Covalent penicillin-protein conjugates elicit anti-drug antibodies that are clonally and functionally restricted.
Lachlan P DeimelLucile MoyniéGuoxuan SunViliyana LewisAbigail TurnerCharles J BuchananSean A BurnapMikhail A KutuzovCarolin M KobrasYana DemyanenkoShabaz MohammadMathew StracyWeston B StruweAndrew J BaldwinJames H NaismithBenjamin G DavisQuentin J SattentauPublished in: Nature communications (2024)
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.
Keyphrases
- small molecule
- immune response
- protein protein
- drug induced
- binding protein
- adverse drug
- amino acid
- magnetic resonance
- high resolution
- cancer therapy
- clinical trial
- emergency department
- type diabetes
- randomized controlled trial
- metabolic syndrome
- climate change
- gram negative
- dendritic cells
- risk assessment
- drug delivery
- human health
- living cells
- insulin resistance
- study protocol