The Scripps Research Institute

Theravance, Inc.

Advanced Medicine, Inc.

Other

University of California

Pharmix Corporation

Scripps Clinic and Research Foundation

University of Rochester

Socratech L.l.c.

University of Southern California

Oregon Health & Science University

Zz Biotech LLC

Mosnier, Laurent O.

Griffin, John H.

John H Griffin

Edmund J Moran

Thomas E Jenkins

Yu-Hua Ji

Jonathan W Wray

Roger Briesewitz

Laurent Mosnier

Andrew Gale

Seok-Ki Choi

Daniel Marquess

Samuel I Rapaport

Dzung T Le

J Kevin Judice

Jessen Yu

Guido Lanza

Andras Gruber

Rolf M Mesters

Maya Natarajan

Mathai Mammen

Martin Sheringham Linsell

Michael Robert Leadbetter

James Bradley Aggen

Timothy J Church

David A Oare

John L Pace

Stephen R Hanson

David Beattie

Elizabeth D Getzoff

Qi-Qi Chen

Scott Armstrong

Lawrence A Harker

Jose M Fernandez

Deborah L Higgins

Dena Marrinucci

Jean-Luc Pellequer

Berislav V Zlokovic

Donald E Schmidt, Jr

David C Green

Peter Kuhn

Hiroshi Deguchi

Kelly Bethel

Robert P Numerof

Berislav Y Zlokovic

Jose A Fernandez

Bonno N Bouma

Rogier Bertina

Annette Von Drygalski

Andrew J Gale

Yongqui Mu

Burton Christensen

Laurent O Mosnier

Owen JT Mccarty

The present application generally relates to methods to prevent or treat bleeding and/or hypocoagulation in an individual in need thereof, and compositions for use in such methods. The methods comprise administration of FVa, preferably an APC resistant FVa (such asFVa), alone or in combination with FVIIa, preferably rhFVIIa (such as NovoSeven&#xae; or another FVIIa having enhanced activity or half-life). When administered in combination, FVa and FVIIa elicit a synergistic benefit when used to treat or prevent bleeding or hypocoagulation in subjects in need thereof, e.g., subjects with a genetic disorder such as hemophilia or an acquired bleeding disorder or other condition associated with bleeding or hypocoagulation such as hemorrhagic stroke or shock, trauma, surgery or dysmenorrhea or individuals who produce inhibitory antibodies against procoagulants such as FVIII or FIX or who have been administered an overdose of an anticoagulant drug such as a direct Xa or direct thrombin inhibitor or a Novel Oral Anti-Coagulant (NOAC) or demonstrate unexplained bleeding. Also, the invention relates to the use of aFVa alone or in combination with FVIIa or other procoagulant or prohemostatic agent to prevent, treat or reverse APC-associated bleeding, e.g., as the result of APC overproduction (such as through serious injury and/or hemorrhagic shock) or APC or other anticoagulant therapy, e.g., in the treatment of inflammatory disorders or sepsis disease.

Therapy for treatment or prevention of conditions associated with bleeding or hypocoagulation

The present invention provides novel PAR1 derived cytoprotective oligopeptides or polypeptides which typically contain at least the first 4 N-terminal residues that are substantially identical to the corresponding N-terminal residues of Met-Argdeleted human PAR1 sequence. These cytoprotective oligopeptides or polypeptides are capable of activating PAR1 and promoting PAR1 cytoprotective signaling activities. The invention also provides engineered cells or transgenic non-human animals which harbor in their genome an altered PAR1 gene that is resistant to cleavage at Argand/or Argresidues. Additionally provided in the invention are methods of screening candidate compounds to identity additional cytoprotective compounds or cytoprotective proteases. The invention further provides therapeutic use or methods of employing a PAR1 derived cytoprotective oligopeptide or polypeptide to treat conditions associated with tissue injuries or undesired apoptosis.

