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US5082930A
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Coupling agents for joining radionuclide metal ions with biologically useful proteins
Assignee: Mallinckrodt Inc
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Filing: 1988-11-23
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Granted: 1992-01-21
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Expires: 2008-11-23
Abstract
Abstract This invention relates to bifunctional coupling agents useful in forming conjugates with biologically useful molecules, such as antibodies. These conjugates can be complexed with radionuclide metal ions to provide materials useful for in vivo diagnostic and therapeutic applications.
Inventors
- 👤 Robert A. Nicolotti
- 👤 Richard T. Dean
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-08 06:09
CPC Classifications
C; C07; C07D; C07D231/00; C07D231/02; C07D231/10; C07D231/12; A; A61; A61K; A61K51/00; A61K51/02; A61K51/04; A61K51/08; A61K51/10; A61K51/1093; C07D207/00; C07D207/46; C07D233/00; C07D233/54; C07D233/56; C07D249/00; C07D249/02; C07D249/08; A61K2121/00; A61K2123/00; G; G01; G01N; G01N2474/00; G01N2474/20; Y; Y10; Y10S; Y10S424/00; Y10S424/809; Y10S435/00; Y10S435/968; Y10S530/00; Y10S530/866
Claims Analysis
Total Claims: 36
Claim 1
Independent Claim
144 words
A coupling agent for joining a radionuclide metal ion with a biologically useful protein or polypeptide molecule comprising a compound of the formulas: ##STR12## wherein R 1 , R 2 , and R 3 are the same or different and each represents a radical selected from the group consisting of alkyls having from 1 to 6 carbon atoms, aryls having from 6 to 8 carbon atoms and alkaryls having 7 to 9 carbon atoms, any of which can be substituted with one or more hydroxyl, alkoxy, carboxy or sulfonate groups; n is either 1 or 2; AA are independently α or β amino acids linked to each other by amide bonds; i is an integer of from 2 to 6; and X is a activating group capable of forming an amide bond with an ε-amino group of said biologically useful protein or polypeptide molecule.
Claim 2
Dependent Claim
144 words
A coupling agent for joining a radionuclide metal ion with a biologically useful protein or polypeptide molecule comprising a compound of the formulas: ##STR12## wherein R 1 , R 2 , and R 3 are the same or different and each represents a radical selected from the group consisting of alkyls having from 1 to 6 carbon atoms, aryls having from 6 to 8 carbon atoms and alkaryls having 7 to 9 carbon atoms, any of which can be substituted with one or more hydroxyl, alkoxy, carboxy or sulfonate groups; n is either 1 or 2; AA are independently α or β amino acids linked to each other by amide bonds; i is an integer of from 2 to 6; and X is a activating group capable of forming an amide bond with an ε-amino group of said biologically useful protein or polypeptide molecule.
Claim 3
Dependent Claim
23 words
The coupling agent of claim 1 wherein X is a member selected from the group consisting of a halogen, N 3 , ##STR13##
Claim 4
Dependent Claim
10 words
The coupling agent of claim 2 wherein X is ##STR14##
Claim 5
Dependent Claim
12 words
The coupling agent of claim 3 wherein i is 3 or 4.
Claim 6
Dependent Claim
13 words
The coupling agent of claim 4 wherein R 1 is methyl or phenyl.
Claim 7
Dependent Claim
115 words
An antibody conjugate of the formula: ##STR15## wherein Ab is the residue of an antibody or fragment thereof; and R 1 , R 2 , and R 3 are the same or different and each represents a radical selected from the group consisting of alkyls having from 1 to 6 carbon atoms, aryls having from 6 to 8 carbon atoms and alkaryls having 7 to 9 carbon atoms, any of which can be substituted with one or more hydroxyl, alkoxy, carboxy or sulfonate groups; n is either 1 or 2; AA are independently α or β amino acids linked to each other by amide bonds; and i is an integer of from 2 to 6.
