Antagonist antibodies that bind to human TGFB1, TGFB2 and to TGFB3 and their use for the treatment of lung fibrosis
The present disclosure relates to TGF-beta antibodies and binding fragments thereof, DNA encoding the same, host cells comprising said DNA and methods of expressing the antibody or binding fragment in a host cell. The disclosure also extends to pharmaceutical compositions comprising the antibody or a binding fragment thereof and use of the antibody, binding fragment and compositions comprising the same in treatment of various diseases including fibrosis.
1. An isolated DNA sequence encoding a heavy chain variable domain of an antagonistic antibody, which antagonistic antibody binds human TGF-beta 1, human TGF-beta 2 and human TGF-beta 3, wherein the encoded heavy chain variable domain comprises a CDR having SEQ ID NO:4 for CDR-H1, a CDR having SEQ ID NO:5 for CDR-H2 and a CDR having SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8 or SEQ ID NO:9 for CDR-H3.
2. An The isolated DNA sequence according to claim 1 , wherein the isolated DNA sequence comprises SEQ ID NO: 53; SEQ ID NO:54; SEQ ID NO: 67; SEQ ID NO: 68; SEQ ID NO:81; SEQ ID NO:82; SEQ ID NO:95 or SEQ ID NO:96.
3. A cloning or expression vector comprising the DNA sequence according to claim 2 .
4. The isolated DNA sequence according to claim 1 , wherein the isolated DNA sequence further encodes a constant domain of the heavy chain and comprises SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 102, or SEQ ID NO: 103.
5. A cloning or expression vector comprising the DNA sequence according to claim 4 .
6. A cloning or expression vector comprising the DNA sequence according to claim 1 .
7. An isolated DNA sequence encoding a light chain variable domain of an antagonistic antibody, which antagonistic antibody binds human TGF-beta 1, human TGF-beta 2 and human TGF-beta 3, wherein the encoded light chain variable domain comprises a CDR having SEQ ID NO:1 for CDR-L1, a CDR having SEQ ID NO:2 for CDR-L2 and a CDR having SEQ ID NO:3 for CDR-L3.
8. The isolated DNA sequence according to claim 7 , wherein the isolated DNA sequence comprises SEQ ID NO: 39 or SEQ ID NO:40.
9. A cloning or expression vector comprising the DNA sequence according to claim 8 .
10. The isolated DNA sequence according to claim 7 , wherein the isolated DNA sequence further encodes a constant domain of the light chain and comprises SEQ ID NO: 46 or SEQ ID NO:47.
11. A cloning or expression vector comprising the DNA sequence according to claim 7 .
12. An isolated DNA sequence encoding a heavy chain variable domain and a light chain variable domain of an antagonistic antibody, which antagonistic antibody binds human TGF-beta 1, human TGF-beta 2 and human TGF-beta 3, wherein the isolated DNA sequence comprises:
a first DNA sequence encoding the heavy chain variable domain, wherein the heavy chain variable domain comprises a CDR having SEQ ID NO:4 for CDR-H1, a CDR having SEQ ID NO:5 for CDR-H2 and a CDR having SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8 or SEQ ID NO:9 for CDR-H3, and
a second DNA sequence encoding the light chain variable domain, wherein the light chain variable domain comprises a CDR having SEQ ID NO:1 for CDR-L1, a CDR having SEQ ID NO:2 for CDR-L2 and a CDR having SEQ ID NO:3 for CDR-L3.
13. A cloning or expression vector comprising the DNA sequence according to claim 12 .
14. A cloning or expression vector according to claim 13 , wherein the vector comprises SEQ ID NO: 39 or SEQ ID NO:40, and/or SEQ ID NO: 53, SEQ ID NO:54, SEQ ID NO: 67, SEQ ID NO:68, SEQ ID NO: 81, SEQ ID NO:82, SEQ ID NO:95 or SEQ ID NO: 96.
15. A host cell comprising one or more cloning or expression vectors according to claim 14 .
16. A process for producing an antagonistic antibody, comprising culturing the host cell of claim 15 and isolating the antibody.
17. The isolated DNA sequence according to claim 12 , wherein the isolated DNA sequence comprises SEQ ID NO: 53; SEQ ID NO:54; SEQ ID NO: 67; SEQ ID NO: 68; SEQ ID NO:81; SEQ ID NO:82; SEQ ID NO:95 or SEQ ID NO:96.
18. The isolated DNA sequence according to claim 12 , wherein the isolated DNA sequence further encodes a constant domain of the heavy chain and comprises SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 102, or SEQ ID NO: 103.
19. The isolated DNA sequence according to claim 12 , wherein the isolated DNA sequence comprises SEQ ID NO: 39 or SEQ ID NO:40.
20. The isolated DNA sequence according to claim 12 , wherein the isolated DNA sequence further encodes a constant domain of the light chain and comprises SEQ ID NO: 46 or SEQ ID NO:47.