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EpiVax_ISPIR_VS_IEDB_comparison_Immunogenicity_of_protein_drugs_Mar2014

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A collegial comparison of EpiVax’s ISPRI system compared to IEDB, in regards to immunogenicity prediction for protein therapeutics. Also, learn how EpiVax predicts clinical immunogenicity and ...

A collegial comparison of EpiVax’s ISPRI system compared to IEDB, in regards to immunogenicity prediction for protein therapeutics. Also, learn how EpiVax predicts clinical immunogenicity and deimmunizes proteins, using bioinformatics tools.

Want to see a video of these slides presented by world-renowned immunologist/vaccinologist, Dr. Annie De Groot, MD, CEO/CSO of EpiVax, Inc? Click this link: http://youtu.be/KnUE_YGH0JI

Contact EpiVax: http://www.epivax.com/contact/

More about ISPRI: http://bit.ly/ISPRI

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EpiVax_ISPIR_VS_IEDB_comparison_Immunogenicity_of_protein_drugs_Mar2014 EpiVax_ISPIR_VS_IEDB_comparison_Immunogenicity_of_protein_drugs_Mar2014 Presentation Transcript

  • EpiVax vs. IEDB A Comparison IMMUNE EPITOPE DATABASE AND ANALYSIS RESOURCE
  • EpiVax Management Team www.epivax.com/about/management-team/ 2 In VivoIn VitroIn Silico Modify sequences to reduce immunogenicity Screenmultiple therapeutic candidates Human SCID Mouse Model HLA Transgenic Mouse Model Either Examine: • Non-sequence- driven immunogenicity • Natural antigen processing and by DCs • Peptide/MHC stability • T cell activation thresholds • Post- translational modification • Formulation- induced changes Perform HLABinding andTCell Assayswith proteins/ target epitopes Rankfor immunogenicity basedon predicted epitopecontent Proceed to Drug Development Investigate artificialLN VaryRatio ofTcellsto dendritic cells Test PBMC Responses The EpiVax Approach to Immunogenicity Screening From: http://bit.ly/The_TCWP - T cell “White Paper”
  • ISPRI is an integrated, interactive set of tools specifically designed for immunogenicity analysis. ISPRI provides the depth of analysis that is necessary to accurately predict clinical immunogenicity ISPRI vs. IEDB in silico services Epitope Mapping Cluster Analysis ARB NN-align SMM align Protein Re- engineering Epitope Ranking Epitope Mapping EpiMatrix ClustiMer /EpiBar OptiMatrix iTEM Immunogenicity Scale DeFT (OptiMatrix) In Vitro / In vivo Assays JanusMatrix JMX-Adjusted Score Target Selection Tregitope Tolerization IEDB is a collection of tools that are not integrated in any coherent fashion. Epitope prediction is possible, but seamless immunogenicity screening and protein re- engineering is not. View slide
  • ISPRI: Developed for Biologics Available Tools 4 • EpiMatrix – Screen the protein sequences of product candidates for the presence of putative T cell epitopes. • Immunogenicity Protein Scale – Rate the immunogenic potential of each submitted sequence on a normalized scale and compare each protein to other immunogenic proteins and antibodies • Tregitope Analysis – Identify within each submitted sequence putative regulatory T-cell epitopes (i.e. sub-regions contained within the submitted sequences which may relate to natural regulatory T cells and which may help to dampen the immune potential of the submitted antibody sequence) • ClustiMer / EpiBar – Identify T-cell epitope clusters contained within product candidates • Immunogenic Cluster Scale – Rate the immunogenic potential of each T-cell epitope cluster on a normalized scale and compare each T-cell epitope cluster to other well-known immunogenic epitope clusters • BlastiMer / JanusMatrix – Blast: Compare epitope clusters against the non-redundant protein or patent database at GenBank – Homology: Compare epitopes to human genome epitopes that have the same TCR face. • OptiMatrix – The protein re-design algorithm that provides a list of critical amino acid residues and potential amino acid substitutions that are conserved in existing databases (based on published seque- nces) and that do not introduce new epitopes. View slide
  • EpiVax vs. IEDB 5 Features EpiVax IEDB Highly Accurate Epitope Prediction  1 Cluster Tool / EpiBar  2 Immunogenicity Scale * X iTEM Analysis * X Tregitope Predictions * X Deimmunization tools  X Human Genome Comparison  X High-Throughput Analysis  X Published Validation  3 Expert Consulting Services  X * These features were developed and validated by, and are only available at, EpiVax. 1 Head to head comparison favors EpiMatrix: see De Groot and Martin, Clinical Immunology, 2009. http://bit.ly/De_Groot_and_Martin 2 IEDB Cluster tool is available, but untested; for EpiVax validation, see “T cell epitope, Friend or Foe” http://bit.ly/T-friend-or-foe 3 Extent of IEDB validation is unknown (positive results may be published, but negative results are not tracked).
