IgE-neutralizing UB-221 mAb, distinct from omalizumab and ligelizumab, exhibits CD23-mediated IgE downregulation and relieves urticaria symptoms
Be-Sheng Kuo, … , Mei-June Liao, Chang Yi Wang
Be-Sheng Kuo, … , Mei-June Liao, Chang Yi Wang
Published August 1, 2022
Citation Information: J Clin Invest. 2022;132(15):e157765. https://doi.org/10.1172/JCI157765.
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Research Article Immunology

IgE-neutralizing UB-221 mAb, distinct from omalizumab and ligelizumab, exhibits CD23-mediated IgE downregulation and relieves urticaria symptoms

Abstract

Over the last 2 decades, omalizumab is the only anti-IgE antibody that has been approved for asthma and chronic spontaneous urticaria (CSU). Ligelizumab, a higher-affinity anti-IgE mAb and the only rival viable candidate in late-stage clinical trials, showed anti-CSU efficacy superior to that of omalizumab in phase IIb but not in phase III. This report features the antigenic-functional characteristics of UB-221, an anti-IgE mAb of a newer class that is distinct from omalizumab and ligelizumab. UB-221, in free form, bound abundantly to CD23-occupied IgE and, in oligomeric mAb-IgE complex forms, freely engaged CD23, while ligelizumab reacted limitedly and omalizumab stayed inert toward CD23; these observations are consistent with UB-221 outperforming ligelizumab and omalizumab in CD23-mediated downregulation of IgE production. UB-221 bound IgE with a strong affinity to prevent FcԑRI-mediated basophil activation and degranulation, exhibiting superior IgE-neutralizing activity to that of omalizumab. UB-221 and ligelizumab bound cellular IgE and effectively neutralized IgE in sera of patients with atopic dermatitis with equal strength, while omalizumab lagged behind. A single UB-221 dose administered to cynomolgus macaques and human IgE (ε, κ)–knockin mice could induce rapid, pronounced serum-IgE reduction. A single UB-221 dose administered to patients with CSU in a first-in-human trial exhibited durable disease symptom relief in parallel with a rapid reduction in serum free-IgE level.

Authors

Be-Sheng Kuo, Chao-Hung Li, Jiun-Bo Chen, Yu-Yu Shiung, Chia-Yu Chu, Chih-Hung Lee, Yaw-Jen Liu, Je-Hung Kuo, Cindy Hsu, Hsiao-Wen Su, Ywan-Feng Li, Annie Lai, Yueh-Feng Ho, Yi-Ning Cheng, Hong-Xuan Huang, Meng-Chung Lung, Ming-Syue Wu, Fu-Hung Yang, Chen-Han Lin, William Tseng, Jasper Yang, Chia-Yin Lin, Pei-Hua Tsai, Heng-Kwei Chang, Yi-Jen Wang, Techeng Chen, Shugene Lynn, Mei-June Liao, Chang Yi Wang

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Figure 6

The IgE-binding affinity of UB-221 and ligelizumab on SPR.

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The IgE-binding affinity of UB-221 and ligelizumab on SPR. Kinetic analy...
Kinetic analyses on SPR of IgE binding to the anti-IgE mAbs UB-221, ligelizumab (Creative Biolabs, TAB755), and omalizumab were performed on SPR. IgG Fc antibodies were first covalently coupled to the surface sensor chip, on which the diluted anti-IgE antibodies were captured. The Expi293-expressed human full-length IgE at 0.312–50 nM was injected and the dissociation was measured under constant buffer flow. The resulting equilibrium dissociation rate constant (KD, binding affinity), association rate constant (ka), and dissociation rate constant (kd) are presented in the table.