Applying MAPPs Assays to Assess Drug Immunogenicity.
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ABSTRACT:
SUBMITTER: Karle AC
PROVIDER: S-EPMC7186346 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
Publications
Applying MAPPs Assays to Assess Drug Immunogenicity.
Frontiers in immunology 20200421
Immunogenicity against biotherapeutic proteins (BPs) and the potential outcome for the patient are difficult to predict. <i>In vitro</i> 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 bio ...[more]
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Project description:An In Vitro Comparative Immunogenicity Assessment (IVCIA) assay was evaluated as a tool for predicting the potential relative immunogenicity of biotherapeutic attributes. Peripheral blood mononuclear cells from up to 50 healthy naïve human donors were monitored up to 8 days for T-cell proliferation, the number of IL-2 or IFN-? secreting cells, and the concentration of a panel of secreted cytokines. The response in the assay to 10 monoclonal antibodies was found to be in agreement with the clinical immunogenicity, suggesting that the assay might be applied to immunogenicity risk assessment of antibody biotherapeutic attributes. However, the response in the assay is a measure of T-cell functional activity and the alignment with clinical immunogenicity depends on several other factors. The assay was sensitive to sequence variants and could differentiate single point mutations of the same biotherapeutic. Nine mAbs that were highly aggregated by stirring induced a higher response in the assay than the original mAbs before stirring stress, in a manner that did not match the relative T-cell response of the original mAbs. In contrast, mAbs that were glycated by different sugars (galactose, glucose, and mannose) showed little to no increase in response in the assay above the response to the original mAbs before glycation treatment. The assay was also used successfully to assess similarity between multiple lots of the same mAb, both from the same manufacturer and from different manufacturers (biosimilars). A strategy for using the IVCIA assay for immunogenicity risk assessment during the entire lifespan development of biopharmaceuticals is proposed.
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Project description:ObjectiveClassic methods for assessing cerebral autoregulation involve a transfer function analysis performed using the Fourier transform to quantify relationship between fluctuations in arterial blood pressure (ABP) and cerebral blood flow velocity (CBFV). This approach usually assumes the signals and the system to be stationary. Such an presumption is restrictive and may lead to unreliable results. The aim of this study is to present an alternative method that accounts for intrinsic non-stationarity of cerebral autoregulation and the signals used for its assessment.MethodsContinuous recording of CBFV, ABP, ECG, and end-tidal CO2 were performed in 50 young volunteers during normocapnia and hypercapnia. Hypercapnia served as a surrogate of the cerebral autoregulation impairment. Fluctuations in ABP, CBFV, and phase shift between them were tested for stationarity using sphericity based test. The Zhao-Atlas-Marks distribution was utilized to estimate the time-frequency coherence (TFCoh) and phase shift (TFPS) between ABP and CBFV in three frequency ranges: 0.02-0.07 Hz (VLF), 0.07-0.20 Hz (LF), and 0.20-0.35 Hz (HF). TFPS was estimated in regions locally validated by statistically justified value of TFCoh. The comparison of TFPS with spectral phase shift determined using transfer function approach was performed.ResultsThe hypothesis of stationarity for ABP and CBFV fluctuations and the phase shift was rejected. Reduced TFPS was associated with hypercapnia in the VLF and the LF but not in the HF. Spectral phase shift was also decreased during hypercapnia in the VLF and the LF but increased in the HF. Time-frequency method led to lower dispersion of phase estimates than the spectral method, mainly during normocapnia in the VLF and the LF.ConclusionThe time-frequency method performed no worse than the classic one and yet may offer benefits from lower dispersion of phase shift as well as a more in-depth insight into the dynamic nature of cerebral autoregulation.
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Project description:The appended raw files, csv files and other documents were deposited in the public domain in support for the publication
Enabling Routine MHC-II Associated Peptide ProteomicS (MAPPs) for Risk Assessment of Drug-Induced Immunogenicity
Guido Steiner, Celine Marban-Doran, Jessica Langer, Tatiana Pimenova, Gonzalo Duran-Pacheco; Denise Sauter; Anja Langenkamp, Corinne Solier, Thomas Singer, Katharine Bray-French, and Axel Ducret
The abstract is appended below:
MHC-II Associated Peptide ProteomicS (MAPPs) is a mass spectrometry-based approach to identify and relatively quantitate naturally processed and presented MHC-II associated peptides that can potentially activate T cells and contribute to the immunogenicity of a drug. Acceptance of the MAPPs technology as an appropriate pre-clinical (and potentially clinical) immunogenicity risk assessment tool depends on its technical stability and robustness but also on the ability to compare results across experiments and donors. To this end, we developed a specialized MAPPs data processing pipeline, dataMAPPs, which presents complex mass spectrometric datasets in the form of heat maps (heatMAPPs) enabling rapid and convenient comparison between conditions and donors. A customized normalization procedure based on identified endogenous peptides standardizes signal intensities within and between donors and enable cross-experimental comparison. We evaluated the technical reproducibility of the MAPPs platform using tool compounds with respect to the most prominent experimental factors and found that the systematic biological differences across donors by far outweighed any technical source of variation. We illustrate the capability of the MAPPs platform to generate data that may be used for pre-clinical risk assessment of drug-induced immunogenicity and discuss its applicability in the clinics.
The raw files and associated data for publicly available compounds are appended in the depository. The database (dataMAPPS publication db.FASTA) that was used to search the raw files is also included.
The current dataset is divided in three sections, each with explaining documentation:
Folder Fig. 2_4_5 contains the raw files, the PEAKS identification files and the quantification files that were used to generate the Fig. 2, 4 and 5 of the publication. The raw files were also used to generate the test files deposited on http://SourceForge.net/projects/datamapps/ which is alsothe source to download the R source code for dataMAPPs.
Folder Fig. 6BC contains the raw files, the PEAKS identification files and the quantification files that were used to generate the Fig. 6 BC. The raw files used to generate Fig. 6A were not included; they have been generated using a compound that is proprietary.
Folder Fig. 8_KLH contains the raw files, the PEAKS identification files and the quantification files that were used to generate the Fig. 8.
2020-05-05 | MSV000085375 | MassIVE
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