  • Epitope Predictions IMMUNE EPITOPE DATABASE AND ANALYSIS RESOURCE
  • Epitope Predictions EpiVax 7 •EpiVax uses EpiMatrix to predict epitopes –matrix based prediction algorithm •Can predict either class I or class II MHC binding –MHC binding is a prerequisite for immunogenicity –Full suite of HLA-based predictions are available; Class II usually used for biologics. –Separate website available for vaccine design: iVAX –http://www.epivax.com/vaccine-design-redesign/ivax-web-based-vaccine-design/ Mature APC MHC II Pocket Epitope Protein
  • Epitope Predictions EpiMatrix [Class II] vs. IEDB De Groot AS, Martin W. Reducing risk, improving outcomes: bioengineering less immunogenic protein therapeutics. Clin Immunol. 2009 May;131(2):189-201 Comparison Data Taken From: Wang P, Sidney J, Dow C, Mothé B, Sette A, et al. (2008) A Systematic Assessment of MHC Class II Peptide Binding Predictions and Evaluation of a Consensus Approach. PLoS Comput Biol 4(4): e1000048. Doi:10.1371/journal.pcbi.1000048 8 Perfect =100% Random = 50% On average, EpiMatrix predicts T cell epitopes more accurately than IEDB. IMMUNE EPITOPE DATABASE AND ANALYSIS RESOURCE
  • Cluster Tools IMMUNE EPITOPE DATABASE AND ANALYSIS RESOURCE
  • 10 Cluster Tools EpiVax - ClustiMer DRB1*0101 DRB1*0301 DRB1*0401 DRB1*0701 DRB1*0801 DRB1*1101 DRB1*1301 DRB1*1501 • T cell epitopes are not randomly distributed throughout protein sequences but instead tend to cluster in specific regions. – These clusters can be very powerful. One or more dominant T-cell epitope clusters can enable significant immune responses to even otherwise low scoring proteins. • ClustiMer is used to identify T-cell epitope clusters. It identifies polypeptides predicted to bind to an unusually large number of HLA alleles. • T-cell epitope clusters make excellent vaccine candidates: – compact; relatively easy to deliver as peptides; highly reactive in-vivo
  • Cluster Analysis IEDB 11 This tool groups epitopes into clusters based on sequence identity. A cluster is defined as a group of sequences which have a sequence similarity greater than the minimum sequence identity threshold specified by the user. This is a different definition than the one used by ClustiMer, and so it will yield different results. Example Results: IEDB Epitope Cluster Analysis is untested and also does not yield a detailed report like ClustiMer, only a simple identification of clusters. IMMUNE EPITOPE DATABASE AND ANALYSIS RESOURCE
  • Immunogenicity Scales IMMUNE EPITOPE DATABASE AND ANALYSIS RESOURCE
  • Immunogenicity Scales EpiVax 13 - 80 - - 70 - - 60 - - 50 - - 40 - - 30 - - 20 - - 10 - - 00 - - -10 - - -20 - - -30 - - -40 - - -50 - - -60 - - -70 - - -80 - Thrombopoietin Erythropoietin IgA Fibrinogen-Gamma Albumin IgG FC Region GMCSF Follitropin-Beta Fibrinogen-Alpha Beta-2-Microglobulin Interferon-Beta GHRH Tetanus Toxin Influenza-HA Tetanus Toxin (825-850) HCV NPC NS3 (1248-1267) Influenza HA (306-319) Tetanus Toxin (947-967) Human CLIP EBV BHRF1(171-189) 20-mer Theoretical Minimum - +40 - - - - +30 - - - - +20 - - - - +10 - - - - 0.0 - - - - -10 - Your Protein Here Your Peptide or Cluster Here EpiVax has developed an immunogenicity scale to compare predicted immunogenicity across whole proteins, clusters and antibodies. This allows for easy comparison between different sequences of different lengths and to known compounds.
