Mallinckrodt, Inc.

Centocor, Inc.

Mallinckrodt Medical, Inc.

Centocor Cardiovascular Imaging Partners, L.p.

Richard T Dean

Robert W Weber

Raymond H Boutin

Robert A Nicolotti

Koon Y Pak

John Lister-James

Dennis W Wester

Jeffrey A Mattis

David H White

Dennis L Nosco

Youlin Lin

Steven R Woulfe

T Jeffrey Dunn

George Brooke Hoey

Dennis Wester

Scott Buttram

Fredrick W Miller

Methods and compositions for enhancing magnetic resonance imaging

A one vial method for labeling a sulfhydryl containing antibody or antibody fragment with technetium-99m is disclosed. The method comprises contacting an antibody mixture comprised of a sulfhydryl containing antibody or antibody fragment and a reducing agent with technetium-99m in an oxidized state. In a preferred embodiment, the antibody mixture further contains a water soluble ligand. A one vial kit for labeling a sulfhydryl containing antibody or antibody fragment with technetium-99m is also disclosed.

One vial method for labeling antibodies with Technetium-99m

Substantially nontoxic manganese or gadolinium complexes of compounds of the formula: ##STR1## wherein n and m=1, 2, 3 or 4, y=1, 2 or 3, and x is selected from the group consisting of S, CHOH and CHSH, are useful for enhancing magnetic resonance images of body organs and tissues. Illustrative manganese and gadolinium complexes of such compounds include disodium [[(2-hydroxytrimethylene)dinitrilo]tetraaceto]manganese(II) and sodium [[(2-hydroxytrimethylene)dinitrilo]tetraaceto)gadolinium(III).

Compositions for enhancing magnetic resonance imaging

A bifunctional coupling agent for joining a sulfhydryl-containing protein or peptide and a metallic radionuclide comprising a sulfhydryl selective electrophile, a chelator containing at least one protected thiol and a organic linking radical which serves to join said electrophile and said chelator is disclosed. A radiodiagnostic precursor comprising an antibody or antibody fragment and the specified bifunctional coupling agent bound to a sulfhydryl group on the antibody or antibody fragment is also disclosed.

Bifunctional coupling agents and radionuclide labeled compositions

The present invention provides cross-linked protein compositions consisting of two or more units of a target-specific protein joined by binding sulfhydryl groups on the target-specific protein units to a sulfhydryl-selective cross-linking agent and a method of making the compositions. These cross-linked protein compositions combine an increase in binding affinity due to the presence of multiple identical binding sites and stability to reduction conditions.

Cross-linking protein compositions having two or more identical binding

A one vial method for labeling a protein, such as an antibody or antibody fragment, with a radiometal such as Tc-99m or a rhenium isotope, is disclosed. The method comprises contacting in a single vial a mixture comprised of a reducing agent and a protein molecule covalently bound to a sulfhydryl containing bifunctional coupling agent with Tc or Re in an oxidized state. A one vial kit for labeling a protein with Tc or Re is also disclosed.

One vial method for labeling protein/linker conjugates with

Methods for rapidly labeling sulfhydryl-containing antibodies or fragments with technetium or rhenium radioisotopes are disclosed. The method generally involves combining an aqueous mixture of the radiometal in an oxidized form, a reducing agent and a water-soluble polyhydroxycarbonylic acid ligand to form a stable complex of the radiometal in its reduced state and contacting the mixture with the sulfhydryl-containing antibody or fragment to produce a radiometal-labeled antibody or fragment.

Method for labeling antibodies with a metal ion

Protein conjugates comprising a protein covalently linked to at least one positively charged agent, so that the protein conjugate has an overall net positive charge in aqueous conditions at physiological pH are disclosed. The positively charged agents comprise polymers of three or more subunits selected from the group consisting of amino acids containing positively charged side chains and alkylamines. These protein conjugates have decreased blood clearance rates compared to conjugates which do not have the positively charged agents. The protein conjugates may further comprise diagnostic or therapeutic radionuclides bound to the protein or the positively charged agent through bifunctional coupling agents.

Proteins modified with positively charged carriers and compositions

A bifunctional coupling agent for joining a sulfhydryl containing protein or peptide and a metallic radionuclide comprising a sulfhydryl selective electrophile, a chelator containing at least one protected thiol and a organic linking radical containing at least one cleavable site which serves to join said electrophile and said chelator is disclosed. A radiodiagnostic or radiotherapeutic precursor comprising an antibody or antibody fragment and the specified bifunctional coupling agent bound to a sulfhydryl group on the antibody or antibody fragment and a radiodiagnostic or radiotherapeutic agent comprising such precursor having a metallic radionuclide bound thereto are also disclosed.

Cleavable bifunctional coupling agents

This invention relates to bifunctional coupling agents useful in forming conjugates with biologically useful molecules, such as antibodies. These conjugates can be complexed with radionuclide metal ions to provide materials useful for in vivo diagnostic and therapeutic applications.

Coupling agents for joining radionuclide metal ions with biologically

Complexes useful as radiopharmaceutical imaging agents comprise technetium bonded to a ligand which generally can be described by the formula: ##STR1## wherein Z is N, C, B or P;

Novel TC-99M complexes

A bifunctional chelating agent for joining an antibody or antibody fragment and a metallic radionuclide is disclosed. The agent consists of a derivative of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid or a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, an organic linking radical which optionally contains a cleavable group, and a function capable of reacting with a site on a protein. Radiodiagnostic or radiotherapeutic precursors comprising an antibody or antibody fragment and the above-described bifunctional chelating agent and radiodiagnostic or radiotherapeutic agent comprising a metallic radionuclide and the above mentioned precursor are also disclosed.

Chelating agents

A simple, rapid and efficient method for labelling sulfhydryl-containing antibodies or antibody fragments with Tc-99m, Rh-186, Rh-188, Rh-189 or Rh-191 is disclosed. Labeled antibodies produced by the method are useful for radio-immunodiagnostic and/or radio-therapeutic purposes.

Substantially nontoxic manganese or gadolinium complexes of compounds of the formula: ##STR1## wherein n and m=1, 2, 3 or 4, y=1, 2 or 3, and x is selected from the group consisting of O, S, CHOH and CHSH, are useful for enhancing magnetic resonance images of body organs and tissues. Illustrative manganese and gadolinium complexes of such compounds include disodium [[ethylenebis(oxyethylenenitrilo)]tetraaceto]-manganese(II), disodium [[(2-hydroxytrimethylene)dinitrilo]-tetraaceto]manganese(II), sodium [[(2-hyroxytrimethylene)dinitrilo]tetraaceto)gadolinium(III).

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Downingtown, PA, United States of America

Richard T Dean