JPWO2020254828A5 - - Google Patents

Claims (31)

A composition comprising a TNF-α binding polypeptide and an IL-7R binding polypeptide, wherein the IL-7R binding polypeptide comprises three complementarity determining regions (CDR1-CDR3) and four framework regions (FR1-FR4 ), CDR1 comprises a sequence sharing 60% or greater sequence identity with SEQ ID NO:9, CDR2 comprises a sequence sharing 50% or greater sequence identity with SEQ ID NO:10, and CDR3 comprises sequence A composition comprising a sequence sharing 60% or more sequence identity with number 11. said TNF-α binding polypeptide comprises three complementarity determining regions (CDR1-CDR3) and four framework regions (FR1-FR4), wherein CDR1 shares greater than 60% sequence identity with SEQ ID NO:1 wherein CDR2 comprises a sequence sharing 50% or greater sequence identity with SEQ ID NO:2, and CDR3 comprises a sequence sharing 60% or greater sequence identity with SEQ ID NO:3. The composition according to . said TNF-α binding polypeptide comprises three complementarity determining regions (CDR1-CDR3) and four framework regions (FR1-FR4), wherein CDR1 shares 80% or more sequence identity with SEQ ID NO:1 wherein CDR2 comprises a sequence sharing 80% or greater sequence identity with SEQ ID NO:2, and CDR3 comprises a sequence sharing 80% or greater sequence identity with SEQ ID NO:3. The composition according to . said IL-7R binding polypeptide comprises 3 complementarity determining regions (CDR1-CDR3) and 4 framework regions (FR1-FR4), wherein CDR1 shares 80% or more sequence identity with SEQ ID NO:9 CDR2 comprises a sequence sharing 80% or more sequence identity with SEQ ID NO:10, and CDR3 comprises a sequence sharing 80% or more sequence identity with SEQ ID NO:11. 4. The composition of any one of 3 through 3. (a) said TNF-α binding polypeptide comprises three complementarity determining regions (CDR1-CDR3) and four framework regions (FR1-FR4), wherein CDR1 comprises SEQ ID NO:1 and CDR2 comprises SEQ ID NO:2; and (b) said IL-7R binding polypeptide comprises three complementarity determining regions (CDR1-CDR3) and four framework regions (FR1-FR4), and CDR1 comprises SEQ ID NO:9, CDR2 comprises SEQ ID NO:10 and CDR3 comprises SEQ ID NO:11. (a) said TNF-α binding polypeptide comprises three complementarity determining regions (CDR1-CDR3) and four framework regions (FR1-FR4), wherein CDR1 consists of SEQ ID NO: 1 and CDR2 consists of SEQ ID NO: 2; and (b) said IL-7R binding polypeptide comprises three complementarity determining regions (CDR1-CDR3) and four framework regions (FR1-FR4), wherein CDR1 consists of consists of SEQ ID NO:9, CDR2 consists of SEQ ID NO:10 and CDR3 consists of SEQ ID NO:11. 7. The composition of any one of claims 1-6, wherein said polypeptide is an antibody or antibody fragment. 8. The composition of claim 7, wherein said polypeptides each comprise or consist of an immunoglobulin chain variable domain. 9. The composition of claim 8, wherein each said polypeptide is selected from VHH, VH, or VL. 10. The composition of claim 9, wherein each said polypeptide is selected from VHH or VH. wherein said TNF-α binding polypeptide binds TNF-α with a Kd of 10 ⁻⁷ M or less and said IL-7R binding polypeptide binds IL-7R with a Kd of 10 ⁻⁷ M or less; 11. The composition according to any one of 1 to 10. The TNF-α binding polypeptide neutralizes human TNF-α cytotoxicity in the L929 assay with an EC50 of 100 nM or less, and the IL-7R binding polypeptide neutralizes IL-7R-dependent human lymphocytes with an EC50 of 100 nM or less. , which neutralizes IL-7-induced STAT5 phosphorylation. (a) said TNF-α binding polypeptide comprises or consists of a sequence sharing at least 75% identity to SEQ ID NO:8;
(b) the IL-7R binding polypeptide comprises or consists of a sequence sharing at least 75% identity to SEQ ID NO: 16; Composition. (a) said TNF-α binding polypeptide comprises or consists of SEQ ID NO:8;
14. The composition of claim 13, wherein (b) said IL-7R binding polypeptide comprises or consists of SEQ ID NO:16. 15. The composition of any one of claims 1-14, wherein said TNF-α binding polypeptide and said IL-7R binding polypeptide are conjugated. 16. The composition of claim 15, wherein said TNF-α binding polypeptide and said IL-7R binding polypeptide are joined by a protease labile peptide linker. 17. The composition of claim 16, wherein said protease labile peptide linker comprises K and/or R residues. said protease labile linker comprises or consists of a sequence (SEQ ID NO: 34) of the format -(G ₄ S) _x -K-(G ₄ S) _y -, wherein x and y are each independently 18. The composition of claim 17, which is 1-5. 19. The composition of claim 18, wherein the protease labile linker comprises or consists of a sequence of the format -(G ₄ S) ₂ -K-(G ₄ S) ₂ - (SEQ ID NO: 21). 20. The composition of any one of claims 1-19, wherein the polypeptide exhibits substantial resistance to one or more proteases present in the small or large intestine. 21. The composition of claim 20, wherein said proteases are trypsin and chymotrypsin. 22. A pharmaceutical composition comprising a composition according to any one of claims 1-21 and a pharmaceutically acceptable excipient. 23. A pharmaceutical composition according to claim 22 , for use as a medicament. 24. The pharmaceutical composition according to claim 23, for use in treating or preventing autoimmune and/or inflammatory diseases. 22. Use of a composition according to any one of claims 1-21 in the manufacture of a medicament for the treatment or prevention of autoimmune and/or inflammatory diseases. 25. The pharmaceutical composition according to claim 24, wherein said autoimmune and/or inflammatory disease is inflammatory bowel disease and/or mucositis. 25. The pharmaceutical composition according to claim 24, wherein said autoimmune and/or inflammatory disease is atopic dermatitis. 27. The pharmaceutical composition according to any one of claims 23-24 or 26, wherein said pharmaceutical composition is for oral administration. 27. The pharmaceutical composition according to any one of claims 23-24 or 26, wherein said pharmaceutical composition is for topical administration. A composition comprising an IL-7R binding polypeptide, together with a TNF-α binding polypeptide for use in the treatment or prevention of autoimmune and/or inflammatory diseases, wherein said IL-7R binding polypeptide contains three complementarity determining regions (CDR1-CDR3) and four framework regions (FR1-FR4), where CDR1 contains a sequence that shares 60% or more sequence identity with SEQ ID NO:9, and CDR2 contains , comprising a sequence sharing 50% or more sequence identity with SEQ ID NO:10, wherein CDR3 comprises a sequence sharing 60% or more sequence identity with SEQ ID NO:11. A composition comprising an IL-7R binding polypeptide for use in the treatment or prevention of autoimmune and/or inflammatory diseases together with a composition comprising a TNF-α binding polypeptide, said IL-7R binding polypeptide contains three complementarity determining regions (CDR1-CDR3) and four framework regions (FR1-FR4), where CDR1 contains a sequence that shares 60% or more sequence identity with SEQ ID NO:9, and CDR2 contains , comprising a sequence sharing 50% or more sequence identity with SEQ ID NO:10, wherein CDR3 comprises a sequence sharing 60% or more sequence identity with SEQ ID NO:11.