Polypeptides, antibody variable domains & antagonists

Abstract

The present invention relates to polypeptides e.g. protease resistant polypeptides, immunoglobulin (antibody) single variable domains e.g. which are protease resistant and also to vascular endothelial growth factor (VEGF) antagonists comprising these. The invention further relates to uses, formulations, and compositions comprising such polypeptides e.g. for delivery to the eye.

1 . A composition comprising an immunoglobulin single variable domain that binds to a target molecule, for ocular delivery. 
     
     
         2 . The composition according to  claim 1 , wherein said immunoglobulin single variable domain is resistant to a protease, wherein the protease is selected from the group consisting of: ocular protease, caspases, calpains, matric metalloproteases, disintegrins, metalloproteinases (ADAMs) and ADAM with thrombospondin mitifs, proteosomes, tissue plasminogen activator, secretases, cathepsin B, cathepsin D, cystatin C, serine protease PRSS1, and ubiquitin proteosome pathway (UPP), for ocular delivery. 
     
     
         3 . The composition according to  claim 1 , which comprises an immunoglobulin single variable domain which binds to a target molecule selected from the group consisting of: VEGF, a VEGF antagonist, TNF receptor, IL-1, IL-17, IL-21, IL-23, Nogo-a, Myelin associated glycoprotein (MAG) and Beta amyloid, for ocular delivery. 
     
     
         4 . The composition according to  claim 3 , wherein said immunoglobulin single variable domain which binds to VEGF comprises an amino acid sequence that is at least 97% identical to the amino acid sequence of DOM15-26-593 as in  FIG. 5 . 
     
     
         5 . The composition according to  claim 4 , wherein the immunoglobulin single variable domain comprises valine at position 6, wherein numbering is according to Kabat. 
     
     
         6 . The composition according to  claim 4 , wherein the immunoglobulin single variable domain comprises leucine at position 99, wherein numbering is according to Kabat. 
     
     
         7 . The composition according to  claim 4 , wherein the immunoglobulin single variable domain comprises lysine at position 30, wherein numbering is according to Kabat. 
     
     
         8 . The composition according to  claim 4 , wherein the immunoglobulin single variable domain comprises an amino acid sequence that is identical to the amino acid sequence of DOM15-26-593. 
     
     
         9 . The composition according to  claim 1 , which further comprises a domain of an antibody constant region, wherein the antibody constant region is antibody Fc region. 
     
     
         10 . The composition according to  claim 9 , wherein said antibody Fc region has the amino acid Fc sequence shown in  FIG. 52   b.    
     
     
         11 . The composition according to  claim 9 , wherein the immunoglobulin single variable domain, is present as a fusion with an Fc and has an amino acid sequence identical to the amino acid sequence of the DOM15-26-593-Fc fusion as in  FIG. 52   a.    
     
     
         12 . The composition according to  claim 1 , which further comprises an ocular penetration enhancer or a viscosity enhancer. 
     
     
         13 . The composition according to  claim 1 , which further comprises a pharmaceutically or physiologically acceptable carrier, diluent, or excipient. 
     
     
         14 . A method of delivering a composition according to  claim 1 , directly to the eye, which comprises administering said composition to the eye by a method selected from the group consisting of: intra-ocular injection, topical delivery to the eye, eye drops or by peri-ocular administration and a slow release formulation. 
     
     
         15 . A method for treating, preventing or diagnosing an eye condition which comprises administering a composition according to  claim 1 , directly to the eye, by a method selected from the group consisting of: intra-ocular injection, topical delivery to the eye, eye drops or by peri-ocular administration and a slow release formulation. 
     
     
         16 . The method according to  claim 14 , wherein the composition is administered to a region of the eye selected from the group consisting of: surface of the eye, tear ducts, lacrimal glands, intra-ocular region, anterior chamber, posterior chamber and the vitreous humour of the eye. 
     
     
         17 . A process for producing a pharmaceutical composition for treating, preventing or diagnosing an eye condition or disease, AMD, Uveitis, glaucoma, dry eye, diabetic retinopathy, or diabetic macular oedema Uveitis, which process comprises mixing (a) a composition of  claim 1  with (b) a pharmaceutically acceptable carrier, diluent or excipient.