Emory University

The General Hospital Corporation

Harvard College

Marschall S Runge

John S Lollar

Edgar Haber

Thomas Quertermous

Christoph Bode

A hybrid procoagulant factor VIII is produced by isolation and recombination of human and other nonhuman mammalian factor VIII subunits or domains, or by genetic engineering of the human and animal factor VIII genes. Subunits or domains of factor VIII that have been purified from human or animal plasma are isolated, and hybrid human/animal factor VIII is produced by (1) mixing either animal heavy chain subunits with human light chain subunits or by mixing human heavy chain subunits with animal light chain subunits, thereby producing human light chain/animal heavy chain and human heavy chain/animal light chain hybrid molecules; or by (2) mixing one or more domains of one species with one or more domains of the other species. These hybrid molecules are isolated by ion exchange chromatography. Alternatively, recombinant DNA methods are used to change elements of animal factor VIII or human factor VIII to the corresponding elements of human factor VIII or animal factor VIII, respectively, to produce hybrid human/animal factor VIII. A recombinant hybrid equivalent factor VIII molecule is produced by substituting amino acid sequence having no known factor VIII sequence identity for specific amino acid sequence in the human or animal factor VIII. The hybrid factor VIII and hybrid equivalent factor VIII molecules are administered to patients having factor VIII deficiency.

Hybrid human/animal factor VIII

Hybrid immunoglobulin-enzyme molecules are provided which are composed of antibodies, or derivatives or fragments thereof, which specifically bind an arterial or venous thrombus that are operably linked to the enzymatically active portions of thrombolytic enzymes such as plasminogen activators. In a preferred embodiment the hybrid molecules specifically bind to fibrin and have fibrinolytic activity. The hybrid molecules of the present invention may be produced by any means, including chemical conjugation, or by means of recombinant DNA, genetic engineering and/or hybridoma technology. Methods for making and using the molecules in diagnosis and therapy are also disclosed.

Hybrid immunoglobulin-thrombolytic enzyme molecules which specifically

Provided is a hybrid Factor VIII having a sequence of amino acids selected from the group of A2 domain fragments 373-540, 373-508, 445-508, 484-508, 404-508, 489-508 and 484-489 according to Seq ID NO 2 substituted with corresponding sequence of porcine or murine Factor VIII. Invention also relates to methods of treatment Factor VIII deficiency with said hybrid Factor VIII.

A hybrid human/animal coagulation factor VIII is produced by isolation and recombination of human and other non-human mammalian factor VIII subunits or domains, or by genetic engineering of the human and animal factor VIII genes. Subunits or domains of factor VIII that have been purified from human or animal plasma are isolated, and hybrid human/animal factor VIII is produced by (1) mixing either animal heavy chain subunits with human light chain subunits or by mixing human heavy chain subunits with animal light chain subunits, thereby producing human light chain/animal heavy chain and human heavy chain/animal light chain hybrid molecules; or by (2) mixing one or more domains of one species with one or more domains of the other species. These hybrid molecules are isolated by ion exchange chromatography. Alternatively, recombinant DNA methods are used to change elements of animal factor VIII or human factor VIII to the corresponding elements of human factor VIII or animal factor VIII, respectively, to produce hybrid human/animal factor VIII.

A hybrid human/porcine coagulation factor VIII is produced by isolation and recombination of human and porcine factor VIII subunits, or by genetic engineering of the human and porcine factor VIII genes. Subunits of factor VIII that have been purified from human or porcine plasma are isolated, and hybrid human/porcine factor VIII is produced by mixing either porcine heavy chain subunits with human light chain subunits or by mixing human heavy chain subunits with porcine light chain subunits, thereby producing human light chain/porcine heavy chain and human heavy chain/porcine light chain hybrid molecules. These hybrid molecules are isolated by ion exchange chromatography. Alternatively, recombinant DNA methods are used to swap elements of porcine factor VIII for the corresponding elements of human factor VIII to produce hybrid human/porcine factor VIII.

Hybrid human/porcine factor VIII

A chimeric molecule that contains a fibrin-binding portion of an antibody covalently linked to an inhibitor of thrombin, which molecule is administered to inhibit thrombus formation and growth.

Growing community of inventors

Atlanta, GA, United States of America

Marschall S Runge