Applying MAPPs Assays to Assess Drug Immunogenicity

Karle, Anette

doi:10.3389/fimmu.2020.00698

Cited by 32 publications

(33 citation statements)

References 29 publications

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“…Interestingly, while protocols for generating moDCs and performing MAPPs assays remain fairly generic, there is mounting evidence that MAPPs are a fairly robust assay and results compare well across studies. 26 , 27 Comparative data from the analysis of infliximab and rituximab using only 15 donors demonstrated a very close alignment with the peptide clusters characterized by Hamze et al . who used more than 30 donors for their MAPPs study.…”

Section: In Vitro Assayssupporting

confidence: 62%

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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Section: In Vitro Assayssupporting

confidence: 62%

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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“…With this reservation, we believe the results presented here strongly suggest that in silico prediction methods can and should serve as a guide, complementing MAPPs assays, for the general assessment of the immunogenicity of therapeutic proteins and the identification of HLA‐II antigen presentation hotspot regions relevant for protein deimmunization 16,17,38,39 …”

Section: Discussionmentioning

confidence: 99%

“…16), and the main goals of using MAPPs have been to understand the causes of immunogenicity, compare biotherapeutic candidates, guide deimmunization and investigate immunogenicity observed in the clinic (reviewed in Ref. 17). In contrast to technologies based on HLA binding only, MAPPs can identify an MHC‐II peptide repertoire from proteins who have been taken up, processed and presented by antigen‐presenting cells – thereby identifying more ‘real’ potential T‐cell epitopes with a lower degree of overpredictiveness.…”

Section: Introductionmentioning

confidence: 99%

Improved prediction of HLA antigen presentation hotspots: Applications for immunogenicity risk assessment of therapeutic proteins

et al. 2020

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SummaryImmunogenicity risk assessment is a critical element in protein drug development. Currently, the risk assessment is most often performed using MHC‐associated peptide proteomics (MAPPs) and/or T‐cell activation assays. However, this is a highly costly procedure that encompasses limited sensitivity imposed by sample sizes, the MHC repertoire of the tested donor cohort and the experimental procedures applied. Recent work has suggested that these techniques could be complemented by accurate, high‐throughput and cost‐effective prediction of in silico models. However, this work covered a very limited set of therapeutic proteins and eluted ligand (EL) data. Here, we resolved these limitations by showcasing, in a broader setting, the versatility of in silico models for assessment of protein drug immunogenicity. A method for prediction of MHC class II antigen presentation was developed on the hereto largest available mass spectrometry (MS) HLA‐DR EL data set. Using independent test sets, the performance of the method for prediction of HLA‐DR antigen presentation hotspots was benchmarked. In particular, the method was showcased on a set of protein sequences including four therapeutic proteins and demonstrated to accurately predict the experimental MS hotspot regions at a significantly lower false‐positive rate compared with other methods. This gain in performance was particularly pronounced when compared to the NetMHCIIpan‐3.2 method trained on binding affinity data. These results suggest that in silico methods trained on MS HLA EL data can effectively and accurately be used to complement MAPPs assays for the risk assessment of protein drugs.

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“…To address these issues, a variety of approaches have been developed [ 228 ], including MHC-associated peptide proteomics (MAPPs) [ 248 , 249 ]. In this in vitro technique, human professional antigen-presenting cells are incubated with the biologic of interest, the biologic is then internalized, processed enzymatically, and presented at the surface by human leukocyte antigen (HLA) class II molecules.…”

Section: Polyspecificty and In Vivo Propertiesmentioning

confidence: 99%

“…Although these methods are highly validated for identifying immunogenic sequences, the assays require analysis of the blood from at least 20 donors to cover the processing and display variability that is often observed for antigen-presenting cells obtained from different individuals. Therefore, a full analysis can take up to eight weeks for approximately ten therapeutic candidates [ 249 ]. Although this method is valuable for determining antigenic liability of biologics without dosing human subjects, MAPPs assays are not practical for early-stage development decisions, as a consequence of the time-intensive and low-throughput nature of this approach.…”

Section: Polyspecificty and In Vivo Propertiesmentioning

confidence: 99%

Toward Drug-Like Multispecific Antibodies by Design

Sawant

Streu

et al. 2020

IJMS

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The success of antibody therapeutics is strongly influenced by their multifunctional nature that couples antigen recognition mediated by their variable regions with effector functions and half-life extension mediated by a subset of their constant regions. Nevertheless, the monospecific IgG format is not optimal for many therapeutic applications, and this has led to the design of a vast number of unique multispecific antibody formats that enable targeting of multiple antigens or multiple epitopes on the same antigen. Despite the diversity of these formats, a common challenge in generating multispecific antibodies is that they display suboptimal physical and chemical properties relative to conventional IgGs and are more difficult to develop into therapeutics. Here we review advances in the design and engineering of multispecific antibodies with drug-like properties, including favorable stability, solubility, viscosity, specificity and pharmacokinetic properties. We also highlight emerging experimental and computational methods for improving the next generation of multispecific antibodies, as well as their constituent antibody fragments, with natural IgG-like properties. Finally, we identify several outstanding challenges that need to be addressed to increase the success of multispecific antibodies in the clinic.

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Applying MAPPs Assays to Assess Drug Immunogenicity

Cited by 32 publications

References 29 publications

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

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

Improved prediction of HLA antigen presentation hotspots: Applications for immunogenicity risk assessment of therapeutic proteins

Toward Drug-Like Multispecific Antibodies by Design

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