PXD052026

PXD052026 is an original dataset announced via ProteomeXchange.

Title	Covalent penicillin-protein conjugates elicit anti-drug antibodies that are clonally and functionally restricted
Description	Many archetypal and emerging classes of small-molecule therapeutics form covalent 38 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 have now probed the B and T cell determinants of drug-specific IgG responses to such conjugates in mice. Deep 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.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:53:22.341.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Sean Burnap
SpeciesList	scientific name: Gallus gallus (Chicken); NCBI TaxID: 9031; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	carbamoylated residue; acetylated residue; monohydroxylated residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2024-05-06 10:49:55	ID requested
1	2024-08-08 10:10:44	announced
⏵ 2	2024-10-22 06:53:22	announced	2024-10-22: Updated project metadata.

10.1038/S41467-024-51138-7;

submitter keyword: B-Lactam,Proteomics

Weston Struwe
contact affiliation	Univeristy of Oxford
contact email	weston.struwe@bioch.ox.ac.uk
lab head
Sean Burnap
contact affiliation	University of Oxford
contact email	sean.burnap@bioch.ox.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD052026
     1. Label: PRIDE project
     2. Name: Covalent penicillin-protein conjugates elicit anti-drug antibodies that are clonally and functionally restricted