  • Immunogenicity Scales IEDB 14 No Immunogenicity Scales are available on IEDB. IMMUNE EPITOPE DATABASE AND ANALYSIS RESOURCE
  • iTEM Analysis IMMUNE EPITOPE DATABASE AND ANALYSIS RESOURCE
  • • iTEM uses HLA-specific EpiMatrix scores to measure potential for response to peptide antigen Can be used to predict which patients (with which HLA) will develop an antibody response in a clinical trial… . . . Immunopharmacogenomics iTEM Analysis EpiVax Individualized T cell Epitope Measure 16 A Method for Individualizing the Prediction of Immunogenicity of Protein Vaccines and Biologic Therapeutics: Individualized T Cell Epitope Measure (iTEM), Apr 2010
  • iTEM Analysis IEDB 17 No such analysis is available on IEDB. IMMUNE EPITOPE DATABASE AND ANALYSIS RESOURCE
  • Tregitope Predictions IMMUNE EPITOPE DATABASE AND ANALYSIS RESOURCE
  • Epitope can be either effector or regulatory Presence of Epitope Indicates Immune Potential Mature APC T reg T eff 19
  • Accounting for Tregitopes results in more accurate predictions. Correlation to observed immunogenicity after accounting for Tregitopes R2=0.76 Tregitope Predictions EpiVax 20 EpiVax discovered and patented sequences called Tregitopes, promiscuous T cell epitopes that have been shown to activate regulatory T cells. In the EpiVax immunogenicity analysis the presence of a Tregitope decreases the potential for immunogenicity. The inclusion of Tregitopes in predictions is particularly crucial in comparing antibodies, which often contain Tregitope sequences.
  • Tregitope Predictions IEDB 21 In IEDB and other tools, the effect of Tregitopes are not taken into account. Instead they will show up as effector epitopes, erroneously increasing the predicted immunogenicity. IMMUNE EPITOPE DATABASE AND ANALYSIS RESOURCE
  • DeImmunization IMMUNE EPITOPE DATABASE AND ANALYSIS RESOURCE
  • DeImmunization EpiVax - OptiMatrix 23 Select a different amino acid and see its effect immediately EpiVax’s OptiMatrix tool allows the user to: • Decrease potential immunogenicity of T cell epitopes by weakening “agretope” (interface with HLA molecule) • identify and iteratively modify key AA residues • OptiMatrix provides a logo report which shows the contribution of each amino acid to overall immunogenicity of the peptide • Change any amino acid and see its affect on immunogenicity in real time • “Best Single Change” function auto calculated the AA modification that results in the most drastic decrease in predicted immunogenicity http://bit.ly/EpiDeFT
  • OptiMatrix Interactive Peptide Deimmunization 24 Frame Frame DRB1*0101 DRB1*0301 DRB1*0401 DRB1*0701 DRB1*0801 DRB1*1101 DRB1*1301 DRB1*1501 Start Stop Z-Score Z-Score Z-Score Z-Score Z-Score Z-Score Z-Score Z-Score 254 PRGYFKIRT 262 -0.23 0 255 RGYFKIRTG 263 -0.2 0 256 GYFKIRTGK 264 -0.19 0 257 YFKIRTGKT 265 -0.9 2.38 2.41 2.51 1.4 2.2 1.98 5 258 FKIRTGKTT 266 -0.83 2.41 2.13 1.69 1.32 1.53 3 259 KIRTGKTTI 267 -0.14 1.44 0 260 IRTGKTTIM 268 0 1.97 1.42 1.48 1 261 RTGKTTIMR 269 -0.21 1.33 0 DRB1*0101 DRB1*0301 DRB1*0401 DRB1*0701 DRB1*0801 DRB1*1101 DRB1*1301 DRB1*1501 Total 2.41 1.97 2.41 2.51 1.69 2.2 1.48 1.98 -- 4.79 1.97 2.41 4.64 1.69 2.2 0 1.98 19.68 2 1 1 2 1 1 0 1 9 Scores Adjusted for Tregitope: -- EpiMatrix Score: 13.08 EpiMatrix Score (w/o flanks): 16.05 Sum of Significant Z scores Count of Significant Z Scores Total Assessments Performed: 64 Hydrophobicity: -0.84 EpiMatrix Score: 13.08 EpiMatrix Score (w/o flanks): 16.05 AA Sequence Hydro- phobicity Hits Summarized Results (25-SEP-2009) Maximum Single Z score OptiMatrix: 24 http://bit.ly/EpiDeFT
