T and B cell epitope analysis for the immunogenicity evaluation and mitigation of antibody-based therapeutics

References

• van Brummelen EM, Ros W, Wolbink G, Beijnen JH, Schellens JH. Antidrug antibody formation in oncology: clinical relevance and challenges. Oncologist. 2016;21(10):1260–16. doi:10.1634/theoncologist.2016-0061.
   PubMed Web of Science ®Google Scholar
• Vaisman-Mentesh A, Gutierrez-Gonzalez M, DeKosky BJ, Wine Y. The molecular mechanisms that underlie the immune biology of anti-drug antibody formation following treatment with monoclonal antibodies. Front Immunol. 2020;11:111951. doi:10.3389/fimmu.2020.01951.
   Web of Science ®Google Scholar
• Boyer-Suavet S, Andreani M, Lateb M, Savenkoff B, Brglez V, Benzaken S, Bernard G, Nachman PH, Esnault V, Seitz-Polski B. Neutralizing anti-Rituximab antibodies and relapse in membranous nephropathy treated with Rituximab. Front Immunol. 2019;10:3069. doi:10.3389/fimmu.2019.03069.
   PubMed Web of Science ®Google Scholar
• Linthorst GE, Hollak CE, Donker-Koopman WE, Strijland A, Aerts JM. Enzyme therapy for fabry disease: neutralizing antibodies toward agalsidase alpha and beta. Kidney Int. 2004;66(4):1589–1595. doi:10.1111/j.1523-1755.2004.00924.x.
   PubMed Web of Science ®Google Scholar
• Sasson SC, Wilkins LE, Watson RA, Jolly C, Brain O, Klenerman P, Olsson-Brown A, Fairfax BP. Identification of neutralising pembrolizumab anti-drug antibodies in patients with melanoma. Sci Rep. 2021;11(1):19253. doi:10.1038/s41598-021-98700-7.
   PubMed Web of Science ®Google Scholar
• Ridker PM, Tardif JC, Amarenco P, Duggan W, Glynn RJ, Jukema JW, Kastelein JJP, Kim AM, Koenig W, Nissen S. et al. Lipid-reduction variability and antidrug-antibody formation with Bococizumab. N Engl J Med. 2017;376(16):1517–1526. doi:10.1056/NEJMoa1614062.
   PubMed Web of Science ®Google Scholar
• Ehrenpreis ED, Ehrenpreis ED. Pharmacokinetic effects of antidrug antibodies occurring in healthy subjects after a single dose of intravenous infliximab. Drugs R D. 2017;17(4):607–613. doi:10.1007/s40268-017-0211-y.
   PubMed Web of Science ®Google Scholar
• Chirmule N, Jawa V, Meibohm B. Immunogenicity to therapeutic proteins: impact on PK/PD and efficacy. AAPS J. 2012;14(2):296–302. doi:10.1208/s12248-012-9340-y.
   PubMed Web of Science ®Google Scholar
• Vultaggio A, Nencini F, Pratesi S, Petroni G, Maggi E, Matucci A. Manifestations of antidrug antibodies response: hypersensitivity and infusion reactions. J Interferon Cytokine Res. 2014;34(12):946–952. doi:10.1089/jir.2012.0139.
   PubMed Web of Science ®Google Scholar
• Chung CH, Mirakhur B, Chan E, Le QT, Berlin J, Morse M, Murphy BA, Satinover SM, Hosen J, Mauro D. et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. N Engl J Med. 2008;358(11):1109–17. doi:10.1056/NEJMoa074943.
   PubMed Web of Science ®Google Scholar
• Krishna M, Nadler SG. Immunogenicity to biotherapeutics - the role of anti-drug immune complexes. Front Immunol. 2016;7:21. doi:10.3389/fimmu.2016.00021.
   PubMed Web of Science ®Google Scholar
• FDA. Immunogenicity assessment for therapeutic protein products. 2014.
   Google Scholar
• EMA. Immunogenicity assessment of biotechnology-derived therapeutic proteins. 2017.
   Google Scholar
• Lotz GP, Benstein K, Bloem K, Buddiger H, Calonder C, Elm S, Fernandez E, Goodman J, Gorovits B, Grudzinska-Goebel J. et al. When to extend monitoring of anti-drug antibodies for high-risk biotherapeutics in clinical trials: an opinion from the european immunogenicity platform COMMENT. AAPS J. 2022;24(3):68. doi:10.1208/s12248-022-00712-2.
   PubMed Web of Science ®Google Scholar
• Bartelds GM, Krieckaert CLM, Nurmohamed MT, van Schouwenburg PA, Lems WF, Twisk JWR, Dijkmans AC, Aarden L, Wolbink GJ. Development of antidrug antibodies against Adalimumab and association with disease activity and treatment failure during long-term follow-up. JAMA. 2011;305(14):1460–68. doi:10.1001/jama.2011.406.
   PubMed Web of Science ®Google Scholar
• Gorovits B, Peng K, Kromminga A. Current considerations on characterization of immune response to multi-domain biotherapeutics. BioDrugs. 2020;34(1):39–54. doi:10.1007/s40259-019-00389-8.
   PubMed Web of Science ®Google Scholar
• Gorovits B, Azadeh M, Buchlis G, Harrison T, Havert M, Jawa V, Long B, McNally J, Milton M, Nelson R. et al. Evaluation of the humoral response to adeno-associated virus-based gene therapy modalities using total antibody assays. AAPS J. 2021;23(6):108. doi:10.1208/s12248-021-00628-3.
