Treatment of autoimmune disorders

Abstract

This invention relates to methods of treating disease with soluble inhibitors of the lymphotoxin pathway having improved properties. This invention also relates to improved LTBR-Ig fusion proteins, and pharmaceutical compositions thereof.

1 .- 83 . (canceled) 
     
     
         84 . A composition comprising an LTβR-Ig fusion protein comprising an LTβR extracellular domain, wherein the LTBR extracellular domain is non-glycosylated at one or more of its N-linked glycosylation sites. 
     
     
         85 . The composition of  claim 84 , wherein the LTβR extracellular domain contains one or more amino acid mutations as compared to SEQ ID NO:21, which remove said one or more N-linked glycosylation sites. 
     
     
         86 . The composition of  claim 84 , wherein the LTβR extracellular domain comprises amino acids 1-194 of SEQ ID NO:10. 
     
     
         87 . The composition of  claim 84 , wherein the LTβR extracellular domain is aglycosylated. 
     
     
         88 . The composition of  claim 84 , wherein the Ig portion of the LTβR-Ig fusion protein contains one or more mutations as compared to SEQ ID NO:22, which removes its N-linked glycosylation sites. 
     
     
         89 . A composition comprising an LTβR-Ig fusion protein comprising one or more mutations as compared to SEQ ID NO:11, wherein said one or more mutations is selected from the group consisting of N13Q, N150Q and N276Q. 
     
     
         90 . The composition of  claim 89 , wherein the LTβR-Ig fusion protein is missing no more than five amino acids from the N-terminus of the mature form of the fusion protein. 
     
     
         91 . The composition of  claim 84  or  89 , wherein the LTβR-Ig fusion proteins are made by expressing a nucleic acid molecule comprising a nucleotide sequence encoding the LTβR-Ig fusion protein in a mammalian cell. 
     
     
         92 . The composition of  claim 84  or  89 , wherein the Ig portion of the LTβR-Ig fusion protein comprises a variant Fc region. 
     
     
         93 . The composition of  claim 92 , wherein the variant Ig portion comprises Fc regions of an IgG1 isotype. 
     
     
         94 . The composition of  claim 92 , wherein the variant Ig portion comprises a mutation in the hinge region. 
     
     
         95 . The composition of  claim 91 , wherein the Ig portion of the LTβR-Ig fusion protein is non-glycosylated. 
     
     
         96 . The composition of  claim 91 , wherein the step of expressing is done at manufacturing scale. 
     
     
         97 . A pharmaceutical composition comprising the composition of  claim 84  or  89  and a pharmaceutically acceptable carrier. 
     
     
         98 . A method of treating an autoimmune disorder in a patient comprising administering an effective amount of the pharmaceutical composition of  claim 97 . 
     
     
         99 . The method of  claim 98  wherein the autoimmune disorder is multiple sclerosis or rheumatoid arthritis. 
     
     
         100 . An isolated polypeptide comprising an LTβR-Ig fusion protein comprising one or more mutations as compared to SEQ ID NO:11, wherein said one or more mutations is selected from the group consisting of N13Q, N150Q and N276Q. 
     
     
         101 . An isolated nucleic acid molecule encoding the polypeptide of  claim 100 . 
     
     
         102 . A vector comprising the nucleic acid molecule of  claim 101 . 
     
     
         103 . An isolated or cultured host cell expressing the vector of  claim 102 . 
     
     
         104 . The cell of  claim 103 , which is a Chinese hamster Ovary (CHO) cell. 
     
     
         105 . An isolated polypeptide comprising an LTβR-Ig fusion protein comprising one or more mutations as compared to SEQ ID NO:5, wherein said one or more mutations is selected from the group consisting of N13Q, N150Q and N276Q, referencing SEQ ID NO:11. 
     
     
         106 . An isolated nucleic acid molecule encoding the polypeptide of  claim 105 . 
     
     
         107 . A vector comprising the nucleic acid molecule of  claim 106 . 
     
     
         108 . An isolated or cultured host cell expressing the vector of  claim 107 . 
     
     
         109 . The cell of  claim 108 , which is a Chinese hamster Ovary (CHO) cell.