Engineered antibody for inhibition of fibrosis

Abstract

A chimeric, humanized or single-chain antibody contains a light chain variable region containing the complementarity determining regions of SEQ ID NO: 1, SEQ ID NO:2 and SEQ ID NO:3, and a heavy chain variable region containing the complementarity determining regions SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6. The antibody or antibody fragment thereof is capable of binding the C-terminal telopeptide of the α2(I) chain of human collagen I, and is useful in the treatment of diseases or disorders associated with excessive collagen fibril.

What is claimed is: 
     
       1. A chimeric, humanized, or single-chain antibody which comprises a light chain variable region comprising complementarity determining regions comprising the amino acid sequences SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, and a heavy chain variable region comprising complementarity determining regions comprising the amino acid sequences SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, or a fragment of said chimeric or humanized antibody, which antibody or antibody fragment binds the C-terminal telopeptide of the α2(I) chain of human collagen I. 
     
     
       2. The antibody or antibody fragment according to  claim 1 , which is a chimeric antibody or fragment of a chimeric antibody, which fragment binds the C-terminal telopeptide of the α2(I) chain of human collagen. 
     
     
       3. The A chimeric, humanized, or single-chain antibody according to  claim 2 , which comprises comprising an antibody light chain comprising three complementarity determining regions of a light variable region having the amino acid sequence shown in SEQ ID NO:10, and an antibody heavy chain comprising three complementarity determining regions of a heavy chain variable region having the amino acid sequence SEQ ID NO:11, or a fragment of said chimeric antibody which, wherein the antibody or the fragment each binds the C-terminal telopeptide of the α2(I) chain of human collagen I. 
     
     
       4. The chimeric, humanized, or single-chain antibody or the fragment according to  claim 3 , wherein said antibody light chain comprises a human antibody light chain constant region, and said antibody heavy chain comprises a human antibody heavy chain constant region, or a fragment of said chimeric antibody which binds the C-terminal telopeptide of the α2(I) chain of human collagen. 
     
     
       5. The chimeric, humanized, or single-chain antibody according to  claim 4 , wherein the human constant regions comprise IgG constant regions. 
     
     
       6. The antibody or antibody fragment according to  claim 1 , which is a humanized antibody or fragment of a humanized antibody, which fragment binds the C-terminal telopeptide of the α2(I) chain of human collagen. 
     
     
       7. The humanized antibody according to  claim 6 , which comprises a human antibody framework region and/or a human antibody constant region, or a fragment of said humanized antibody which binds the C-terminal telopeptide of the α2(I) chain of human collagen. 
     
     
       8. The humanized antibody according to  claim 6 , which comprises a human antibody constant region. 
     
     
       9. The humanized antibody according to  claim 8 , wherein the constant region comprises an IgG constant region. 
     
     
       10. The antibody according to claim  1  3, which is a single chain antibody. 
     
     
       11. The single chain antibody according to  claim 10 , wherein the single chain antibody comprises a light chain variable region having the amino acid sequence shown in SEQ ID NO:10, and a heavy chain variable region having the amino acid sequence shown in SEQ ID NO:11. 
     
     
       12. The single chain antibody according to claim  11  10, wherein the antibody further comprises a linker comprising a sequence of one or more amino acids linking said light chain variable region and said heavy chain variable region. 
     
     
       13. The single chain antibody according to  claim 12 , wherein the linker comprises the amino acid sequence Gly-Gly-Ser or the amino acid sequence Gly-Gly-Gly-Gly-Ser (SEQ ID NO:29). 
     
     
       14. The single chain antibody according to  claim 12 , wherein the linker connects the carboxy terminus of said light chain variable region to the amino terminus of said heavy chain variable region. 
     
     
       15. The single chain antibody according to  claim 13 , wherein the linker comprises from two to twelve repeats of the amino acid sequence Gly-Gly-Ser, or from two to twelve repeats of the amino acid sequence Gly-Gly-Gly-Gly-Ser (SEQ ID NO:29). 
     
     
       16. The single chain antibody according to  claim 15 , comprising the amino acid sequence shown in SEQ ID NO:12. 
     
     
       17. The single chain antibody according to  claim 12 , wherein the linker connects the carboxy terminus of said heavy chain variable region to the amino terminus of said light chain variable region. 
     
     
       18. The single chain antibody according to  claim 17 , wherein the linker comprises from two to twelve repeats of the amino acid sequence Gly-Gly-Ser, or from two to twelve repeats of the amino acid sequence Gly-Gly-Gly-Gly-Ser (SEQ ID NO:29). 
     
     
       19. The single chain antibody according to  claim 18 , comprising the amino acid sequence shown in SEQ ID NO:16. 
     
     
       20. A pharmaceutical composition comprising the antibody or antibody the fragment according to claim  1  3and a pharmaceutically acceptable carrier. 
     
     
       21. The chimeric, humanized, or single-chain antibody or the fragment according to claim 3, wherein the antibody or fragment each comprises the light variable region having the amino acid sequence shown in SEQ ID NO:10 and the heavy chain variable region having the amino acid sequence SEQ ID NO:11.