   PubMed Web of Science ®Google Scholar
• Verdera HC, Kuranda K, Mingozzi F. AAV vector immunogenicity in humans: a long journey to successful gene transfer. Mol Ther. 2020;28(3):723–746. doi:10.1016/j.ymthe.2019.12.010.
   PubMed Web of Science ®Google Scholar
• Gorovits B, Koren E. Immunogenicity of chimeric antigen receptor T-cell therapeutics. BioDrugs. 2019;33(3):275–284. doi:10.1007/s40259-019-00354-5.
   PubMed Web of Science ®Google Scholar
• Wagner DL, Fritsche E, Pulsipher MA, Ahmed N, Hamieh M, Hegde M, Ruella M, Savoldo B, Shah NN, Turtle CJ. et al. Immunogenicity of CAR T cells in cancer therapy. Nat Rev Clin Oncol. 2021;18(6):379–393. doi:10.1038/s41571-021-00476-2.
   PubMed Web of Science ®Google Scholar
• Crudele JM, Chamberlain JS. Cas9 immunity creates challenges for CRISPR gene editing therapies. Nat Commun. 2018;9(1):3497. doi:10.1038/s41467-018-05843-9.
   PubMedGoogle Scholar
• Charlesworth CT, Deshpande PS, Dever DP, Camarena J, Lemgart VT, Cromer MK, Vakulskas CA, Collingwood MA, Zhang LY, Bode NM. et al. Identification of preexisting adaptive immunity to Cas9 proteins in humans. Nat Med. 2019;25(2):249–254. doi:10.1038/s41591-018-0326-x.
   PubMed Web of Science ®Google Scholar
• Murphy K, Weaver C. B-cell activation by antigen and helper T cells. In: Janeway’s editors. Immunobiology (Edition 9). B-cell activation by antigen and helper T cells. 2017. p. 400–21.
   Google Scholar
• Ishida T, Wang X, Shimizu T, Nawata K, Kiwada H. Pegylated liposomes elicit an anti-PEG IgM response in a T cell-independent manner. J Control Release. 2007;122(3):349–355. doi:10.1016/j.jconrel.2007.05.015.
   PubMed Web of Science ®Google Scholar
• Roche PA, Furuta K. The ins and outs of MHC class II-mediated antigen processing and presentation. Nat Rev Immunol. 2015;15(4):203–216. doi:10.1038/nri3818.
   PubMed Web of Science ®Google Scholar
• Koren E, Smith HW, Shores E, Shankar G, Finco-Kent D, Rup B, Barrett YC, Devanarayan V, Gorovits B, Gupta S. et al. Recommendations on risk-based strategies for detection and characterization of antibodies against biotechnology products. J Immunol Methods. 2008;333(1–2):1–9. doi:10.1016/j.jim.2008.01.001.
   PubMed Web of Science ®Google Scholar
• Gorovits B, Wakshull E, Pillutla R, Xu Y, Manning MS, Goyal J. Recommendations for the characterization of immunogenicity response to multiple domain biotherapeutics. J Immunol Methods. 2014;408:4081–12. doi:10.1016/j.jim.2014.05.010.
   Web of Science ®Google Scholar
• Lauren A, Goodman J, Blaes J, Cook J, Cowan KJ, Dahlback M, Grudzinska-Goebel J, McManus D, Nelson R, Pihl S. et al. A strategic approach to nonclinical immunogenicity assessment: a recommendation from the European Bioanalysis Forum. Bioanalysis. 2021;13(7):537–549. doi:10.4155/bio-2021-0028.
   PubMed Web of Science ®Google Scholar
• Myler H, Pedras-Vasconcelos J, Phillips K, Hottenstein CS, Chamberlain P, Devanaryan V, Gleason C, Goodman J, Manning MS, Purushothama S. et al. Anti-drug antibody validation testing and reporting harmonization. AAPS J. 2021;24(1):4. doi:10.1208/s12248-021-00649-y.
   PubMed Web of Science ®Google Scholar
• Ducret A, Ackaert C, Bessa J, Bunce C, Hickling T, Jawa V, Kroenke MA, Lamberth K, Manin A, Penny HL. et al. Assay format diversity in pre-clinical immunogenicity risk assessment: toward a possible harmonization of antigenicity assays. Mabs-austin. 2022;14(1):1993522. doi:10.1080/19420862.2021.1993522.
   PubMed Web of Science ®Google Scholar
• Gokemeijer J, Wen Y, Jawa V, Mitra-Kaushik S, Chung S, Goggins A, Kumar S, Lamberth K, Liao K, Lill J. et al. Survey outcome on immunogenicity risk assessment tools for biotherapeutics: an insight into consensus on methods, application, and utility in drug development. AAPS J. 2023;25(4):55. doi:10.1208/s12248-023-00820-7.
   PubMed Web of Science ®Google Scholar
• Tangri S, Mothe BR, Eisenbraun J, Sidney J, Southwood S, Briggs K, Zinckgraf J, Bilsel P, Newman M, Chesnut R. et al. Rationally engineered therapeutic proteins with reduced immunogenicity. J Immunol. 2005;174(6):3187–3196. doi:10.4049/jimmunol.174.6.3187.
   PubMed Web of Science ®Google Scholar
• Ettinger RA, Liberman JA, Gunasekera D, Puranik K, James EA, Thompson AR, Pratt KP. FVIII proteins with a modified immunodominant T-cell epitope exhibit reduced immunogenicity and normal FVIII activity. Blood Adv. 2018;2(4):309–322. doi: 10.1182/bloodadvances.2017013482.
   PubMed Web of Science ®Google Scholar
• Azam A, Mallart S, Illiano S, Duclos O, Prades C, Maillere B. Introduction of non-natural amino acids into T-Cell epitopes to mitigate peptide-specific T-Cell responses. Front Immunol. 2021;12:12. doi:10.3389/fimmu.2021.637963.
