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Engineering of anti-human interleukin-4 receptor alpha antibodies with potent antagonistic activity

Kim, JE | Jung, K  | Kim, JA | Kim, SH  | Park, HS  | Kim, YS
Scientific reports, 9. : 7772-7772, 2019
Journal Title
Scientific reports
Development of antagonistic antibody (Ab) against interleukin-4 receptor alpha (IL-4Ralpha) subunit of IL-4/IL-13 receptors is a promising therapeutic strategy for T helper 2 (TH2)-mediated allergic diseases such as asthma and atopic dermatitis. Here we isolated anti-human IL-4Ralpha antagonistic Abs from a large yeast surface-displayed human Ab library and further engineered their complementarity-determining regions to improve the affinity using yeast display technology, finally generating a candidate Ab, 4R34.1.19. When reformatted as human IgG1 form, 4R34.1.19 specifically bound to IL-4Ralpha with a high affinity (KD approximately 178 pM) and effectively blocked IL-4- and IL-13-dependent signaling in a reporter cell system at a comparable level to that of the clinically approved anti-IL-4Ralpha dupilumab Ab analogue. Epitope mapping by alanine scanning mutagenesis revealed that 4R34.1.19 mainly bound to IL-4 binding sites on IL-4Ralpha with different epitopes from those of dupilumab analogue. Further, 4R34.1.19 efficiently inhibited IL-4-dependent proliferation of T cells among human peripheral blood mononuclear cells and suppressed the differentiation of naive CD4(+) T cells from healthy donors and asthmatic patients into TH2 cells, the activities of which were comparable to those of dupilumab analogue. Our work demonstrates that both affinity and epitope are critical factors for the efficacy of anti-IL-4Ralpha antagonistic Abs.
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Journal Papers > Hospital > Clinical Trial Center
Journal Papers > School of Medicine / Graduate School of Medicine > Allergy
Ajou Authors
김, 승현  |  박, 해심  |  정, 근옥
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