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 2

Interactions of anti-IgE mAbs in free or IgE-complex form with CD23.

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Interactions of anti-IgE mAbs in free or IgE-complex form with CD23. Ant...
Anti-IgE mAbs, in free form or in mAb-IgE complex form, may interact with CD23 in an indirect fashion. (A) On CD23-immobilized ELISA with IgE preloaded, UB-221 in a free form exhibited strong binding to the CD23-bound IgE, estimated to be 10-fold more abundant than ligelizumab, as shown with EC50 values (mean ± SD, n = 3) of 38.4 ± 3.6 versus 402 ± 47.3 ng/mL, while omalizumab was relatively inactive. (B) On CD23+ SKW6.4 B lymphoma cells with IgE preabsorbed and analyzed by flow cytometry, UB-221 in a free form exhibited again strong binding to the CD23-bound IgE, with a maximum binding MFI value (mean ± SD, n = 3) of 1,828 ± 331, while ligelizumab presented an approximately 4-fold lower binding, with a maximal MFI of 503 ± 26.6, and omalizumab remained inactive; the differential cellular binding events are shown on FACS histograms on the right exemplified by 2 mAb concentrations at 0.156 and 5.0 mg/mL. (C) On CD23-immobilized ELISA, UB-221 in preformed UB-221–IgE complexes also exhibited strong binding to CD23, with an EC50 of 41.6 ± 4.6 ng/mL, nearly the same as that observed with CD23-bound IgE, while ligelizumab-IgE complexes almost lost the ability to bind CD23, and the omalizumab-IgE complexes stayed inert toward CD23. (D) On CD23+ SKW6.4 cells, the preformed UB-221–IgE complex again exhibited strong binding to the cells, with a maximal MFI value (mean ± SD, n = 3) of 1,280 ± 90.2, while ligelizumab almost lost the binding ability, presenting only a minor binding with a maximal MFI of 191 ± 8.5, and omalizumab was inactive; the differential cellular binding events are shown on FACS histograms on the right exemplified by 2 mAb concentrations at 0.625 and 10 μg/mL. Overall, UB-221 in free or complex form can interact freely with CD23, while ligelizumab in free form can bind limitedly to CD23-bound IgE and in IgE-complex form loses its binding capability, and omalizumab essentially stays inert toward CD23.