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#2-16E. Next-Generation Anti-IgE: Achieving Rapid Desensitization by Maximizing Disruptive Potency (JACI, 2025)
2025年10月23日 05:00·10分24秒
Physicians treating severe allergic diseases often face challenges with current anti-IgE therapies, such as omalizumab, which requires frequent, high-dose administrations and struggles to treat patients with very high total IgE levels due to its moderate affinity. This study addresses these limitations by developing C03-H1L2 and C03-H2L2, next-generation omalizumab variants that retain epitope specificity while achieving approximately 10-fold higher IgE binding affinity than omalizumab Fab fragments. The core finding is that by enhancing both affinity and utilizing engineered Fab flexibility, these variants drastically improve their disruptive potency—the ability to actively remove prebound IgE from the high-affinity receptor FcεRI. In a passive systemic anaphylaxis mouse model, a single dose of the C03 variants rapidly and completely desensitized allergic effector cells within 36 hours, fully preventing antigen-induced anaphylaxis, an effect omalizumab did not achieve in the same timeframe. However, clinicians must note that these promising results are derived from a mouse model, and the crucial aspects of long-term safety and efficacy in chronic human disease require further clinical investigation, especially given past development halts for similar high-affinity candidates. Ultimately, these data provide a vital conceptual basis for developing next-generation anti-IgE antibodies that could accelerate treatment efficacy and overcome current dosing barriers for patients needing rapid systemic desensitization.
Citation: Brigger D, Guntern P, Pennington LF, van Brummelen R, Jardetzky TS, Eggel A. High-affinity omalizumab variants with optimized disruptive potency prevent anaphylaxis in vivo. J Allergy Clin Immunol. 2025. DOI: 10.1016/j.jaci.2025.05.028
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