Quantitative HLA‐class‐II/factor VIII (FVIII) peptidomic variation in dendritic cells correlates with the immunogenic potential of therapeutic FVIII proteins in hemophilia A

Diego, Vincent P.; Luu, Bernadette W.; Hofmann, Marco H.; Dinh, Long V.; Almeida, Marcio; Powell, Jerry S.; Rajalingam, Raja; Peralta, Juan M.; Kumar, Satish; Curran, Joanne E.; Sauna, Zuben E.; Kellerman, Roberta; Park, Yara; Key, Nigel S.; Escobar, Miguel A.; Huynh, Huy; Verhagen, A. M. W.; Williams‐Blangero, Sarah; Lehmann, Paul; Maraskovsky, Eugene; Blangero, John; Howard, Tom E.

doi:10.1111/jth.14647

Cited by 5 publications

(8 citation statements)

References 72 publications

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“…and Jankowski et al. ( 37 , 38 ). To cover the in silico prediction tools as a frequently used pipeline with great potential in epitope prediction, we compared our mapped peptides for the model antigens not only with IEDB and literature but also with NetMHCpan-4.1 and NetMHCIIpan-4.0 prediction results.…”

Section: Resultsmentioning

confidence: 90%

“…The BDD-rFVIII as model antigen represents a special case because previous publications by Diego et al. ( 37 ) and Jankowski et al. ( 38 ) provided detailed data on mapped epitopes for BDD-rFVIII gained with the ProPresent Antigen Presentation Assay by ProImmune ( 39 – 41 ).…”

Section: Resultsmentioning

confidence: 99%

“…The mapped peptides of BDD-rFVIII were additionally compared to the epitope data published by Diego et al. ( 37 ). To include the high potential of in silico prediction tools and facilitate an overall comparison of our data, we included the prediction results for all antigen/HLA combinations by NetMHCpan-4.1 (for HLA-I) and NetMHCIIpan-4.0 (for HLA-II) ( 34 , 35 ).…”

Section: Resultsmentioning

confidence: 99%

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FASTMAP—a flexible and scalable immunopeptidomics pipeline for HLA- and antigen-specific T-cell epitope mapping based on artificial antigen-presenting cells

Weisbrod,

Capriotti,

Hofmann

et al. 2024

Front. Immunol.

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The study of peptide repertoires presented by major histocompatibility complex (MHC) molecules and the identification of potential T-cell epitopes contribute to a multitude of immunopeptidome-based treatment approaches. Epitope mapping is essential for the development of promising epitope-based approaches in vaccination as well as for innovative therapeutics for autoimmune diseases, infectious diseases, and cancer. It also plays a critical role in the immunogenicity assessment of protein therapeutics with regard to safety and efficacy concerns. The main challenge emerges from the highly polymorphic nature of the human leukocyte antigen (HLA) molecules leading to the requirement of a peptide mapping strategy for a single HLA allele. As many autoimmune diseases are linked to at least one specific antigen, we established FASTMAP, an innovative strategy to transiently co-transfect a single HLA allele combined with a disease-specific antigen into a human cell line. This approach allows the specific identification of HLA-bound peptides using liquid chromatography–tandem mass spectrometry (LC-MS/MS). Using FASTMAP, we found a comparable spectrum of endogenous peptides presented by the most frequently expressed HLA alleles in the world’s population compared to what has been described in literature. To ensure a reliable peptide mapping workflow, we combined the HLA alleles with well-known human model antigens like coagulation factor VIII, acetylcholine receptor subunit alpha, protein structures of the SARS-CoV-2 virus, and myelin basic protein. Using these model antigens, we have been able to identify a broad range of peptides that are in line with already published and in silico predicted T-cell epitopes of the specific HLA/model antigen combination. The transient co-expression of a single affinity-tagged MHC molecule combined with a disease-specific antigen in a human cell line in our FASTMAP pipeline provides the opportunity to identify potential T-cell epitopes/endogenously processed MHC-bound peptides in a very cost-effective, fast, and customizable system with high-throughput potential.

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Section: Resultsmentioning

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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FASTMAP—a flexible and scalable immunopeptidomics pipeline for HLA- and antigen-specific T-cell epitope mapping based on artificial antigen-presenting cells

Weisbrod,

Capriotti,

Hofmann

et al. 2024

Front. Immunol.

