Alteration of pharmacokinetics of proteins by charge modification
AssigneeNeoRx Corporation
InventorsAlton C. Morgan, Jr., Gowsala P. Sivam, Paul G. Abrams
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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.
Claims11
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.
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.
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.
Dependencies are inferred from the claim text.