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

ABSTRACT 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.

[1]  Thomas Singer,et al.  Enabling Routine MHC-II Associated Peptide ProteomicS (MAPPs) for Risk Assessment of Drug-Induced Immunogenicity. , 2020, Journal of proteome research.

[2]  M. Nielsen,et al.  Immunopeptidomic Data Integration to Artificial Neural Networks Enhances Protein-Drug Immunogenicity Prediction , 2020, Frontiers in Immunology.

[3]  Anette C. Karle.  Applying MAPPs Assays to Assess Drug Immunogenicity , 2020, Frontiers in Immunology.

[4]  A. Sette,et al.  Major Histocompatibility Complex Binding, Eluted Ligands, and Immunogenicity: Benchmark Testing and Predictions , 2020, Frontiers in Immunology.

[5]  F. Kolbinger,et al.  T cell epitope mapping of secukinumab and ixekizumab in healthy donors , 2020, mAbs.

[6]  J. Willency,et al.  Post-hoc assessment of the immunogenicity of three antibodies reveals distinct immune stimulatory mechanisms , 2020, mAbs.

[7]  J. Blangero,et al.  Quantitative HLA‐class‐II/factor VIII (FVIII) peptidomic variation in dendritic cells correlates with the immunogenic potential of therapeutic FVIII proteins in hemophilia A , 2020, Journal of thrombosis and haemostasis : JTH.

[8]  Russ B. Altman,et al.  Predicting HLA class II antigen presentation through integrated deep learning , 2019, Nature Biotechnology.

[9]  George Coukos,et al.  Robust prediction of HLA class II epitopes by deep motif deconvolution of immunopeptidomes , 2019, Nature Biotechnology.

[10]  Jennifer G. Abelin,et al.  Defining HLA-II Ligand Processing and Binding Rules with Mass Spectrometry Enhances Cancer Epitope Prediction. , 2019, Immunity.

[11]  Maciej J. Swat,et al.  A Quantitative Systems Pharmacology Consortium Approach to Managing Immunogenicity of Therapeutic Proteins , 2019, CPT: pharmacometrics & systems pharmacology.

[12]  R. Geiger,et al.  A single T cell epitope drives the neutralizing anti-drug antibody response to natalizumab in multiple sclerosis patients , 2019, Nature Medicine.

[13]  S. Mallal,et al.  Characterization of Magnitude and Antigen Specificity of HLA-DP, DQ, and DRB3/4/5 Restricted DENV-Specific CD4+ T Cell Responses , 2019, Front. Immunol..

[14]  Z. Sauna,et al.  Peptides identified on monocyte-derived dendritic cells: a marker for clinical immunogenicity to FVIII products. , 2019, Blood advances.

[15]  S. Balu-Iyer,et al.  Immunogenicity of Protein Pharmaceuticals. , 2019, Journal of pharmaceutical sciences.

[16]  O. Yogurtçu,et al.  Predictive model for Zika virus RNA minipool nucleic acid testing in outbreak scenarios , 2019, Transfusion.

[17]  M. Pallardy,et al.  Evaluation of in vitro Assays to Assess the Modulation of Dendritic Cells Functions by Therapeutic Antibodies and Aggregates , 2019, Front. Immunol..

[18]  A. Takeiri,et al.  MHC-associated peptide proteomics enabling highly sensitive detection of immunogenic sequences for the development of therapeutic antibodies with low immunogenicity , 2018, mAbs.

[19]  P. Bousso,et al.  A human immune system mouse model with robust lymph node development , 2018, Nature Methods.

[20]  Sandeep Kumar Dhanda,et al.  Predicting HLA CD4 Immunogenicity in Human Populations , 2018, Front. Immunol..

[21]  P. Chow,et al.  Development of a new patient-derived xenograft humanised mouse model to study human-specific tumour microenvironment and immunotherapy , 2018, Gut.

[22]  A. ten Brinke,et al.  Mass spectrometry-assisted identification of ADAMTS13-derived peptides presented on HLA-DR and HLA-DQ , 2018, Haematologica.

[23]  A. Loercher,et al.  Detection of Memory B Activity Against a Therapeutic Protein in Treatment-Naïve Subjects , 2018, The AAPS Journal.

[24]  C. Murawsky,et al.  Strategies for Generating Diverse Antibody Repertoires Using Transgenic Animals Expressing Human Antibodies , 2018, Front. Immunol..

