Kishimoto, Takashi

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Engineering Conferences InternationalECI Digital ArchivesVaccine Technology IV ProceedingsSpring 5-21-2012Rational design of a fully synthetic nanoparticle-based vaccine for smoking cessatioTakashi KishimotoSelecta BiosciencesFollow this and additional works at: http://dc.engconfintl.org/vaccine_ivPart of the Biomedical Engineering and Bioengineering CommonsThis Conference Proceeding is brought to you for free and open access by the Proceedings at ECI Digital Archives. It has been accepted for inclusion inVaccine Technology IV by an authorized administrator of ECI Digital Archives. For more information, please contact franco@bepress.com.Recommended CitationTakashi Kishimoto, "Rational design of a fully synthetic nanoparticle-based vaccine for smoking cessatio" in "Vaccine Technology IV",B. Buckland, University College London, UK; J. Aunins, Janis Biologics, LLC; P. Alves , ITQB/IBET; K. Jansen, Wyeth VaccineResearch Eds, ECI Symposium Series, (2013). http://dc.engconfintl.org/vaccine_iv/3Rational Design of Synthetic VaccinesECI Vaccine TechnologyPortugal            May 2012Shaping the Immune ResponseOutline1) Targeted Synthetic Vaccine Particles (tSVP)2) SEL-068 – Anti-nicotine vaccine for smoking cessation2The Intersection of Immunology and NanotechnologyRobert Langer, ScDInstitute ProfessorMITNeed for new vaccine technology• Rapidly mutating pathogens (e.g. HIV, malaria)• Immunosenescence3Omid Farokhzad, MDAssociate ProfessorHarvard Medical SchoolUlrich von Andrian, MD, PhDProfessorHarvard Medical School• Chronic infections• Cancer• Autoimmune diseases and allergies• Other chronic diseases   (e.g. Alzheimer’s disease, cardiovascular disease, smoking cessation)Rational Design of targeted Synthetic Vaccine Particles (tSVP)nanometers10-1 1 101 102 103 104 105 106 108107Water Glucose Antibody Virus Bacteria Cancer Cell Tennis BallA period.4tSVPVirus (e.g. influenza virus)B-Cell AntigenT-Cell AntigenBiocompatible MatrixAdjuvantNanoparticles Enable Targeted Delivery of Immunological Instructions to the Lymph Node•Targeted delivery to DCCONFIDENTIALConfidential •Therapeutic Vaccines• Cancer • HIV• HCV• Other chronic Infections• Prophylactic Vaccines• Infectious diseases• Therapeutic Vaccines• Addiction• Cancer5Self-assembling Manufacturing Process of Synthetic VaccinesPLGAPEGB antigenComponents ProductionSelf-assemblyFinished Particles46Advantages of  synthetic tSVP production :• Scalability• Stable and Reproducible• Fast to the clinic • Cost efficientAdjuvantT antigenassembly• High Batch consistency• Nanoparticle Formation Vessel for 10 g scale (~10,000 doses)• Total batch time <10h (w/o drying and filling)Successful GMP manufacturing demonstrated to support Ph 1 trialtSVP-Encapsulated Adjuvant  is Targeted to the Draining Lymph NodeIL-12 (p40), pg/ml100120140 tSVP [OVA + adjuvant]NP-OVA, no adjuvantNP-OVA + admixed adjuvant Lymph Node IFN-γ Lymph Node IL-12(p40)2500030000tSVP [OVA + adjuvant] NP-OVA, no adjuvantNo adjuvantFree adjuvantSVP adjuvant7Time after inoculation (hrs)0 4 24 48 72IL-12 (p40), pg/ml020406080Time after inoculation (hrs)0 4 24 48 72IFN- γγ γγ, pg/ml05000100001500020000NP-OVA + admixed adjuvant tSVP-Encapsulated Adjuvant  Minimizes Systemic Cytokine Production100001200014000 tSVP [OVA + adjuvant]NP-OVA, no adjuvantNP-OVA, admixed adjuvantTNF-alpha (pg/ml)10001200tSVP [OVA + adjuvant]NP-OVA, no aduvantNP-OVA, admixed adjuvantPlasma IL-6Plasma TNF-αNo adjuvantSVP adjuvant8•tSVP encapsulation of TLR agonist minimizes systemic cytokine secretion Time after injection (hrs)0 1 2 3 4 5 6IL-6 (pg/mL)2000400060008000Time after inoculation (hrs)0.0 0.5 1.0 1.5 2.0 2.5 3.0TNF-alpha (pg/ml)0200400600800Free adjuvantPercent R-848 Release, 37o CPercent R-848 Release6080100Controlled Adjuvant ReleaseAdjuvant can be released at a wide range of targeted ratesRelease %Percent Adjuvant Release, 37 CTime, h0 50 100 150 200Percent R-848 Release02040Nanoparticles 62-2Nanoparticles 62-4Nanoparticles 62-6Nanoparticles 62-89Ideal immune response is correlated with duration of TLR receptor stimulationPercent Release %Universal T-Help Antigen to Boost Response and Enable Universal VaccinesAllelic variantAllele frequency Peptide DHLA-DRB1*0101 5.4 4.99HLA-DRB1*0301 13.7 3.81HLA-DRB1*0401 4.6 2.02Predicted crossreactivityto Selecta's Epitope D% Memory Cells1.52.02.5Human PBMC recall responseAlgorithm to identify promiscuous MHC class II-binding peptides10HLA-DRB1*0404 3.6 1.79HLA-DRB1*0405 6.2 4.94HLA-DRB1*0701 13.5 0.5HLA-DRB1*0802 4.9 0.7HLA-DRB1*0901 6.2 0.36HLA-DRB1*1101 11.8 3.13HLA-DRB1*1302 7.7 1.7HLA-DRB1*1501 12.2 3.02EpitopeA B C D% Memory Cells0.00.51.0Recall response to peptide D observed in 50 of 50 human donorsSmall Molecule Antigen* Viral Peptide Antigen*tSVP Induction of Robust Antibody Responses to Wide Range of Antigens Adjuvant Sparing withProtein Antigen*10X admix adjuvant11* Subcutaneous injection  in miceFreesmallmolecule+ adjuvanttSVPTM w/oadjuvanttSVPTM Freepeptide+ alumtSVPTMw/oT cellantigentSVPTM tSVPTM w/oadjuvanttSVPTMw/oadjuvant+admix adjuvanttSVPTM w. 1/10thadjuvantOva peptide pulsed target cellsControl peptidepulsed target cellstSVP.Ova-immunized ControlFluorescent-labeled target cellstSVP Induction of In vivo CTL Responses1218 hrs 18 hrsAntigen-specific killing of ova-pulsed target cells100NP-OVA-R848 PBSEfficacy and Memory in E.G7 Tumor ModelTherapeutic Dosing Regimen Survivors re-challenged with tumor 2-3 months later100tSVP-immunized long term survivorstSVPSalineTime after tumor inoculation (days)0 10 20 30 40 50 60 70Tumor free animals (%)02040608013Time after tumor inoculation (days)6 8 10 12 14 16 18 20 22Tumor free animals (%)020406080 (n = 8)Non-immunized, tumor-naïve mice (n = 5)Time after tumor challenge (Days)Tumor-free animals (%)Outline1) Targeted Synthetic Vaccine Particles (tSVP)2) SEL-068 – Anti-nicotine vaccine for smoking cessation14High prevalence with worldwide smoking population >1B• 46 million adult smokers in USA – 70% desire to quit (CDC)• Smoking costs the US $97.6 billion/yr in direct healthcare costs• 50% of smokers live in BRIC countriesHigh remaining unmet medical needSmoking Cessation• 12 months abstinence rates for current treatment just over 20%• High relapse risksSmoking cessation is a worldwide priority for health care providers• Fast track status for smoking cessation products in the US• Favorable health economics for smoking cessation products (costs per year of life saved) • High market growth from current $3.8B to over $5.0B in next 5 years15Nicotine vaccine creates nicotine specific antibodies that bind free nicotine and prevent it from crossing the blood-brain barrierNicotine Vaccine for Smoking Cessation and Relapse Prevention (SEL-068)16NicotineUniversal T help peptideTLR agonistNicVax - Nabi (Phase 