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In vivo, both the resulting conjugates and their off-target side-conjugates have the potential to elicit antibodies, with implications for allergy and drug sequestration. Although \u03b2-lactam antibiotics are a drug class long associated with these immunological phenomena, the molecular underpinnings of off-target drug-protein conjugation and consequent drug-specific immune responses remain incomplete. Here, using the classical \u03b2-lactam penicillin G (PenG), we probe the B and T cell determinants of drug-specific IgG responses to such conjugates in mice. Deep B cell clonotyping reveals a dominant murine clonal antibody class encompassing phylogenetically-related <jats:italic>IGHV1<\/jats:italic>, <jats:italic>IGHV5<\/jats:italic> and <jats:italic>IGHV10<\/jats:italic> subgroup gene segments. Protein NMR and x-ray structural analyses reveal that these drive structurally convergent binding modes in adduct-specific antibody clones. Their common primary recognition mechanisms of the penicillin side-chain moiety (phenylacetamide in PenG)\u2014regardless of CDRH3 length\u2014limits cross-reactivity against other \u03b2-lactam antibiotics. This immunogenetics-guided discovery of the limited binding solutions available to antibodies against side products of an archetypal covalent inhibitor now suggests future potential strategies for the \u2018germline-guided reverse engineering\u2019 of such drugs away from unwanted immune responses.<\/jats:p>","DOI":"10.1038\/s41467-024-51138-7","type":"journal-article","created":{"date-parts":[[2024,8,10]],"date-time":"2024-08-10T09:02:26Z","timestamp":1723280546000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Covalent penicillin-protein conjugates elicit anti-drug antibodies that are clonally and functionally restricted"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3803-871X","authenticated-orcid":false,"given":"Lachlan P.","family":"Deimel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucile","family":"Moyni\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoxuan","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4882-336X","authenticated-orcid":false,"given":"Viliyana","family":"Lewis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3995-6558","authenticated-orcid":false,"given":"Abigail","family":"Turner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1840-5706","authenticated-orcid":false,"given":"Charles J.","family":"Buchanan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean A.","family":"Burnap","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3386-4350","authenticated-orcid":false,"given":"Mikhail","family":"Kutuzov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolin M.","family":"Kobras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6628-1912","authenticated-orcid":false,"given":"Yana","family":"Demyanenko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2640-9560","authenticated-orcid":false,"given":"Shabaz","family":"Mohammed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathew","family":"Stracy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0594-226X","authenticated-orcid":false,"given":"Weston B.","family":"Struwe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7579-8844","authenticated-orcid":false,"given":"Andrew J.","family":"Baldwin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6744-5061","authenticated-orcid":false,"given":"James","family":"Naismith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5056-407X","authenticated-orcid":false,"given":"Benjamin G.","family":"Davis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7170-1937","authenticated-orcid":false,"given":"Quentin J.","family":"Sattentau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,8,10]]},"reference":[{"key":"51138_CR1","doi-asserted-by":"publisher","first-page":"996","DOI":"10.1021\/bi00895a027","volume":"3","author":"HN Eisen","year":"1964","unstructured":"Eisen, H. 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