Masp isoforms as inhibitors of complement activation

Abstract

The present invention relates to novel ficolin-associated polypeptides, and polypeptides derived from these ficolin-associated polypeptides for the use in the treatment of conditions associated with inflammation, apoptosis, autoimmunity, coagulation, thrombotic or coagulopathic related diseases, as well as the use as biomarkers. The present invention further relates to anti-bodies recognising such novel ficolin-associated polypeptides, and polypeptides derived thereof, nucleic acid molecules encoding such polypeptides, vectors and host cells used in the production of the polypeptides.

1 . An isolated ficolin-associated polypeptide. 
     
     
         2 . (canceled) 
     
     
         3 . The polypeptide according to  claim 1 , wherein said polypeptide is capable of associating with mannose-binding lectin (MBL), with any one of ficolin-1, ficolin-2, or ficolin-3, with any one of C1q, lung surfactant proteins SP-A and/or SP-D, and intracellular collagen-like defence molecules, such as CL-L1, or with a specific acceptor protein, such as a specific receptor. 
     
     
         4 - 6 . (canceled) 
     
     
         7 . The polypeptide according to  claim 1 , wherein said polypeptide comprises the amino acid sequence 20-297 of SEQ NO:3, or a functional variant thereof. 
     
     
         8 . The polypeptide according to  claim 1 , wherein said polypeptide comprises the amino acid sequence 20-380 of SEQ NO:1 or a functional variant thereof. 
     
     
         9 . The polypeptide according to  claim 1 , wherein said polypeptide comprises the amino acid sequence 16-296 of SEQ ID NO:9 or a functional variant thereof. 
     
     
         10 . (canceled) 
     
     
         11 . The polypeptide according to  claim 1 , wherein said polypeptide is N-linked glycosylated at one or two amino acids corresponding to a position selected from 49 and 178 of SEQ NO:1. 
     
     
         12 - 15 . (canceled) 
     
     
         16 . A polypeptide comprising the amino acid sequence of SEQ ID NO:4 or variants or immunologic fragment thereof. 
     
     
         17 - 20 . (canceled) 
     
     
         21 . An antibody that specifically binds a polypeptide according to  claim 1 . 
     
     
         22 . An isolated nucleic acid molecule encoding a polypeptide of  claim 1 . 
     
     
         23 . (canceled) 
     
     
         24 . A vector comprising an isolated nucleic acid molecule according to  claim 1 . 
     
     
         25 . A host cell comprising a vector according to  claims 24 . 
     
     
         26 - 28 . (canceled) 
     
     
         29 . A method for producing an isolated ficolin-associated polypeptide, said method comprising cultivating a host cell as defined in  claim 25  in an appropriate growth medium under conditions allowing expression of the polynucleotide construct and recovering the resulting ficolin-associated polypeptide from the culture medium. 
     
     
         30 . A composition comprising the polypeptide as defined in  claim 1 . 
     
     
         31 . A pharmaceutical composition comprising the polypeptide as defined in  claim 1 . 
     
     
         32 . A method for detecting a ficolin-associated polypeptide in a biological sample, said method comprising:
 a) obtaining a biological sample;   b) contacting said biological sample with an antibody according to  claim 21 ; and   c) detecting complexes of said antibody and said polypeptide, if any;   
       as an indication of the presence of said polypeptide in said sample. 
     
     
         33 . A polypeptide as defined in  claim 1  for use as a medicament. 
     
     
         34 - 44 . (canceled) 
     
