US5171563A
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Cleavable linkers for the reduction of non-target organ retention of immunoconjugates
Assignee: Poniard Pharmaceuticals Inc
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Filing: 1992-02-10
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Granted: 1992-12-15
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Expires: 2012-02-10
Abstract
Abstract A process for reducing the non-target organ accumulation of immunoconjugates administered in vivo during therapeutic or diagnostic procedures involves the use of immunoconjugates comprising linkers that are cleavable at the non-target organs. The linkers are cleavable under conditions present, or induced, at one or more non-target organs, which include the kidneys or the liver.
Inventors
- 👤 Paul G. Abrams
- 👤 John M. Reno
- 👤 Alan R. Fritzberg
- 👤 Ananthachari Srinivasan
- 👤 David C. Anderson
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 00:42
CPC Classifications
A; A61; A61K; A61K51/00; A61K51/02; A61K51/04; A61K51/08; A61K51/10; A61K51/1093; A61K47/00; A61K47/50; A61K47/51; A61K47/62; A61K47/65; A61K51/088; A61K2121/00; A61K2123/00; Y; Y10; Y10S; Y10S530/00; Y10S530/807
Claims Analysis
Total Claims: 35
Claim 1
Independent Claim
56 words
A method for reducing non-target site accumulation of an effector moiety, comprising administering to a human or mammalian host a conjugate comprising an effector moiety attached to a targeting protein through a linker and administering to the host a cleaving agent that effects cleavage of the linker at one or more non-target sites within the host.
Claim 2
Independent Claim
56 words
A method for reducing non-target site accumulation of an effector moiety, comprising administering to a human or mammalian host a conjugate comprising an effector moiety attached to a targeting protein through a linker and administering to the host a cleaving agent that effects cleavage of the linker at one or more non-target sites within the host.
Claim 3
Dependent Claim
12 words
The method of claim 1 wherein the non-target sites are the kidneys.
Claim 4
Dependent Claim
33 words
The method of claim 2 wherein the cleaving agent is a compound that lowers the pH of the host's urine to an acidic pH, and the linker is cleaved at the acidic pH.
Claim 5
Dependent Claim
23 words
The method of claim 3 wherein the linker comprises an ester group that is cleaved by esterases in the kidney at acidic pH.
Claim 6
Dependent Claim
12 words
The method of claim 3 wherein the cleaving agent is ammonium chloride.
Claim 7
Dependent Claim
15 words
The method of claim 5 wherein methenamine mandelate additionally is administered as a cleaving agent.
Claim 8
Dependent Claim
24 words
The method of claim 2 wherein the cleaving agent is a compound that raises the pH of the host's urine to a basic pH.
Claim 9
Dependent Claim
21 words
The method of claim 7 wherein the cleaving agent is selected from the group consisting of ascorbate salts and bicarbonate salts.
Claim 10
Dependent Claim
15 words
The method of claim 7 or 8 wherein the linker comprises at least one ester.
Claim 11
Dependent Claim
69 words
The method of claim 9 wherein the linker comprises the following chemical structure: ##STR22## wherein q is 0 to about 5, m is from 1 to 6, n is from 2 to about 5, p is from 1 to about 4, and each R' is independently selected from hydrogen and a lower alkyl group, wherein at least one R' is a lower alkyl group of from 1-6 carbon atoms.
Claim 12
Dependent Claim
35 words
The method of claim 9 wherein the linker comprises the following chemical structure: ##STR23## wherein m is 0 or 1, q is from 1 to about 3, and n is from 2 to about 5.
Claim 13
Dependent Claim
15 words
The method of claim 7 or 8 wherein the linker comprises a hindered disulfide bond.
Claim 14
Dependent Claim
63 words
The method of claim 12 wherein the linker comprises the following chemical structure: --(CH.sub.2).sub.n --R.sub.1 --S--S--(CH.sub.2).sub.n -- wherein each n represents an integer from 1 to about 4; and R 1 represents either a phenyl ring or ##STR24## wherein R 2 is a methyl group or phenyl ring, R 3 is a phenyl ring, and m represents an integer from 0 to 1.
Claim 15
Dependent Claim
23 words
The method of claim 2 wherein the cleaving agent is an enzyme that accumulates in the host's kidneys after administration to the host.
Claim 16
Dependent Claim
21 words
The method of claim 14 wherein the linker is an oligopeptide and the enzyme is a protease that cleaves said oligopeptide.