   Web of Science ®Google Scholar
• Hamze M, Meunier S, Karle A, Gdoura A, Goudet A, Szely N, Pallardy M, Carbonnel F, Spindeldreher S, Mariette X. et al. Characterization of CD4 T cell epitopes of infliximab and Rituximab identified from healthy donors. Front Immunol. 2017;8. doi:10.3389/fimmu.2017.00500.
   PubMed Web of Science ®Google Scholar
• Xue L, Hickling T, Song R, Nowak J, Rup B. Contribution of enhanced engagement of antigen presentation machinery to the clinical immunogenicity of a human interleukin (IL)-21 receptor-blocking therapeutic antibody. Clin Exp Immunol. 2016;183(1):102–13. doi:10.1111/cei.12711.
   PubMed Web of Science ®Google Scholar
• Karle A, Spindeldreher S, Kolbinger F. 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. Mabs-austin. 2016;8(3):536–50. doi:10.1080/19420862.2015.1136761.
   PubMed Web of Science ®Google Scholar
• Lamberth K, Reedtz-Runge SL, Simon J, Klementyeva K, Pandey GS, Padkjaer SB, Pascal V, Leon IR, Gudme CN, Buus S. et al. Post hoc assessment of the immunogenicity of bioengineered factor VIIa demonstrates the use of preclinical tools. Sci Transl Med. 2017;9(372). doi:10.1126/scitranslmed.aag1286.
   PubMed Web of Science ®Google Scholar
• Cassotta A, Mikol V, Bertrand T, Pouzieux S, Le Parc J, Ferrari P, Dumas J, Auer M, Deisenhammer F, Gastaldi M. et al. A single T cell epitope drives the neutralizing anti-drug antibody response to natalizumab in multiple sclerosis patients. Nat Med. 2019;25(9):1402–1407. doi:10.1038/s41591-019-0568-2.
   PubMed Web of Science ®Google Scholar
• Wilkinson I, Anderson S, Fry J, Julien LA, Neville D, Qureshi O, Watts G, Hale G, Karagiannis SN. Fc-engineered antibodies with immune effector functions completely abolished. PloS One. 2021;16(12):e0260954. doi:10.1371/journal.pone.0260954.
   PubMed Web of Science ®Google Scholar
• Sekiguchi N, Kubo C, Takahashi A, Muraoka K, Takeiri A, Ito S, Yano M, Mimoto F, Maeda A, Iwayanagi Y. et al. MHC-associated peptide proteomics enabling highly sensitive detection of immunogenic sequences for the development of therapeutic antibodies with low immunogenicity. Mabs-austin. 2018;10(8):1168–1181. doi:10.1080/19420862.2018.1518888.
   PubMed Web of Science ®Google Scholar
• Mazor R, Vassall AN, Eberle JA, Beers R, Weldon JE, Venzon DJ, Tsang KY, Benhar I, Pastan I. Identification and elimination of an immunodominant T-cell epitope in recombinant immunotoxins based on pseudomonas exotoxin a. Proc Natl Acad Sci U S A. 2012;109(51):E3597–3603. doi:10.1073/pnas.1218138109.
   PubMed Web of Science ®Google Scholar
• Steven J, Muller MR, Carvalho MF, Ubah OC, Kovaleva M, Donohoe G, Baddeley T, Cornock D, Saunders K, Porter AJ. et al. In vitro maturation of a humanized Shark VNAR domain to improve its biophysical properties to facilitate clinical development. Front Immunol. 2017;8:81361. doi:10.3389/fimmu.2017.01361.
   Web of Science ®Google Scholar
• Zinsli LV, Stierlin N, Loessner MJ, Schmelcher M. Deimmunization of protein therapeutics – recent advances in experimental and computational epitope prediction and deletion. Comput Struct Biotechnol J. 2021;19:19315–29. doi:10.1016/j.csbj.2020.12.024.
   Web of Science ®Google Scholar
• Steinitz KN, van Helden PM, Binder B, Wraith DC, Unterthurner S, Hermann C, Schuster M, Ahmad RU, Weiller M, Lubich C. 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. Blood. 2012;119(17):4073–4082. doi:10.1182/blood-2011-08-374645.
   PubMed Web of Science ®Google Scholar
• Wang P, Sidney J, Kim Y, Sette A, Lund O, Nielsen M, Peters B. Peptide binding predictions for HLA DR, DP and DQ molecules. BMC Bioinf. 2010;11(1):11568. doi:10.1186/1471-2105-11-568.
   Google Scholar
• Karle AC. Applying MAPPs assays to assess drug immunogenicity. Front Immunol. 2020;11:11. doi:10.3389/fimmu.2020.00698.
   PubMed Web of Science ®Google Scholar
• Lee MV, Saad OM, Wong S, LaMar J, Kamen L, Ordonia B, Melendez R, Hassanzadeh A, Chung S, Kaur S. Development of a semi-automated MHC-associated peptide proteomics (MAPPs) method using streptavidin bead-based immunoaffinity capture and nano LC-MS/MS to support immunogenicity risk assessment in drug development. Front Immunol. 2023;14:14. doi:10.3389/fimmu.2023.1295285.
   Web of Science ®Google Scholar
• Hartman K, Steiner G, Siegel M, Looney CM, Hickling TP, Bray-French K, Springer S, Marban-Doran C, Ducret A. Expanding the MAPPs assay to accommodate MHC-II Pan Receptors for improved predictability of potential T cell epitopes. Biology (Basel). 2023;12(9):1265. doi:10.3390/biology12091265.
