A single T cell epitope drives the neutralizing anti-drug antibody response to natalizumab in multiple sclerosis patients

Cassotta, Antonino; Mikol, Vincent; Bertrand, Thomas; Pouzieux, Stéphanie; Parc, Josiane Le; Ferrari, Paul; Dumas, Jacques; Auer, Michael; Deisenhammer, Florian; Gastaldi, Matteo; Franciotta, Diego; Silacci-Fregni, Chiara; Rodriguez, Blanca Fernandez; Giacchetto-Sasselli, Isabella; Foglierini, Mathilde; Jarrossay, David; Geiger, Roger; Sallusto, Federica; Lanzavecchia, Antonio; Piccoli, Luca

doi:10.1038/s41591-019-0568-2

Cited by 51 publications

(67 citation statements)

References 34 publications

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“…Two of these regions were located in HFR3 and the HFR4, both of which did not induce specific T cell clones. The third presented region at the interface of LFR2 and CDR2 was also recognized by natalizumabreactive T cell clones (10). This study shows, that natalizumabspecific B cells were able to recognize and internalize natalizumab via their BCR and subsequently present a natalizumab-derived peptide sequence that was verified as a natalizumab-specific T cell epitope.…”

Section: Natalizumabmentioning

confidence: 52%

“…This study shows, that natalizumabspecific B cells were able to recognize and internalize natalizumab via their BCR and subsequently present a natalizumab-derived peptide sequence that was verified as a natalizumab-specific T cell epitope. The interplay of linear HLA-DR associated peptide presentation by APCs, subsequent T cell response and T cell-mediated activation of B cells which are also presenting linear HLA-DR associated peptides upon BCR mediated antigenspecific protein uptake (Figure 1) are demonstrated in this study (10). A comparison of presented sequence regions and identified T cell epitopes is shown in Figure 3.…”

Section: Natalizumabmentioning

confidence: 54%

“…Despite the fact that a clinical validation of the MAPPs assay will remain a challenge, a biological validation has been shown in several cases over the past years. Data generated as part of the ABIRISK project as well as independent studies show that presented sequence regions identified via MAPPs matched T cell epitopes identified from drug naive healthy donors and treated patients that had developed immunogenicity (7)(8)(9)(10)(11)(12). Together, these studies show that MAPPs assays applied by independent research groups and performed on different donor sets yield comparable results.…”

Section: Discussionmentioning

confidence: 71%

“…MAPPs data has also been shown to be more meaningful than soluble HLA class II peptide binding assay data (8). MAPPs assays have been shown to be a useful tool to interrogate clinical immunogenicity root causes by determining the natural presentation of peptides and confirming the relevance of T cell epitopes that have been identified via peptide library T cell epitope mapping approaches (7)(8)(9)(10)(11). Moreover, recent data suggests, that MAPPs-assisted T cell epitope mapping with MAPPs assay-derived peptide sequences could enable the identification of "authentic" T cell epitopes (11).…”

Section: Discussionmentioning

confidence: 99%

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Applying MAPPs Assays to Assess Drug Immunogenicity

Karle

2020

Front. Immunol.

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Immunogenicity against biotherapeutic proteins (BPs) and the potential outcome for the patient are difficult to predict. In vitro assays that can help to assess the immunogenic potential of BPs are not yet used routinely during drug development. MAPPs (MHC-associated peptide proteomics) is one of the assays best characterized regarding its value for immunogenicity potential assessment. This review is focusing on recent studies that have employed human HLA class II-MAPPs assays to rank biotherapeutic candidates, investigate clinical immunogenicity, and understand mechanistic root causes of immunogenicity. Advantages and challenges of the technology are discussed as well as the different areas of application.

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Section: Natalizumabmentioning

confidence: 52%

Section: Natalizumabmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Applying MAPPs Assays to Assess Drug Immunogenicity

Karle

2020

Front. Immunol.

