Modified antibodies for enhanced hepatocyte clearance

In a method of treating a human patient having a tumor or infectious lesion, comprising parenterally, but non-systemically, injecting into said patient a therapeutically effective amount of an antibody or antibody fragment which specifically binds to a marker produced by or associated with said tumor or infectious lesion,

• the improvement wherein said antibody or antibody fragment is modified by being conjugated to, or having exposed thereon, a plurality of terminal glycoside residues which bind to the human hepatocyte asialoglycoprotein receptor.

In a method of treating a human patient having a tumor or infectious lesion, comprising injecting into said patient intravenously a therapeutically effective amount of an antibody or antibody fragment, conjugated to a radioisotope, toxin or drug, wherein said antibody or antibody fragment conjugate specifically binds to a marker produced by or associated with said tumor or infectious lesion,

• The improvement wherein said antibody or antibody fragment conjugate is modified by being further conjugated to, or having exposed thereon, a plurality of terminal glycoside residues which bind to the human hepatocyte asialoglycoprotein receptor;
• and wherein said method further comprises injecting into said patient intravenously, at, prior to or subsequent to the injection of said modified antibody or antibody fragment conjugate, an amount of a competitive inhibitor of binding to the hepatocyte asialoglycoprotein receptor sufficient to inhibit or significantly retard hepatocyte clearance of circulating modified conjugate, for a time sufficient to permit uptake of said modified conjugate by said tumor or infectious lesion, after which time said modified conjugate is cleared from the circulation.

In a method of imaging a human patient having a tumor or infectious lesion, comprising parenterally, but non-systemically, injecting into said patient a diagnostically effective amount of an antibody or antibody fragment, conjugated to a radioisotope or magnetic resonance image enhancing agent, wherein said antibody or antibody fragment conjugate specifically binds to a marker produced by or associated with said tumor or infectious lesion;

• and obtaining a scintigraphic or magnetic resonance image of said tumor or infectious lesion,
• the improvement wherein said antibody or antibody fragment conjugate is modified by being further conjugated to, or having exposed thereon, a plurality of terminal glycoside residues which bind to the human hepatocyte asialoglycoprotein receptor.

In a method of imaging a human patient having a tumor or infectious lesion, comprising injecting into said patient intravenously a diagnostically effective amount of an antibody or antibody fragment, conjugated to a radioisotope or magnetic resonance image enhancing agent, wherein said antibody or antibody fragment conjugate specifically binds to a marker produced by or associated with said tumor or infectious lesion;

• and obtaining a scintigraphic or magnetic resonance image of said tumor or infectious lesion,
• the improvement wherein said antibody or antibody fragment conjugate is modified by being further conjugated to, or having exposed thereon, a plurality of terminated glycoside residues which bind to the human hepatocyte asialoglycoprotein receptor;
• and wherein said method further comprises injecting into said patient intravenously, at, prior to or subsequent to the injection of said modified antibody or antibody fragment conjugate, an amount of a competitive inhibitor of binding to the hepatocyte asialoglycoprotein receptor sufficient to inhibit or significantly retard hepatocyte clearance of circulating modified conjugate, for a time sufficient to permit uptake of said modified conjugate by said tumor or infectious lesion, after which time said modified conjugate is cleared from the circulation.

A modified antibody conjugate, comprising an antibody or antibody fragment which specifically binds a marker which is produced by or associated with a tumor or infectious lesion, said antibody or antibody fragment being conjugated to a radioisotope, a magnetic resonance image enhancing agent, a toxin or a drug, said antibody or antibody fragment being further conjugated to, or having exposed thereon, a plurality of terminal glycoside residues which bind to the human hepatocyte asialoglycoprotein receptor.

A sterile, injectable preparation for human therapeutic use, comprising:

• (a) a therapeutically effective amount of a modified antibody or antibody fragment which specifically binds a marker which is produced by or associated with a tumor or infectious lesion, said antibody or antibody fragment being conjugated to, or having exposed thereon, a plurality of terminal glycoside residues which bind to the human hepatocyte asialoglycoprotein receptor;
• and (b) a pharmaceutically acceptable sterile injection vehicle.

A sterile, injectable preparation for imaging a tumor or infectious lesion in a human patient, comprising:

• (a) a diagnostically effective amount of a modified antibody or antibody fragment which specifically binds a marker which is produced by or associated with a tumor or infectious lesion, said antibody or antibody fragment being conjugated to a radioisotope or a magnetic resonance image enhancing agent, said antibody or antibody fragment being further conjugated to, or having exposed thereon, a plurality of terminal glycoside residues which bind to the human hepatocyte asialoglycoprotein receptor;
• and (b) a pharmaceutically acceptable sterile injection vehicle.

A kit for preparing a sterile, injectable preparation for human therapeutic use, comprising, in one or more suitable sterile containers:

• (a) a therapeutically effective amount of a modified antibody or antibody fragment which specifically binds a marker which is produced by or associated with a tumor or infectious lesion, said antibody or antibody fragment being conjugated to, or having exposed thereon, a plurality of terminal glycoside residues which bind to the human hepatocyte asialoglycoprotein receptor;
• and (b) a pharmaceutically acceptable sterile injection vehicle.

A kit for preparing a sterile, injectable preparation for imaging a tumor or infectious lesion in a human patient, comprising, in one or more suitable sterile containers:

• (a) a diagnostically effective amount of a modified antibody or antibody fragment which specifically binds a marker which is produced by or associated with a tumor or infectious lesion, said antibody or antibody fragment being conjugated to or adapted for conjugation to a radioisotope or magnetic resonance image enhancing agent, said antibody or antibody fragment being further conjugated to, or having exposed thereon, a plurality of terminal glycoside residues which bind to the human hepatocyte asialoglycoprotein receptor;
• and (b) a pharmaceutically acceptable sterile injection vehicle.