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.