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“…Such mechanisms may allow B cells of various specificities to receive help from T cells specific for an unlinked antigen, an idiotope, and has been shown in mouse models to induce immunoglobulin class switching and cause production of auto-antibodies triggering auto-immune disease (12,19,20). An analogous immune response is the generation of anti-drug antibodies to therapeutic monoclonal antibodies (mAbs), where T cell epitopes were mapped to the variable regions (21)(22)(23)(24). Variable region of mAbs may be chimeric or only partly humanized, providing additional potentially immunogenic idiotopes.…”

Section: Introductionmentioning

confidence: 99%

CD4+ T Cells in the Blood of MS Patients Respond to Predicted Epitopes From B cell Receptors Found in Spinal Fluid

et al. 2020

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B cells are important pathogenic players in multiple sclerosis (MS), but their exact role is not known. We have previously demonstrated that B cells from cerebrospinal fluid (CSF) of MS patients can activate T cells that specifically recognize antigenic determinants (idiotopes) from their B cell receptors (BCRs). The aim of this study was to evaluate whether in silico prediction models could identify antigenic idiotopes of immunoglobulin heavy-chain variable (IGHV) transcriptomes in MS patients. We utilized a previously assembled dataset of CSF IGHV repertoires from MS patients. To guide selection of potential antigenic idiotopes, we used in silico predicted HLA-DR affinity, endosomal processing, as well as transcript frequency from nine MS patients. Idiotopes with predicted low affinity and low likelihood of cathepsins cleavage were inert controls. Peripheral blood mononuclear cells from these patients were stimulated with the selected idiotope peptides in presence of anti-CD40 for 12 h. T cells were then labeled for activation status with anti-CD154 antibodies and CD3 + CD4 + T cells phenotyped as memory (CD45RO +) or naïve (CD45RO −), with potential for brain migration (CXCR3 and/or CCR6 expression). Anti-CD14 and-CD8 were utilized to exclude monocytes and CD8 + T cells. Unstimulated cells or insulin peptides were negative controls, and EBNA-1 peptides or CD3/CD28 beads were positive controls. The mean proportion of responding memory CD4 + T cells from all nine MS patients was significantly higher for idiotope peptides with predicted high HLA-DR affinity and high likelihood of cathepsin cleavage, than toward predicted inert peptides. Responses were mainly observed toward peptides affiliated with the CDR3 region. Activated memory CD4 + T cells expressed the chemokine receptor CCR6, affiliated with a Th17 phenotype and allowing passage into the central nervous system (CNS). This in vitro study suggests that that antigenic properties of BCR idiotopes can be identified in silico using HLA affinity and endosomal processing predictions. It further indicates that MS patients have a memory T cell repertoire capable of recognizing frequent BCR idiotopes found in endogenous CSF, and that these T cells express chemokine receptors allowing them to reach the CSF B cells expressing these idiotopes.

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QTY code designed antibodies for aggregation prevention: A structural bioinformatic and computational study

Li,

Wang,

Tao

et al. 2023

Proteins

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Therapeutic monoclonal antibodies are the most rapidly growing class of molecular medicine, and they are beneficial to the treatment of a broad spectrum of human diseases. However, the aggregation of antibodies during the process of manufacture, distribution, and storage poses significant challenges, potentially compromising efficacy and inducing adverse immune responses. We previously conceived a QTY (glutamine, threonine, tyrosine) code, a simple tool for enhancing protein water‐solubility by systematically pairwise replacing hydrophobic residues L (leucine), V (valine)/I (isoleucine), and F (phenylalanine). The QTY code offers a promising alternative to traditional methods of controlling aggregation in integral transmembrane proteins. In this study, we designed variants of four antibodies applying the QTY code, changing only the β‐sheets. Through the structure‐based aggregation analysis, we found that these QTY antibody variants demonstrated significantly decreased aggregation propensity compared to their wild‐type counter parts. Our results of molecular dynamics simulations showed that the design by QTY code is capable of maintaining the antigen‐binding affinity and structural stability. Our structural informatic and computational study suggests that the QTY code offers a significant potential in mitigating antibody aggregation.

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A single T cell epitope drives the neutralizing anti-drug antibody response to natalizumab in multiple sclerosis patients

Cited by 51 publications

References 34 publications

Applying MAPPs Assays to Assess Drug Immunogenicity

Applying MAPPs Assays to Assess Drug Immunogenicity

CD4+ T Cells in the Blood of MS Patients Respond to Predicted Epitopes From B cell Receptors Found in Spinal Fluid

QTY code designed antibodies for aggregation prevention: A structural bioinformatic and computational study

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