US5322678A
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Alteration of pharmacokinetics of proteins by charge modification
Assignee: Poniard Pharmaceuticals Inc
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Filing: 1988-02-17
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Granted: 1994-06-21
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Expires: 2008-02-17
Abstract
Abstract There is disclosed charge-modified conjugates comprising a targeting protein bound to a therapeutic or diagnostic agent. Charge-modifying a conjugate to cause an acidic shift in the isoelectric point results in prolonged serum half-life upon in vivo administration and is useful to accumulate a therapeutic agent at the target site. Conversely, charge-modification to cause a basic shift in the isoelectric point of the conjugate reduces serum half-life upon in vivo use for diagnostic imaging purposes and results in higher target-to-background ratios.
Inventors
- 👤 Alton C. Morgan, Jr.
- 👤 Gowsala P. Sivam
- 👤 Paul G. Abrams
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-29 04:25
CPC Classifications
B; B82; B82Y; B82Y5/00; A; A61; A61K; A61K47/00; A61K47/50; A61K47/51; A61K47/68; A61K47/6801; A61K47/6803; A61K47/6811; A61K47/6817; A61K47/6829; A61K47/6891; A61K47/6893; A61K51/00; A61K51/02; A61K51/04; A61K51/08; A61K51/10; A61K51/1093; A61P; A61P35/00; A61P43/00; A61K2123/00
Claims Analysis
Total Claims: 14
Claim 1
Independent Claim
125 words
A conjugate for therapeutic administration, comprising a therapeutic radionuclide chelated within a ligand attached to a charge-modified monoclonal antibody or monoclonal antibody fragment, wherein the monoclonal antibody or monoclonal antibody fragment is charge-modified by reaction of positively-charged amino acid(s) on said monoclonal antibody or monoclonal antibody fragment with an anion-forming reagent, thereby producing negatively-charged derivatives of said amino acid(s); wherein the monoclonal antibody or monoclonal antibody fragment is reacted with an amount of said anion-forming reagent sufficient to effect an acidic shift of at least 1/10 of a pH unit in the isoelectric point of the monoclonal antibody or monoclonal antibody fragment; and the conjugate has a serum half-life that is increased by at least about 10% compared to that of a corresponding non-charge-modified conjugate.
Claim 2
Dependent Claim
125 words
A conjugate for therapeutic administration, comprising a therapeutic radionuclide chelated within a ligand attached to a charge-modified monoclonal antibody or monoclonal antibody fragment, wherein the monoclonal antibody or monoclonal antibody fragment is charge-modified by reaction of positively-charged amino acid(s) on said monoclonal antibody or monoclonal antibody fragment with an anion-forming reagent, thereby producing negatively-charged derivatives of said amino acid(s); wherein the monoclonal antibody or monoclonal antibody fragment is reacted with an amount of said anion-forming reagent sufficient to effect an acidic shift of at least 1/10 of a pH unit in the isoelectric point of the monoclonal antibody or monoclonal antibody fragment; and the conjugate has a serum half-life that is increased by at least about 10% compared to that of a corresponding non-charge-modified conjugate.
Claim 3
Dependent Claim
38 words
The conjugate of claim 1, wherein the monoclonal antibody or monoclonal antibody fragment is charge-modified by reaction with a reagent selected from the group consisting of succinic anhydride, phthalic anhydride, maleic anhydride, alpha halo acids, bromoacetate, and iodoacetate.
Claim 4
Dependent Claim
29 words
The conjugate of claim 2, wherein the reagent is succinic anhydride offered in a reagent to antibody molar ratio within the range of from about 1:1 to abut 25:1.
Claim 5
Dependent Claim
45 words
The conjugate of claim 1 wherein the monoclonal antibody or monoclonal antibody fragment is reacted with an amount of said anion-forming reagent sufficient to effect an acidic shift of about one pH unit in the isoelectric point of the monoclonal antibody or monoclonal antibody fragment.
Claim 6
Dependent Claim
11 words
The conjugate of claim 1 wherein the reagent is succinic anhydride.
Claim 7
Dependent Claim
101 words
A conjugate for therapeutic administration, comprising a therapeutic radionuclide chelated within a ligand attached to a charge-modified monoclonal antibody or monoclonal antibody fragment, wherein the conjugate has a serum half-life that is increased by at least about 10% compared to that of a corresponding non-charge-modified conjugate; wherein the monoclonal antibody or monoclonal antibody fragment is charge-modified by reaction with a reagent selected from the group consisting of succinic anhydride, phthalic anhydride, maleic anhydride, alpha halo acids, bromoacetate, and iodoacetate; and the reagent is offered in a reagent to antibody molar ratio within the range of from about 1:1 to about 25:1.
Claim 8
Dependent Claim
101 words
A conjugate for therapeutic administration, comprising a therapeutic radionuclide chelated within a ligand attached to a charge-modified monoclonal antibody or monoclonal antibody fragment, wherein the conjugate has a serum half-life that is increased by at least about 10% compared to that of a corresponding non-charge-modified conjugate; wherein the monoclonal antibody or monoclonal antibody fragment is charge-modified by reaction with a reagent selected from the group consisting of succinic anhydride, phthalic anhydride, maleic anhydride, alpha halo acids, bromoacetate, and iodoacetate; and the reagent is offered in a reagent to antibody molar ratio within the range of from about 1:1 to about 25:1.
Claim 9
Dependent Claim
11 words
The conjugate of claim 6 wherein the reagent is succinic anhydride.
Claim 10
Dependent Claim
126 words
A conjugate for therapeutic administration, comprising: a therapeutic moiety attached to a charge-modified antibody or antibody fragment; wherein the antibody or antibody fragment is charge-modified by reaction of positively-charged amino acid(s) on said antibody or antibody fragment with an anion-forming reagent, thereby producing negatively-charged derivatives of said amino acid(s); wherein the antibody or antibody fragment is reacted with an amount of said anion-forming reagent sufficient to: a) effect on acidic shift of at least 1/10 of a pH unit in the isoelectric point of the antibody or antibody fragment; and to b) increase the serum half-life of the antibody or antibody fragment such that the conjugate has a serum half-life that is increased by at least about 10% compared to that of a corresponding non-charge-modified conjugate.
Claim 11
Dependent Claim
126 words
A conjugate for therapeutic administration, comprising: a therapeutic moiety attached to a charge-modified antibody or antibody fragment; wherein the antibody or antibody fragment is charge-modified by reaction of positively-charged amino acid(s) on said antibody or antibody fragment with an anion-forming reagent, thereby producing negatively-charged derivatives of said amino acid(s); wherein the antibody or antibody fragment is reacted with an amount of said anion-forming reagent sufficient to: a) effect on acidic shift of at least 1/10 of a pH unit in the isoelectric point of the antibody or antibody fragment; and to b) increase the serum half-life of the antibody or antibody fragment such that the conjugate has a serum half-life that is increased by at least about 10% compared to that of a corresponding non-charge-modified conjugate.
Claim 12
Dependent Claim
12 words
The conjugate of claim 8, wherein the therapeutic moiety is a radionuclide.
Claim 13
Dependent Claim
27 words
The conjugate of claim 8 wherein the charge modification effects a shift of about 1 pH unit in the isoelectric point of the antibody or antibody fragment.
Claim 14
Dependent Claim
15 words
A conjugate of claim 2 or 6 wherein the reagent is a cyclic acid anhydride.
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| 3.5 Years (Year 4) | 1997-06-20 | 1997-12-20 | 1998-06-21 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2001-06-20 | 2001-12-20 | 2002-06-21 | $3760.00 | Window Closed / Lapsed |
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