  • OptiMatrix See the effects of amino acid substitution in real-time Confidential 25 OptiMatrix: Click multiple times to continue deimmunizing 25 http://bit.ly/EpiDeFT
  • DeImmunization IEDB 26 No such tool is available on IEDB. IMMUNE EPITOPE DATABASE AND ANALYSIS RESOURCE
  • High Throughput Analysis IMMUNE EPITOPE DATABASE AND ANALYSIS RESOURCE
  • 28 High Throughput Analysis EpiVax The High-Throughput analysis allows users to compare a large number potential antibody candidates by ranking the immunogenicity of heavy and light chains. http://www.epivax.com/immunogenicity-screening/ht_report/
  • High Throughput Analysis IEDB 29 No such analysis is available on IEDB. IMMUNE EPITOPE DATABASE AND ANALYSIS RESOURCE
  • Human Genome Comparison 30 IMMUNE EPITOPE DATABASE AND ANALYSIS RESOURCE
  • Human Genome Comparison EpiVax - JanusMatrix Each MHC ligand has two faces, The MHC-binding face (agretope), and the TCR-interacting face (epitope) TCR MHC The JanusMatrix algorithm searches for putative MHC ligands which are identical at the contact residues but may vary at the MHC-binding residues. • Identical T cell-facing residues • Same HLA allele and minimally different MHC-facing residues Find predicted 9-mer ligands with: http://www.ncbi.nlm.nih.gov/pubmed/23584251 MHC/HLA TCR
  • Human Genome Comparison IEDB 32 No such analysis is available on IEDB. IMMUNE EPITOPE DATABASE AND ANALYSIS RESOURCE
  • Expert Consulting Services IMMUNE EPITOPE DATABASE AND ANALYSIS RESOURCE
  • Expert Consulting Services EpiVax 34 Algorithms only go so far in immunogenicity prediction – immunoinformatics expertise is the greatest tool contained in the ISPRI system. We have worked with the ISPRI tools since 1998 and can help interpret the data for your team. Annie De Groot, MD (CEO) William Martin (CIO) http://www.epivax.com/about/epivax-team/
  • In Silico Immunogenicity Screening Services 35 ISPRI Website: Cloud-based Interactive Protein Screening and Reengineering Interface, leased to large pharma world-wide. Your scientists use ISPRI to predict overall and regional immunogenicity. Available for annual lease for a set number of protein sequences (Limited) or Unlimited Sequences. Includes continued consultation and training with experts at EpiVax. http://bit.ly/ISPRI PreDeFT: Highly detailed in silico immunogenicity analysis covering overall and regional immunogenic potential of a protein therapeutic. Delivered as a “FDA ready” report. EpiVax “Genius Team” uses ISPRI for you. http://bit.ly/PreDeFT HT Screening: High-throughput immunogenicity screening of large sets of antibody heavy-light chain combinations, for overall and comparative immunogenic potential. http://bit.ly/PreDeFTht DeFT: (Deimmunization of a Functional Therapeutic) is a tested process of analysis, reengineering and confirmation. http://bit.ly/EpiDeFT Sales contacts: amarcello@epivax.com (US/other) or pdegroot@epivax.com (EUR)
  • Expert Consulting Services IEDB 36 No expert consulting services are available through IEDB. IMMUNE EPITOPE DATABASE AND ANALYSIS RESOURCE
