IgE-neutralizing UB-221 mAb, distinct from omalizumab and ligelizumab, exhibits CD23-mediated IgE downregulation and relieves urticaria symptoms
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
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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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 4

UB-221 induces a pronounced inhibition of IgE protein production and IgE mRNA expression in human PBMCs.

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UB-221 induces a pronounced inhibition of IgE protein production and IgE...
In the presence of UB-221, omalizumab, or ligelizumab (UBP lot), human PBMCs from 3 to 5 healthy donors were stimulated with human recombinant IL-4 and an anti–human CD40 antibody to undergo de novo IgE synthesis. (A–E) The effects on IgE protein production were focused on day 11 by each anti-IgE mAb at doses of (A) 1 μg/mL (n = 3), (B) 3 μg/mL (n = 5), (C) 10 μg/mL (n = 5), (D) 20 μg/mL (n = 5), and (E) 80 μg/mL (n = 5). The total IgE in cell culture supernatant samples was quantified by ELISA. (F and G) In a separate set of donors (n = 5), the effects on IgE mRNA expression in lysates of PBMCs stimulated with human recombinant IL-4 and anti–human CD40 antibody in the presence of UB-221, ligelizumab, or omalizumab were studied at (F) 1 μg/mL or (G) 20 μg/mL. The mRNA expression in cell cultures on day 11 was analyzed by real-time PCR. The percentages of IgE protein/mRNA reduction were calculated based on the total IgE/mRNA levels from the respective untreated cells, which were set as 100%. The percentage reduction values of IgE protein and IgE mRNA are shown in Supplemental Table 1B and Supplemental Table 2, respectively. Data are shown as mean ± SEM. Different treatments were compared relative to the untreated group using 2-way ANOVA with Tukey’s multiple comparison test referenced to untreated controls. *P < 0.05; **P <0.01; ***P < 0.001.