2)**% continuous abstinence (week 8-52)18%20%40%60%Nic002 – Cytos (Phase 2)*% continuous abstinence (week 8-52)42%21%26%21%20%40%60%Prior Clinical Studies Validate the Vaccine Approach to Smoking Cessation178% 6%0%0%Two independent studies indicate that an effective vaccine for smoking cessation can be achieved if antibody titers can be increased across a greater percentage of the populationOptimization of an Anti-Nicotine Nanoparticle-Nicotine Ig, GMT (50% max. O.D.)100001000001000000nicotine AbTiter18αα αα-Nicotine Ig, GMT (50% max. O.D.)1001000NicotineTLR 7/8 agonistMHC II peptideSol--NP--NPSolSolNP-NPNPNP-NPSolNPNPNPSolNPNPNPAnti-nicotine Anti-Nicotine Antibody vs Nicotine AUCAnti-Nicotine IgG vs Nicotine AUC19Persistence of Anti-Nicotine AntibodiesAnti-nicotine Ab  ( µµ µµg/ml)101001000SEL-068No peptide NPMice immunized on Days 0, 14, 28, and 18020DaysAnti-nicotine Ab  (0 50 100 150 200 250 300 350 400 450 5000.010.11↑ ↑↑ ↑SEL-068: High Antibody Titers Across Mice and Non-Human Primates100001000001000000Mice(n=5 per group)nicotintiter100001000001000000Rhesus Monkeys(n=4, 1 per group)nicotine titer100001000001000000NicotiineTiterCynomolgus Monkeys(n=50, 10 per group)211001000•R&D and Tox Scale• d0, d14, d28• Antibody titers at d40Anti-nicotinSaline1001000• R&D Scale •d0, d28, d56• Antibody titers at d70Anti-nicotine titerNicotine pre-exposureNicotine pre-exposure, 8 mgSaline1001000Anti-Nicotiine• d1, d29, d57• Antibody titers at d85• Tox scale =P1 scale High Specificity for NicotineCompound % Cross-reactivityNicotine 100Cotinine 3.7Nornicotine 7.6Nicotine-N-Oxide <1Compound % Cross-reactivityCytisine <1Iproniazid phosphate <1Mecamylamine <1Preliminary dataNorcotinine <1Cotinine-N-Oxide <1Acetylcholine <1Buspirone HCL <1Buproprion HCl <122• Specificity determined by competition ELISA to immobilized poly L-lysine-nicotine• Percent crossreactivity determined as described in Pentel et al., JPET, 2006, 317: 660-666Acetylcholine <1Choline <1Niacin <1Serotonin <1Dopamine <1γ-Aminobutyric acid (GABA) <1SummarytSVP Platform• Self-assembling, biocompatible nanoparticles• Directed delivery of TLR agonists to lymph node• Universal T cell help peptide• High antibody titers to poorly immunogenic antigens• Efficient in vivo induction of CTL activity23• Antigen-specific immune toleranceSEL-068 Anti-nicotine vaccine• Dose-dependent anti-nicotine response• High titers in mice and two species of non-human primates• Long term persistance of titers• GLP tox study in NHP shows no evidence of systemic toxicities• Successful GMP manufacturing and initiation of Ph 123SEL-068Product Development Timeline• Selecta begins operations Fall, 2008• Nicotine program initiated 2009• >100 formulations made and tested 2009-2010• Clinical Candidate selected Q4 2010• GLP toxicology study in NHP initiated Feb, 2011Start of program to first subject dosed• GLP Tox complete, no systemic findings Aug, 2011• GMP supplies released Aug, 2011• Phase 1  Clinical trial initiated Nov, 201124< 3 yearsSelecta self-assembling, synthetic nanoparticle platform enables rapid iterative optimization of development candidates and scale up to GMP

Rational design of a fully synthetic nanoparticle-based vaccine for smoking cessatio

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Rational design of a fully synthetic nanoparticle-based vaccine for smoking cessatio

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