   PubMedGoogle Scholar
• Di Ianni A, Fraone T, Balestra P, Cowan K, Riccardi Sirtori F, Barbero L. Assessing MAPPs assay as a tool to predict the immunogenicity potential of protein therapeutics. Life Sci Alliance. 2024;7(1):e202302095. doi:10.26508/lsa.202302095.
   PubMedGoogle Scholar
• Siegel M, Steiner G, Franssen LC, Carratu F, Herron J, Hartman K, Looney CM, Ducret A, Bray-French K, Rohr O. et al. Validation of a dendritic cell and CD4+ T Cell restimulation assay contributing to the immunogenicity risk evaluation of biotherapeutics. Pharmaceutics. 2022;14(12):2672. doi:10.3390/pharmaceutics14122672.
   PubMed Web of Science ®Google Scholar
• Cohen S, Myneni S, Batt A, Guerrero J, Brumm J, Chung S. Immunogenicity risk assessment for biotherapeutics through in vitro detection of CD134 and CD137 on T helper cells. Mabs-austin. 2021;13(1):1898831. doi:10.1080/19420862.2021.1898831.
   PubMed Web of Science ®Google Scholar
• Spindeldreher S, Karle A, Correia E, Tenon M, Gottlieb S, Huber T, Maillere B, Kolbinger F. T cell epitope mapping of secukinumab and ixekizumab in healthy donors. Mabs-austin. 2020;12(1):1707418. doi:10.1080/19420862.2019.1707418.
   PubMed Web of Science ®Google Scholar
• USPI. 2018.
   Google Scholar
• Walsh RE, Lannan M, Wen Y, Wang X, Moreland CA, Willency J, Knierman MD, Spindler L, Liu L, Zeng W. et al. Post-hoc assessment of the immunogenicity of three antibodies reveals distinct immune stimulatory mechanisms. Mabs-austin. 2020;12(1):1764829. doi:10.1080/19420862.2020.1764829.
   PubMed Web of Science ®Google Scholar
• Nilvebrant J, Rockberg J. An introduction to Epitope mapping. Methods Mol Biol. 2018:17851–10. doi:10.1007/978-1-4939-7841-0_1.
   Google Scholar
• Reineke U, Schutkowski M. Epitope mapping protocols. Preface Meth Mol Biol. 2009;524:v–vi. https://link.springer.com/book/10.1007/978-1-59745-450-6.
   Google Scholar
• Potocnakova L, Bhide M, Pulzova LB. An introduction to B-cell epitope mapping and in silico epitope prediction. J Immunol Res. 2016;2016:6760830. doi:10.1155/2016/6760830.
   PubMed Web of Science ®Google Scholar
• Stubenrauch K, Kunzel C, Vogel R, Tuerck D, Schick E, Heinrich J. Epitope characterization of the ADA response directed against a targeted immunocytokine. J Pharm Biomed Anal. 2015;114:114296–304. doi:10.1016/j.jpba.2015.05.029.
   Web of Science ®Google Scholar
• Vainshtein I, Sun B, Roskos LK, Liang M. A novel approach to assess domain specificity of anti-drug antibodies to moxetumomab pasudotox, an immunotoxin with two functional domains. J Immunol Methods. 2020;477:112688. doi:10.1016/j.jim.2019.112688.
   PubMed Web of Science ®Google Scholar
• Luong M, Wang Y, Donnelly BB, Lepsy C. Addressing domain specificity in the development of a cell-based binding assay for the detection of neutralizing antibodies against a CD47xPD-L1 bispecific antibody. AAPS J. 2023;25(6):91. doi:10.1208/s12248-023-00856-9.
   PubMed Web of Science ®Google Scholar
• Homann A, Rockendorf N, Kromminga A, Frey A, Jappe U. B cell epitopes on infliximab identified by oligopeptide microarray with unprocessed patient sera. J Transl Med. 2015;13(1):339. doi: 10.1186/s12967-015-0706-7.
   PubMedGoogle Scholar
• Homann A, Rockendorf N, Kromminga A, Frey A, Platts-Mills TA, Jappe U. Glycan and peptide IgE epitopes of the TNF-alpha blockers Infliximab and adalimumab - precision diagnostics by cross-reactivity immune profiling of pient sera. Theranostics. 2017;7(19):4699–709. doi:10.7150/thno.20654.
   PubMed Web of Science ®Google Scholar
• Buus S, Rockberg J, Forsstrom B, Nilsson P, Uhlen M, Schafer-Nielsen C. High-resolution mapping of linear antibody epitopes using ultrahigh-density peptide microarrays. Molecular & Cellular Proteomics: MCP. 2012;11(12):1790–1800. doi:10.1074/mcp.M112.020800.
   PubMed Web of Science ®Google Scholar
• Lin J, Sampson HA. IgE epitope mapping using peptide microarray immunoassay. Methods Mol Biol. 2017:1592177–87. doi:10.1007/978-1-4939-6925-8_14.
   Google Scholar
• Rockberg J, Lofblom J, Hjelm B, Uhlen M, Stahl S. Epitope mapping of antibodies using bacterial surface display. Nat Methods. 2008;5(12):1039–1045. doi:10.1038/nmeth.1272.
   PubMed Web of Science ®Google Scholar
• Hudson EP, Uhlen M, Rockberg J. Multiplex epitope mapping using bacterial surface display reveals both linear and conformational epitopes. Sci Rep. 2012;2(1):706. doi:10.1038/srep00706.
   PubMed Web of Science ®Google Scholar
• Dingens AS, Haddox HK, Overbaugh J, Bloom JD. Comprehensive mapping of HIV-1 escape from a broadly neutralizing antibody. Cell Host Microbe. 2017;21(6):777–87. doi:10.1016/j.chom.2017.05.003.