Claim 8
Dependent Claim
115 words
An antibody conjugate of the formula: ##STR15## wherein Ab is the residue of an antibody or fragment thereof; and R 1 , R 2 , and R 3 are the same or different and each represents a radical selected from the group consisting of alkyls having from 1 to 6 carbon atoms, aryls having from 6 to 8 carbon atoms and alkaryls having 7 to 9 carbon atoms, any of which can be substituted with one or more hydroxyl, alkoxy, carboxy or sulfonate groups; n is either 1 or 2; AA are independently α or β amino acids linked to each other by amide bonds; and i is an integer of from 2 to 6.
Claim 9
Dependent Claim
20 words
The antibody conjugate of claim 6, wherein Ab is the residue of a F(ab') 2 fragment of a monoclonal antibody.
Claim 10
Dependent Claim
24 words
The antibody conjugate of claim 6, wherein Ab is the residue of a Fab' fragment of a monoclonal antibody to a tumor associated antigen.
Claim 11
Dependent Claim
21 words
The antibody conjugate of claim 6, wherein Ab is the residue of a Fab' fragment of a monoclona antibody to CEA.
Claim 12
Dependent Claim
12 words
The antibody conjugate of claim 6, wherein i is 3 or 4.
Claim 13
Dependent Claim
13 words
The antibody conjugate of claim 6, wherein R 1 is methyl or phenyl.
Claim 14
Dependent Claim
6 words
The compound N-(3-sulfosuccinimidyl) S-acetylmercaptoacetylglycylglycylglycinate sodium salt.
Claim 15
Dependent Claim
6 words
The compound N-(3-sulfosuccinimidyl) S-acetylmercaptoacetylglycylglycylglycinate sodium salt.
Claim 16
Dependent Claim
6 words
The compound N-(3-sulfosuccinimidyl) S-benzoylmercaptoacetylglycylglycylglycinate sodium salt.
Claim 17
Dependent Claim
6 words
The compound N-(3-sulfosuccinimidyl) S-benzoylmercaptoacetylglycylglycylglycinate sodium salt.
Claim 18
Dependent Claim
21 words
An antibody-radiounuclide complex comprising the antibody conjugate of claim 6 and a radionuclide metal selected from radioisotopes of technetium and rhenium.
Claim 19
Dependent Claim
19 words
An antibody-radionuclide complex as claimed in claim 19, wherein the radionuclide is selected from Tc-99m, Re-186, Re-188 and Re-189.
Claim 20
Dependent Claim
20 words
The antibody complex of claim 14, wherein Ab is the residue of a F(ab') 2 fragment of a monoclonal antibody.
Claim 21
Dependent Claim
24 words
The antibody complex of cliam 14, wherein Ab is the residue of a Fab' fragment of a monoclonal antibody to a tumor associated antigen.
Claim 22
Dependent Claim
24 words
The antibody complex of cliam 14, wherein Ab is the residue of a Fab' fragment of a monoclonal antibody to a tumor associated antigen.
Claim 23
Dependent Claim
21 words
The antibody complex of claim 14, wherein Ab is the residue of a Fab' fragment of a monoconal antibody to CEA.
Claim 24
Dependent Claim
12 words
The antibody complex of claim 14, wherein i is 3 or 4.
Claim 25
Dependent Claim
13 words
The antibody complex of claim 19, wherein R 1 is methyl or phenyl.
Claim 26
Dependent Claim
37 words
A method of detecting and localizing a tumor in vivo which comprises parenterally administering to a subject an antibody-radionuclide complex of claim 19 and photoscanning the subject to determine the site of the antibody complex in vivo.
Claim 27
Dependent Claim
12 words
The method of claim 21, wherein the antibodyradionuclide complex is administered intravenously.
