PXD013599 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | A single T cell epitope drives the neutralizing anti-idiotypic antibody response to natalizumab in patients with multiple sclerosis |
Description | Natalizumab (NZM), a humanized monoclonal IgG4 antibody to α4 integrins, is used to treat patients with relapsing-remitting multiple sclerosis (MS)1,2, but in about 9% of the cases neutralizing anti-drug antibodies (ADAs) are induced leading to therapy discontinuation3,4. 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 response 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 study identifies the basis of T-B collaboration that drives neutralizing anti-idiotypic antibodies to NZM and delineates an approach to develop a deimmunized version of the drug. |
HostingRepository | PRIDE |
AnnounceDate | 2019-07-15 |
AnnouncementXML | Submission_2019-07-15_08:25:52.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 |
Dataset History
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. |
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 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 | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD013599
- Label: PRIDE project
- Name: A single T cell epitope drives the neutralizing anti-idiotypic antibody response to natalizumab in patients with multiple sclerosis