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EP0446071A2
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EP
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Tris-maleimido compounds as intermediates in trifunctional antibody synthesis
Assignee: Hybritech Inc
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Filing: 1991-03-08
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Granted: —
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Expires: 2011-03-08
Abstract
Abstract The present invention is directed to a compound for use as an intermediate in the production of novel trifunctional antibody-like compounds. More particularly, the present invention is directed to a compound of the formula : wherein X is wherein k =1 or 0 ; wherein Z is -0-, or -NH-; wherein s = 1 or 0; wherein n = 1 or 0 ; wherein q = 1 or 0; wherein Y is -S-S-, -O-, or -NH-; wherein Y' is -S-S-, -O-, or -NH-; wherein p or m may be the same or different and are integers ranging from 0 to 20 with the provisos that when n = 0, the sum of m and p is an integer ranging from 1 to 20, whereas when n = 1, p and m are each an integer that is at least 1 and the sum of p and m is an integer ranging from 2 to 20 ; wherein R 1 is straight or branched chain lower alkyl having from 1 to 6 carbon atoms or lower alkoxy having from 1-6 carbon atoms ; and wherein R 2 is hydrogen, phenyl, -COOH, or straight or branched chain lower alkyl having from 1-6 carbon atoms, with the proviso that the lower alkyl moiety may be mono substituted by -NH 2 , -OH, or -COOH. The compound of the present invention is useful as a trivalent coupling agent for linking Fab'-like fragments to form both bifunctional and trifunctional antibody-like compounds.
Inventors
- 👤 Clarence N. Ahlem
- 👤 Ann E. Huang
- 👤 Leslie D. Anderson
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-11-09 10:12
CPC Classifications
C; C07; C07D; C07D207/00; C07D207/02; C07D207/44; C07D207/444; C07D207/448; C07D207/452; C07K; C07K1/00; C07K1/10; C07K16/00; C07K16/46; C07K16/468; A; A61; A61K; A61K38/00
Claims Analysis
Total Claims: 35
Claim 1
Independent Claim
188 words
A compound of the formula wherein X is wherein k = 1 or 0; wherein Z is -0-, or -NH-: wherein s = 1 or 0; wherein n = 1 or 0; wherein q = 1 or 0; wherein Y is -S-S-, , -O-, or -NH-; wherein Y' is -S-S-, -O-, or -NH-: wherein p or m may be the same or different and are integers ranging from 0 to 20 with the provisos that when n = 0, the sum of m and p is an integer ranging from 1 to 20, whereas when n = 1, p and m are each an integer that is at least 1 and the sum of p and m is an integer ranging from 2 to 20; wherein R 1 is straight or branched chain lower alkyl having from 1 to 6 carbon atoms or lower alkoxy having from 1-6 carbon atoms; and wherein R 2 is hydrogen phenyl, -COOH, or straight or branched chain lower alkyl having from 1-6 carbon atoms with the proviso that the lower alkyl moiety may be monosubstituted by -NH 2 , -OH, or -COOH.
Claim 2
Dependent Claim
188 words
A compound of the formula wherein X is wherein k = 1 or 0; wherein Z is -0-, or -NH-: wherein s = 1 or 0; wherein n = 1 or 0; wherein q = 1 or 0; wherein Y is -S-S-, , -O-, or -NH-; wherein Y' is -S-S-, -O-, or -NH-: wherein p or m may be the same or different and are integers ranging from 0 to 20 with the provisos that when n = 0, the sum of m and p is an integer ranging from 1 to 20, whereas when n = 1, p and m are each an integer that is at least 1 and the sum of p and m is an integer ranging from 2 to 20; wherein R 1 is straight or branched chain lower alkyl having from 1 to 6 carbon atoms or lower alkoxy having from 1-6 carbon atoms; and wherein R 2 is hydrogen phenyl, -COOH, or straight or branched chain lower alkyl having from 1-6 carbon atoms with the proviso that the lower alkyl moiety may be monosubstituted by -NH 2 , -OH, or -COOH.
