Methods of modulating immunological responses by administering truncated baff receptors

Abstract

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 .- 47 . (canceled) 
     
     
         48 . A method for modulating B cell development, antibody production, or cytokine production in a patient in need thereof, comprising administering a therapeutically effective amount of a glycoprotein to the patient, 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). 
     
     
         49 . The method of  claim 48 , wherein the extracellular domain of the non-naturally occurring BAFF-R has at least one O-linked glycan. 
     
     
         50 . The method of  claim 49 , wherein the O-linked glycan is attached on an amino acid that corresponds to threonine 18 or threonine 41 of SEQ ID NO: 1. 
     
     
         51 . The method of  claim 49 , 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. 
     
     
         52 . The method of  claim 49 , wherein the extracellular domain of the non-naturally occurring BAFF-R comprises amino acids 14 to 43 of SEQ ID NO: 1. 
     
     
         53 . The method of  claim 52 , wherein the deletion corresponds to amino acid 50 to amino acid 56 of SEQ ID NO: 1. 
     
     
         54 . The method of  claim 52 , wherein the deletion corresponds to amino acid 50 to amino acid 63 of SEQ ID NO: 1. 
     
     
         55 . The method of  claim 52 , wherein the deletion corresponds to amino acid 50 to amino acid 72 of SEQ ID NO: 1. 
     
     
         56 . The method of  claim 48 , 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. 
     
     
         57 . The method of  claim 48 , 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. 
     
     
         58 . The method of  claim 52 , 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. 
     
     
         59 . The method of  claim 48 , 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.   
     
     
         60 . The method of  claim 48 , 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. 
     
     
         61 . The method of  claim 60 , 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. 
     
     
         62 . The method of  claim 60 , 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. 
     
     
         63 . The method of  claim 60 , wherein the glycoprotein further 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. 
     
     
         64 . The method of  claim 63 , wherein the portion of the immunoglobulin constant region is from IgG1 or IgG4. 
     
     
         65 . The method of  claim 64 , wherein the portion of the immunoglobulin constant region comprises amino acids 3 to 227 of SEQ ID NO:4. 
     
     
         66 . A method for modulating B cell development, antibody production, or cytokine production in a patient in need thereof, comprising administering a therapeutically effective amount of a BAFF-R polypeptide to the patient, wherein the BAFF-R polypeptide comprises amino acids 14 to 56 of SEQ ID NO:1 and has mutations at amino acids 50, 51, and 56 of SEQ ID NO: 1, wherein amino acid 50 is not serine or threonine, amino acid 51 is not serine or threonine, and amino acid 56 is not serine or threonine. 
     
     
         67 . The method of  claim 66 , wherein the BAFF-R polypeptide comprises amino acids 14 to 63 of SEQ ID NO:1. 
     
     
         68 . The method of  claim 67 , wherein the BAFF-R polypeptide has a mutation at amino acid 63 of SEQ ID NO: 1, wherein amino acid 63 is not serine or threonine.