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This study used immunized cattle, known for producing antibodies with ultra-long CDRH3 domains, to generate 33 mAbs, ten of which had ultra-long CDRH3s (&gt;50 amino acids). Of these, mAbs P7 and 99, demonstrated broad and potent neutralization. Notably, mAb P7 neutralized all tested variants, including SARS-CoV-1, with IC50 values between 0.05 and 9.2\u03bcg\/mL, and showed cross-reactivity with RBDs from various sarbecoviruses. Structural analysis revealed that mAb 99 binds the spike protein's RBD at the ACE2 binding site. Although the exact binding of P7 wasn't resolved, evidence suggests it targets a hidden epitope, promoting spike trimer dissociation via its extended CDRH3. In Syrian hamsters, both mAbs significantly reduced lung viral loads. These results support the potential of bovine-derived mAbs, particularly those with ultra-long CDRH3s, for future antiviral therapies.<\/jats:p>","DOI":"10.1101\/2025.01.03.631215","type":"posted-content","created":{"date-parts":[[2025,1,25]],"date-time":"2025-01-25T00:43:46Z","timestamp":1737765826000},"source":"Crossref","is-referenced-by-count":1,"title":["An ultra-long heavy chain bovine antibody neutralizes SARS-CoV-2 and reacts broadly with sarbecoviruses."],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9685-6318","authenticated-orcid":false,"given":"Theocharis","family":"Tsoleridis","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4213-5758","authenticated-orcid":false,"given":"Chengcheng","family":"Fan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily 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