Claim 3
Dependent Claim
9 words
The compound according to Claim 1 wherein Y is
Claim 4
Dependent Claim
8 words
The compound according to Claim 2 which is:
Claim 5
Dependent Claim
8 words
The compound according to Claim 2 which is:
Claim 6
Dependent Claim
8 words
A compound according to Claim 1 which is:
Claim 7
Dependent Claim
8 words
The compound according to Claim 1 which is:
Claim 8
Dependent Claim
41 words
The compound according to Claim 1 wherein n = 0, s = 0, and m and p are each an integer that is at least 1 and the sum of m and p is an integer from 2 to about 20.
Claim 9
Dependent Claim
8 words
The compound according to Claim 7 which is:
Claim 10
Dependent Claim
8 words
The compound according to Claim 1 which is:
Claim 11
Dependent Claim
8 words
The compound according to Claim 1 which is:
Claim 12
Dependent Claim
8 words
The compound according to Claim 1 which is:
Claim 13
Dependent Claim
15 words
A trivalent coupling agent for covalently linking Fab'-like fragments comprising a compound of a formula:
Claim 14
Dependent Claim
15 words
A trivalent coupling agent for covalently linking Fab'-like fragments comprising a compound of a formula:
Claim 15
Dependent Claim
176 words
wherein X is wherein k = is 1 or 0; wherein Z is -O-, or -NH-; wherein s = 1 or 0; wherein n = 1 or 0; wherein q = 1 or 0; wherein Y is -S-S-, -0-, or -NH-: wherein Y' is -S-S-, . -O-, or -NH-; wherein p and m may be the same or different and are integers ranging from 1 to 20 with the provisos that when n = 0 the sum of m and p is an integer ranging from 1 to 20, whereas when n = 1, p and m are each an integer that is at least 1 and the sum of m and p ranges from 2 to 20; wherein R 1 is straight or branched chain lower alkyl having from about 1 to about 6 carbon atoms or lower alkyloxy; and wherein R 2 is hydrogen, phenyl, -COOH or straight or branched chain lower alkyl having from 1-6 carbon atoms with the proviso that the lower alkyl moiety may be monosubstituted by -NH-, -OH-, or COOH.
Claim 16
Dependent Claim
176 words
wherein X is wherein k = is 1 or 0; wherein Z is -O-, or -NH-; wherein s = 1 or 0; wherein n = 1 or 0; wherein q = 1 or 0; wherein Y is -S-S-, -0-, or -NH-: wherein Y' is -S-S-, . -O-, or -NH-; wherein p and m may be the same or different and are integers ranging from 1 to 20 with the provisos that when n = 0 the sum of m and p is an integer ranging from 1 to 20, whereas when n = 1, p and m are each an integer that is at least 1 and the sum of m and p ranges from 2 to 20; wherein R 1 is straight or branched chain lower alkyl having from about 1 to about 6 carbon atoms or lower alkyloxy; and wherein R 2 is hydrogen, phenyl, -COOH or straight or branched chain lower alkyl having from 1-6 carbon atoms with the proviso that the lower alkyl moiety may be monosubstituted by -NH-, -OH-, or COOH.
Claim 17
Dependent Claim
10 words
The trivalent coupling agent of Claim 12 wherein Y is
Claim 18
Dependent Claim
9 words
The trivalent coupling agent of Claim 13 which is:
Claim 19
Dependent Claim
9 words
The trivalent coupling agent of Claim 13 which is:
Claim 20
Dependent Claim
9 words
The trivalent coupling agent of Claim 12 which is:
Claim 21
Dependent Claim
9 words
The trivalent coupling agent of Claim 12 which is:
Claim 22
Dependent Claim
42 words
The trivalent coupling agent of Claim 12 wherein n = 0, s = 0 and m and p are each an integer that is at least 1 and the sum of m and p is an integer from 2 to about 20.
