EpiVax_Tregitope_Overview_2013

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EpiVax Non-Confidential Overview of the Tregitope Technology.

June 2013

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EpiVax_Tregitope_Overview_2013

  1. 1. Tregitope OverviewNon-confidential1Annie De Groot M.D. CEO/CSOBill Martin, COO/CIO
  2. 2. EpiVax Corporate Summary• Founded 1998 – cash positive since inception• Privately Held (De Groot, Martin Principals)• Better Vaccine and Protein Design – Services• Development of Immunomodulatory Products (Vaccines,Tregitope)• Successful mix of services and grant-funded research:14% growth, year over year, without venture funding.2
  3. 3. Management Teamhttp://www.epivax.com/about/management-team/• Dr. Anne De Groot, CEO/CSO• William Martin, Chief Information Officer• Dr. Leslie Cousens, Director of Protein Therapeutics• Dr. Lenny Moise, Director of Vaccine Research• Anthony Marcello, Business Development Associate3
  4. 4. EpiVax: Four Core Strengthswww.epivax.comEpitope ServicesEpitope MappingHLA BindingT cell assaysIn vivo assays (HLA Tg mice)Fee for ServiceVaccinesGrant funded R & DExcellent proof of principleGrant Funded2nd GenerationTherapeuticsSelect targetsFunded Res. Or Joint DevtDevelop molecule and licenseSponsored Research /Joint DevelopmentImmuno-modulationTregitopesIn preclinical development- may be largemarket - allergy, autoimmunityOptions available forselected “Field of Use”4
  5. 5. Discovery of Tregitopes5Tregitopes, discovered by Anne De Groot and Bill Martin at EpiVax, are linearsequences of amino acids contained within the framework of monoclonalantibodies and immunoglobulin G; the original finding was published in the journalBlood in 2008. Since their discovery, EpiVax has compiled substantial evidencelinking Tregitopes to the activation of natural regulatory T cells. By selectivelyactivating these natural regulatory T cells, Tregitopes can dampen unwantedimmune responses.Preliminary studies carried out by EpiVax and collaborators indicate thatTregitopes may be useful for inducing tolerance to transplants, protein drugs, andblood replacement therapies, as well as for the treatment of allergies. EpiVaxbelieves Tregitopes may explain the effectiveness of intravenous immunoglobulinG (IVIG), widely utilized as an autoimmune treatment.NIH SBIR grants coupled with private foundation funds have brought total pre-clinical funding for Tregitopes to more than $3.4M in the past 4 years.Tregitopes – Quick Summary
  6. 6. Discovery of Tregitopes6EpiVax Screens mAbsFor immunogenicityFound Epitopes that areHighly conservedTolerated or ignored?(David W. Scott connection)Tregs?. . . Test hypothesisAPC Tregitope peptidederived from IgGDiscovery of Tregitopes
  7. 7. Published in Blood, 25 July 2008Reprints available on requestOriginal Publicationhttp://www.epivax.com/publications/tregitope-publications/
  8. 8. Previous Evidence of TregEpitope in Fc domainConstantin Baxevanis, et al.:– 1986 hFc could induce tolerance in mice– CH3 could not induce tolerance– “Tolerogenic epitopes may exist in CH2 domain”Eur. J. Immunol. 1986.16: 1013-1016= No Tolerance= TolerancehFcCH3CH2CH3CH3
  9. 9. Fc Fusion Studies (David Scott Lab)– 1996 Ag-IgG fusion could induce tolerance– 2000 MHC CII essential in tolerance induction– 2004 GAD-IgG induces CD4+CD25+ Tregs–Also see work by Habib Zaghouani et al.Evidence of Tregitopes in IgG= ToleranceCH2CH3AgCH1