   PubMed Web of Science ®Google Scholar
• Greaney AJ, Loes AN, Crawford KHD, Starr TN, Malone KD, Chu HY, Bloom JD. Comprehensive mapping of mutations in the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human plasma antibodies. Cell Host Microbe. 2021;29(3):463–76. doi:10.1016/j.chom.2021.02.003.
   PubMed Web of Science ®Google Scholar
• Greaney AJ, Eguia RT, Starr TN, Khan K, Franko N, Logue JK, Lord SM, Speake C, Chu HY, Sigal A. et al. The SARS-CoV-2 delta variant induces an antibody response largely focused on class 1 and 2 antibody epitopes. PloS Pathog. 2022;18(6):e1010592. doi:10.1371/journal.ppat.1010592.
   PubMed Web of Science ®Google Scholar
• Garrett ME, Galloway JG, Wolf C, Logue JK, Franko N, Chu HY, Matsen FA, Overbaugh JM. Comprehensive characterization of the antibody responses to SARS-CoV-2 spike protein finds additional vaccine-induced epitopes beyond those for mild infection. Elife. 2022;11:e73490. doi:10.7554/eLife.73490.
   PubMed Web of Science ®Google Scholar
• Dingens AS, Pratap P, Malone K, Hilton SK, Ketas T, Cottrell CA, Overbaugh J, Moore JP, Klasse PJ, Ward AB. et al. High-resolution mapping of the neutralizing and binding specificities of polyclonal sera post-HIV env trimer vaccination. Elife. 2021;10:e64281. doi:10.7554/eLife.64281.
   PubMed Web of Science ®Google Scholar
• Roth AJ, Ooi JD, Hess JJ, van Timmeren MM, Berg EA, Poulton CE, McGregor J, Burkart M, Hogan SL, Hu Y. et al. Epitope specificity determines pathogenicity and detectability in ANCA-associated vasculitis. J Clin Invest. 2013;123(4):1773–1783. doi:10.1172/JCI65292.
   PubMed Web of Science ®Google Scholar
• Al-Majdoub M, Opuni KF, Koy C, Glocker MO. Facile fabrication and instant application of miniaturized antibody-decorated affinity columns for higher-order structure and functional characterization of TRIM21 epitope peptides. Anal Chem. 2013;85(21):10479–10487. doi:10.1021/ac402559m.
   PubMed Web of Science ®Google Scholar
• Stander S, Grauslund LR, Scarselli M, Norais N, Rand K. Epitope mapping of polyclonal antibodies by hydrogen-deuterium exchange mass spectrometry (HDX-MS). Anal Chem. 2021;93(34):11669–78. doi:10.1021/acs.analchem.1c00696.
   PubMed Web of Science ®Google Scholar
• Schick AJ 3rd, Lundin V, Low J, Peng K, Vandlen R, Wecksler AT. Epitope mapping of anti-drug antibodies to a clinical candidate bispecific antibody. Mabs-austin. 2022;14(1):e2028337. doi:10.1080/19420862.2022.2028337.
   PubMed Web of Science ®Google Scholar
• Bianchi M, Turner HL, Nogal B, Cottrell CA, Oyen D, Pauthner M, Bastidas R, Nedellec R, McCoy LE, Wilson IA. et al. Electron-microscopy-based epitope mapping defines specificities of polyclonal antibodies elicited during HIV-1 BG505 envelope trimer immunization. Immunity. 2018;49(2):288–300. doi:10.1016/j.immuni.2018.07.009.
   PubMed Web of Science ®Google Scholar
• Jumper J, Evans R, Pritzel A, Green T, Figurnov M, Ronneberger O, Tunyasuvunakool K, Bates R, Zidek A, Potapenko A. et al. Highly accurate protein structure prediction with AlphaFold. Nature. 2021;596(7873):583–589. doi:10.1038/s41586-021-03819-2.
   PubMed Web of Science ®Google Scholar
• Brouwer PJM, Antanasijevic A, Ronk AJ, Muller-Krauter H, Watanabe Y, Claireaux M, Perrett HR, Bijl TPL, Grobben M, Umotoy JC. et al. Lassa virus glycoprotein nanoparticles elicit neutralizing antibody responses and protection. Cell Host Microbe. 2022;30(12):1759–72. doi:10.1016/j.chom.2022.10.018.
   PubMed Web of Science ®Google Scholar
• Han J, Schmitz AJ, Richey ST, Dai YN, Turner HL, Mohammed BM, Fremont DH, Ellebedy AH, Ward AB. Polyclonal epitope mapping reveals temporal dynamics and diversity of human antibody responses to H5N1 vaccination. Cell Rep. 2021;34(4):108682. doi:10.1016/j.celrep.2020.108682.
   PubMed Web of Science ®Google Scholar
• FDA. Immunogenicity testing of therapeutic protein products — developing and validating assay for anti-drug antibody detection. 2019.
   Google Scholar
• Lewis KB, Hughes RJ, Epstein MS, Josephson NC, Kempton CL, Kessler CM, Key NS, Howard TE, Kruse-Jarres R, Lusher JM. et al. Phenotypes of allo- and autoimmune antibody responses to FVIII characterized by surface plasmon resonance. PloS One. 2013;8(5):e61120. doi:10.1371/journal.pone.0061120.
   PubMed Web of Science ®Google Scholar
• Larman HB, Zhao Z, Laserson U, Li MZ, Ciccia A, Gakidis MA, Church GM, Kesari S, Leproust EM, Solimini NL. et al. Autoantigen discovery with a synthetic human peptidome. Nat Biotechnol. 2011;29(6):535–541. doi:10.1038/nbt.1856.