Claim 23
Dependent Claim
9 words
The trivalent coupling agent of Claim 18 which is:
Claim 24
Dependent Claim
9 words
The trivalent coupling agent of Claim 12 which is:
Claim 25
Dependent Claim
9 words
The trivalent coupling agent of Claim 12 which is:
Claim 26
Dependent Claim
9 words
The trivalent coupling agent of Claim 12 which is:
Claim 27
Independent Claim
188 words
A method for extending the length of one of the three linker arms of the compound of Formula I, which method comprises: (a) combining the compound of Formule I at pH 5-8 with an Fab'-like fragment having at least 2 free sulfhydryl groups to form a maleimide-Fab' complex having a single reactive maleimide extending distally therefrom; (b) combining the maleimide-Fab' complex from step (a) at pH 5-8 with a compound of the formula: HS-(CH 2 ) t -SH II wherein the subscript "t" is an integer from 2 to about 20, said compound of Formula II being combined in an amount effective to prevent intermolecular crosslinking between molecules of said Fab'-maleimide complex, said combination forming a coupled product between said maleimide-Fab' complex and said compound of Formula I said coupled product having an extended linker arm with an -SH moiety extending distally therefrom; (c) combining the coupled product of Step (b) at pH 5-8 with an amount of a bis-maleimide effective to prevent intermolecular crosslinking between molecules of said coupled product to form a maleimide-Fab' complex having an extended linker arm with a reactive maleimide at its terminus.
Claim 28
Independent Claim
188 words
A method for extending the length of one of the three linker arms of the compound of Formula I, which method comprises: (a) combining the compound of Formule I at pH 5-8 with an Fab'-like fragment having at least 2 free sulfhydryl groups to form a maleimide-Fab' complex having a single reactive maleimide extending distally therefrom; (b) combining the maleimide-Fab' complex from step (a) at pH 5-8 with a compound of the formula: HS-(CH 2 ) t -SH II wherein the subscript "t" is an integer from 2 to about 20, said compound of Formula II being combined in an amount effective to prevent intermolecular crosslinking between molecules of said Fab'-maleimide complex, said combination forming a coupled product between said maleimide-Fab' complex and said compound of Formula I said coupled product having an extended linker arm with an -SH moiety extending distally therefrom; (c) combining the coupled product of Step (b) at pH 5-8 with an amount of a bis-maleimide effective to prevent intermolecular crosslinking between molecules of said coupled product to form a maleimide-Fab' complex having an extended linker arm with a reactive maleimide at its terminus.
Claim 29
Dependent Claim
13 words
The method of Claim 23 wherein the pH in Step (a) is 5-7.
Claim 30
Dependent Claim
13 words
The method of Claim 23 wherein the pH in Step (b) is 5-7.
Claim 31
Independent Claim
15 words
The method of Claims 24 wherein the pH in Steps (a) and (b) is 5-7.
Claim 32
Independent Claim
39 words
The method of Claims 23 or 26 wherein the Fab'-like fragment is derived from an antibody that is a member of the group consisting of human IgG, primate IgG, mouse IgG,, mouse IgG 2a and mouse IgG 2b .
Claim 33
Dependent Claim
21 words
The method of Claim 26 wherein the bis-maleimide is selected from the group consisting of BMME; BMP; N,N'-o-phenylenedimaleimide; N,N'-p-phenylenedimaleimide; and N,N'-(oxydimethylene)dimaleimide.
Claim 34
Dependent Claim
30 words
The method of Claim 23 wherein in Step (b), the compound of Formula II is combined in at least a 10 fold molar excess relative to said maleimide Fab' complex.
Claim 35
Dependent Claim
28 words
The method of Claim 29 wherein in Step (c) the bis-maleimide is combined in at least a 10 fold molarexcess relative to the coupled product of Step (b).
References Cited (Backward Citations)
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