Polypeptides

Abstract

There is provided inter alia a polypeptide comprising an immunoglobulin chain variable domain which binds to TNF-alpha, wherein the immunoglobulin chain variable domain comprises three complementarity determining regions (CDR1-CDR3) and four framework regions (FR1-FR4), wherein CDR1-CDR3 and FR1-FR4 are as defined in the specification.

1 . A construct comprising at least one polypeptide which is an immunoglobulin chain variable domain which binds to TNF-alpha and comprises a set of three complementarity determining regions (CDRs) comprising CDR1, CDR2 and CDR3, wherein the respective SEQ ID Nos of CDR1, CDR2 and CDR3 of said set are selected from the group consisting of:
 (a) SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3,   (b) SEQ ID NO: 1, SEQ ID NO: 63 and SEQ ID NO: 70,   (c) SEQ ID NO: 1, SEQ ID NO: 64 and SEQ ID NO: 70,   (d) SEQ ID NO: 1, SEQ ID NO: 65 and SEQ ID NO: 70,   (e) SEQ ID NO: 59, SEQ ID NO: 66 and SEQ ID NO: 71,   (f) SEQ ID NO: 60, SEQ ID NO: 67, and SEQ ID NO: 70,   (g) SEQ ID NO: 1, SEQ ID NO: 67 and SEQ ID NO: 70,   (h) SEQ ID NO: 1, SEQ ID NO: 68 and SEQ ID NO: 72,   (i) SEQ ID NO: 1, SEQ ID NO: 69 and SEQ ID NO: 70,   (j) SEQ ID NO: 1, SEQ ID NO: 62 and SEQ ID NO: 70,   (k) SEQ ID NO: 1, SEQ ID NO: 69 and SEQ ID NO: 3,   (l) SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 70,   (m) SEQ ID NO: 1, SEQ ID NO: 61 and SEQ ID NO: 70 and   (n) SEQ ID NO: 1, SEQ ID NO: 62 and SEQ ID NO: 3;   and at least one different polypeptide.   
     
     
         2 . The construct according to  claim 1  wherein the immunoglobulin chain variable domain is a heavy chain variable domain. 
     
     
         3 . The construct according to  claim 2  wherein the heavy chain variable domain comprises a sequence sharing 90% or greater sequence identity with SEQ ID NO: 8. 
     
     
         4 . The construct according to  claim 3  wherein the heavy chain variable domain comprises a sequence sharing 99% or greater sequence identity with SEQ ID NO: 8. 
     
     
         5 . The construct according to  claim 4  wherein the heavy chain variable domain comprises SEQ ID NO: 8. 
     
     
         6 . The construct according to  claim 2  wherein the heavy chain variable domain consists of a sequence sharing 90% or greater sequence identity with SEQ ID NO: 8. 
     
     
         7 . The construct according to  claim 3  wherein the heavy chain variable domain consists of a sequence sharing 99% or greater sequence identity with SEQ ID NO: 8. 
     
     
         8 . The construct according to  claim 7  wherein the heavy chain variable domain consists of SEQ ID NO: 8. 
     
     
         9 . The construct according to  claim 1  wherein the different polypeptide is an immunoglobulin chain variable domain. 
     
     
         10 . The construct according to  claim 9  wherein the different polypeptide which is an immunoglobulin chain variable domain is a heavy chain variable domain. 
     
     
         11 . The construct according to  claim 1  wherein the different polypeptide binds to IL-7R. 
     
     
         12 . The construct according to  claim 1  wherein the different polypeptide binds to IL-23. 
     
     
         13 . The construct according to  claim 1  wherein the polypeptides are connected by at least one linker. 
     
     
         14 . The construct according to  claim 13  wherein the polypeptides are connected by at least one protease-labile linker. 
     
     
         15 . The construct according to  claim 13  wherein the polypeptides are all connected by non-protease-labile linkers. 
     
     
         16 . The construct according to  claim 1  which is substantially resistant to one or more proteases present in the stomach or the small or large intestine. 
     
     
         17 . The construct according to  claim 1  comprised within a pharmaceutical composition with one or more pharmaceutically acceptable diluents or carriers. 
     
     
         18 . The construct according to  claim 1  which neutralises human TNF-alpha cytotoxicity in the normal L929 assay with an EC50 of 0.5 nM or less. 
     
     
         19 . A method of treating autoimmune and/or inflammatory disease comprising administering to a person in need thereof a therapeutically effective amount of the polypeptide of  claim 1 . 
     
     
         20 . The method of treating autoimmune and/or inflammatory disease according to  claim 19  wherein the polypeptide is administered orally.