Self Cite

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“…While not specifically discussed in the manuscript, we found it important to test all compounds using a panel of donors that showed an HLA-DRB1 allele frequency that broadly reflects the world population. It has been demonstrated that certain HLA alleles were associated with an increased immunogenic response towards certain biopharmaceuticals [20][21][22][23][24][25]. Nevertheless, in the context of use of this preclinical assay carried out in 30 donors, we primarily investigated whether compounds may be at risk of inducing an enhanced immunogenic response in a general population.…”

Section: Discussionmentioning

confidence: 99%

Validation of a Dendritic Cell and CD4+ T Cell Restimulation Assay Contributing to the Immunogenicity Risk Evaluation of Biotherapeutics

et al. 2022

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Immunogenicity, defined as the ability to provoke an immune response, can be either wanted (i.e., vaccines) or unwanted. The latter refers to an immune response to protein or peptide therapeutics, characterized by the production of anti-drug antibodies, which may affect the efficacy and/or the safety profiles of these drugs. Consequently, evaluation of the risk of immunogenicity early in the development of biotherapeutics is of critical importance for defining their efficacy and safety profiles. Here, we describe and validate a fit-for-purpose FluoroSpot-based in vitro assay for the evaluation of drug-specific T cell responses. A panel of 24 biotherapeutics with a wide range of clinical anti-drug antibody response rates were tested in this assay. We demonstrated that using suitable cutoffs and donor cohort sizes, this assay could identify most of the compounds with high clinical immunogenicity rates (71% and 78% for sensitivity and specificity, respectively) while we characterized the main sources of assay variability. Overall, these data indicate that the dendritic cell and CD4+ T cell restimulation assay published herein could be a valuable tool to assess the risk of drug-specific T cell responses and contribute to the selection of clinical candidates in early development.

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“…While these are not necessarily T cell epitopes, it is a highly sensitive and robust method to investigate potential liabilities within a protein sequence or to compare antigen presentation profiles between very similar biologics, as exemplified in the investigation of therapeutic Factor VIII proteins for the treatment of hemophilia A. 32 , 92 Therefore, it is reasonable to expect the MAPPs platform could also be used to profile biosimilars or to assess the effect of formulation on the immunogenic profile of a lead biotherapeutic.…”

Section: Conclusion and Future Developmentsmentioning

confidence: 99%

Assay format diversity in pre-clinical immunogenicity risk assessment: Toward a possible harmonization of antigenicity assays

Ducret

Ackaert

Bessa

et al. 2021

mAbs

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A major impediment to successful use of therapeutic protein drugs is their ability to induce anti-drug antibodies (ADA) that can alter treatment efficacy and safety in a significant number of patients. To this aim, in silico , in vitro, and in vivo tools have been developed to assess sequence and other liabilities contributing to ADA development at different stages of the immune response. However, variability exists between similar assays developed by different investigators due to the complexity of assays, a degree of uncertainty about the underlying science, and their intended use. The impact of protocol variations on the outcome of the assays, i.e., on the immunogenicity risk assigned to a given drug candidate, cannot always be precisely assessed. Here, the Non-Clinical Immunogenicity Risk Assessment working group of the European Immunogenicity Platform (EIP) reviews currently used assays and protocols and discusses feasibility and next steps toward harmonization and standardization.

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Quantitative HLA‐class‐II/factor VIII (FVIII) peptidomic variation in dendritic cells correlates with the immunogenic potential of therapeutic FVIII proteins in hemophilia A

Abstract: This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as

Cited by 5 publications

References 72 publications

FASTMAP—a flexible and scalable immunopeptidomics pipeline for HLA- and antigen-specific T-cell epitope mapping based on artificial antigen-presenting cells

FASTMAP—a flexible and scalable immunopeptidomics pipeline for HLA- and antigen-specific T-cell epitope mapping based on artificial antigen-presenting cells

Validation of a Dendritic Cell and CD4+ T Cell Restimulation Assay Contributing to the Immunogenicity Risk Evaluation of Biotherapeutics

Assay format diversity in pre-clinical immunogenicity risk assessment: Toward a possible harmonization of antigenicity assays

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