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 3

Formation of UB-221–IgE complexes in PBS and human serum.

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Formation of UB-221–IgE complexes in PBS and human serum. A study of UB-...
A study of UB-221–IgE complex formation in PBS solution and human serum was conducted using fluorescence detection system–analytical ultracentrifugation (FDS-AUC), in which the Alexa Fluor 488–conjugated UB-221 was used as a marker. The human IgE and UB-221 were mixed in PBS and serum at a dynamic range of molar ratios from 1:1 through 1:10, and the formed complexes were analyzed by FDS-AUC as described in the Methods. The overall results of FDS-AUC suggest that a molar excess of either UB-221 or IgE would result in the formation of smaller complexes, while the largest complexes are formed at an equimolar ratio; the presence of UB-221–IgE complexes in an equimolar ratio at x:y or y:x (e.g., 1:3 or 3:1) would produce a similar complex pattern; and complex profiles in PBS and serum are similar, except that broadening peaks are seen associated with serum samples likely due to higher viscosity and other physicochemical mechanisms. C(S) represents the sedimentation coefficient distribution values with 68% confidence level; S20,W(S) represents the apparent sedimentation s-values that were converted to s20,W using density and viscosity of the buffer solutions measured on densitometer and viscometer.