Covalent penicillin-protein conjugates elicit anti-drug antibodies that are clonally and functionally restricted

Lachlan P. Deimel (), Lucile Moynié, Guoxuan Sun, Viliyana Lewis, Abigail Turner, Charles J. Buchanan, Sean A. Burnap, Mikhail Kutuzov, Carolin M. Kobras, Yana Demyanenko, Shabaz Mohammed, Mathew Stracy, Weston B. Struwe, Andrew J. Baldwin, James Naismith, Benjamin G. Davis () and Quentin J. Sattentau ()
Additional contact information
Lachlan P. Deimel: University of Oxford
Lucile Moynié: Harwell Science and Innovation Campus
Guoxuan Sun: Harwell Science and Innovation Campus
Viliyana Lewis: Harwell Science and Innovation Campus
Abigail Turner: Harwell Science and Innovation Campus
Charles J. Buchanan: Harwell Science and Innovation Campus
Sean A. Burnap: University of Oxford
Mikhail Kutuzov: University of Oxford
Carolin M. Kobras: University of Oxford
Yana Demyanenko: Harwell Science and Innovation Campus
Shabaz Mohammed: Harwell Science and Innovation Campus
Mathew Stracy: University of Oxford
Weston B. Struwe: University of Oxford
Andrew J. Baldwin: Harwell Science and Innovation Campus
James Naismith: Harwell Science and Innovation Campus
Benjamin G. Davis: Harwell Science and Innovation Campus
Quentin J. Sattentau: University of Oxford

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract Many archetypal and emerging classes of small-molecule therapeutics form covalent protein adducts. 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 β-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 β-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 IGHV1, IGHV5 and IGHV10 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)—regardless of CDRH3 length—limits cross-reactivity against other β-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 ‘germline-guided reverse engineering’ of such drugs away from unwanted immune responses.

Date: 2024
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DOI: 10.1038/s41467-024-51138-7

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