PXD054823
PXD054823 is an original dataset announced via ProteomeXchange.
Dataset Summary
| Title | Development and qualification of a dendritic cell internalization assay contributing to the immunogenicity risk evaluation of biotherapeutics |
| Description | The appended raw files, csv files and other documents were deposited into the public domain in support for the publication "Development and characterization of a dendritic cell internalization assay contributing to the immunogenicity risk evaluation of biotherapeutics" by Michel Siegel, Aman Padamsey, Anna-Lena Bolender, Patrick Hargreaves, Axel Ducret, Johannes Fraidling, Katharina Hartmann, Cary M. Looney, Olivier Rohr, Tim Hickling, Thomas Kraft, Celine Marban-Doran. The abstract reads as follows: Assessing immunogenicity risks during the development of biotherapeutics is crucial. Given the complexity of immunogenicity - influenced by myriad biological, immunological, and patient-specific factors - Individual risk assessments are poorly predictive, necessitating a holistic approach to immunogenicity risk assessment. Anti-drug antibody production starts with the internalization of drugs by antigen presenting cells such as dendritic cells, which present drug-derived peptides to CD4+ T cells as peptide-MHC-II complexes. Assessing dendritic cell function is common in preclinical immunogenicity risk assessments, including presentation of potential T cell epitopes using the MAPPs assay. However, other aspects of dendritic cell biology are often overlooked. To better understand the dendritic cell contribution to immunogenicity, we developed two flow cytometry-based assays: the dendritic cell internalization assay and the dendritic cell activation assay. Our assay addresses two issues with existing methods for measuring internalization into antigen presenting cells; lack of specificity for the cellular compartment of internalization or the recycling of internalized antibodies, and the increased risk of aggregation, when using a large payload for the detection of antibodies, that would lead to activation of irrelevant scavenger receptors in the context of dendritic cell internalization. We also developed a DC activation assay, improving on various aspects of its relevance for immunogenicity risk assessment compared to previously published protocols. Additionally, we identified DC-SIGN (CD209) and CD80 as crucial for understanding dendritic cell activation mechanisms leading to immunogenicity. To evaluate the performance of these two assays, we used a set of marketed therapeutic antibodies. The dendritic cell internalization assay revealed differences in internalization rates for marketed therapeutic antibodies, even those targeting the same antigen (e.g. PCSK9-targeting antibodies: bococizumab, evolocumab and alirocumab or TNF-targeting antibodies: adalimumab and infliximab), potentially accounting for differential immunogenicity liabilities. The DC activation assay also showed different patterns of DC activation between bococizumab, which rapidly accumulates within the lysosomes, and the other PCSK9-targeting antibodies (evolocumab and alirocumab), giving new insights into specific immunogenicity profiles. Overall, this study provides valuable information for future risk assessments of therapeutic antibodies in development. doi: 10.3389/fimmu.2024.1406804 The data deposited here were used to generate the supplementary figure 3. |
| HostingRepository | MassIVE |
| AnnounceDate | 2024-08-13 |
| AnnouncementXML | Submission_2024-08-13_02:33:52.150.xml |
| DigitalObjectIdentifier | |
| ReviewLevel | Non peer-reviewed dataset |
| DatasetOrigin | Original dataset |
| RepositorySupport | Unsupported dataset by repository |
| PrimarySubmitter | Axel Ducret |
| SpeciesList | scientific name: Homo sapiens; common name: human; NCBI TaxID: 9606; |
| ModificationList | Deamidated; Gln->pyro-Glu; Oxidation |
| Instrument | Q Exactive HF-X |
Dataset History
| Revision | Datetime | Status | ChangeLog Entry |
|---|---|---|---|
| 0 | 2024-08-12 11:51:46 | ID requested | |
| ⏵ 1 | 2024-08-13 02:33:52 | announced |
Publication List
| no publication |
Keyword List
| submitter keyword: dendritic cell, CD internalization assay, MAPPs, immunogenicity, ATR-107, Ixekizumab, Bevacizumab, Adalimumab, Bococizumab, Briakinumab |
Contact List
| Axel Ducret | |
|---|---|
| contact affiliation | Roche Innovation Center Basel |
| contact email | axel.ducret@roche.com |
| lab head | |
| Axel Ducret | |
| contact affiliation | F. Hoffmann-La Roche Ltd |
| contact email | axel.ducret@roche.com |
| dataset submitter | |
Full Dataset Link List
| MassIVE dataset URI |
| 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://massive.ucsd.edu/v08/MSV000095578/ |
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