US2007092513A1PendingUtilityA1

ErbB4 antagonists

63
Individually held — no corporate assignee on recordPriority: Sep 1, 2000Filed: Oct 13, 2006Published: Apr 26, 2007
Est. expirySep 1, 2020(expired)· nominal 20-yr term from priority
Inventors:Mary GerritsenMark Sliwkowski
A61P 9/00A61P 9/12A61P 13/10A61P 21/00C07K 16/32C07K 2317/92G01N 33/5061C07K 2317/73A61K 38/00C07K 14/82C07K 2319/30C07K 2317/76C07K 14/4756C07K 2319/00
63
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Claims

Abstract

The present invention concerns methods and means for controlling excessive proliferation and/or migration of smooth muscle cells, and in particular for treating stenosis, by using antagonists of a native ErbB4 receptor. The invention further concerns a method for the identification of ErbB4 agonists and antagonists capable of inhibiting or enhancing the proliferation or migration of smooth muscle cells.

Claims

exact text as granted — not AI-modified
1 . A method for controlling excessive proliferation or migration of smooth muscle cells comprising treating said smooth muscle cells with an effective amount of an antagonist of a native ErbB4 receptor.  
     
     
         2 . The method of  claim 1  wherein the control is prevention of excessive proliferation or migration of smooth muscle cells.  
     
     
         3 . The method of  claim 1  wherein the control is inhibition of excessive proliferation or migration of smooth muscle cells.  
     
     
         4 . The method of  claim 3  wherein said inhibition is total inhibition.  
     
     
         5 . The method of  claim 1  wherein said smooth muscle cells are pyloric smooth muscle cells.  
     
     
         6 . The method of  claim 1  wherein said smooth muscle cells are urinary bladder smooth muscle cells.  
     
     
         7 . The method of  claim 1  wherein said smooth muscle cells are those of an airway passage.  
     
     
         8 . The method of  claim 1  wherein said excessive proliferation or migration of smooth muscle cells results in stenosis.  
     
     
         9 . The method of  claim 1  wherein said smooth muscle cells are vascular smooth muscle cells.  
     
     
         10 . The method of  claim 9  wherein said vascular smooth muscle cells are human.  
     
     
         11 . The method of  claim 9  wherein said vascular smooth muscle cells are human aortic smooth muscle cells.  
     
     
         12 . The method of  claim 9  wherein said excessive proliferation or migration of smooth muscle cells results in vascular stenosis.  
     
     
         13 . The method of  claim 12  wherein said vascular stenosis is further characterized by excessive proliferation or migration of endothelial cells.  
     
     
         14 . The method of  claim 13  wherein said stenosis is restenosis.  
     
     
         15 . The method of  claim 1  wherein the ErbB4 receptor antagonist is an immunoadhesin.  
     
     
         16 . The method of  claim 15  wherein said immunoadhesin comprises an extracellular domain sequence of a native ErbB4 receptor.  
     
     
         17 . The method of  claim 16  wherein said native ErbB4 receptor is human.  
     
     
         18 . The method of  claim 17  wherein the native human ErbB4 receptor extracellular domain sequence is fused to an immunoglobulin heavy chain constant region sequence.  
     
     
         19 . The method of  claim 18  wherein said immunoglobulin is of IgG isotype.  
     
     
         20 . The method of  claim 19  wherein said immunoglobulin is of IgG1, IgG2 or IgG3 isotype.  
     
     
         21 . The method of  claim 19  wherein said immunoadhesin comprises at least one IgG immunoglobulin light chain.  
     
     
         22 . The method of  claim 1  wherein said antagonist is an antibody.  
     
     
         23 . The method of  claim 22  wherein said antibody is a neutralizing antibody against a native ErbB4 receptor.  
     
     
         24 . The method of  claim 23  wherein said antibody is a chimeric, humanized or human antibody.  
     
     
         25 . The method of  claim 23  wherein said antibody is glycosylated.  
     
     
         26 . The method of  claim 23  wherein said antibody binds essentially the same epitope as an antibody produced by a hybridoma selected from the group consisting of HER4.10H1.1A1 (ATCC Accession Number PTA-2828), HER4.1C6.A11 (ATCC Accession Number PTA-2829), HER4.3B9.2C9 (ATCC Accession Number PTA-2826), HER4.1A6.5B3 (ATCC Accession Number PTA-2827) and HER4.8B1.2H2 (ATCC Accession Number PTA-2825).  
     
     
         27 . The method of  claim 23  wherein said antibody has complementarity determining region (CDR) residues from an antibody produced by a hybridoma selected from the group consisting of HER4.10H1.1A1 (ATCC Accession Number PTA-2828), HER4.1C6.A11 (ATCC Accession Number PTA-2829), HER4.3B9.2C9 (ATCC Accession Number PTA-2826), HER4.1A6.5B3 (ATCC Accession Number PTA-2827) and HER4.8B1.2H2 (ATCC Accession Number PTA-2825).  
     