[25]  Qingfeng Chen,et al.  Humanized Mice as Unique Tools for Human-Specific Studies , 2018, Archivum Immunologiae et Therapiae Experimentalis.

[26]  A. ten Brinke,et al.  Monitoring T-Cell Responses in Translational Studies: Optimization of Dye-Based Proliferation Assay for Evaluation of Antigen-Specific Responses , 2017, Front. Immunol..

[27]  J. Chan,et al.  A Novel Human Systemic Lupus Erythematosus Model in Humanised Mice , 2017, Scientific Reports.

[28]  S. Lacroix-Desmazes,et al.  CD4 T cells specific for factor VIII are present at high frequency in healthy donors and comprise naïve and memory cells. , 2017, Blood advances.

[29]  E. Jáuregui,et al.  Immunogenicity in Protein and Peptide Based-Therapeutics: An Overview. , 2017, Current protein & peptide science.

[30]  K. Lamberth,et al.  Quantitative analysis of the CD4+ T cell response to therapeutic antibodies in healthy donors using a novel T cell:PBMC assay , 2017, PloS one.

[31]  X. Mariette,et al.  Characterization of CD4 T Cell Epitopes of Infliximab and Rituximab Identified from Healthy Donors , 2017, Front. Immunol..

[32]  J. Huwyler,et al.  Extensive Chemical Modifications in the Primary Protein Structure of IgG1 Subvisible Particles Are Necessary for Breaking Immune Tolerance. , 2017, Molecular pharmaceutics.

[33]  Georgios A. Dalkas,et al.  SEPIa, a knowledge-driven algorithm for predicting conformational B-cell epitopes from the amino acid sequence , 2017, BMC Bioinformatics.

[34]  D. Greiner,et al.  Humanized Mouse Models of Clinical Disease. , 2017, Annual review of pathology.

[35]  G. S. Pandey,et al.  Post hoc assessment of the immunogenicity of bioengineered factor VIIa demonstrates the use of preclinical tools , 2017, Science Translational Medicine.

[36]  M. Joubert,et al.  Use of In Vitro Assays to Assess Immunogenicity Risk of Antibody-Based Biotherapeutics , 2016, PloS one.

[37]  Vibha Jawa,et al.  Evaluating Immunogenicity Risk Due to Host Cell Protein Impurities in Antibody-Based Biotherapeutics , 2016, The AAPS Journal.

[38]  P. Nair,et al.  Immunogenicity of Biotherapeutics: Causes and Association with Posttranslational Modifications , 2016, Journal of immunology research.

[39]  H. Weiner,et al.  Therapeutic anti-CD3 monoclonal antibodies: from bench to bedside. , 2016, Immunotherapy.

[40]  W. Jiskoot,et al.  Mouse Models for Assessing Protein Immunogenicity: Lessons and Challenges. , 2016, Journal of pharmaceutical sciences.

[41]  J. Schlom,et al.  A fully human IgG1 anti-PD-L1 MAb in an in vitro assay enhances antigen-specific T-cell responses , 2016, Clinical & translational immunology.

[42]  J. Greenbaum,et al.  T‐cell recognition is shaped by epitope sequence conservation in the host proteome and microbiome , 2016, Immunology.

[43]  H. Myler,et al.  Pre-existing Antibody: Biotherapeutic Modality-Based Review , 2016, The AAPS Journal.

[44]  F. Kolbinger,et al.  Secukinumab, a novel anti–IL-17A antibody, shows low immunogenicity potential in human in vitro assays comparable to other marketed biotherapeutics with low clinical immunogenicity , 2016, mAbs.

[45]  T. Hickling,et al.  Contribution of enhanced engagement of antigen presentation machinery to the clinical immunogenicity of a human interleukin (IL)‐21 receptor‐blocking therapeutic antibody , 2016, Clinical and experimental immunology.

[46]  E. Havrdová,et al.  Standardizing terms, definitions and concepts for describing and interpreting unwanted immunogenicity of biopharmaceuticals: recommendations of the Innovative Medicines Initiative ABIRISK consortium , 2015, Clinical and experimental immunology.

[47]  Paolo Vicini,et al.  Therapeutic outcomes, assessments, risk factors and mitigation efforts of immunogenicity of therapeutic protein products. , 2015, Cellular immunology.

[48]  M. Pallardy,et al.  Ectosomes from neutrophil‐like cells down‐regulate nickel‐induced dendritic cell maturation and promote Th2 polarization , 2015, Journal of leukocyte biology.

