The glycosylation and pharmacokinetics of CTLA4Ig produced in rice cells.
Cytotoxic T-lymphocyte antigen 4-immunoglobulin (CTLA4Ig) has immunosuppressive activity and the ability to induce immune tolerance. There has been no report of its glycosylation ratio or of the role of its glycans. We investigated the terminal sialylation of rice cell-derived recombinant human CTLA4Ig (rrhCTLA4Ig) using lectins. The glycosylation ratios of rrhCTLA4Ig and Chinese hamster ovary (CHO) cell-derived recombinant human CTLA4Ig (crhCTLA4Ig) were evaluated by chemical deglycosylation. After intravenous (i.v.) or subcutaneous (s.c.) administration to rats, the pharmacokinetics of rrhCTLA4Ig and crhCTLA4Ig as well as of their deglycosylated forms were evaluated. rrhCTLA4Ig does not have terminal sialic acids and its glycosylation ratio was slightly lower than that of crhCTLA4Ig. Its terminal elimination half-life (T(1/2)) was shorter than that of crhCTLA4Ig following i.v. administration. However, the half-life was significantly prolonged and was similar with that of crhCTLA4Ig following s.c. administration. Moreover, the deglycosylated forms of both preparations were cleared from the circulation faster than the native forms. These results suggest that the presence of glycans on rrhCTLA4Ig and crhCTA4Ig are important for their in vivo stability. In addition, the glycan structure of rrhCTLA4Ig is more effective in maintaining in vivo stability after s.c. administration than after i.v. administration although the glycans on rrhCTLA4Ig lack terminal sialic acids, suggesting that its glycans have the potential for in vivo stability.
Kim
Hyoung Jin
HJ
College of Pharmacy, Chung-Ang University, Seoul, South Korea.
Kim
Hong-Jin
HJ
D000069594:Abatacept; D000818:Animals; D019540:Area Under Curve; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004591:Electrophoresis, Polyacrylamide Gel; D004921:Erythropoietin / Q000493:pharmacokinetics; D006031:Glycosylation; D006207:Half-Life; D006801:Humans; D018796:Immunoconjugates / Q000378:metabolism* / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D019158:N-Acetylneuraminic Acid / Q000737:chemistry; D012275:Oryza / Q000378:metabolism*; D030821:Plants, Genetically Modified; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000737:chemistry / Q000493:pharmacokinetics
D018796:Immunoconjugates; D011994:Recombinant Proteins; D004921:Erythropoietin; D000069594:Abatacept; D019158:N-Acetylneuraminic Acid