   PubMed Web of Science ®Google Scholar
• Geysen HM, Meloen RH, Barteling SJ. Use of peptide synthesis to probe viral antigens for epitopes to a resolution of a single amino acid. Proc Natl Acad Sci U S A. 1984;81(13):3998–4002. doi:10.1073/pnas.81.13.3998.
   PubMed Web of Science ®Google Scholar
• Scharnetzki D, Stappers F, Lenders M, Brand E. Detailed epitope mapping of neutralizing anti-drug antibodies against recombinant alpha-galactosidase a in patients with fabry disease. Mol Genet Metab. 2020;131(1–2):229–34. doi: 10.1016/j.ymgme.2020.08.005.
   PubMed Web of Science ®Google Scholar
• Gimenez G, Benede S, Lin J. IgE epitope mapping using peptide microarray immunoassay. Methods Mol Biol. 2016:1352251–61. doi:10.1007/978-1-4939-3037-1_19.
   Google Scholar
• Heiss K, Heidepriem J, Fischer N, Weber LK, Dahlke C, Jaenisch T, Loeffler FF. Rapid response to pandemic threats: Immunogenic epitope detection of pandemic pathogens for diagnostics and vaccine development using peptide microarrays. J Proteome Res. 2020;19(11):4339–4354. doi:10.1021/acs.jproteome.0c00484.
   PubMed Web of Science ®Google Scholar
• Domina M, Lanza Cariccio V, Benfatto S, D’Aliberti D, Venza M, Borgogni E, Castellino F, Biondo C, D’Andrea D, Grassi L. et al. Rapid profiling of the antigen regions recognized by serum antibodies using massively parallel sequencing of antigen-specific libraries. PloS One. 2014;9(12):e114159. doi:10.1371/journal.pone.0114159.
   PubMed Web of Science ®Google Scholar
• Cohen O, Mechaly A, Sabo T, Alcalay R, Aloni-Grinstein R, Seliger N, Kronman C, Mazor O, Plotkin SA. Characterization and epitope mapping of the polyclonal antibody repertoire elicited by ricin holotoxin-based vaccination. Clin Vaccine Immunol. 2014;21(11):1534–1540. doi:10.1128/CVI.00510-14.
   PubMedGoogle Scholar
• CLIPST M conformational and discontinuous epitope mapping.
   Google Scholar
• Davidson E, Doranz BJ. A high-throughput shotgun mutagenesis approach to mapping B-cell antibody epitopes. Immunology. 2014;143(1):13–20. doi:10.1111/imm.12323.
   PubMed Web of Science ®Google Scholar
• Araya CL, Fowler DM. Deep mutational scanning: assessing protein function on a massive scale. Trends Biotechnol. 2011;29(9):435–442. doi:10.1016/j.tibtech.2011.04.003.
   PubMed Web of Science ®Google Scholar
• Fowler DM, Fields S. Deep mutational scanning: a new style of protein science. Nat Methods. 2014;11(8):801–807. doi:10.1038/nmeth.3027.
   PubMed Web of Science ®Google Scholar
• Onda M, Nagata S, FitzGerald DJ, Beers R, Fisher RJ, Vincent JJ, Lee B, Nakamura M, Hwang J, Kreitman RJ. et al. Characterization of the B cell epitopes associated with a truncated form of pseudomonas exotoxin (PE38) used to make immunotoxins for the treatment of cancer patients. J Immunol. 2006;177(12):8822–8834. doi:10.4049/jimmunol.177.12.8822.
   PubMed Web of Science ®Google Scholar
• Onda M, Beers R, Xiang L, Nagata S, Wang QC, Pastan I. An immunotoxin with greatly reduced immunogenicity by identification and removal of B cell epitopes. Proc Natl Acad Sci U S A. 2008;105(32):11311–11316. doi:10.1073/pnas.0804851105.
   PubMed Web of Science ®Google Scholar
• Weldon JE, Xiang L, Chertov O, Margulies I, Kreitman RJ, FitzGerald DJ, Pastan I. A protease-resistant immunotoxin against CD22 with greatly increased activity against CLL and diminished animal toxicity. Blood. 2009;113(16):3792–800. doi:10.1182/blood-2008-08-173195.
   PubMed Web of Science ®Google Scholar
• Zhang H, Cui W, Gross ML. Mass spectrometry for the biophysical characterization of therapeutic monoclonal antibodies. FEBS Lett. 2014;588(2):308–317. doi:10.1016/j.febslet.2013.11.027.
   PubMed Web of Science ®Google Scholar
• Zhao Y, Chalt BT. Protein epitope mapping by mass spectrometry. Anal Chem. 1994;66(21):3723–26. doi: 10.1021/ac00093a029.
   PubMed Web of Science ®Google Scholar
• Liu XR, Huang RY, Zhao F, Chen G, Tao L. Advances in mass spectrometry-based epitope mapping of protein therapeutics. J Pharm Biomed Anal. 2022;215:215114754. doi:10.1016/j.jpba.2022.114754.
   Web of Science ®Google Scholar
• Opuni KFM, Al-Majdoub M, Yefremova Y, El-Kased RF, Koy C, Glocker MO. Mass spectrometric epitope mapping. Mass Spectrom Rev. 2018;37(2):229–241. doi: 10.1002/mas.21516.
   PubMed Web of Science ®Google Scholar
• Liu XR, Zhang MM, Gross ML. Mass spectrometry-based protein footprinting for higher-order structure analysis: fundamentals and applications. Chem Rev. 2020;120(10):4355–4454. doi:10.1021/acs.chemrev.9b00815.
