US4569789A
Expired / Lapsed
US
⏱️ 0.0 years remaining
Acid-cleavable compound, use in protein conjugates and drug delivery systems
Assignee: Dana Farber Cancer Institute Inc
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Filing: 1985-04-26
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Granted: 1986-02-11
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Expires: 2005-04-26
Abstract
Abstract Amino-sulfhydryl cross-linking reagents that are cleavable under mildly acidic conditions are disclosed. Also disclosed are methods of making the cross-linkers, as well as methods of using the cross-linkers, e.g., to deliver a biologically active substance across the membranes of selected cells in a heterogeneous cell population; once inside the cell the active substance is released, intact, by the transient, mild acidity of certain cell structures. Finally, a method of characterizing complex multi-chain protein structures is disclosed.
Inventors
- 👤 Walter A. Blattler
- 👤 John M. Lambert
- 👤 Peter D. Senter
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 08:54
CPC Classifications
C; C07; C07D; C07D207/00; C07D207/02; C07D207/44; C07D207/444; C07D207/448; C07D207/452; A; A61; A61P; A61P35/00; C07D405/00; C07D405/02; C07D405/12
Claims Analysis
Total Claims: 19
Claim 1
Independent Claim
137 words
An acid-cleavable complex for controlled release of an amino-group-containing substance to a liquid medium, said complex comprising said amino-group-containing substance, a sulfide-linked protein, and an acid cleavable linker between the sulfide-linked protein and the amino-group-containing substance, said complex comprising one of the two following units: ##STR6## where: one of X and Y is O - ; the other of X and Y is the residue of the amino-group-containing substance whose amino nitrogen forms an amide link with a carbonyl group of the maleic acid function; Z is the sulfide-linked protein, including the sulfur of that link; R 1 and R 2 are independently selected from H and alkyl group of C 5 or less; and A is a bridge unit; and ##STR7## where X, Y, Z, R 2 , and A are as defined above, and s=2-5.
Claim 2
Dependent Claim
137 words
An acid-cleavable complex for controlled release of an amino-group-containing substance to a liquid medium, said complex comprising said amino-group-containing substance, a sulfide-linked protein, and an acid cleavable linker between the sulfide-linked protein and the amino-group-containing substance, said complex comprising one of the two following units: ##STR6## where: one of X and Y is O - ; the other of X and Y is the residue of the amino-group-containing substance whose amino nitrogen forms an amide link with a carbonyl group of the maleic acid function; Z is the sulfide-linked protein, including the sulfur of that link; R 1 and R 2 are independently selected from H and alkyl group of C 5 or less; and A is a bridge unit; and ##STR7## where X, Y, Z, R 2 , and A are as defined above, and s=2-5.
Claim 3
Dependent Claim
51 words
The complex of claim 1 wherein A comprises the unit ##STR8## where R 3 , R 4 , R 5 , and R 6 are independently selected from H, halogens, alkoxy and alkyl groups of C 5 or less, and tertiary amines; and B is a linker to the maleimido function.
Claim 4
Dependent Claim
59 words
The complex of claim 2 wherein R 3 , R 4 , R 5 , R 6 , and B are selected so that the sulfur attached to the aromatic ring of A has pK a low enough in the corresponding thiophenol such that during formation of the sulfide group in A, competing reactions of OH - are avoided.
Claim 5
Dependent Claim
11 words
The complex of claim 1 wherein the protein comprises an antibody.
Claim 6
Dependent Claim
149 words
An acid-cleavable complex for controlled release of a biologically active amino-group-containing substance to a liquid medium, said complex comprising said amino-group-containing substance, a sulfide-linked substance comprising a cell binding partner for a cell surface receptor, and an acid cleavable linker between the sulfide-linked substance and the amino-group-containing substance, said complex comprising one of the two following units: ##STR9## where: one of X and Y is O - ; the other of X and Y is the residue of the amino-group-containing substance whose amino nitrogen forms an amide link with a carbonyl group of the maleic acid function; Z is the sulfide-linked substance, including the sulfur of that link; R 1 and R 2 are independently selected from H and alkyl groups of C 5 or less; and A is a bridge unit; and ##STR10## where X, Y, Z, R 2 , and A are as defined above, and s=2-5.
Claim 7
Dependent Claim
149 words
An acid-cleavable complex for controlled release of a biologically active amino-group-containing substance to a liquid medium, said complex comprising said amino-group-containing substance, a sulfide-linked substance comprising a cell binding partner for a cell surface receptor, and an acid cleavable linker between the sulfide-linked substance and the amino-group-containing substance, said complex comprising one of the two following units: ##STR9## where: one of X and Y is O - ; the other of X and Y is the residue of the amino-group-containing substance whose amino nitrogen forms an amide link with a carbonyl group of the maleic acid function; Z is the sulfide-linked substance, including the sulfur of that link; R 1 and R 2 are independently selected from H and alkyl groups of C 5 or less; and A is a bridge unit; and ##STR10## where X, Y, Z, R 2 , and A are as defined above, and s=2-5.
Claim 8
Dependent Claim
51 words
The complex of claim 5 wherein A comprises the unit ##STR11## where R 3 , R 4 , R 5 , and R 6 are independently selected from H, halogens, alkoxy and alkyl groups of C 5 or less, and tertiary amines; and B is a linker to the maleimido function.
Claim 9
Dependent Claim
60 words
The complex of claim 6 wherein R 3 , R 4 , R 5 , R 6 , and B are selected so that the sulfur attached to the aromatic ring of A has a pK a low enough in the corresponding thiophenol such that during formation of the sulfide group in A, competing reactions of OH - are avoided.
Claim 10
Dependent Claim
65 words
The complex of claim 5 wherein said cell-surface receptor is an antigen and said binding partner is an antibody to that antigen which is transported across cell membranes containing said receptor, whereby the complex is capable of binding to the receptor and of being transported across the membrane, and the biologically active substance is released when the pH of the local intracellular environment is decreased.
Claim 11
Dependent Claim
13 words
The complex of claim 5 wherein said biologically active substance is a peptide.
Claim 12
Dependent Claim
12 words
The complex of claim 5 wherein said biologically active substance is cytotoxic.
Claim 13
Dependent Claim
14 words
The complex of claim 10 wherein said cytotoxic substance is a protein synthesis inhibitor.
Claim 14
Dependent Claim
13 words
The complex of claim 11 wherein said cytotoxin comprises a ribosomal inactivating protein.
Claim 15
Dependent Claim
22 words
The complex of claim 12 wherein said cytotoxin comprises a pokeweed antiviral protein, gelonin, the ricin A-chain, abrin A-chain, or modeccin A-chain.
Claim 16
Dependent Claim
18 words
The complex of claim 5 wherein said cell binding partner is an antibody to a T-cell surface antigen.
Claim 17
Dependent Claim
16 words
The complex of claim 14 wherein said T-cell surface antigen is T3, T4, T11, or T12.
Claim 18
Dependent Claim
18 words
The complex of claim 5 wherein said cell binding partner is an antibody to a tumor-associated surface antigen.
Claim 19
Dependent Claim
13 words
The complex of claim 5 wherein said cell binding partner is J5 antibody.
References Cited (Backward Citations)
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1989-02-10 | 1989-08-12 | 1990-02-11 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1993-02-10 | 1993-08-12 | 1994-02-11 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1997-02-10 | 1997-08-12 | 1998-02-11 | $7700.00 | Window Closed / Lapsed |