Claim 28
Independent Claim
178 words
A method of producing an antibody conjugate for in vivo diagnostic or therapeutic use which comprises: (a) enzymatically cleaving the Fc fragment from an antibody to a tumor-associated antigen which cleaves to produce an F(ab)' 2 dimer; (b) reducing the F(ab)' 2 dimer to produce two Fab' fragments; and (c) reacting the Fab' fragments with a coupling agent of the formula: ##STR16## wherein R 1 , R 2 and R 3 are the same or different and each represents a radical selected from the group consisting of alkyls having from 1 to 6 carbon atoms, aryls having from 6 to 8 carbon atoms and alkaryls having 7 to 9 carbon atoms, any of which can be substituted with one or more hydroxyl, or alkoxy, carboxy or sulfonate groups; n is either 1 or 2; AA are independently α or β amino acids linked to each other by amide bonds; i is an integer of from 2 to 6; and X is an activating group capable of forming an amide bond with an ε-amino group of said Fab' fragment.
Claim 29
Independent Claim
178 words
A method of producing an antibody conjugate for in vivo diagnostic or therapeutic use which comprises: (a) enzymatically cleaving the Fc fragment from an antibody to a tumor-associated antigen which cleaves to produce an F(ab)' 2 dimer; (b) reducing the F(ab)' 2 dimer to produce two Fab' fragments; and (c) reacting the Fab' fragments with a coupling agent of the formula: ##STR16## wherein R 1 , R 2 and R 3 are the same or different and each represents a radical selected from the group consisting of alkyls having from 1 to 6 carbon atoms, aryls having from 6 to 8 carbon atoms and alkaryls having 7 to 9 carbon atoms, any of which can be substituted with one or more hydroxyl, or alkoxy, carboxy or sulfonate groups; n is either 1 or 2; AA are independently α or β amino acids linked to each other by amide bonds; i is an integer of from 2 to 6; and X is an activating group capable of forming an amide bond with an ε-amino group of said Fab' fragment.
Claim 30
Dependent Claim
22 words
The method of claim 23, wherein X is a member selected from the group consisting of a halogen, N 3 , ##STR17##
Claim 31
Dependent Claim
13 words
The method of claim 23, wherein the antibody is cleaved with preactivated papain.
Claim 32
Dependent Claim
14 words
The method of claim 23, wherein the antibody is a monoclonal antibody to CEA.
Claim 33
Dependent Claim
11 words
The method of claim 23 wherein i is 3 or 4.
Claim 34
Dependent Claim
12 words
The method of claim 23, wherein R 1 is methyl or phenyl.
Claim 35
Dependent Claim
130 words
A coupling agent for joining a radionuclide metal ion with a biologically useful protein or polypeptide molecule comprising a compound of the formula: ##STR18## wherein R 1 represents a radical selected from the group consisting of alkyls having from 1 to 6 carbon atoms, aryls having from 6 to 8 carbon atoms and alkaryls having 7 to 9 carbon atoms, any of which can be substituted with one or more hydroxyl, alkoxy, carboxy or sulfonate groups; n is either 1 or 2; AA are independently α or β amino acids linked to each other by amide bonds; i is an integer of from 2 to 6; and X is a activating group capable of forming an amide bond with an ε-amino group of said biologically useful protein or polypeptide molecule.
Claim 36
Dependent Claim
130 words
A coupling agent for joining a radionuclide metal ion with a biologically useful protein or polypeptide molecule comprising a compound of the formula: ##STR18## wherein R 1 represents a radical selected from the group consisting of alkyls having from 1 to 6 carbon atoms, aryls having from 6 to 8 carbon atoms and alkaryls having 7 to 9 carbon atoms, any of which can be substituted with one or more hydroxyl, alkoxy, carboxy or sulfonate groups; n is either 1 or 2; AA are independently α or β amino acids linked to each other by amide bonds; i is an integer of from 2 to 6; and X is a activating group capable of forming an amide bond with an ε-amino group of said biologically useful protein or polypeptide molecule.
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USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1995-01-20 | 1995-07-22 | 1996-01-21 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1999-01-20 | 1999-07-22 | 2000-01-21 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2003-01-20 | 2003-07-22 | 2004-01-21 | $7700.00 | Window Closed / Lapsed |