Claim 17
Dependent Claim
50 words
The method of claim 15 wherein the oligopeptide comprises a histidine residue without two proline residues on the carboxyl-terminal side of the histidine, immediately adjacent to the histidine, and the protease is a serine protease derived from subtilisin by replacing or deleting the histidine residue at position 64 in subtilisin.
Claim 18
Dependent Claim
37 words
The method of claim 1 wherein the cleaving agent is a reducing agent, the non-target site is the liver and/or the kidneys, and said reducing agent accumulates in at least one of the non-target sites after administration.
Claim 19
Dependent Claim
23 words
The method of claim 17 wherein the reducing agent is selected from the group consisting of glutathione, cysteine, N-acetyl cysteine, and derivatives thereof.
Claim 20
Dependent Claim
15 words
The method of claim 17 or 18 wherein the linker comprises a hindered disulfide bond.
Claim 21
Dependent Claim
63 words
The method of claim 19 wherein the linker comprises the following chemical structure: --(CH.sub.2).sub.n --R.sub.1 --S--S--(CH.sub.2).sub.n -- wherein each n represents an integer from 1 to about 4: and R 1 represents either a phenyl ring or ##STR25## wherein R 2 is a methyl group or phenyl ring, R 3 is a phenyl ring, and m represents an integer from 0 to 1.
Claim 22
Dependent Claim
13 words
The method of claim 1 wherein the effector moiety comprises a diagnostic agent.
Claim 23
Dependent Claim
27 words
The method of claim 21 wherein the diagnostic agent is selected from the group consisting of diagnostic radionuclides, nuclear magnetic resonance contrast agents, and X-ray contrast agents.
Claim 24
Dependent Claim
35 words
The method of claim 22 wherein the diagnostic radionuclide is selected from the group consisting of 99m Tc, 111 In, 113 In, 123 I, 76 Br, 18 F, 97 Ru, 203 Pb, and 64 Cu.
Claim 25
Dependent Claim
13 words
The method of claim 1 wherein the effector moiety comprises a therapeutic agent.
Claim 26
Dependent Claim
16 words
The method of claim 24 wherein the therapeutic agent is a therapeutic radionuclide or a drug.
Claim 27
Dependent Claim
41 words
The method of claim 25 wherein the therapeutic radionuclide is selected from the group consisting of 186 Re, 188 Re, 212 Bi, 109 Pd, 67 Cu, 131 I, 211 At, 77 Br, 105 Rh, .sup. 198Au, 199 Au and 212 Pb.
Claim 28
Dependent Claim
22 words
The method of claim 22, 23, 25 or 26 wherein the radionuclide is a radionuclide metal in the form of a chelate.
Claim 29
Dependent Claim
36 words
The method of claim 27 wherein the radionuclide metal is selected from 99m Tc , 186 Re, and 188 Re and the chelate comprises a total of four donor atoms selected from nitrogen and sulfur atoms.
Claim 30
Dependent Claim
24 words
The method of claim 22, 23, 25 or 26 wherein the radionuclide is a radiohalogen attached by a single bond to a binding molecule.
Claim 31
Dependent Claim
25 words
The method of claim 1 wherein the targeting protein is selected from the group consisting of antibodies, hormones, enzymes, biologic response modifiers, and fragments thereof.
Claim 32
Dependent Claim
17 words
The method of claim 30 wherein the targeting protein is a monoclonal antibody or a fragment thereof.
Claim 33
Dependent Claim
16 words
The method of claim 31 wherein the monoclonal antibody or fragment thereof binds to cancer cells.
Claim 34
Dependent Claim
54 words
The method of claim 7 or 8 wherein the effector moiety is a radionuclide metal and the linker comprises a compound that binds the radionuclide metal to form a chelate, wherein the bonds between the radionuclide metal and donor atoms in the chelate are rendered more susceptible to oxidative cleavage at a basic pH.
Claim 35
Dependent Claim
48 words
The method of claim 33 wherein the conjugate is of the formula: ##STR26## wherein M is a radionuclide of rhenium, P is a targeting protein, n is an integer of from about 2 to 4, and each X group independently is chosen from ═0 and H 2 .
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| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
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| 3.5 Years (Year 4) | 1995-12-15 | 1996-06-15 | 1996-12-15 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1999-12-15 | 2000-06-15 | 2000-12-15 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2003-12-15 | 2004-06-15 | 2004-12-15 | $7700.00 | Window Closed / Lapsed |