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

Authors

  • L.P. Deimel
  • L. Moynié
  • G. Sun
  • V. Lewis
  • A. Turner
  • C.J. Buchanan
  • S.A. Burnap
  • M. Kutuzov
  • C.M. Kobras
  • Y. Demyaneko
  • S. Mohammed
  • M. Stracy
  • W.B. Struwe
  • A.J. Baldwin
  • J. Naismith
  • B.G. Davis
  • Q.J. Sattentau

Journal

  • Nature Communications

Citation

  • Nat Commun 15 (1): 6851

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.


DOI

doi:10.1038/s41467-024-51138-7