  10. 10. What’s the Evidence?(1) HLA Binding(4) Bystander Suppression. . . and antigen-specifictolerance induction(2) nTreg induction(3) aTreg induction6/13/2013 10(5) Modify APC Phenotype
  11. 11. Are there other examples in the literature?11
  12. 12. Edratide - TGF-beta andFoxP3 expression (Human)
  13. 13. Edratide – HLA RestrictionFrame Frame DRB1*0101 DRB1*0301 DRB1*0401 DRB1*0701 DRB1*0801 DRB1*1101 DRB1*1301 DRB1*1501Start Stop Z-Score Z-Score Z-Score Z-Score Z-Score Z-Score Z-Score Z-Score1 GYYWSWIRQ 9 -1.01 -1.63 -1.79 0.16 0.07 -1.37 -0.74 -0.79 -0.42 02 YYWSWIRQP 10 -1.14 -0.15 0.31 0.37 1.11 -0.10 1.06 -0.48 -0.70 03 YWSWIRQPP 11 -1.18 0.14 0.52 0.68 0.89 0.80 1.16 0.31 0.40 04 WSWIRQPPG 12 -1.08 1.48 -0.31 1.05 0.05 1.19 1.77 0.14 0.15 15 SWIRQPPGK 13 -1.41 -0.08 -0.92 -0.50 -0.96 0.55 0.26 0.26 -0.01 06 WIRQPPGKG 14 -1.37 2.29 1.27 1.97 1.28 2.62 2.35 0.88 1.26 47 IRQPPGKGE 15 -1.66 0.12 0.10 0.08 0.18 0.63 -0.59 0.97 0.03 08 RQPPGKGEE 16 -2.54 -2.45 0.29 -2.38 -2.31 -0.21 -1.45 -0.13 -0.65 09 QPPGKGEEW 17 -2.14 -1.47 -1.99 -1.62 -1.00 -2.67 -2.50 -2.86 -2.21 010 PPGKGEEWI 18 -1.26 -2.63 -1.56 -3.15 -1.36 -1.52 -2.36 -1.54 -2.89 011 PGKGEEWIG 19 -1.12 -1.50 -1.15 -1.61 -1.87 -1.80 -0.76 -2.12 -0.89 0DRB1*0101 DRB1*0301 DRB1*0401 DRB1*0701 DRB1*0801 DRB1*1101 DRB1*1301 DRB1*1501 Total2.29 1.27 1.97 1.28 2.62 2.35 0.97 1.26 --2.29 0.00 1.97 0.00 2.62 4.12 0.00 0.00 11.001.00 0.00 1.00 0.00 1.00 2.00 0.00 0.00 5.00Top 10%*Top 5% Top 1%Hydrophobic amino acid sequences scoring above 2.0 can be difficult to synthesize as peptides. Mutated amino acids are indicated in red typeface.EpiMatrix Cluster Detail ReportFile: MOZES_HCDR1 Sequence: HCRD1 Cluster: 1March 29, 2012 (Epx Ver. 1.2)Z score indicates the potential of a 9-mer frame to bind to a given HLA allele; the strength of the score is indicated by the blue shading.All scores in the Top 5% (Z-Score >= 1.64) are considered "Hits". *Scores in the top 10% (shown but not highlighted) are considered elevated, other scores are grayed out for simplicity.Frames containing four or more alleles scoring above 1.64 are referred to as Epi-Bars and are highlighted in yellow. These frames have an increased likelihood of binding to HLA.Frames conserved in IgG antibodies and believed to be either passively tolerated or actively regulatory are highlighted in green.Flanking amino acids, added to stabilize the cluster during in-vitro testing, are presented in blue type face and underlined.Total Assessments Performed: 88 Hydrophobicity: -1.09 EpiMatrix Score: 1.93 EpiMatrix Score (w/o flanks): 1.93Scores Adjusted for Tregitope: -- EpiMatrix Score: -7.30 EpiMatrix Score (w/o flanks): -7.30HitsSummarized Results (29-MAR-2012)Maximum Single Z scoreSum of Significant Z scoresCount of Significant Z ScoresAASequence &nbspHydro- &nbspphobicityThe hCDR1 peptide: GYYWSWIRQPPGKGEEWIGThe pCDR1 peptide: TGYYMQWVKQSPEKSLEWIGThe pCDR3 peptide: YYCARFLWEPYAMDYWGQGS
  14. 14. 14DiaPep 277Also somewhat HLA-restricted
  15. 15. Tregitope Collaberator Checklist - Relevant toAutoimmunity?15 Tregitopes induce adaptive tolerance in C57Bl/6, D011.10, OTII Tregitopes suppress/treat diabetes in NOD model (Scott/EpiVax) Tregitopes suppress transplant rejection in CD28 KO mice (Scott) Tregitopes suppression = IVIG in OVA/Allergy Model (Mazer) Tregitopes suppress immune responses to AAV capsid (Mingozzi)Tregitopes cause expansion of Tregs – iTreg or nTreg?.Details (and slides) for the above are available under CDA.Contact: amarcello@epivax.com