Protease activated receptor-1 (PAR1) derived cytoprotective polypeptides and related methods

The present invention provides novel PAR 1 derived cytoprotective oligopeptides or polypeptides which typically contain at least the first 4 N-terminal residues that are substantially identical to the corresponding N-terminal residues of Met-Argdeleted human PAR 1 sequence. These cytoprotective oligopeptides or polypeptides are capable of activating PAR 1 and promoting PAR 1 cytoprotective signaling activities. The invention also provides engineered cells or transgenic non-human animals which harbor in their genome an altered PAR 1 gene that is resistant to cleavage at Argand/or Argresidues. Additionally provided in the invention are methods of screening candidate compounds to identity additional cytoprotective compounds or cytoprotective proteases. The invention further provides therapeutic use or methods of employing a PAR 1 derived cytoprotective oligopeptide or polypeptide to treat conditions associated with tissue injuries or undesired apoptosis.

Protease Activated Receptor-1 (PAR1) Derived Cytoprotective Polypeptides and Related Methods

Variants (mutants) of recombinant activated protein C (APC) or recombinant protein C (prodrug, capable of being converted to APC) that have substantial reductions in anticoagulant activity but that retain normal levels of anti-apoptotic activity are provided. Three examples of such recombinant APC mutants are KKK191-193AAA-APC, RR229/230AA-APC, and RR229/230AA plus KKK191-193AAA-APC. APC variants and prodrugs of the invention have the desirable property of being cytoprotective (anti-apoptotic effects), while having significantly reduced risk of bleeding. The invention also provides a method of using the APC variants or prodrugs of the invention to treat subjects who will benefit from APC's cytoprotective activities that are independent of APC's anticoagulant activity. These subjects include patients at risk of damage to blood vessels or tissue in various organs caused, at least in part, by apoptosis. At risk patients include, for example, those suffering (severe) sepsis, ischemia/reperfusion injury, ischemic stroke, acute myocardial infarction, acute or chronic neurodegenerative diseases, or those undergoing organ transplantation or chemotherapy, among other conditions. Methods of screening for variants of recombinant protein C or APC that are useful in accordance with the invention are also provided.

Activated protein C variants with normal cytoprotective activity but reduced anticoagulant activity

The present invention provides methods for revealing, detecting, and analyzing circulating tumor cells in the blood of a subject. Revealing detectable circulating tumor cells allows for early stage detection and diagnosis in addition to long term prognosis in subjects with cancer. Additionally, enrichment allows for robust detection and clinically meaningful analysis of low volume samples for use in clinical settings as well as innovative methods for the treatment of cancers.

Methods for the detection of circulating tumor cells

Protein S is a significant neuroprotectant when administered after focal ischemic stroke and prevents hypoxic/re-oxygenation injury. Purified human plasma-derived or recombinant protein S improves motor neurological function after stroke, and reduced brain infarction and edema. Protein S also enhances post-ischemic reperfusion and reduced brain fibrin and neutrophil deposition. Cortical neurons are protected from hypoxia/re-oxygenation-induced apoptosis. Thus, protein S and variants thereof are prototypes of a class of agents for preventing injury of the nervous system. In particular, a disease or other pathological condition (e.g., stroke) may be treated with such agents having one or more protein S activities (e.g., anti-thrombotic and anti-inflammatory activities, direct cellular neuronal protective effects) although the latter activities are not be required.

Protein S protects the nervous system from injury

The present invention relates to methods of introducing one or more cysteine residues into a polypeptide which permit the stabilization of the polypeptide by formation of at least one bond, preferably a disulfide bond, between different domains of the polypeptide. The invention also relates to polypeptides containing such introduced cysteine residue(s), nucleic acids encoding such polypeptides and pharmaceutical compositions comprising such polypeptides or nucleic acids. The invention also relates to vectors, viral particles and host cells containing such nucleic acids, and methods of using them to produce the polypeptides of the invention. Exemplified polypeptides include plasma proteins, including hepatocyte growth factor activator and plasma hyaluronin binding protein, as well as blood coagulation factors, such as Factor VIII, Factor V, Factor XII and prothrombin.