  • Published Validation 37 IMMUNE EPITOPE DATABASE AND ANALYSIS RESOURCE
  • ISPRI Validation in Print (A Sample) 38 Koren E, De Groot AS, Jawa V, Beck KD, Boone T, Rivera D, Li L, Mytych D, Koscec M, Weeraratne D, Swanson S, Martin W. Clinical validation of the “in silico” prediction of immunogenicity of a human recombinant therapeutic protein Clin Immunol. 2007 Jul. http://bit.ly/epiClinVal De Groot AS, Martin W. Reducing risk, improving outcomes: bioengineering less immunogenic protein therapeutics. Clin Immunol. 2009 May;131(2):189-201. http://bit.ly/epiClinIm Jawa, V., Cousens, L., & De Groot, A. S. (2013). Immunogenicity of Therapeutic Fusion proteins: Contributory Factors and Clinical Experience. Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges, 75-90. http://bit.ly/epiFcFuse Jawa V, Cousens LP, Awwad M, Wakshull E, Kropshofer H, De Groot AS. T-cell dependent immunogenicity of protein therapeutics: Preclinical assessment and mitigation http://bit.ly/The_TCWP
  • 39 1: De Groot AS, Ardito M, Terry F, Levitz L, Ross T, Moise L, Martin W. Low immunogenicity predicted for emerging avian-origin H7N9: implication for influenza vaccine design. Hum Vaccin Immunother. 2013 May;9(5):950-6. doi: 10.4161/hv.24939. Epub 2013 May 1. PubMed PMID: 23807079; PubMed Central PMCID: PMC3899161. 2: Cousens LP, Tassone R, Mazer BD, Ramachandiran V, Scott DW, De Groot AS. Tregitope update: mechanism of action parallels IVIg. Autoimmun Rev. 2013 Jan;12(3):436-43. doi: 10.1016/j.autrev.2012.08.017. Epub 2012 Aug 28. Review. PubMed PMID: 22944299. 3: De Groot AS, Cousens L, Mingozzi F, Martin W. Tregitope peptides: the active pharmaceutical ingredient of IVIG? Clin Dev Immunol. 2013;2013:493138. doi: 10.1155/2013/493138. Epub 2013 Dec 25. PubMed PMID: 24454476; PubMed Central PMCID: PMC3886585. 4: Cou5sens LP, Najafian N, Mingozzi F, Elyaman W, Mazer B, Moise L, Messitt TJ, Su Y, Sayegh M, High K, Khoury SJ, Scott DW, De Groot AS. In vitro and in vivo studies of IgG-derived Treg epitopes (Tregitopes): a promising new tool for tolerance induction and treatment of autoimmunity. J Clin Immunol. 2013 Jan;33 Suppl 1:S43-9. doi: 10.1007/s10875-012-9762-4. Epub 2012 Sep 2. Review. PubMed PMID: 22941509; PubMed Central PMCID: PMC3538121. 5: Jawa V, Cousens LP, Awwad M, Wakshull E, Kropshofer H, De Groot AS. T-cell dependent immunogenicity of protein therapeutics: Preclinical assessment and mitigation. Clin Immunol. 2013 Dec;149(3):534-55. doi: 10.1016/j.clim.2013.09.006. Epub 2013 Sep 25. Review. PubMed PMID: 24263283. 6: 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 Nov;6(6):651-62. doi: 10.1586/17512433.2013.835698. PubMed PMID: 24164613. 7: Hui DJ, Basner-Tschakarjan E, Chen Y, Davidson RJ, Buchlis G, Yazicioglu M, Pien GC, Finn JD, Haurigot V, Tai A, Scott DW, Cousens LP, Zhou S, De Groot AS, Mingozzi F. Modulation of CD8+ T cell responses to AAV vectors with IgG-derived MHC class II epitopes. Mol Ther. 2013 Sep;21(9):1727-37. doi: 8.1038/mt.2013.166. Epub 2013 Jul 16. PubMed PMID: 23857231. 4: Su Y, Rossi R, De Groot AS, Scott DW. Regulatory T cell epitopes (Tregitopes) in IgG induce tolerance in vivo and lack immunogenicity per se. J Leukoc Biol. 2013 Aug;94(2):377-83. doi: 10.1189/jlb.0912441. Epub 2013 May 31. PubMed PMID: 23729499. 