Antibodies to IL-6 and use thereof
The present invention is directed to antibodies and fragments thereof and humanized versions thereof having binding specificity for IL-6. Another embodiment of this invention relates to the antibodies described herein, and binding fragments thereof, comprising the sequences of the V H , V L and CDR polypeptides described herein, and the polynucleotides encoding them. The invention also contemplates conjugates of anti-IL-6 antibodies and binding fragments thereof conjugated to one or more functional or detectable moieties. The invention also contemplates methods of making said anti-IL-6 antibodies and binding fragments thereof. Embodiments of the invention also pertain to the use of anti-IL-6 antibodies, and binding fragments thereof, for the diagnosis, assessment and treatment of diseases and disorders associated with IL-6. These antibodies may bind at least one of soluble IL-6, cell surface expressed IL-6, IL-6/IL-6R and/or prevent the association of IL-6 and IL-6R, the association of IL-6/IL-6R and gp130 and or the formation of IL-6/IL-6R/gp130 multimers and thereby inhibit a biological effect associated with any of the foregoing.
1. A method of producing an anti-IL-6 antibody comprising a light chain polypeptide or variable light chain polypeptide and a heavy chain polypeptide or variable heavy chain polypeptide, said method comprising culturing a recombinant yeast or mammalian cell which expresses a first nucleic acid sequence encoding said light chain polypeptide or variable light chain polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOS:2, 20, and 651; and which recombinant cell further expresses a second nucleic acid sequence encoding a heavy chain polypeptide or variable heavy chain polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOS:3, 18, 19, 657, and 658.
2. The method of claim 1 wherein the first or second nucleic acid sequence is comprised of yeast or human preferred codons.
3. The method of claim 1 wherein the recombinant host cell is a mammalian cell.
4. The method of claim 1 wherein the mammalian host cell is a CHO, COS, BHK, or HEK-293 cell.
5. The method of claim 1 wherein the recombinant host cell is a yeast cell.
6. The method of claim 5 wherein the yeast cell is haploid, diploid or tetraploid.
7. The method of claim 5 wherein the yeast host cell is a Pichia cell selected from Pichia pastoris, Pichia methanolica , and Pichia angusta.
8. The method of claim 7 wherein the Pichia yeast comprise auxotrophic strains.
9. The method of claim 8 wherein said auxotrophic strains comprise P. pastoris strains met1, lys3, ura3 and ade1.
10. The method of claim 5 wherein the recombinant yeast cell is polyploidal.
11. The method of claim 1 wherein the light chain polypeptide comprises the variable light chain polypeptide of SEQ ID NO: 20 or SEQ ID NO: 651 and further comprises the kappa constant light chain polypeptide of SEQ ID NO: 586 and the heavy chain polypeptide comprises the variable heavy chain polypeptide of any one of SEQ ID NOS: 18, 19, 657 and 658 and further comprises the gamma-1 constant heavy chain of SEQ ID NO: 588.
12. The method of claim 1 wherein the light chain polypeptide comprises the variable light chain polypeptide of SEQ ID NO: 20 and further comprises the kappa constant light chain polypeptide of SEQ ID NO: 586 and the heavy chain polypeptide comprises the variable heavy chain polypeptide of SEQ ID NO: 18 and further comprises the gamma-1 constant heavy chain of SEQ ID NO: 588.
13. The method of claim 12 , wherein the recombinant host cell comprises a diploidal Pichia pastoris cell.
14. The method of claim 1 wherein the light chain polypeptide comprises the variable light chain polypeptide of SEQ ID NO: 20 and further comprises the kappa constant light chain polypeptide of SEQ ID NO: 586 and the heavy chain polypeptide comprises the variable heavy chain polypeptide of SEQ ID NO: 19 and further comprises the gamma-1 constant heavy chain of SEQ ID NO: 588.
15. The method of claim 14 , wherein the recombinant host cell comprises a diploidal Pichia pastoris cell.
16. The method of claim 1 wherein the light chain polypeptide comprises the variable light chain polypeptide of SEQ ID NO: 20 and the further comprises kappa constant light chain polypeptide of SEQ ID NO: 586 and the heavy chain polypeptide comprises the variable heavy chain polypeptide of SEQ ID NO: 657 and further comprises the gamma-1 constant heavy chain of SEQ ID NO: 588.
17. The method of claim 16 , wherein the recombinant host cell comprises a diploidal Pichia pastoris cell.
18. The method of claim 1 wherein the light chain polypeptide comprises the variable light chain polypeptide of SEQ ID NO: 20 and further comprises the kappa constant light chain polypeptide of SEQ ID NO: 586 and the heavy chain polypeptide comprises the variable heavy chain polypeptide of SEQ ID NO: 658 and further comprises the gamma-1 constant heavy chain of SEQ ID NO: 588.
19. The method of claim 18 , wherein the recombinant host cell comprises a diploidal Pichia pastoris cell.
20. The method of claim 1 wherein the recombinant cell is engineered to express protein disulfide isomerase (PDI).
21. The method of claim 11 wherein the recombinant host cell comprises a diploidal Pichia pastoris cell.