Stabilized proteins with engineered disulfide bonds

A conditioning apparatus for conditioning a treated fluid includes a conditioning chamber for containing a flow of a treated fluid and an exchange element disposed within said conditioning chamber having one or more fluid passages formed therein filled with a saline solution. The exchange element has a semi-permeable membrane that allows fluid transfer between said treated fluid and said saline solution through said semi-permeable membrane.

Conditioning apparatus

Oncokinase fusion polypeptides associated with hyperproliferative disorders and the polynucleotides encoding for such fusion polypeptides are provided. The fusion polypeptides have a C-terminal tyrosine kinase domain fused to an N-terminal domain that is not normally fused to the C-terminal tyrosine kinase domain and they possess constitutively activated tyrosine kinase activity. Also provided are methods for detecting and identifying the fusion polypeptides and polynucleotides and methods of diagnosing disease conditions associated with the fusion polypeptides and polynucleotides. In addition, screening assays for identifying agents useful for treating disease conditions associated with such fusion polypeptides and polynucleotides are provided. Furthermore, methods of treating disease conditions associated with the presence of the fusion polypeptides are provided.

Oncokinase fusion polypeptides associated with hyperproliferative and related disorders, nucleic acids encoding the same and methods for detecting and identifying the same

Variants (mutants) of recombinant activated protein C (APC) or recombinant protein C (prodrug, capable of being converted to APC) that have substantial reductions in anticoagulant activity but that retain normal levels of anti-apoptotic activity are provided. Two examples of such recombinant APC mutants are KKK191-193AAA-APC and RR229/230M-APC. APC variants and prodrugs of the invention have the desirable property of being cytoprotective (anti-apoptotic effects), while having significantly reduced risk of bleeding. The invention also provides a method of using the APC variants or prodrugs of the invention to treat subjects who will benefit from APC's cytoprotective activities that are independent of APC's anticoagulant activity. These subjects include patients at risk of damage to blood vessels or tissue in various organs caused, at least in part, by apoptosis. At risk patients include, for example, those suffering (severe) sepsis, ischemia/reperfusion injury, ischemic stroke, acute myocardial infarction, acute or chronic neurodegenerative diseases, or those undergoing organ transplantation or chemotherapy, among other conditions. Methods of screening for variants of recombinant protein C or APC that are useful in accordance with the invention are also provided.

Disclosed are multibinding compounds which are muscarinic receptor antagonists. The multibinding compounds of this invention containing from 2 to 10 ligands covalently attached to one or more linkers. Each ligand is, independently of each other, a muscarinic receptor antagonist or an allosteric modulator provided that at least one of said ligand is a muscarinic receptor antagonist. The multibinding compounds of this invention are useful in the treatment and prevention of diseases such as chronic obstructive pulmonary disease, chronic bronchitis, irritable bowel syndrome, urinary incontinence, and the like.

Muscarinic receptor antagonists

Compounds of formula (I) in which R, R, Rand Rhave the meanings given in the specification, are receptor tyrosine kinase inhibitors useful in the treatment of proliferative disorders, such as cancer.

Indolinone derivatives

The present invention provides compositions of matter, kits and methods for their use in the treatment of MAP kinase-related conditions and/or HMG-CoA reductase-related conditions. In particular, the invention provides compositions for treating inflammatory and/or cardiovascular conditions in an animal subject by inhibiting p38&#x3b1; MAP kinase and/or HMG-CoA reductase, as well as providing formulations and modes of administering such compositions. The invention further provides methods for the rational design of inhibitors of MAP kinase, HMG-CoA reductase, or both for use in the practice of the present invention.

Compositions and treatments for inhibiting kinase and/or HMG-CoA reductase

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Atherton, CA, United States of America

John H Griffin