[49]  T. Singer,et al.  The Immunogenicity of Antibody Aggregates in a Novel Transgenic Mouse Model , 2015, Pharmaceutical Research.

[50]  C. Smales,et al.  Measurement and control of host cell proteins (HCPs) in CHO cell bioprocesses. , 2014, Current opinion in biotechnology.

[51]  James Robinson,et al.  The IPD and IMGT/HLA database: allele variant databases , 2014, Nucleic Acids Res..

[52]  P Vicini,et al.  A Mechanistic, Multiscale Mathematical Model of Immunogenicity for Therapeutic Proteins: Part 1—Theoretical Model , 2014, CPT: pharmacometrics & systems pharmacology.

[53]  P. Greenberg,et al.  Antigen-specific activation and cytokine-facilitated expansion of naive, human CD8+ T cells , 2014, Nature Protocols.

[54]  A. D. De Groot,et al.  Tregitope Peptides: The Active Pharmaceutical Ingredient of IVIG? , 2013, Clinical & developmental immunology.

[55]  C. Rice,et al.  Utility of Humanized BLT Mice for Analysis of Dengue Virus Infection and Antiviral Drug Testing , 2013, Journal of Virology.

[56]  Eric W. Cross,et al.  T cell responses: naive to memory and everything in between. , 2013, Advances in physiology education.

[57]  Antonio Cosma,et al.  Overnight Resting of PBMC Changes Functional Signatures of Antigen Specific T- Cell Responses: Impact for Immune Monitoring within Clinical Trials , 2013, PloS one.

[58]  T. Arora,et al.  Development of a human antibody tolerant mouse model to assess the immunogenicity risk due to aggregated biotherapeutics. , 2013, Journal of pharmaceutical sciences.

[59]  Marcelo A. Navarrete,et al.  Usage of standardized antigen-presenting cells improves ELISpot performance for complex protein antigens. , 2013, Journal of immunological methods.

[60]  Prabhavathi Maddineni,et al.  Comparison of whole blood and PBMC assays for T-cell functional analysis , 2013, BMC Research Notes.

[61]  Jianzhu Chen,et al.  GM-CSF and IL-4 Stimulate Antibody Responses in Humanized Mice by Promoting T, B, and Dendritic Cell Maturation , 2012, The Journal of Immunology.

[62]  M. Shipkova,et al.  Surface markers of lymphocyte activation and markers of cell proliferation. , 2012, Clinica chimica acta; international journal of clinical chemistry.

[63]  M. Greenblatt,et al.  Graft versus Host Disease in the Bone Marrow, Liver and Thymus Humanized Mouse Model , 2012, PloS one.

[64]  C. Lubich,et al.  CD4+ T-cell epitopes associated with antibody responses after intravenously and subcutaneously applied human FVIII in humanized hemophilic E17 HLA-DRB1*1501 mice. , 2012, Blood.

[65]  Michele A. Soltis,et al.  Frequency of Epitope-Specific Naive CD4+ T Cells Correlates with Immunodominance in the Human Memory Repertoire , 2012, The Journal of Immunology.

[66]  David Baltimore,et al.  Antibody-based Protection Against HIV Infection by Vectored ImmunoProphylaxis , 2011, Nature.

[67]  H. Schwarz,et al.  Maintenance and break of immune tolerance against human factor VIII in a new transgenic hemophilic mouse model. , 2011, Blood.

[68]  J. D. Di Santo,et al.  Functional CD47/signal regulatory protein alpha (SIRPα) interaction is required for optimal human T- and natural killer- (NK) cell homeostasis in vivo , 2011, Proceedings of the National Academy of Sciences.

[69]  T. Berg,et al.  CD154, a marker of antigen‐specific stimulation of CD4 T cells, is associated with response to treatment in patients with chronic HCV infection , 2011, Journal of viral hepatitis.

[70]  B. Maillère,et al.  Quantitative analysis of the CD4 T‐cell repertoire specific to therapeutic antibodies in healthy donors , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[71]  N. Chirmule,et al.  Considerations for optimization and validation of an in vitro PBMC derived T cell assay for immunogenicity prediction of biotherapeutics. , 2010, Clinical immunology.

[72]  Cedrik M. Britten,et al.  Response definition criteria for ELISPOT assays revisited , 2010, Cancer Immunology, Immunotherapy.