     
         45 . A method for the treatment of any indication associated with inflammation, apoptosis and/or autoimmunity such as for the treatment of any autoimmune conditions such as Addison's disease, autoimmune hemolytic anemia, autoimmune thyroiditis, Crohn's disease, Graves' disease, Guillain-Barre syndrome, systemic lupus erythematosus (SLE), lupus nephritis, multiple sclerosis, myasthenia gravis, psoriasis, primary biliary cirrhosis, rheumatoid arthritis and uveitis, asthma, atherosclerosis, Type I diabetes, psoriasis, various allergies, or for the treatment of any inflammatory disorder selected from the group consisting of appendicitis, peptic ulcer, gastric ulcer, duodenal ulcer, peritonitis, pancreatitis, ulcerative colitis, pseudomembranous colitis, acute colitis, ischemic colitis, diverticulitis, epiglottitis, achalasia, cholangitis, cholecystitis, hepatitis, Crohn's disease, enteritis, Whipple's disease, allergy, immune complex disease, organ ischemia, reperfusion injury, organ necrosis, hay fever, sepsis, septicemia, endotoxic shock, cachexia, hyperpyrexia, eosinophilic granuloma, granulomatosis, sarcoidosis septic abortion, epididymitis, vaginitis, prostatitis, urethritis, bronchitis, emphysema, rhinitis, pneumonitis, pneumotransmicroscopicsilicovolcanoconiosis, alvealitis, bronchiolitis, pharyngitis, pleurisy, sinusitis, influenza, respiratory syncytial virus infection, HIV infection, hepatitis B virus infection, hepatitis C virus infection, disseminated bacteremia, Dengue fever, candidiasis, malaria, filariasis, amebiasis, hydatid cysts, burns, dermatitis, dermatomyositis, sunburn, urticaria, warts, wheals, vasulitis, angiitis, endocarditis, arteritis, atherosclerosis, thrombophlebitis, pericarditis, myocarditis, myocardial ischemia, periarteritis nodosa, rheumatic fever, Alzheimer's disease, coeliac disease, congestive heart failure, adult respiratory distress syndrome, meningitis, encephalitis, multiple sclerosis, cerebral infarction, cerebral embolism, Guillame-Barre syndrome, neuritis, neuralgia, spinal cord injury, paralysis, uveitis, arthritides, arthralgias, osteomyelitis, fasciitis, Paget's disease, gout, periodontal disease, rheumatoid arthritis, synovitis, myasthenia gravis, thyroiditis, systemic lupus erythematosis, Goodpasture's syndrome, Behcet's syndrome, allograft rejection, graft-versus-host disease, Type I diabetes, ankylosing spondylitis, Berger's disease, Reiter's syndrome and Hodgkin's disease, keratitis, Type 2 diabetes, cystic fibrosis, myocardial infarction, reperfusion injury, stroke, dermatomyositis, metabolic syndrome, systemic inflammatory response syndrome, sepsis, multiple organ failure, disseminated intravascular coagulation, anaphylactic shock. Vascular complication and nephropathy associated with type 1 and/or type 2 diabetes, meningitis, bacterial septicaemia, complicated malaria, atypic haemolytic uremic syndrome, haemolytic uremic syndrome, age related macular degeneration, paroxysmal nocturnal hemoglobinuria, snake venom bite, burn injury, and complications to organ transplantations, or for the treatment of any inflammatory disorder selected from the group consisting of organ ischemia, reperfusion injury, organ necrosis, vasulitis, endocarditis, atherosclerosis, thrombophlebitis, pericarditis, myocarditis, myocardial ischemia, periarteritis nodosa, rheumatic fever, congestive heart failure, adult respiratory distress syndrome, cerebral infarction, cerebral embolism, or vascular complications and nephropathy associated with type 1 and/or type 2 diabetes, or for the treatment of any indications associated with coagulation, thrombotic or coagulopathic related diseases including inflammatory response and chronic thromboembolic diseases or disorders associated with fibrin formation including vascular disorders such as thrombosis, such as deep venous thrombosis, arterial thrombosis, post surgical thrombosis, coronary artery bypass graft (CABG), percutaneous transdermal coronary angioplastry (PTCA), platelet deposition stroke, tumor growth, tumor metastasis, angiogenesis, thrombolysis, atherosclerosis, restenosis, such as arteriosclerosis and/or restenosis following angioplasty, acute and chronic indications such as inflammation, sepsis, septic shock, septicemia, hypotension, adult respiratory distress syndrome (ARDS), systemic inflammatory response syndrome (SIRS), disseminated intravascular coagulopathy (DIC), pulmonary embolism, pathological platelet deposition, myocardial infarction, or the prophylactic treatment of mammals with atherosclerotic vessels at risk for thrombosis, venoocclusive disease following peripheral blood progenitor cell (PBPC) transplantation, hemolytic uremic syndrome (HUS), and thrombotic thrombocytopenic purpura (TTP) and rheumatic fever, inflammatory response and chronic thromboembolic diseases or disorders associated with fibrin formation, for preventing the occurrence of thromboembolic complications in identified high risk patients, such as those undergoing surgery or those with congestive heart failure, for the treatment of a medical condition associated with the heart, or for the treatment of a medical condition associated with a deficiency in a ficolin-associated polypeptide; the method comprising administering a therapeutically or prophylactically effective amount of a polypeptide as defined in  claim 1  to a subject in need thereof. 
     
     
         46 - 53 . (canceled) 
     
     
         54 . A method of detecting the presence of a nucleic acid encoding a ficolin-associated polypeptide in a biological sample, the method comprising
 a) obtaining a biological sample;   b) contacting said biological sample with a nucleic acid probe according to  claim 22 ; and   c) detecting complexes of said a nucleic acid probe and said nucleic acid encoding said ficolin-associated polypeptide, if any;   
       as an indication of the presence of said nucleic acid encoding said polypeptide in said sample. 
     
     
         55 . A method for diagnosing a disorder associated with aberrant expression of a ficolin-associated polypeptide, comprising obtaining a biological sample from a patient and measuring the expression in said biological sample of said ficolin-associated polypeptide, wherein increased or decreased expression of said ficolin-associated polypeptide in said biological sample compared to a control indicates that said patient suffers from a disorder associated with aberrant expression of a ficolin-associated polypeptide. 
     
