wherein n3 is 2-6. Also claimed are hydrazides, semicarbazides, and thiosemicarbazides of ω-mercaptocarboxylic acids which lack SPACER diamine.
Inventors
- 👤 Danute E. Nitecki
- 👤 Margaret Moreland
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-07 20:59
CPC Classifications
G; G01; G01N; G01N33/00; G01N33/48; G01N33/50; G01N33/53; G01N33/543; G01N33/54353; C; C07; C07D; C07D213/00; C07D213/02; C07D213/04; C07D213/60; C07D213/62; C07D213/70; C07D213/71
Claims Analysis
Total Claims: 11
Claim 1
Independent Claim
11 words
An immunoglobulin-linker complex in which an immunoglobulin is conjugated to 1-{3-(2-pyridyldithio)propionamido}-12-{5-hydrazidoglutaramido}-4,9-dioxadodecane.
Claim 2
Dependent Claim
11 words
An immunoglobulin-linker complex in which an immunoglobulin is conjugated to 1-{3-(2-pyridyldithio)propionamido}-12-{5-hydrazidoglutaramido}-4,9-dioxadodecane.
Claim 3
Dependent Claim
62 words
An immunoglobulin-linker complex in which an immunoglobulin is conjugated to the compound selected from those of the formula L--S--(CH 2 ) n1 CONHNH 2 , L--S--(CH 2 ) n1 NHCONHNH 2 and L--S--(CH 2 ) n1 NHCSNHNH 2 wherein L is a leaving group selected from --H or --S--Ar, wherein Ar represents optionally substituted phenyl or pyridyl; and n 1 is 2-4.
Claim 4
Dependent Claim
62 words
An immunoglobulin-linker complex in which an immunoglobulin is conjugated to the compound selected from those of the formula L--S--(CH 2 ) n1 CONHNH 2 , L--S--(CH 2 ) n1 NHCONHNH 2 and L--S--(CH 2 ) n1 NHCSNHNH 2 wherein L is a leaving group selected from --H or --S--Ar, wherein Ar represents optionally substituted phenyl or pyridyl; and n 1 is 2-4.
Claim 5
Dependent Claim
16 words
The complex of claim 1, wherein said immunoglobulin is bound to 1-{3-(2-pyridyldithio)propionamido}-12-{5-hydrazidoglutaramido}-4,9-dioxadodecane through a disulfide linkage.
Claim 6
Dependent Claim
16 words
The complex of claim 2, wherein said immunoglobulin is bound to 1-{3-(2-pyridyldithio)propionamido}-12-{5-hydrazidoglutaramido}-4,9-dioxadodecane through a disulfide linkage.
Claim 7
Independent Claim
141 words
A method of making an immunoglobulin-linker complex, comprising the steps of: (a) providing a linker of the formula L--S--(CH 2 ) n1 --CONH--SPACER--NH--X wherein L is a leaving group selected from --H or --S--Ar, wherein Ar represents optionally substituted phenyl or pyridyl; n 1 =2-4; X is selected from --CO--Y--CONHNH 2 , a hydrazide; ##STR14## a hydrazine; ##STR15## a hydrazine; --CO--Y--NH--CONHNH 2 , a semicarbazide; and --CO--Z--NH--CSNHNH 2 , a thiosemicarbazide; wherein Y is alkylene or oxaalkylene and Z is alkylene, oxaalkylene, or a polypeptide residue bridging the N-terminal amino group and C-terminal carboxy group of said polypeptide; the SPACER is oxaalkylene or is oxaalkylene substituted with hydroxyl; and (b) oxidizing an immunoglobulin so as to provide an aldehyde residue on the immunoglobulin; (c) reacting the oxidized immunoglobulin with the --NHX moiety on the linker so that immunoglobulin linker is provided.
Claim 8
Independent Claim
141 words
A method of making an immunoglobulin-linker complex, comprising the steps of: (a) providing a linker of the formula L--S--(CH 2 ) n1 --CONH--SPACER--NH--X wherein L is a leaving group selected from --H or --S--Ar, wherein Ar represents optionally substituted phenyl or pyridyl; n 1 =2-4; X is selected from --CO--Y--CONHNH 2 , a hydrazide; ##STR14## a hydrazine; ##STR15## a hydrazine; --CO--Y--NH--CONHNH 2 , a semicarbazide; and --CO--Z--NH--CSNHNH 2 , a thiosemicarbazide; wherein Y is alkylene or oxaalkylene and Z is alkylene, oxaalkylene, or a polypeptide residue bridging the N-terminal amino group and C-terminal carboxy group of said polypeptide; the SPACER is oxaalkylene or is oxaalkylene substituted with hydroxyl; and (b) oxidizing an immunoglobulin so as to provide an aldehyde residue on the immunoglobulin; (c) reacting the oxidized immunoglobulin with the --NHX moiety on the linker so that immunoglobulin linker is provided.
Claim 9
Dependent Claim
29 words
The method of claim 5, further comprising reacting the immunoglobulin-linker complex with a sulfhydryl-containing moiety so that the complex is bound to the sulfhydryl-containing moiety through a disulfide bond.
Claim 10
Dependent Claim
36 words
A method of making an immunoglobulin-linker complex according to claim 5, wherein the oxaalkylene spacer is --(CH 2 ) n2 --O--(CH 2 ) n2 --O--(CH 2 ) n2 -- wherein each n 2 is independently 2-4.
Claim 11
Dependent Claim
25 words
A method of making an immunoglobulin-linker complex according to claim 5, wherein the oxaalkylene spacer substituted with hydroxyl is ##STR16## wherein n 3 is 2-6.
References Cited (Backward Citations)
US4867973A
Cited
EP0294294A2
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1994-07-22 | 1995-01-21 | 1995-07-23 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1998-07-22 | 1999-01-21 | 1999-07-23 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2002-07-22 | 2003-01-21 | 2003-07-23 | $7700.00 | Window Closed / Lapsed |