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PXD013599 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleA single T cell epitope drives the neutralizing anti-idiotypic antibody response to natalizumab in patients with multiple sclerosis
DescriptionNatalizumab (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 variable region. 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.
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterAntonino Cassotta
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListNo PTMs are included in the dataset
InstrumentQ Exactive
Dataset History
RevisionDatetimeStatusChangeLog Entry
02019-04-23 04:30:06ID requested
12019-07-15 08:25:52announced
22019-07-16 00:30:17announcedUpdated project metadata.
Publication List
Dataset with its publication pending
Keyword List
curator keyword: Biomedical
submitter keyword: human, MHC-II peptidomics, multiple sclerosis, antibody therapy
Contact List
Luca Piccoli
contact affiliationInstitute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland.
contact emailluca.piccoli@irb.usi.ch
lab head
Antonino Cassotta
contact affiliationInstitute for Research in Biomedicine, Università della Svizzera italiana
contact emailantonino.cassotta@irb.usi.ch
dataset submitter
Full Dataset Link List
Dataset FTP location
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PRIDE project URI
Repository Record List
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