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Articles by Y Sekimori
Total Records ( 2 ) for Y Sekimori
  T Igawa , H Tsunoda , T Tachibana , A Maeda , F Mimoto , C Moriyama , M Nanami , Y Sekimori , Y Nabuchi , Y Aso and K. Hattori

Fc engineering to increase the binding affinity of IgG antibodies to FcRn has been reported to reduce the elimination of IgG antibodies. Herein, we present a novel non-FcRn-dependent approach to reduce the elimination of IgG antibodies. Pharmacokinetic studies conducted in normal mice of various humanized IgG4 antibodies, which had identical constant regions but different variable region sequences, revealed that an antibody with a lower isoelectric point (pI) has a longer half-life. These antibodies exhibited comparable binding affinity to FcRn, and with the antibodies with lower pIs, a longer half-life was also observed in β2-microglobulin knockout mice, suggesting that differences in the pharmacokinetics were due to a non-FcRn-dependent mechanism. On the basis of our findings, we attempted to engineer the pharmacokinetic properties of a humanized anti-IL6 receptor IgG1 antibody. Selected substitutions in the variable region, without substitution in the Fc region, lowered the pI but did not reduce the biological activity and showed a significant reduction in the clearance of the antibody in cynomolgus monkey. These results suggest that lowering the pI by engineering the variable region could reduce the elimination of IgG antibodies and could provide an alternative to Fc engineering of IgG antibodies.

  T Igawa , H Tsunoda , Y Kikuchi , M Yoshida , M Tanaka , A Koga , Y Sekimori , T Orita , Y Aso , K Hattori and M. Tsuchiya

Thrombopoietin receptor agonist humanized VB22B single-chain diabody (hVB22B (scFv)2) was found to be expressed as a mixture of two conformational isomers, a single-chain diabody form and a bivalent scFv form, which had different VH/VL (variable region of the heavy chain/light chain) association patterns. The single-chain diabody form showed significantly higher biological activity than the bivalent scFv form and, when incubated at elevated temperatures, exhibited novel isomerization to the inactive bivalent scFv form. Therefore, therapeutic development of hVB22B (scFv)2 would require separation of the purified single-chain diabody form from the mixture of the two conformational isomers and also inhibition of isomerization into an inactive bivalent scFv form during storage. Novel VH/VL interface engineering in hVB22 (scFv)2, in which hydrogen bonding between H39 and L38 was substituted with electrostatic interaction to enhance the desired VH/VL association and inhibit the undesired VH/VL association, enabled selective expression of the desired conformational isomer without any reduction in biological activity or thermal stability. Moreover, VH/VL interface-engineered hVB22 (scFv)2 was completely resistant to isomerization. Because the hydrogen bonding interaction between H39 and L38 and the surrounding residues are highly conserved in human antibody sequences, VH/VL interface engineering could be generally applied to various (scFv)2 molecules for selective expression and inhibition of the isomerization of conformational isomers.

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