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| Item Type: | Article |
|---|---|
| Title: | Covalent penicillin-protein conjugates elicit anti-drug antibodies that are clonally and functionally restricted |
| Creators Name: | Deimel, L.P., Moynié, L., Sun, G., Lewis, V., Turner, A., Buchanan, C.J., Burnap, S.A., Kutuzov, M., Kobras, C.M., Demyaneko, Y., Mohammed, S., Stracy, M., Struwe, W.B., Baldwin, A.J., Naismith, J., Davis, B.G. and Sattentau, Q.J. |
| 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. |
| Keywords: | Anti-Bacterial Agents, B-Lymphocytes, Cross Reactions, Immunoglobulin G, Penicillin G, Penicillins, X-Ray Crystallography, Animals, Mice |
| Source: | Nature Communications |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 15 |
| Number: | 1 |
| Page Range: | 6851 |
| Date: | 10 August 2024 |
| Additional Information: | Erratum in: Nat Commun 15(1): 7955 |
| Official Publication: | https://doi.org/10.1038/s41467-024-51138-7 |
| PubMed: | View item in PubMed |
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