[73]  G. Stiegler,et al.  Inhibition of In Vivo HIV Infection in Humanized Mice by Gene Therapy of Human Hematopoietic Stem Cells with a Lentiviral Vector Encoding a Broadly Neutralizing Anti-HIV Antibody , 2010, Journal of Virology.

[74]  Bjoern Peters,et al.  Five HLA-DP Molecules Frequently Expressed in the Worldwide Human Population Share a Common HLA Supertypic Binding Specificity , 2010, The Journal of Immunology.

[75]  W. Koff,et al.  Optimization of a dendritic cell-based assay for the in vitro priming of naïve human CD4+ T cells. , 2010, Journal of immunological methods.

[76]  F. Sallusto,et al.  Human naive and memory CD4+ T cell repertoires specific for naturally processed antigens analyzed using libraries of amplified T cells , 2009, The Journal of experimental medicine.

[77]  R. Swanstrom,et al.  Suppression of Human Immunodeficiency Virus Type 1 (HIV-1) Viremia with Reverse Transcriptase and Integrase Inhibitors, CD4+ T-Cell Recovery, and Viral Rebound upon Interruption of Therapy in a New Model for HIV Treatment in the Humanized Rag2−/−γc−/− Mouse , 2009, Journal of Virology.

[78]  Andrew D. Luster,et al.  Induction of Robust Cellular and Humoral Virus-Specific Adaptive Immune Responses in Human Immunodeficiency Virus-Infected Humanized BLT Mice , 2009, Journal of Virology.

[79]  A. Chakraborty,et al.  T cell sensing of antigen dose governs interactive behavior with dendritic cells and sets a threshold for T cell activation , 2008, Nature Immunology.

[80]  A. Haase,et al.  Antiretroviral Pre-exposure Prophylaxis Prevents Vaginal Transmission of HIV-1 in Humanized BLT Mice , 2008, PLoS medicine.

[81]  Y. Belkaid,et al.  Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid , 2007, The Journal of experimental medicine.

[82]  H. Zarour,et al.  Differential capacity of T cell priming in naive donors of promiscuous CD4+ T cell epitopes of HCV NS3 and Core proteins , 2007, European journal of immunology.

[83]  J. Bluestone,et al.  Analysis of T-Cell Assays to Measure Autoimmune Responses in Subjects With Type 1 Diabetes , 2006, Diabetes.

[84]  K. Akashi,et al.  Development of functional human blood and immune systems in NOD/SCID/IL2 receptor γ chainnull mice , 2005 .

[85]  S. Scheurer,et al.  Bet v 1142-156 is the dominant T-cell epitope of the major birch pollen allergen and important for cross-reactivity with Bet v 1-related food allergens. , 2005, The Journal of allergy and clinical immunology.

[86]  Antonio Lanzavecchia,et al.  Central memory and effector memory T cell subsets: function, generation, and maintenance. , 2004, Annual review of immunology.

[87]  T. Rothoeft,et al.  Antigen dose, type of antigen‐presenting cell and time of differentiation contribute to the T helper 1/T helper 2 polarization of naive T cells , 2003, Immunology.

[88]  Sylvia Janetzki,et al.  A panel of MHC class I restricted viral peptides for use as a quality control for vaccine trial ELISPOT assays. , 2002, Journal of immunological methods.

[89]  H. Volk,et al.  Improving the in vitro antigen specific T cell proliferation assay: the use of interferon-alpha to elicit antigen specific stimulation and decrease bystander proliferation. , 2001, Journal of immunological methods.

[90]  G. Hämmerling,et al.  Structural features of the invariant chain fragment CLIP controlling rapid release from HLA-DR molecules and inhibition of peptide binding. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[91]  C Oseroff,et al.  Development of high potency universal DR-restricted helper epitopes by modification of high affinity DR-blocking peptides. , 1994, Immunity.

[92]  F. Sallusto,et al.  Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha , 1994, The Journal of experimental medicine.

[93]  Yi-Ying Chen,et al.  B-Cell ELISpot Assay to Quantify Antigen-Specific Antibody-Secreting Cells in Human Peripheral Blood Mononuclear Cells. , 2018, Methods in molecular biology.

[94]  S. Goral.  The three‐signal hypothesis of lymphocyte activation/targets for immunosuppression , 2011 .

[95]  V. Taneja,et al.  HLA class II transgenic mice mimic human inflammatory diseases. , 2008, Advances in immunology.

[96]  K. Akashi,et al.  Development of functional human blood and immune systems in NOD/SCID/IL2 receptor {gamma} chain(null) mice. , 2005, Blood.