PXD055197

PXD055197 is an original dataset announced via ProteomeXchange.

Title	Internalization of therapeutic antibodies into Dendritic cells as a risk factor for immunogenicity
Description	The appended raw files, csv files and other documents were deposited into the public domain in support for the publication "Internalization of therapeutic antibodies into Dendritic cells as a risk factor for immunogenicity" by Michel Siegel, Anna-Lena Bolender, Axel Ducret, Johannes Fraidling, Katharina Hartman, Cary M Looney, Olivier Rohr, Timothy Hickling, Martin Lechmann, Celine Marban-Doran and Thomas Kraft. The abstract reads as follows: "Immunogenicity, defined as the unwanted immune response triggered by the administration of therapeutic antibodies, leads to the production of anti-drug antibodies and is a significant risk factor for the development of therapeutic antibodies. Immunogenicity is a multifactorial phenomenon and risk factors influencing each and every step of the immune response may have major overall consequences. Previously, it has been observed that biophysical properties such as positive charge patches affect the biodistribution of therapeutic antibodies, pharmacokinetic properties like nonspecific clearance by altering their uptake into endothelial cells. The internalization of therapeutic antibodies into dendritic cells plays a crucial role in immunogenicity. Cellular internalization is mainly facilitated by nonspecific endocytosis or fluid phase pinocytosis. It involves the cell engulfing surrounding fluid, leading to the internalization of its contents. The biophysical properties of therapeutic antibodies, such as positive charge patches, can influence this process as described for endothelial cells. We therefore hypothesize that internalization of therapeutic antibodies into dendritic cells is influenced by their biophysical properties. Investigating the link between charge patches and dendritic cells internalization using tool antibodies with large positive or negative charge patches, we observed that antibodies with large positive charge patches showed higher lysosomal accumulation and epitope presentation, an important risk factor for immunogenicity. To understand the subsequent impact on T cell activation, we inserted a CD4+ T cell epitope from ovalbumin (a model antigen with well-characterized T cell epitopes) into the same tool compounds. This insertion led to no significant changes in dendritic cell internalization or T cell epitope presentation compared to wild-type antibodies, allowing for a direct comparison of the impact of internalization T cell epitope presentation on T cell activation. However, the insertion of the ovalbumin CD4+ T cell epitope into the tool antibodies increased the occurrence of a specific T cell response, coupled with enhanced internalization and epitope presentation. This increased activation is a key risk factor in immunogenicity, emphasizing the need for careful consideration during the development of biotherapeutics. In conclusion, positive charge patches-mediated internalization and presentation significantly influence the immunogenicity of therapeutic antibodies." doi: 10.3389/fimmu.2024.1406643 The data deposited here supports the generation of Fig. 2 and 4 of this manuscript.
HostingRepository	MassIVE
AnnounceDate	2024-08-26
AnnouncementXML	Submission_2024-08-26_05:05:01.842.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	Gln->pyro-Glu; oxidation; Deamidated
Instrument	Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2024-08-26 03:51:43	ID requested
⏵ 1	2024-08-26 05:05:02	announced

no publication

submitter keyword: monocyte-derived dendritic cell (moDC), immunogenicity, MAPPs, MHC-II peptides, internaiization assay, charge patches

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

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/MSV000095695/