     
         28 . A method for treating stenosis in a mammalian patient comprising administering to said patient an effective amount of an antagonist of a native mammalian ErbB4 receptor.  
     
     
         29 . The method of  claim 28  wherein said patient is human.  
     
     
         30 . The method of  claim 29  wherein said stenosis is vascular stenosis.  
     
     
         31 . The method of  claim 30  wherein said vascular stenosis is restenosis.  
     
     
         32 . The method of  claim 28  wherein said antagonist is an immunoadhesin.  
     
     
         33 . The method of  claim 32  wherein said immunoadhesin comprises an extracellular domain sequence of a native human ErbB4 receptor.  
     
     
         34 . The method of  claim 33  wherein said extracellular domain sequence is fused to an immunoglobulin heavy chain constant region sequence.  
     
     
         35 . The method of  claim 34  wherein said immunoglobulin is of IgG isotype.  
     
     
         36 . The method of  claim 28  wherein said antagonist is an antibody.  
     
     
         37 . The method of  claim 36  wherein said antibody is a neutralizing antibody against a native human ErbB4 receptor.  
     
     
         38 . The method of  claim 36  wherein said antibody binds essentially the same epitope as an antibody produced by a hybridoma selected from the group consisting of HER4.10H1.1A1 (ATCC Accession Number PTA-2828), HER4.1 C6.A11 (ATCC Accession Number PTA-2829), HER4.3B9.2C9 (ATCC Accession Number PTA-2826), HER4.1A6.5B3 (ATCC Accession Number PTA-2827) and HER4.8B1.2H2 (ATCC Accession Number PTA-2825).  
     
     
         39 . The method of  claim 36  wherein said antibody has complementarity determining region (CDR) residues from an antibody produced by a hybridoma selected from the group consisting of HER4.10H1.1A1 (ATCC Accession Number PTA-2828), HER4.1C6.A11 (ATCC Accession Number PTA-2829), HER4.3B9.2C9 (ATCC Accession Number PTA-2826), HER4.1A6.5B3 (ATCC Accession Number PTA-2827) and HER4.8B1.2H2 (ATCC Accession Number PTA-2825).  
     
     
         40 . The method of  claim 28  wherein said antagonist is administered as an injection or infusion.  
     
     
         41 . The method of  claim 28  wherein said treatment additionally reduces hypertension associated with said stenosis.  
     
     
         42 . The method of  claim 28  wherein said treatment is prevention.  
     
     
         43 . The method of  claim 28  wherein said stenosis is pyloric stenosis.  
     
     
         44 . The method of  claim 28  wherein said stenosis is thickening of the urinary bladder wall.  
     
     
         45 . The method of  claim 28  wherein said stenosis is part of an obstructive airway disease.  
     
     
         46 . A method for treating stenosis in a mammalian patient comprising introducing into a cell of said patient a nucleic acid encoding an antagonist of an ErbB4 receptor.  
     
     
         47 . The method of  claim 46  wherein said patient is human.  
     
     
         48 . The method of  claim 47  wherein said antagonist is an immunoadhesin.  
     
     
         49 . The method of  claim 48  wherein said immunoadhesin comprises an extracellular domain sequence of a native human ErbB4 receptor fused to an immunoglobulin heavy chain constant region sequence.  
     
     
         50 . The method of  claim 47  wherein said antagonist is an antibody.  
     
     
         51 . The method of  claim 50  wherein said antibody is a neutralizing antibody against a native ErbB4 receptor.  
     
     
         52 . The method of  claim 51  wherein said antibody is a chimeric, humanized or human antibody.  
     
     
         53 . The method of  claim 51  wherein said antibody binds essentially the same epitope as an antibody produced by a hybridoma selected from the group consisting of HER4.10H1.1A1 (ATCC Accession Number PTA-2828), HER4.1C6.A11 (ATCC Accession Number PTA-2829), HER4.3B9.2C9 (ATCC Accession Number PTA-2826), HER4.1A6.5B3 (ATCC Accession Number PTA-2827) and HER4.8B1.2H2 (ATCC Accession Number PTA-2825).  
     
     
         54 . The method of  claim 51  wherein said antibody has complementarity determining region (CDR) residues from an antibody produced by a hybridoma selected from the group consisting of HER4.10H1.1A1 (ATCC Accession Number PTA-2828), HER4.1C6.A11 (ATCC Accession Number PTA-2829), HER4.3B9.2C9 (ATCC Accession Number PTA-2826), HER4.1A6.5B3 (ATCC Accession Number PTA-2827) and HER4.8B1.2H2 (ATCC Accession Number PTA-2825).  
     
     
         55 . The method of  claim 46  wherein said nucleic acid is introduced in vivo.  
     
     
         56 . The method of  claim 46  wherein said nucleic acid is introduced ex vivo.  
     
