University of Pennsylvania

University of Virginia Patent Foundation

The Children's Hospital of Philadelphia

The University of Birmingham

Douglas B Cines

Abd Al-Roof Higazi

Mark I Greene

Zheng Cai

Zhiqiang Zhu

Vladimir R Muzykantov

Juan Carlos Murciano

Ronald P Taylor

Klaus T Preissner

Khalil Bdeir

Mortimer Poncz

Bi-Sen Ding

Triantafylios Chavakis

Sergei V Zaitsev

Triantafyllos Chavakis

Steve P Watson

Bruce Sachais

Provided herein are isolated antibodies or antibody fragments thereof that immunospecifically bind to platelet factor 4 (PF4). In some embodiments the isolated antibodies or antigen-binding fragments thereof comprise a light chain CDR and framework region comprising SEQ ID NO: 4 and a heavy chain CDR and framework region comprising SEQ ID NO: 10. Also provided herein are methods for treating heparin-induced thrombocytopenia (HIT) and methods for reducing the likelihood that subject will become afflicted with HIT. Further disclosed are uses of the isolated antibodies or antibody fragments in the treatment of HIT or the manufacture of compositions for the treatment of HIT.

Fully humanized anti-platelet factor 4 antibodies that treat heparin-induced thrombocytopenia

The present invention provides a mutant protein which has the same amino acid sequence of a wild type PF4 monomer except that (i) at least one amino acid of the wild type PF4 monomer has been deleted, (ii) at least one amino acid of the wild type PF4 monomer has been replaced by another amino acid, or (iii) a combination of such changes has been made. The present invention also provides methods of treating or reducing the likelihood of HIT, treating angiogenesis, treating abnormal cell growth, or affecting coagulation pathologies that lead to thrombus formation, by administering such mutant proteins to a patient.

Atomic description of immune complex that causes heparin-induced thrombocytopenia

The present invention provides a humanized antibody or antibody fragment comprising (a) a humanized light chain comprising 1) Complementarity Determining Region (CDR)-L1, the sequence of which is identical to the sequence of SEQ ID NO: 3; 2) CDR-L2, the sequence of which is identical to the sequence of SEQ ID NO: 4; and 3) CDR-L3, the sequence of which is identical to the sequence of SEQ ID NO: 5, and (b) a humanized heavy chain comprising 1) CDR-H1, the sequence of which is identical to the sequence of SEQ ID NO: 6; 2) CDR-H2, the sequence of which is identical to the sequence of SEQ ID NO: 7; and 3) CDR-H3, the sequence of which is identical to the sequence of SEQ ID NO: 8, as well as methods for treating, diagnosing, and monitoring the progression of HIT. The present invention also provides methods for assessing the antigenicity and ability to cause HIT of anionic anticoagulants. The present invention also provides a mutant protein which has the same amino acid sequence of a wild type PF4 monomer except that (i) at least one amino acid of the wild type PF4 monomer has been deleted, (ii) at least one amino acid of the wild type PF4 monomer has been replaced by another amino acid, or (iii) a combination of such changes has been made. The present invention also provides methods of treating or reducing the likelihood of HIT, treating angiogenesis, treating abnormal cell growth, or affecting coagulation pathologies that lead to thrombus formation, by administering such mutant proteins to a patient.

Fusion proteins comprising a single chain antigen-binding domain (scFv) of a monoclonal antibody, linked to an anti-thrombotic agent, anti-inflammatory agent, or a pro-drug thereof are provided, where the polypeptide binds to a binding site (antigen) expressed on the surface of a red blood cell at a density greater than 5,000 copies per red blood cell. Pharmaceutical compositions comprising these fusion proteins, and methods of delivering an anti-thrombotic agent to the surface of a red blood cell via delivery of these fusion proteins, and methods of treating or preventing thrombosis, tissue ischemia, acute myocardial infarction (AMI), ischemic stroke, cerebrovascular disease, pulmonary embolism, or ischemic peripheral vascular disease via administration of the fusion proteins or compositions comprising same are also provided.

Targeting recombinant therapeutics to circulating red blood cells

The present invention relates to the inhibition of angiogenesis by neutrophil alpha-defensins. Further, the present invention relates to methods involving the inhibition of endothelial cell adhesion to the extracellular matrix, endothelial cell apoptosis, and endothelial cell angiogenesis mediated by alpha-defensins.

Inhibition of angiogenesis by neutrophil alpha-defensins

Recombinant nucleic acid molecules are constructed with a first sequence encoding a transgene under the control of regulatory sequences that direct expression of the transgene product in a hematopoietic stem cell, or a progenitor cell therefrom or cell differentiated therefrom. In one embodiment, the cell which expresses the transgene is a secretory cell. The cell is a megakaryotic progenitor cell, or a cell further differentiated therefrom, such as a platelet. The cell is a granulocyte/macrophage progenitor cell or a cell further differentiated therefrom, such as a mast cell or neutrophils. Such host cells containing the molecule or the molecule itself are employed in methods for treating or preventing infection, inflammation or vascular injuries or any disorders involving or mediated by cells of the hematopoietic lineage.

Delivery vehicle for recombinant proteins

Compositions and methods for prevention and treatment of uncontrolled formation of intravascular fibrin clots are provided wherein fibrinolytic or anticoagulant drugs are biocompatibly coupled to red blood cell carriers.

Compositions and methods for prevention and treatment of uncontrolled formation of intravascular fibrin clots

The present invention relates to the inhibition of angiogenesis by neutrophil alpha-defensins. Further, the present invention relates to methods involving the inhibition of endothelial cell adhesion to the extracellular matrix, endothelial cell apoptosis, and endothelial cell angiogenesis.mediated by alpha-defensins.

Inhibition of adhesion and migration of an endothelial cell to fibronectin by neutrophil alpha-defensins

The present invention relates to compositions and methods comprising one or more domains of urokinase-type plasminogen activator (uPA) in an amount effective to modulate one or more of the contractility and angiogenic activity of a mammalian muscle or endothelial cell or tissue for use in the treatment of a disease or condition having as a symptom thereof one or more of abnormal muscle cell or tissue contractility and abnormal angiogenic activity. The one or more domains of uPA can be present in the inventive compositions and methods either as part of the full uPA molecule in either single chain or two chain form (scuPA or tcuPA), or as an isolated polypeptide, or a fragment of the uPA molecule (e.g., the amino terminal fragment 'ATF'), or a deletion mutant of the uPA molecule. The inventive methods comprise administering to a mammal afflicted with such a disease or condition the inventive composition, and modulating one or more of the contractility and the angiogenic activity of the muscle or endothelial cell or tissue, thereby treating the disease or condition. Kits for treating such diseases are also included.

Compositions and methods for modulating muscle cell and tissue contractility

The invention includes compositions and methods for promoting internalization and degradation of urokinase-type plasminogen activator.

Compositions and methods for promoting internalization and degradation of urokinase-type plasminogen activator

Compositions and methods for prevention and treatment of uncontrolled formation of intravascular fibrin clots, which are capable of selective dissolution of pathological nascent clots formed intravascularly, with minimal risk of unwanted dissolution of pre-existing hemostatic clots, are provided wherein fibrinolytic or anticoagulant drugs are biocompatibly coupled to red blood cell carriers.

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Wynnewood, PA, United States of America

Douglas B Cines