   PubMed Web of Science ®Google Scholar
• Masson GR, Burke JE, Ahn NG, Anand GS, Borchers C, Brier S, Bou-Assaf GM, Engen JR, Englander SW, Faber J. et al. Recommendations for performing, interpreting and reporting hydrogen deuterium exchange mass spectrometry (HDX-MS) experiments. Nat Methods. 2019;16(7):595–602. doi:10.1038/s41592-019-0459-y.
   PubMed Web of Science ®Google Scholar
• Zhang Q, Noble KA, Mao Y, Young NL, Sathe SK, Roux KH, Marshall AG. Rapid screening for potential epitopes reactive with a polycolonal antibody by solution-phase H/D exchange monitored by FT-ICR mass spectrometry. J Am Soc Mass Spectrom. 2013;24(7):1016–1025. doi:10.1007/s13361-013-0644-7.
   PubMed Web of Science ®Google Scholar
• Hambly DM, Gross ML. Laser flash photolysis of hydrogen peroxide to oxidize protein solvent-accessible residues on the microsecond timescale. J Am Soc Mass Spectrom. 2005;16(12):2057–2063. doi:10.1016/j.jasms.2005.09.008.
   PubMed Web of Science ®Google Scholar
• Horita S, Nomura Y, Sato Y, Shimamura T, Iwata S, Nomura N. High-resolution crystal structure of the therapeutic antibody pembrolizumab bound to the human PD-1. Sci Rep. 2016;6(1):35297. doi:10.1038/srep35297.
   PubMedGoogle Scholar
• Cheng Y, Grigorieff N, Penczek PA, Walz T. A primer to single-particle cryo-electron microscopy. Cell. 2015;161(3):438–449. doi:10.1016/j.cell.2015.03.050.
   PubMed Web of Science ®Google Scholar
• Bangaru S, Antanasijevic A, Kose N, Sewall LM, Jackson AM, Suryadevara N, Zhan X, Torres JL, Copps J, de la Pena AT. et al. Structural mapping of antibody landscapes to human betacoronavirus spike proteins. Sci Adv. 2022;8(18):eabn2911. doi:10.1126/sciadv.abn2911.
   PubMed Web of Science ®Google Scholar
• Gokemeijer J, Jawa V, Mitra-Kaushik S. How close are we to profiling immunogenicity risk using in silico algorithms and in vitro methods?: an industry perspective. AAPS J. 2017;19(6):1587–1592. doi:10.1208/s12248-017-0143-z.
   PubMed Web of Science ®Google Scholar
• Doneva N, Doytchinova I, Dimitrov I. Predicting Immunogenicity Risk in Biopharmaceuticals. Symmetry. 2021;13(3):338. doi:10.3390/sym13030388.
   Google Scholar
• Gonzalez-Galarza FF, McCabe A, Santos E, Jones J, Takeshita L, Ortega-Rivera ND, Cid-Pavon GMD, Ramsbottom K, Ghattaoraya G, Alfirevic A. et al. Allele frequency net database (AFND) 2020 update: gold-standard data classification, open access genotype data and new query tools. Nucleic Acids Res. 2020;48(D1):D783–88. doi:10.1093/nar/gkz1029.
   PubMed Web of Science ®Google Scholar
• MacLachlan BJ, Dolton G, Papakyriakou A, Greenshields-Watson A, Mason GH, Schauenburg A, Besneux M, Szomolay B, Elliott T, Sewell AK. et al. Human leukocyte antigen (HLA) class II peptide flanking residues tune the immunogenicity of a human tumor-derived epitope. J Biol Chem. 2019;294(52):20246–20258. doi:10.1074/jbc.RA119.009437.
   PubMed Web of Science ®Google Scholar
• Nielsen M, Lundegaard C, Lund O. Prediction of MHC class II binding affinity using SMM-align, a novel stabilization matrix alignment method. BMC Bioinf. 2007;8(1):8238. doi:10.1186/1471-2105-8-238.
   Google Scholar
• Nielsen M, Lund O. NN-align. An artificial neural network-based alignment algorithm for MHC class II peptide binding prediction. BMC Bioinf. 2009;10(1):10296. doi:10.1186/1471-2105-10-296.
   Google Scholar
• Nielsen M, Lundegaard C, Blicher T, Peters B, Sette A, Justesen S, Buus S, Lund O, Nussinov R. Quantitative predictions of peptide binding to any HLA-DR molecule of known sequence: NetMHCIIpan. PLoS Comput Biol. 2008;4(7):e1000107. doi:10.1371/journal.pcbi.1000107.
   PubMed Web of Science ®Google Scholar
• Reynisson B, Alvarez B, Paul S, Peters B, Nielsen M. NetMHCpan-4.1 and NetMHCIIpan-4.0: improved predictions of MHC antigen presentation by concurrent motif deconvolution and integration of MS MHC eluted ligand data. Nucleic Acids Res. 2020;48(W1):W449–W454. doi:10.1093/nar/gkaa379.
   PubMed Web of Science ®Google Scholar
• Nielsen M, Lundegaard C, Blicher T, Lamberth K, Harndahl M, Justesen S, Roder G, Peters B, Sette A, Lund O. et al. NetMHCpan, a method for quantitative predictions of peptide binding to any HLA-A and -B locus protein of known sequence. PloS One. 2007;2(8):e796. doi:10.1371/journal.pone.0000796.
   PubMed Web of Science ®Google Scholar
• Paul S, Karosiene E, Dhanda SK, Jurtz V, Edwards L, Nielsen M, Sette A, Peters B. Determination of a predictive cleavage motif for eluted major histocompatibility complex class II ligands. Front Immunol. 2018;9:91795. doi:10.3389/fimmu.2018.01795.
