Means and methods for treating angiogenesis-related diseases

Abstract

The present invention is concerned with a protein oligomer comprising at least two NC-1 monomers of human collagen 18 or fragments of an NC-1 monomer of human collagen 18 for use in the treatment or prevention of an angiogenesis-related disease. The invention further pertains to a fusion protein comprising a NC-1 monomer of human collagen 18 and a Fc domain of an immunoglobulin. The invention also relates to a fusion protein comprising: a) an endostatin peptide or endostatin-derived peptide and b) the RGD motif and/or PHSRN motif of Fibronectin. The invention further relates to a kit comprising the protein oligomer or fusion proteins of the invention.

1 - 19 . (canceled) 
     
     
         20 . A method for treating or preventing an angiogenesis-related disease in a patient in the need thereof, comprising administering to the patient a therapeutically effective dose of a protein oligomer comprising at least two NC-1 monomers of human collagen 18 or fragments of an NC-1 monomer of human collagen 18, thereby treating or preventing the angiogenesis-related disease in the patient. 
     
     
         21 . The method of  claim 20 , wherein the NC-1 monomer of human collagen 18 comprises an oligomerization domain, a hinge region, and/or an endostatin domain or fragments of the endostatin domain and, optionally a recombinant protease cleavage site within the hinge region. 
     
     
         22 . The method of  claim 21 , wherein the oligomerization domain comprises a non-triple helical trimerization domain of human collagen 18, an Fc domain and/or an artificial oligomerization domain. 
     
     
         23 . The method of  claim 22 , wherein the Fc domain is from IgG. 
     
     
         24 . The method of  claim 22 , wherein the artificial oligomerization domain comprises a single mutation at position 7 of the endostatin domain in which glutamine is replaced by cysteine. 
     
     
         25 . The method of  claim 21 , wherein the recombinant protease cleavage site within the hinge region is an enterokinase or thrombin cleavage site. 
     
     
         26 . The method of  claim 20 , wherein the domain arrangement within the NC-1 monomer of human collagen 18 is oligomerization domain—hinge region—endostatin domain or endostatin domain—hinge region—oligomerization domain. 
     
     
         27 . The method of  claim 20 , wherein the angiogenesis-related disease is selected from the group consisting of angiogenesis-dependent cancer, solid tumors, melanomas, tumor metastases, blood born tumors, leukemias, benign tumors, hemangiomas, acoustic neuromas, neurofibromas, trachomas, pyogenic granulomas, rheumatoid arthritis, psoriasis, ocular angiogenic diseases, diabetic retinopathy, retinopathy of prematurity, macular degeneration, corneal graft rejection, neovascular glaucoma, retrolental fibroplasias, rubeosis, Osler-Webber syndrome, myocardial angiogenesis, plaque neovascularization, telangiectasia, hemophiliac joints, angiofibroma, wound granulation, diseases of excessive or abnormal stimulation of endothelial cells, intestinal adhesions, atherosclerosis, scleroderma, hypertrophic scars (keloids), diseases that have angiogenesis as a pathologic consequence, cat scratch disease (Rochele minalia quintosa), and ulcers ( Helobacter pylori ). 
     
     
         28 . A fusion protein comprising an NC-1 monomer of human collagen 18 and an Fc domain of an immunoglobulin. 
     
     
         29 . The fusion protein of  claim 28 , wherein the NC-1 monomer of human collagen 18 comprises an oligomerization domain, a hinge region and/or an endostatin domain and, optionally a recombinant protease cleavage site within the hinge region. 
     
     
         30 . The fusion protein of  claim 29 , wherein the oligomerization domain comprises a non-triple helical trimerization domain of human collagen 18 and/or an artificial oligomerization domain. 
     
     
         31 . The fusion protein of  claim 29 , wherein the Fc domain is from IgG. 
     
     
         32 . The fusion protein of  claim 30 , wherein the artificial oligomerization domain comprises a single mutation at position 7 of the endostatin domain in which glutamine is replaced by cysteine. 
     
     
         33 . The fusion protein of  claim 29 , wherein the recombinant protease cleavage site within the hinge region is an enterokinase or thrombin cleavage site. 
     
     
         34 . The fusion protein of  claim 28 , wherein the domain arrangement of the fusion protein is (a) Fc domain—oligomerization domain—hinge region—endostatin domain or (b) oligomerization domain—hinge region—endostatin domain—Fc domain or (c) Fc domain—endostatin domain—hinge region—oligomerization domain or (d) endostatin domain—hinge region—oligomerization domain—Fc domain. 
     
     
         35 . A fusion protein comprising:
 (a) an endostatin peptide or endostatin-derived peptide; and   (b) the ROD motif and/or PHSRN motif of fibronectin.   
     
     
         36 . A medicament or diagnostic composition comprising the fusion protein of  claim 28 . 
     
     
         37 . A medicament or diagnostic composition comprising the fusion protein of  claim 35 . 
     
     
         38 . A kit comprising the fusion protein of  claim 28 . 
     
     
         39 . A kit comprising the fusion protein of  claim 35 . 
     
     
         40 . A method for predicting the response of a cancer patient to an applied cancer therapy, comprising the steps of:
 (a) measuring the level of fibronectin, in a sample of the patient by using the NC-1 oligomer referred to in  claim 20 , and   (b) predicting the response of the patient to the cancer therapy, wherein low levels of fibronectin as compared to a reference level of a healthy subject is indicative for a non-response of the patient to the applied cancer therapy.   
     
     
         41 . A method for predicting the response of a cancer patient to an applied cancer therapy, comprising the steps of:
 (a) measuring the level of fibronectin in a sample of the patient by using the fusion protein of  claim 28 , and   (b) predicting the response of the patient to the cancer therapy, wherein low levels of fibronectin as compared to a reference level of a healthy subject is indicative for a non-response of the patient to the applied cancer therapy.   
     
     
         42 . A method for treating or preventing an angiogenesis-related disease in a patient in need thereof, comprising administering to the patient a therapeutically effective dose of the fusion protein of  claim 28 , thereby treating or preventing the angiogenesis-related disease in the patient. 
     
     
         43 . A method for treating or preventing an angiogenesis-related disease in a patient in need thereof, comprising administering to the patient a therapeutically effective dose of the fusion protein of  claim 35 , thereby treating or preventing the angiogenesis-related disease in the patient.