     
         56 - 63 . (canceled) 
     
     
         64 . Use of a polypeptide as defined in  claim 1  as a biomarker in blood and tissue for diagnosis and/or prognosis of an autoimmune, metabolic and/or inflammatory condition such as Addison's disease, autoimmune hemolytic anemia, autoimmune thyroiditis, Crohn's disease, Graves' disease, Guillain-Barre syndrome, systemic lupus erythematosus (SLE), lupus nephritis, multiple sclerosis, myasthenia gravis, psoriasis, primary biliary cirrhosis, rheumatoid arthritis and uveitis, asthma, atherosclerosis, Type I diabetes, psoriasis, various allergies, or for the treatment of any inflammatory disorder selected from the group consisting of appendicitis, peptic ulcer, gastric ulcer, duodenal ulcer, peritonitis, pancreatitis, ulcerative colitis, pseudomembranous colitis, acute colitis, ischemic colitis, diverticulitis, epiglottitis, achalasia, cholangitis, cholecystitis, hepatitis, Crohn's disease, enteritis, Whipple's disease, allergy, immune complex disease, organ ischemia, reperfusion injury, organ necrosis, hay fever, sepsis, septicemia, endotoxic shock, cachexia, hyperpyrexia, eosinophilic granuloma, granulomatosis, sarcoidosis, septic abortion, epididymitis, vaginitis, prostatitis, urethritis, bronchitis, emphysema, rhinitis, pneumonitis, pneumotransmicroscopicsilicovolcanoconiosis, alvealitis, bronchiolitis, pharyngitis, pleurisy, sinusitis, influenza, respiratory syncytial virus infection, HIV infection, hepatitis B virus infection, hepatitis C virus infection, disseminated bacteremia, Dengue fever, candidiasis, malaria, filariasis, amebiasis, hydatid cysts, burns, dermatitis, dermatomyositis, sunburn, urticaria, warts, wheals, vasulitis, angiitis, endocarditis, arteritis, atherosclerosis, thrombophlebitis, pericarditis, myocarditis, myocardial ischemia, periarteritis nodosa, rheumatic fever, Alzheimer's disease, coeliac disease, congestive heart failure, adult respiratory distress syndrome, meningitis, encephalitis, multiple sclerosis, cerebral infarction, cerebral embolism, Guillame-Barre syndrome, neuritis, neuralgia, spinal cord injury, paralysis, uveitis, arthritides, arthralgias, osteomyelitis, fasciitis, Paget's disease, gout, periodontal disease, rheumatoid arthritis, synovitis, myasthenia gravis, thyroiditis, systemic lupus erythematosis, Goodpasture's syndrome, Behcet's syndrome, allograft rejection, graft-versus-host disease, Type I diabetes, ankylosing spondylitis, Berger's disease, Reiter's syndrome and Hodgkin's disease, keratitis, Type 2 diabetes, cystic fibrosis, myocardial infarction, reperfusion injury, stroke, dermatomyositis, metabolic syndrome, systemic inflammatory response syndrome, sepsis, multiple organ failure, disseminated intravascular coagulation, anaphylactic shock. Vascular complication and nephropathy associated with type 1 and/or type 2 diabetes, meningitis, bacterial septicaemia, complicated malaria, atypic haemolytic uremic syndrome, haemolytic uremic syndrome, age related macular degeneration, paroxysmal nocturnal hemoglobinuria, snake venom bite, burn injury, and complications to organ transplantations, or for the treatment of any inflammatory disorder selected from the group consisting of organ ischemia, reperfusion injury, organ necrosis, vasulitis, endocarditis, atherosclerosis, thrombophlebitis, pericarditis, myocarditis, myocardial ischemia, periarteritis nodosa, rheumatic fever, congestive heart failure, adult respiratory distress syndrome, cerebral infarction, cerebral embolism, or vascular complications and nephropathy associated with type 1 and/or type 2 diabetes, or for the treatment of any indications associated with coagulation, thrombotic or coagulopathic related diseases including inflammatory response and chronic thromboembolic diseases or disorders associated with fibrin formation including vascular disorders such as thrombosis, such as deep venous thrombosis, arterial thrombosis, post surgical thrombosis, coronary artery bypass graft (CABG), percutaneous transdermal coronary angioplastry (PTCA), platelet deposition stroke, tumor growth, tumor metastasis, angiogenesis, thrombolysis, atherosclerosis, restenosis, such as arteriosclerosis and/or restenosis following angioplastry, acute and chronic indications such as inflammation, sepsis, septic shock, septicemia, hypotension, adult respiratory distress syndrome (ARDS), systemic inflammatory response syndrome (SIRS), disseminated intravascular coagulopathy (DIC), pulmonary embolism, pathological platelet deposition, myocardial infarction, or the prophylactic treatment of mammals with atherosclerotic vessels at risk for thrombosis, venoocclusive disease following peripheral blood progenitor cell (PBPC) transplantation, hemolytic uremic syndrome (HUS), and thrombotic thrombocytopenic purpura (TTP) and rheumatic fever, inflammatory response and chronic thromboembolic diseases or disorders associated with fibrin formation, for preventing the occurrence of thromboembolic complications in identified high risk patients, such as those undergoing surgery or those with congestive heart failure, for the treatment of a medical condition associated with the heart, or for the treatment of a medical condition associated with a deficiency in a ficolin-associated polypeptide.