     
         57 . A method for treating hypertension associated with vascular stenosis in a mammalian patient, comprising administering to said patient an effective amount of an antagonist of a native mammalian ErbB4 receptor.  
     
     
         58 . The method of  claim 57  wherein said antagonist is a small molecule.  
     
     
         59 . A pharmaceutical composition for the treatment of stenosis in a mammalian patient comprising an effective amount of an antagonist of a native mammalian ErbB4 receptor, in admixture with a pharmaceutically acceptable carrier.  
     
     
         60 . A method for identifying a molecule that inhibits or enhances the proliferation or migration of smooth muscle cells, comprising the steps of: 
 (a) contacting a polypeptide comprising an amino acid sequence having at least 85% sequence identity with the amino acid sequence of the extracellular domain of a native ErbB4 receptor and retaining the ability to control excessive proliferation or migration of smooth muscle cells, with a candidate molecule; and    (b) determining whether the candidate molecule inhibits or enhances the ability of said polypeptide to control excessive proliferation or migration of smooth muscle cells.    
     
     
         61 . The method of  claim 60  wherein said polypeptide comprises the extracellular domain of a native ErbB4 receptor.  
     
     
         62 . The method of  claim 61  wherein said receptor is human.  
     
     
         63 . The method of  claim 61  wherein said polypeptide is an immunoadhesin.  
     
     
         64 . The method of  claim 60  wherein said molecule enhances the ability of said polypeptide to control excessive proliferation or migration of smooth muscle cells.  
     
     
         65 . The method of  claim 64  wherein said molecule is selected from the group consisting of antibodies and small molecules.  
     
     
         66 . An antibody that binds essentially the same epitope of ErbB4 as an antibody produced by a hybridoma selected from the group consisting of HER4.10H1.1A1 (ATCC Accession Number PTA-2828), HER4.1C6.A11 (ATCC Accession Number PTA-2829), HER4.3B9.2C9 (ATCC Accession Number PTA-2826), HER4.1A6.5B3 (ATCC Accession Number PTA-2827) and HER4.8B1.2H2 (ATCC Accession Number PTA-2825).  
     
     
         67 . An antibody that has complementarity determining region (CDR) residues from an antibody produced by a hybridoma selected from the group consisting of HER4.10H1.1A1 (ATCC Accession Number PTA-2828), HER4.1C6.A11 (ATCC Accession Number PTA-2829), HER4.3B9.2C9 (ATCC Accession Number PTA-2826), HER4.1A6.5B3 (ATCC Accession Number PTA-2827) and HER4.8B1.2H2 (ATCC Accession Number PTA-2825).  
     
     
         68 . An antibody selected from the group consisting of an antibody produced by a hybridoma selected from the group consisting of HER4.10H1.1A1 (ATCC Accession Number PTA-2828), HER4.1C6.A11 (ATCC Accession Number PTA-2829), HER4.3B9.2C9 (ATCC Accession Number PTA-2826), HER4.1A6.5B3 (ATCC Accession Number PTA-2827) and HER4.8B1.2H2 (ATCC Accession Number PTA-2825).  
     
     
         69 . An antibody that binds essentially the same epitope of ErbB4 bound by an antibody selected from the group consisting of anti-ErbB4 monoclonal antibodies 4-1440, 4-1460, 4-1473, 4-1492 and 4-1464.  
     
     
         70 . An antibody that has complementarity determining region (CDR) residues from an antibody selected from the group consisting of anti-ErbB4 monoclonal antibodies 4-1440, 4-1460, 4-1473, 4-1492 and 4-1464.  
     
     
         71 . An antibody which binds to ErbB4 with high affinity.  
     
     
         72 . The antibody of  claim 71  which binds to ErbB4 with a Kd of less than 100 nM.  
     
     
         73 . The antibody of  claim 71  which binds to ErbB4 with a Kd of less than 50 nM.  
     
     
         74 . The antibody of  claim 71  which binds to ErbB4 with a Kd of less than 10 nM.  
     
     
         75 . The antibody of  claim 71  which is a humanized antibody.  
     
     
         76 . The antibody of  claim 71  which is a human antibody.  
     
     
         77 . The antibody of  claim 71  which is an antibody fragment.  
     
     
         78 . An antibody which is capable of binding to both ErbB4 and ErbB3.  
     
     
         79 . The antibody of  claim 78  which binds ErbB4 with high affinity.  
     
     
         80 . The antibody of  claim 78  which binds both ErbB4 and ErbB3 with high affinity.  
     
     
         81 . An antibody which binds to ErbB4 and reduces heregulin binding thereto.  
     
     
         82 . The antibody of  claim 81  which binds ErbB4 with high affinity.  
     
     
         83 . An antibody which binds to ErbB4 and reduces heregulin-induced tyrosine phosphorylation thereof.  
     
     
         84 . The antibody of  claim 83  which binds ErbB4 with high affinity.

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