Method of treating B cell cancers by administering truncated BAFF receptors
View Patent ↗The disclosure provides a non-naturally occurring BAFF-R glycoprotein having a deletion in the extracellular domain which results in an altered O-linked glycosylation pattern. The disclosure also provides methods and pharmaceutical compositions for treating B-cell- and T-cell-mediated disorders.
1. A method for treating a B cell cancer comprising administering a therapeutically effective amount of a glycoprotein to a patient in need of treatment, thereby treating the B cell cancer, wherein the glycoprotein comprises the extracellular domain of a non-naturally occurring BAFF-R (BAFF receptor), wherein the extracellular domain of the non-naturally occurring BAFF-R has a deletion which results in an altered O-linked glycosylation pattern, and wherein the non-naturally occurring BAFF-R retains the ability to bind to BAFF (B-cell-activating factor of the TNF family).
2. The method of claim 1 , wherein the extracellular domain of the non-naturally occurring BAFF-R has at least one O-linked glycan.
3. The method of claim 2 , wherein the O-linked glycan is attached on an amino acid that corresponds to threonine 18 or threonine 41 of SEQ ID NO:1.
4. The method of claim 2 , wherein the O-linked glycan is attached on an amino acid that corresponds to threonine 18, threonine 41, or serine 8 of SEQ ID NO:1.
5. The method of claim 2 , wherein the extracellular domain of the non-naturally occurring BAFF-R comprises amino acids 4 to 43 of SEQ ID NO: 1.
6. The method of claim 5 , wherein the deletion corresponds to amino acid 50 to amino acid 56 of SEQ ID NO:1.
7. The method of claim 5 , wherein the deletion corresponds to amino acid 50 to amino acid 63 of SEQ ID NO:1.
8. The method of claim 5 , wherein the deletion corresponds to amino acid 50 to amino acid 72 of SEQ ID NO:1.
9. The method of claim 5 , wherein the extracellular domain of the non-naturally occurring BAFF-R has at least two amino acid substitutions, wherein the substituted amino acids correspond to amino acid positions 21 and 28 of SEQ ID NO: 1.
10. The method of claim 1 , wherein the extracellular domain of the non-naturally occurring BAFF-R comprises a polypeptide having an amino acid sequence substantially identical to SEQ ID NO:1 from amino acid 13 to amino acid 43.
11. The method of claim 1 , wherein the extracellular domain of the non-naturally occurring BAFF-R comprises a polypeptide having an amino acid sequence substantially identical to SEQ ID NO:1 from amino acid 14 to amino acid 43.
12. The method of claim 1 , wherein the extracellular domain of the non-naturally occurring BAFF-R consists of an amino acid sequence selected from the group consisting of:
(a) amino acids 13 to 43 of SEQ ID NO:1;
(b) amino acids 14 to 43 of SEQ ID NO:1;
(c) amino acids 1 to 49 of SEQ ID NO:1;
(d) amino acids 8 to 49 of SEQ ID NO:1;
(e) amino acids 13 to 49 of SEQ ID NO:1;
(f) amino acids 14 to 49 of SEQ ID NO:1; or
(g) amino acids 1 to 49 of SEQ ID NO:7.
13. The method of claim 1 , wherein the extracellular domain of the non-naturally occurring BAFF-R, comprises an amino acid sequence from amino acid 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 of SEQ ID NO:1 to amino acid 43, 44, 45, 46, 47, 48, or 49 of SEQ ID NO:1.
14. The method of claim 13 , wherein the amino acid corresponding to position 21 of SEQ ID NO:1 is valine and the amino acid corresponding to position 28 of SEQ ID NO:1 is leucine.
15. The method of claim 13 , wherein the amino acid corresponding to position 21 of SEQ ID NO:1 is asparagine and the amino acid corresponding to position 28 of SEQ ID NO:1 is proline.
16. The method of claim 13 , wherein the glycoprotein further comprises at least a portion of an immunoglobulin constant region and optionally a linker joining the amino acid sequence to the portion of the immunoglobulin constant region, wherein the linker does not include amino acids 50 to 56 of SEQ ID NO:1.
17. The method of claim 16 , wherein the portion of the immunoglobulin constant region is from IgG1 or IgG4.
18. The method of claim 17 , wherein the portion of the immunoglobulin constant region comprises amino acids 3 to 227 of SEQ ID NO:4.
19. The method of claim 1 , wherein the B cell cancer is a pre-B or B cell leukemia.
20. The method of claim 19 , wherein the pre-B or B cell leukemia is plasma cell leukemia.
21. The method of claim 1 , wherein the B cell cancer is a chronic or acute lymphocytic leukemia.
22. The method of claim 1 , wherein the B cell cancer is myeloma.
23. The method of claim 22 , wherein the myeloma is multiple myeloma.
24. The method of claim 22 , wherein the myeloma is plasma cell myeloma.
25. The method of claim 22 , wherein the myeloma is endothelial myeloma.
26. The method of claim 22 , wherein the myeloma is giant cell myeloma.
27. The method of claim 1 , wherein the B cell cancer is lymphoma.
28. The method of claim 27 , wherein the lymphoma is non-Hodgkin's lymphoma.