   Web of Science ®Google Scholar
• Nielsen M, Lundegaard C, Lund O, Kesmir C. The role of the proteasome in generating cytotoxic T-cell epitopes: insights obtained from improved predictions of proteasomal cleavage. Immunogenetics. 2005;57(1–2):33–41. doi:10.1007/s00251-005-0781-7.
   PubMed Web of Science ®Google Scholar
• De Groot AS, Moise L, McMurry JA, Wambre E, Van Overtvelt L, Moingeon P, Scott DW, Martin W. Activation of natural regulatory T cells by IgG fc-derived peptide “tregitopes”. Blood. 2008;112(8):3303–11. doi:10.1182/blood-2008-02-138073.
   PubMed Web of Science ®Google Scholar
• De Groot AS, Tassone R, Cousens LP, Terry F, Martin R, Ardito MT, Martin WD. In-silico prediction of HLA-DP and -DQ epitope content is poorly correlated with clinical immunogenicity of therapeutic proteins. 2013.
   Google Scholar
• Gutierrez A, Terry F, Martin WD, De Groot AS. New regression Model predicts antibody immunogenicity based on effector and regulatory T cell epitope content. 2018.
   Google Scholar
• De Groot AS, Terry F, Cousens L, Martin W. Beyond humanization and de-immunization: tolerization as a method for reducing the immunogenicity of biologics. Expert Rev Clin Pharmacol. 2013;6(6):651–662. doi:10.1586/17512433.2013.835698.
   PubMed Web of Science ®Google Scholar
• Glaesner W, Vick AM, Millican R, Ellis B, Tschang SH, Tian Y, Bokvist K, Brenner M, Koester A, Porksen N. et al. Engineering and characterization of the long-acting glucagon-like peptide-1 analogue LY2189265, an Fc fusion protein. Diabetes Metab Res Rev. 2010;26(4):287–296. doi:10.1002/dmrr.1080.
   PubMed Web of Science ®Google Scholar
• Winterling K, Martin WD, De Groot AS, Daufenbach J, Kistner S, Schuttrumpf J. Development of a novel fully functional coagulation factor VIII with reduced immunogenicity utilizing an in silico prediction and deimmunization approach. J Thromb Haemost. 2021;19(9):2161–2170. doi:10.1111/jth.15413.
   PubMed Web of Science ®Google Scholar
• Jespersen MC, Peters B, Nielsen M, Marcatili P. BepiPred-2.0: improving sequence-based B-cell epitope prediction using conformational epitopes. Nucleic Acids Res. 2017;45(W1):W24–W29. doi:10.1093/nar/gkx346.
   PubMed Web of Science ®Google Scholar
• Clifford JN, Hoie MH, Deleuran S, Peters B, Nielsen M, Marcatili P. BepiPred-3.0: Improved B-cell epitope prediction using protein language models. Protein Sci. 2022;31(12):e4497. doi:10.1002/pro.4497.
   PubMed Web of Science ®Google Scholar
• Barlow DJ, Edwards MS, Thornton JM. Continuous and discontinuous protein antigenic determinants. Nature. 1986;322(6081):747–748. doi:10.1038/322747a0.
   PubMed Web of Science ®Google Scholar
• Høie MH, Gade FS, Johansen JM, Würtzen C, Winther O, Nielsen M, Marcatili P. DiscoTope-3.0: improved B-cell epitope prediction using inverse folding latent representations. Front Immunol. 2024;15:15. doi:10.3389/fimmu.2024.1322712.
   Web of Science ®Google Scholar
• Ponomarenko J, Bui HH, Li W, Fusseder N, Bourne PE, Sette A, Peters B. ElliPro: a new structure-based tool for the prediction of antibody epitopes. BMC Bioinf. 2008;9(1):514. doi:10.1186/1471-2105-9-514.
   PubMed Web of Science ®Google Scholar
• Cia G, Pucci F, Rooman M. Critical review of conformational B-cell epitope prediction methods. Brief Bioinform. 2023;24(1):bbac567. doi:10.1093/bib/bbac567.
   PubMed Web of Science ®Google Scholar
• Lin J, Lee SL, Russell AM, Huang RF, Batt MA, Chang SS, Ferrante A, Verdino P, Henry KA. A structure-based engineering approach to abrogate pre-existing antibody binding to biotherapeutics. PloS One. 2021;16(7):e0254944. doi:10.1371/journal.pone.0254944.
   PubMed Web of Science ®Google Scholar
• Nagata S, Pastan I. Removal of B cell epitopes as a practical approach for reducing the immunogenicity of foreign protein-based therapeutics. Adv Drug Deliv Rev. 2009;61(11):977–985. doi:10.1016/j.addr.2009.07.014.
   PubMed Web of Science ®Google Scholar
• Goyal G, Prabhala P, Mahajan G, Bausk B, Gilboa T, Xie L, Zhai Y, Lazarovits R, Mansour A, Kim MS. et al. Ectopic Lymphoid follicle formation and human seasonal influenza vaccination responses recapitulated in an organ-on-a-chip. Adv Sci. 2022;9(14):e2103241. doi:10.1002/advs.202103241.
   Web of Science ®Google Scholar
• Jiskoot W, Kijanka G, Randolph TW, Carpenter JF, Koulov AV, Mahler HC, Joubert MK, Jawa V, Narhi LO. Mouse models for assessing protein immunogenicity: Lessons and challenges. J Pharm Sci. 2016;105(5):1567–1575. doi:10.1016/j.xphs.2016.02.031.
   PubMed Web of Science ®Google Scholar