9: Moise L, Gutierrez AH, Bailey-Kellogg C, Terry F, Leng Q, Abdel Hady KM, VerBerkmoes NC, Sztein MB, Losikoff PT, Martin WD, Rothman AL, De Groot AS. The two-faced T cell epitope: examining the host-microbe interface with JanusMatrix. Hum Vaccin Immunother. 2013 Jul;9(7):1577-86. doi: 10.4161/hv.24615. Epub 2013 Apr 12. PubMed PMID. 10: Cousens LP, Su Y, McClaine E, Li X, Terry F, Smith R, Lee J, Martin W, Scott DW, De Groot AS. Application of IgG-derived natural Treg epitopes (IgG Tregitopes) to antigen-specific tolerance induction in a murine model of type 1 diabetes. J Diabetes Res. 2013;2013:621693. doi: 10.1155/2013/621693. Epub 2013 Apr 23. PubMed PMID: 23710469; 11: Elfaki ME, Khalil EA, De Groot AS, Musa AM, Gutierrez A, Younis BM, Salih KA, El-Hassan AM. Immunogenicity and immune modulatory effects of in silico predicted L. donovani candidate peptide vaccines. Hum Vaccin Immunother. 2012 Dec 1;8(12):1769-74. doi: 10.4161/hv.21881. Epub 2012 Aug 24. PubMed PMID: 22922767; PubMed Central 12: Cousens LP, Mingozzi F, van der Marel S, Su Y, Garman R, Ferreira V, Martin W, Scott DW, De Groot AS. Teaching tolerance: New approaches to enzyme replacement therapy for Pompe disease. Hum Vaccin Immunother. 2012 Oct;8(10):1459-64. doi: 10.4161/hv.21405. Epub 2012 Oct 1. PubMed PMID: 23095864; PubMed 13. Gutiérrez AH, Moise L, De Groot AS. Of [Hamsters] and men: a new perspective on host cell proteins. Hum Vaccin Immunother. 2012 Sep;8(9):1172-4. doi: 10.4161/hv.22378. Epub 2012 Sep 1. PubMed PMID: 23124469; PubMed Central PMCID: PMC3579895. 14: van der Marel S, Majowicz A, Kwikkers K, van Logtenstein R, te Velde AA, De Groot AS, Meijer SL, van Deventer SJ, Petry H, Hommes DW, Ferreira V. Adeno-associated virus mediated delivery of Tregitope 167 ameliorates experimental colitis. World J Gastroenterol. 2012 Aug 28;18(32):4288-99. doi: 10.3748/wjg.v18.i32.4288. PubMed PMID: 22969191. 15: Moise L, Song C, Martin WD, Tassone R, De Groot AS, Scott DW. Effect of HLA DR epitope de-immunization of Factor VIII in vitro and in vivo. Clin Immunol. 2012 Mar;142(3):320-31. doi: 10.1016/j.clim.2011.11.010. Epub 2011 Dec 8. PubMed PMID: 22222093; PubMed Central PMCID: PMC3288193. 16: Inaba H, Martin W, Ardito M, De Groot AS, De Groot LJ. The role of glutamic or aspartic acid in position four of the epitope binding motif and thyrotropin receptor-extracellular domain epitope selection in Graves' disease. J Clin Endocrinol Metab. 2010 Jun;95(6):2909-16. doi: 10.1210/jc.2009-2393. Epub 2010 Apr 14. PubMed PMID: 20392871; PubMed Central 17: De Groot AS, Baker M, Cohen T. Species neutral correlates of immunogenicity for vaccines and protein therapeutics: fact or science fiction. Hum Vaccin. 2010 May;6(5):371. 18: Scott DW, De Groot AS. Can we prevent immunogenicity of human protein drugs? Ann Rheum Dis. 2010 Jan;69 Suppl 1:i72-76. doi: 10.1136/ard.2009.117564. Review. 19: Cohen T, Moise L, Ardito M, Martin W, De Groot AS. A method for individualizing the prediction of immunogenicity of protein vaccines and biologic therapeutics: individualized T cell epitope measure (iTEM). J Biomed Biotechnol. 2010;2010. pii: 961752. doi: 10.1155/2010/961752. Epub 2010 Jul 18. PubMed PMID: 20706613; PubMed Central PMCID: 20: De Groot AS. Exploring the immunome: A brave new world for human vaccine development. Hum Vaccin. 2009 Dec;5(12):790-3. Epub 2009 Dec 15. PubMed PMID: 20009527. 