{"doi":"10.1073/pnas.2424889122","title":"A monoclonal anti-hemagglutinin stem antibody modified with zanamivir protects against both influenza A and B viruses","abstract":"Influenza remains a significant public health threat. Both monoclonal antibodies and small-molecule inhibitors can target the influenza surface glycoproteins hemagglutinin (HA) or neuraminidase (NA) for prevention and treatment of influenza. Here, we combine the strengths of anti-influenza antibodies and small molecules by site-specific conjugation of the NA inhibitor zanamivir to MEDI8852, an HA-specific fully human monoclonal antibody. MEDI8852 targets the conserved stem region of HA and inhibits HA-mediated fusion of the viral and host cell membranes. Elimination of virus-infected cells involves Fcγ receptor–mediated effector functions. The efficacy of MEDI8852 is limited to influenza A viruses. Zanamivir, on the other hand, binds to the active site of NA in both influenza A and B viruses to inhibit NA activity and virus release. However, because of its small size, zanamivir has a short half-life and requires repeated dosing at high concentrations. We produced a MEDI8852–zanamivir antibody–drug conjugate (ADC) that engages Fc-mediated effector functions and benefits from neonatal Fc receptor (FcRn)-mediated recycling. The MEDI8852–zanamivir conjugate extends the circulatory half-life of zanamivir, targets both influenza HA and NA, and shows enhanced antibody-dependent cellular cytotoxicity (ADCC) compared to MEDI8852 alone. The MEDI8852–zanamivir conjugate protected mice from a lethal (10 × LD 50 ) challenge with influenza A and B viruses at a dose similar to that required for broadly neutralizing anti-NA antibodies, with the added advantage of simultaneously targeting NA (influenza A and B) and HA (influenza A).","journal":"Proceedings of the National Academy of Sciences","year":2025,"id":525480,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9498,"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":1059477,"name":"Thomas Balligand","orcid":"0000-0003-0156-8936","position":1,"is_corresponding":false},{"id":1223667,"name":"Camille M. Le Gall","orcid":"0000-0002-5890-5115","position":2,"is_corresponding":false},{"id":245647,"name":"Hidde L. Ploegh","orcid":"0000-0002-1090-6071","position":3,"is_corresponding":false},{"id":307191,"name":"Xin Liu","orcid":"0000-0002-9105-317X","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:50:21.274116Z","pmid":"40193611","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":[]}