PXD013599

PXD013599 is an original dataset announced via ProteomeXchange.

Title	A single T cell epitope drives the neutralizing anti-drug antibody response to natalizumab in multiple sclerosis patients
Description	Natalizumab (NZM), a humanized monoclonal IgG4 antibody to α4 integrins, is used to treat patients with relapsing-remitting multiple sclerosis (MS), but in about 6% of the cases persistent neutralizing anti-drug antibodies (ADAs) are induced leading to therapy discontinuation. To understand the basis of the ADA response and the mechanism of ADA-mediated neutralization, we performed an in-depth analysis of the B and T cell responses in two patients. By characterizing a large panel of NZM-specific monoclonal antibodies, we found that, in both patients, the response was polyclonal and targeted different epitopes of the NZM idiotype. The neutralizing activity was acquired through somatic mutations and correlated with a slow dissociation rate, a finding that was supported by structural data. Interestingly, in both patients, the analysis of the CD4+ T cell response, combined with mass spectrometry-based peptidomics, revealed a single immunodominant T cell epitope spanning the FR2-CDR2 region of the NZM light chain. Moreover, a CDR2-modified version of NZM was not recognized by T cells, while retaining binding to α4 integrins. Collectively, our integrated analysis identifies the basis of T-B collaboration that leads to ADA-mediated therapeutic resistance and delineates an approach to design novel deimmunized antibodies for autoimmune disease and cancer treatment.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_04:58:49.508.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Antonino Cassotta
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2019-04-23 04:30:06	ID requested
1	2019-07-15 08:25:52	announced
2	2019-07-16 00:30:17	announced	Updated project metadata.
⏵ 3	2024-10-22 04:58:51	announced	2024-10-22: Updated project metadata.

Cassotta A, Mikol V, Bertrand T, Pouzieux S, Le Parc J, Ferrari P, Dumas J, Auer M, Deisenhammer F, Gastaldi M, Franciotta D, Silacci-Fregni C, Fernandez Rodriguez B, Giacchetto-Sasselli I, Foglierini M, Jarrossay D, Geiger R, Sallusto F, Lanzavecchia A, Piccoli L, A single T cell epitope drives the neutralizing anti-drug antibody response to natalizumab in multiple sclerosis patients. Nat Med, 25(9):1402-1407(2019) [pubmed]

10.1038/s41591-019-0568-2;

curator keyword: Biomedical

submitter keyword: antibody therapy, MHC-II peptidomics, multiple sclerosis,human

Luca Piccoli
contact affiliation	Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland.
contact email	luca.piccoli@irb.usi.ch
lab head
Antonino Cassotta
contact affiliation	Institute for Research in Biomedicine, Università della Svizzera italiana
contact email	antonino.cassotta@irb.usi.ch
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2019/10/PXD013599

PRIDE project URI

• PRIDE
  1. PXD013599
     1. Label: PRIDE project
     2. Name: A single T cell epitope drives the neutralizing anti-drug antibody response to natalizumab in multiple sclerosis patients