21: Weber CA, Mehta PJ, Ardito M, Moise L, Martin B, De Groot AS. T cell epitope: friend or foe? Immunogenicity of biologics in context. Adv Drug Deliv Rev. 2009 Sep 30;61(11):965-76. doi: 10.1016/j.addr.2009.07.001. Epub 2009 Jul 18. Review. PubMed PMID: 19619593. 22: De Groot AS, Martin W. Reducing risk, improving outcomes: bioengineering less immunogenic protein therapeutics. Clin Immunol. 2009 May;131(2):189-201. doi: 10.1016/j.clim.2009.01.009. Epub 2009 Mar 6. Review. PubMed PMID: 19269256. 23: 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 Oct 15;112(8):3303-11. doi: 10.1182/blood-2008-02-138073. Epub 2008 Jul 25. . 24: De Groot AS, McMurry J, Moise L. Prediction of immunogenicity: in silico paradigms, ex vivo and in vivo correlates. Curr Opin Pharmacol. 2008 Oct;8(5):620-6. doi: 10.1016/j.coph.2008.08.002. Epub 2008 Sep 19. Review. PubMed PMID: 18775515. 25: De Groot AS, Scott DW. Immunogenicity of protein therapeutics. Trends Immunol. 2007 Nov;28(11):482-90. Epub 2007 Oct 25. Review. PubMed PMID: 17964218. 26: De Groot AS, Moise L. Prediction of immunogenicity for therapeutic proteins: state of the art. Curr Opin Drug Discov Devel. 2007 May;10(3):332-40. Review. PubMed PMID: 17554860. 27: De Groot AS, Goldberg M, Moise L, Martin W. Evolutionary deimmunization: an ancillary mechanism for self-tolerance? Cell Immunol. 2006 Dec;244(2):148-53. Epub 2007 Apr 18. 28: De Groot AS. Immunomics: discovering new targets for vaccines and therapeutics. Drug Discov Today. 2006 Mar;11(5-6):203-9. Review. PubMed PMID: 6580597. 29: De Groot AS, Knopp PM, Martin W. De-immunization of therapeutic proteins by T-cell epitope modification. Dev Biol (Basel). 2005;122:171-94. Review. PubMed PMID: 16375261. 30: De Groot AS, Rayner J, Martin W. Modelling the immunogenicity of therapeutic proteins using T cell epitope mapping. Dev Biol (Basel). 2003;112:71-80. PubMed PMID: 12762506. Published Validation EpiVax: > 60 Publications in Protein Therapeutics http://www.epivax.com/publications/
  • Published Validation Biologic Therapeutics IEDB 40 Paul S, Kolla RV, Sidney J, Weiskopf D, Fleri W, Kim Y, Peters B, Sette A. Evaluating the immunogenicity of protein drugs by applying in vitro MHC binding data and the immune epitope database and analysis resource. Clin Dev Immunol. 2013;2013:467852. doi: 10.1155/2013/467852. Epub 2013 Oct 8. IMMUNE EPITOPE DATABASE AND ANALYSIS RESOURCE
  • EpiVax Services 41 http://www.epivax.com/
  • 42 CIO/DIRECTOR OF BIOINFORMATICS Bill Martin martinb@epivax.com BIOINFORMATICS PROGRAM MANAGER Frances Terry fterry@epivax.com BIOINFORMATICS PROGRAMMER/ANALYST Jacob Tivin jtivin@epivax.com EpiVax “Genius” Team BDA – SALES INQUIRES Anthony Marcello amarcello@epivax.com Phoebe De Groot De Groot@epivax.com
  • Accessing the Tools Contact Jason Del Pozzo: bda@epivax.com Confidential 43 PreDeFT: Fee for service in silico immunogenicity analysis. Performed on a protein by protein basis. Pricing based on length of sequence(s). Limited ISPRI Website: Limited access to EpiVax’ Interactive Protein Screening and Reengineering Interface. Available for set numbers of proteins. Unlimited ISPRI Website: Unlimited access to EpiVax’ Interactive Protein Screening and Reengineering Interface. Available in three year lease periods. Fee for Service: HLA Binding Assays, HLA Transgenic Mice, ELISpot Assays. 43EpiVax Confidential