Protein modulators

Abstract

The present invention relates to modulators of the Neuregulin (NRG) family, particularly NRG1 and more particularly NRG1β, and most particularly NRG1β1. The present invention also relates to the use of such modulators to inhibit goblet cell hyperplasia and therefore also relates to the use of such modulators in the treatment or prevention of human diseases and disorders featuring pathological mucus production such as COPD, CF, chronic bronchitis and asthma.

1 . A modulator of NRG1 which modulates or inhibits the interaction between NRG1 and a cognate receptor to inhibit goblet cell hyperplasia. 
     
     
         2 . The modulator of  claim 1  wherein the NRG1 is NRG1α or a member of the NRG1β family. 
     
     
         3 . The modulator of  claim 2  wherein the member of the NRG1β family is NRG1β1. 
     
     
         4 . The modulator of  claim 1  wherein the NRG1 is the membrane bound and/or soluble form of NRG1. 
     
     
         5 . The modulator of  claim 1  wherein the modulator is a low molecular weight chemical entity. 
     
     
         6 . The modulator of  claim 1  wherein the modulator is an antibody. 
     
     
         7 . The modulator of  claim 6  wherein the antibody is a monoclonal. 
     
     
         8 . The modulator of  claim 7  wherein the antibody is a human, humanized or chimeric antibody. 
     
     
         9 . The antibody of  claim 6  wherein the antibody binds with NRG1 and modulates or inhibits the interaction between the NRG1 and one or more of its cognate receptors. 
     
     
         10 . The antibody of  claim 9  wherein the antibody preferentially binds with NRG1β1 (compared with NRG1α. 
     
     
         11 . The antibody of  claim 9  wherein the antibody specifically binds with NRG1β1 compared to NRG1α. 
     
     
         12 . The antibody of  claim 6  wherein the antibody comprises a human constant region of IgG1 or IgG4. 
     
     
         13 . Use of a modulator of  claim 1  in the manufacture of a medicament for the treatment of a disease or disorder featuring aberrant mucus production. 
     
     
         14 . Use of  claim 13  wherein the disease or disorder is respiratory. 
     
     
         15 . Use of  claim 14  wherein the disease or disorder is COPD, cystic fibrosis (CF), chronic bronchitis, asthma. 
     
     
         16 . Use of  claim 13  wherein the disease or disorder is human. 
     
     
         17 . Use of the modulator of  claim 1  in the manufacture of a medicament for the prevention or slowing the onset and/or ameliorating the symptoms of a disease featuring aberrant mucus production. 
     
     
         18 . A method of treating a human patient afflicted with a disease or disorder featuring aberrant mucus production, wherein the method comprises the step of:
 administering to said patient a therapeutically effective amount of a modulator of  claim 1 .   
     
     
         19 . A method of identifying a modulator of  claim 1  which method comprises;
 (a) providing a candidate modulator; 
 (b) contacting said modulator with said NRG1; 
 (c) determining whether said candidate modulator modulates or inhibits the interaction between the NRG1 of with its cognate receptor, wherein the ability of the candidate modulator to modulate or inhibit the interaction between NRG1 and its cognate receptor is correlated with the ability of the modulator to inhibit goblet cell hyperplasia. 
 
     
     
         20 . A pharmaceutical composition comprising a modulator of  claim 1  together with a pharmaceutically acceptable carrier. 
     
     
         21 . A method of treating a human patient afflicted with a respiratory disease or disorder characterized by aberrant mucus production which method comprises the step of:
 co-administering an inhibitor that inhibits the interaction between NRG1 and ErbB2, ErbB3, and/or the ErbB2/ErbB3 heterodimer, together with:   one or more agents selected from the group consisting of:   an anti-human IL-13 agent which inhibits the interaction between human IL-13 and its cognate human receptor; an anti-human IL-4 agent which inhibits the interaction between human IL-45 and its human IL-4 receptor; an anti-human IL-5 agent which inhibits the interaction between human IL-5 and its cognate receptor; and/or an anti-IgE agent which inhibits the interaction between human IgE and its cognate receptor.   
     
     
         22 . The method of  claim 21  wherein the NRG1 is NRG1β1. 
     
     
         23 . The method of  claim 21  wherein the inhibitor that inhibits the interaction between NRG1 and the ErbB2/ErbB3 heterodimer is an antibody that binds to NRG1. 
     
     
         24 . The method of  claim 21  wherein the respiratory disease or disorder characterized by aberrant mucus production is selected from the group consisting of: COPD, cystic fibrosis (CF), and chronic bronchitis. 
     
     
         25 . The method of  claim 21  wherein the inhibitor inhibits the interaction between NRG1 and the ErbB2/ErbB3 heterodimer. 
     
     
         26 . A pharmaceutical composition comprising a modulator of  claim 1  together with a pharmaceutically acceptable carrier for the treatment of COPD, cystic fibrosis (CF), asthma, chronic bronchitis, diseases of the lower respiratory tract such as respiratory infections, emphysema, pneumonia. 
     
     
         27 . The modulator of  claim 1 , wherein the cognate receptor is selected from the group consisting of: ErbB2, ErbB3, and ErbB2/3 heterodimer. 
     
     
         28 . The antibody of  claim 9 , wherein the one or more cognate receptors is selected from the group consisting of: ErbB2, ErbB3, and ErbB2/3 heterodimer. 
     
     
         29 . The use of  claim 13 , wherein the disease or disorder featuring aberrant mucus production is in a human patient. 
     
     
         30 . The use of  claim 17 , wherein the disease featuring aberrant mucus production is selected from the group consisting of: CORD, cystic fibrosis (CF), chronic bronchitis, and asthma. 
     
     
         31 . The method of  claim 18 , wherein the disease featuring aberrant mucus production is selected from the group consisting of: COPD, cystic fibrosis (CF), chronic bronchitis, and asthma. 
     
     
         32 . The method of  claim 19 , wherein the cognate receptor is selected from the group consisting of: ErbB2, ErbB3, and ErbB2/3 heterodimer.