Dataset Information

Elucidation of B-cell specific drug immunogenicity liabilities via a novel ex vivo assay

ABSTRACT: The appended raw files, csv files and other documents were deposited in the public domain in support for the publication "Elucidation of B-cell specific drug immunogenicity liabilities via a novel ex vivo assay" by Cary M Looney, Axel Ducret, Guido Steiner, Karen Dernick, Katharina Hartman, Michel Siegel, Timothy Hickling, Alex Odermatt, Celine Marban-Doran. The abstract is as follows: The advent of large molecule therapeutics has revolutionized treatment options for previously unmet medical needs. This advent has also led to an increased impact of immunogenicity on drug efficacy and safety. In order to maximize the potential of large molecule therapeutics, immunogenicity-related liabilities must be identified as early in development as possible, using an integrated risk assessment that takes into account the various cell types and processes involved. Here, we describe the development of an ex vivo B-cell immunogenicity assay, to capture a key component of the immune response that has been missing from previously published ex vivo immunogenicity assays. Plasmablasts/plasma cells were preferentially expanded in this assay, a subset of which were drug-specific and presented drug-specific peptides on MHC Class II. This assay represents an important tool in the immunogenicity risk assessment toolkit, to allow liabilities to be identified and mitigated early in the drug development process.

INSTRUMENT(S): timsTOF Pro 2

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Axel Ducret

PROVIDER: MSV000097151 | MassIVE | Wed Feb 19 00:49:00 GMT 2025

SECONDARY ACCESSION(S): PXD060948

REPOSITORIES: MassIVE

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Elucidation of B-cell specific drug immunogenicity liabilities via a novel <i>ex vivo</i> assay.

Looney Cary M CM Ducret Axel A Steiner Guido G Dernick Karen K Hartman Katharina K Siegel Michel M Hickling Timothy T Odermatt Alex A Marban-Doran Céline C

Frontiers in immunology 20250604

The advent of large molecule therapeutics has revolutionized treatment options for previously unmet medical needs. This advent has also led to an increased impact of immunogenicity on drug efficacy and safety. In order to maximize the potential of large molecule therapeutics, immunogenicity-related liabilities must be identified as early in development as possible, using an integrated risk assessment that takes into account the various cell types and processes involved. Here, we describe the dev ...[more]

PMID: 40534885

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Project 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.

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Elucidation of B-cell specific drug immunogenicity liabilities via a novel ex vivo assay

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Elucidation of B-cell specific drug immunogenicity liabilities via a novel <i>ex vivo</i> assay.

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Elucidation of B-cell specific drug immunogenicity liabilities via a novel ex vivo assay

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Elucidation of B-cell specific drug immunogenicity liabilities via a novel &lt;i&gt;ex vivo&lt;/i&gt; assay.

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OmicsDI is part of the ELIXIR infrastructure

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Elucidation of B-cell specific drug immunogenicity liabilities via a novel <i>ex vivo</i> assay.