{"doi":"10.1016/j.jaci.2025.05.028","title":"High-affinity omalizumab variants with optimized disruptive potency prevent anaphylaxis in vivo","abstract":"BACKGROUND: Omalizumab, a therapeutic mAb targeting IgE, is approved for the treatment of multiple allergic indications. However, its moderate affinity for IgE necessitates frequent high-dose administrations, limiting its therapeutic use and efficacy. Attempts to develop next-generation anti-IgE antibodies with improved affinity, such as ligelizumab or HAE1, have yielded alternatives that are either less safe or not demonstrably superior. OBJECTIVE: We sought to generate optimized omalizumab variants featuring 2 specific molecular enhancements: increased IgE binding affinity while preserving epitope specificity to enhance target neutralization and improved potency to actively dissociate prebound IgE from its high-affinity receptor FcεRI. METHODS: Using a targeted yeast display selection strategy applied to mutated omalizumab libraries, we identified the anti-IgE clone C03 and engineered 2 flexible variants, C03-H1L2 and C03-H2L2. RESULTS: The C03 antibodies demonstrated approximately 10-fold higher IgE binding affinity compared with omalizumab, resulting in superior inhibition of IgE binding to FcεRI. Furthermore, C03-H1L2 and C03-H2L2 exhibited enhanced potency in displacing FcεRI-bound IgE from humanized mouse mast cells and human basophils without triggering spontaneous cell activation. In a systemic anaphylaxis mouse model, single-dose administration of the flexible C03 variants, in contrast to omalizumab, desensitized allergic effector cells within 36 hours, fully preventing antigen-induced anaphylaxis. CONCLUSIONS: These findings underscore the importance of engineering next-generation anti-IgE therapies with higher affinity and disruptive potency to optimize current treatment approaches.","journal":"Journal of Allergy and Clinical Immunology","year":2025,"id":524653,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9535,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":247572,"name":"Pascal Guntern","orcid":"0000-0001-8840-8577","position":1,"is_corresponding":false},{"id":394833,"name":"Luke F. Pennington","orcid":"0000-0002-7947-8714","position":2,"is_corresponding":false},{"id":1398222,"name":"Robin van Brummelen","orcid":"0000-0003-1182-8519","position":3,"is_corresponding":false},{"id":226838,"name":"Theodore S. Jardetzky","orcid":"0000-0002-3664-0072","position":4,"is_corresponding":false},{"id":247575,"name":"Alexander Eggel","orcid":"0000-0001-8746-3339","position":5,"is_corresponding":false},{"id":248853,"name":"Daniel Brigger","orcid":null,"position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-19T02:50:12.083054Z","pmid":"41081658","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}