  16. 16. Anticipated Applications16 Antigen specific tolerance induction (De-immunization ofbiotherapeutics). Treatment of Autoimmune Disease (MS, T1D, others yet to bestudied) Treatment of Allergy
  17. 17. How Tregitopes are used in our Web BasedImmunogenicity Screening Platform - ISPRI17
  18. 18. 18Correlation of antibody immunogenicity withoutTregitope adjusted EPX ScoresCorrelation to observed Immunogenicity before accounting for TregitopesR2=0.17
  19. 19. Factoring in Tregitopes. . .T cell response depends on:T cell epitope content – Tregitope content + HLA of subjectProtein Immunogenicity can be RankedepitopeProtein Therapeutic1 + 1 - Regulatory T cell epitope* = ResponseepitopeepitopeImmunogenicity Scale for Monoclonals196/13/2013 Confidential
  20. 20. 20Correlation of antibody immunogenicity withTregitope adjusted EPX ScoresAccounting for Tregitopes results in more accurate predictions.Correlation to observed immunogenicity after accounting for TregitopesR2=0.76
  21. 21. Antibodies: A Special Case- 80 -- 70 -- 60 -- 50 -- 40 -- 30 -- 20 -- 10 -- 00 -- -10 -- -20 -- -30 -- -40 -- -50 -- -60 -- -70 -- -80 -IgG FC RegionNuvion (0%)Avastin (0%)AB01 (EPX Adjusted Score: -46.98)AB02 (EPX Adjusted Score: -44.48)AB03 (EPX Adjusted Score: -44.81)AB04 (EPX Adjusted Score: -45.81)AB05 (EPX Adjusted Score: -45.88)AB06 (EPX Adjusted Score: -47.85)AB07 (EPX Adjusted Score: -46.99)AB08 (EPX Adjusted Score: -46.30)AB09 (EPX Adjusted Score: -47.40)AB10 (EPX Adjusted Score: -45.88)AB11 (EPX Adjusted Score: -47.40)Synagis (1%)Simulect (1.4%)Humira (12%)Bivatuzumab (6.7%)Remicade (26%)Rituxan (27%)Campath (45%)Humicade (7%)Reopro (5.8%)Tysabri (7%)LeukArrest (0%)Herceptin (0.1%)New drug216/13/2013 ConfidentialDue to the presence of Tregitopes, antibodies tend to fall loweron the immunogenicity scale.We have developed a refined method using regressionanalysis to predict the immunogenicity of antibody sequencesbased on observed clinical responses.We have found that a balance in favor of Tregitope (regulatory)content over neo-epitope (effector) content is correlated withreduced clinical immunogenicity.NeoEpitopeContentTregitope ContentHigh LowLowAvastin (0%)Herceptin (0%)Mylotarg (3%)Simulect (1%)Synagis (1%)HighCampath (45%)Remicade (26%)Rituxan (27%)
  22. 22. Leslie Cousens and Annie De GrootEpiVax, Inc.Mechanism of Tregitope Action:In Vitro Studies226/13/2013 Confidential EpiVax
  23. 23. APCCD4TeffCD4+CD25+TregNotchMHCClassIITCRCD28/CTLA4CD80/CD86IL-10Identifying Tregitope Mechanisms ofAction at the Immunological SynapseILT3236/13/2013 Confidential EpiVax
  24. 24. Thanking our CollaboratorsEpiVax, Inc.William MartinLenny MoiseLeslie CousensTim MussetMatt ArditoRyan TassoneMcGillUniversityBruce MazurCiro PiccirilloAmir MassoudDartmouthCollegeChris Bailey-KelloggPartial funding bythe NIHUniformedServicesUniversity of theHealth SciencesDavid ScottYan SuXin LiUniversity ofMarylandAchsah KeeganPreeta DesguptaChildren’sHospital ofPhiladelphiaKatherine HighFederico MingozziDaniel Hui9/28/2012Harvard Brigham &Women’s HospitalMo SayeghNadar NajafianFrancesca D’AddioCiara MageeSamia KhouryWassim ElyamanInstitute forImmunology andInformaticsAnne De GrootLoren FastAlan RothmanDenice SperoDuke UniversityPriya KishnaniDwight Koeberl
  25. 25. EpiVax: Four Core StrengthsConfidential25

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