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

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.; Sattentau, Q.J.

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

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Item Type:	Article
Title:	Covalent penicillin-protein conjugates elicit anti-drug antibodies that are clonally and functionally restricted
Creators:	Deimel, L.P. ORCID: https://orcid.org/0000-0003-3803-871X, Moynié, L., Sun, G., Lewis, V. ORCID: https://orcid.org/0000-0002-4882-336X, Turner, A. ORCID: https://orcid.org/0000-0002-3995-6558, Buchanan, C.J. ORCID: https://orcid.org/0000-0002-1840-5706, Burnap, S.A., Kutuzov, M. ORCID: https://orcid.org/0000-0003-3386-4350, Kobras, C.M., Demyaneko, Y. ORCID: https://orcid.org/0000-0002-6628-1912, Mohammed, S. ORCID: https://orcid.org/0000-0003-2640-9560, Stracy, M., Struwe, W.B. ORCID: https://orcid.org/0000-0003-0594-226X, Baldwin, A.J. ORCID: https://orcid.org/0000-0001-7579-8844, Naismith, J. ORCID: https://orcid.org/0000-0001-6744-5061, Davis, B.G. ORCID: https://orcid.org/0000-0002-5056-407X and Sattentau, Q.J. ORCID: https://orcid.org/0000-0001-7170-1937
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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