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Articles by Y Aso
Total Records ( 3 ) for Y Aso
  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.

  N Masuyama , T Kuronita , R Tanaka , T Muto , Y Hirota , A Takigawa , H Fujita , Y Aso , J Amano and Y. Tanaka

HM1.24/Bst2/CD317 is a protein highly expressed in multiple myeloma cells and has unique topology with two membrane anchor domains, an NH2-terminal transmembrane domain and a glycosylphosphatidylinositol attached to the COOH terminus. We show here that human HM1.24 is localized not only on the cell surface but also in the trans-Golgi network and/or recycling endosomes, where it resides in detergent-resistant microdomains, lipid rafts. In contrast to other glycosylphosphatidylinositol-anchored proteins, HM1.24 was internalized from lipid rafts on the cell surface by clathrin-mediated endocytosis. Interestingly, a non-canonical tyrosine-based motif, which contains two tyrosine residues, Tyr-6 and Tyr-8, present in the NH2-terminal cytoplasmic tail, was essential for endocytosis through interaction with an a-adaptin, but not µ2-subunit, of the AP-2 complex. Indeed, an appendage domain of -adaptin was identified as a protein interacting with the cytoplasmic tail of HM1.24. Furthermore, overexpression of the appendage domain of -adaptin in cells depleted of -adaptin could rescue the clathrin-mediated endocytosis of HM1.24 but not of the transferrin receptor. Taken together, our findings suggest that clathrin-dependent endocytosis of human HM1.24 from the cell surface lipid rafts is mediated by direct interaction with -adaptin.

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