Impact of human sequences in variable domains of therapeutic antibodies on the location of CD4 T-cell epitopes

Meunier, Sylvain; Hamze, Moustafa; Karle, Anette; Bourayne, Marie de; Gdoura, Abdelaziz; Spindeldreher, Sebastian; Maillère, Bernard

doi:10.1038/s41423-019-0304-3

Cited by 13 publications

(22 citation statements)

References 7 publications

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“…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: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Applying MAPPs Assays to Assess Drug Immunogenicity

Karle

2020

Front. Immunol.

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“… T cell epitopes of therapeutic antibodies. T cell epitopes have been identified from T cells collected from healthy donors (red) or from patients who develop an ADA response (green) to rituximab, infliximab ( 53 ), adalimumab, natalizumab ( 72 ), and ixekizumab ( 73 ). Each bar corresponds to an individual response.…”

Section: Mabs-specific Cd4 T Cell Epitopes and Their Relationship Witmentioning

confidence: 99%

“…T cell epitopes have been identified in multiple therapeutic antibodies, including infliximab ( 53 ), rituximab ( 53 ), adalimumab ( 72 ), natalizumab ( 72 ), ixekizumab ( 73 ) by deriving CD4 T cell lines from cells collected from healthy donors ( Figure 2 ). The location of CD4 T cell epitopes was found to be very specific for each therapeutic antibody ( Figure 2 ).…”

Section: Mabs-specific Cd4 T Cell Epitopes and Their Relationship Witmentioning

confidence: 99%

“…To provide insights on the mechanisms leading to the T cell specificity, affinity of the mAb peptides for HLA-DR molecules, which are common worldwide was evaluated and the mAb peptides presented by HLA-DR molecules of mAb-loaded dendritic cells were identified. mAb-specific T cell epitopes are often found to bind to HLA-DR molecules with good affinity ( 53 , 72 ). For example, HCDR3 of adalimumab is a hot-spot of good binders to HLA-DR molecules ( 72 ) and contains the vast majority of identified T cell epitopes.…”

Section: Mabs-specific Cd4 T Cell Epitopes and Their Relationship Witmentioning

confidence: 99%

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Specificity of the T Cell Response to Protein Biopharmaceuticals

et al. 2020

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The anti-drug antibody (ADA) response is an undesired humoral response raised against protein biopharmaceuticals (BPs) which can dramatically disturb their therapeutic properties. One particularity of the ADA response resides in the nature of the immunogens, which are usually human(ized) proteins and are therefore expected to be tolerated. CD4 T cells initiate, maintain and regulate the ADA response and are therefore key players of this immune response. Over the last decade, advances have been made in characterizing the T cell responses developed by patients treated with BPs. Epitope specificity and phenotypes of BP-specific T cells have been reported and highlight the effector and regulatory roles of T cells in the ADA response. BP-specific T cell responses are assessed in healthy subjects to anticipate the immunogenicity of BP prior to their testing in clinical trials. Immunogenicity prediction, also called preclinical immunogenicity assessment, aims at identifying immunogenic BPs and immunogenic BP sequences before any BP injection in humans. All of the approaches that have been developed to date rely on the detection of BP-specific T cells in donors who have never been exposed to BPs. The number of BP-specific T cells circulating in the blood of these donors is therefore limited. T cell assays using cells collected from healthy donors might reveal the weak tolerance induced by BPs, whose endogenous form is expressed at a low level. These BPs have a complete human sequence, but the level of their endogenous form appears insufficient to promote the negative selection of autoreactive T cell clones. Multiple T cell epitopes have also been identified in therapeutic antibodies and some other BPs. The pattern of identified T cell epitopes differs across the antibodies, notwithstanding their humanized, human or chimeric nature. However, in all antibodies, the non-germline amino acid sequences mainly found in the CDRs appear to be the main driver of immunogenicity, provided they can be presented by HLA class II molecules. Considering the fact that the BP field is expanding to include new formats and gene and cell therapies, we face new challenges in understanding and mastering the immunogenicity of new biological products.

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Antibodies internalization mechanisms by dendritic cells and their role in therapeutic antibody immunogenicity

Lteif,

Pallardy,

Turbica

2023

Eur J Immunol

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Internalization and processing by antigen‐presenting cells such as dendritic cells (DCs) are critical steps for initiating a T‐cell response to therapeutic antibodies. Consequences are the production of neutralizing antidrug antibodies altering the clinical response, the presence of immune complexes, and, in some rare cases, hypersensitivity reactions. In recent years, significant progress has been made in the knowledge of cellular uptake mechanisms of antibodies in DCs. The uptake of antibodies could be directly related to their immunogenicity by regulating the quantity of materials entering the DCs in relation to antibody structure. Here, we summarize the latest insights into cellular uptake mechanisms and pathways in DCs. We highlight the approaches to study endocytosis, the impact of endocytosis routes on T‐cell response, and discuss the link between how DCs internalize therapeutic antibodies and the potential mechanisms that could give rise to immunogenicity. Understanding these processes could help in developing assays to evaluate the immunogenicity potential of biotherapeutics.

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Impact of human sequences in variable domains of therapeutic antibodies on the location of CD4 T-cell epitopes

Cited by 13 publications

References 7 publications

Applying MAPPs Assays to Assess Drug Immunogenicity

Applying MAPPs Assays to Assess Drug Immunogenicity

Specificity of the T Cell Response to Protein Biopharmaceuticals

Antibodies internalization mechanisms by dendritic cells and their role in therapeutic antibody immunogenicity

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