Fostering Clinical Development for HIV-1 Vaccine

Transcription

1 W Fostering Clinical Development for HIV-1 Vaccine Ravimiarenduse alane seminar 9. oktoobril Tallinnas Mart Ustav, PhD CSO, SVP 1 FIT Biotech Founded in 1995 Operations in Tampere, Finland and Tartu, Estonia Headcount 35 Clinical stage biotech company with in-house cgmp facility Proprietary vector platform technology, GTU Technology targeted at delivery of DNA to elicit both CMI and humoral immunity Superior efficacy and safety to any other DNA or viral vectors Validated through HIV therapeutic Phase II trial in treatment naive patients

2 DNA Vaccines Effective in induction of immune response in small laboratory animals, however, have failed in larger animals and humans Likely reason for weak performance of the DNA vaccines in larger animals and humans is poor delivery and low capacity of vectors for antigen expression in vivo Delivery and expression properties must be improved To Improve - Modify the Vector & Delivery Papillomaviruses and Herpesviruses (BPV1, Epstein-Barr Virus, HHV8) maintain their genomes as multi-copy nuclear plasmids in latently infected proliferating cells. Single viral DNA-binding protein and specific multimeric binding sites of this protein in the viral genome provide segregation function for the virus genome This protein is frequently a specific viral transcription activator

3 Mechanism of BPV1 Maintenance in Dividing Cells 5 Segregation/partitioning BINDING SITES GENE OF INTEREST GTU GENE Expression enhancement 6

4 Expression of Gene of Interest 5 4 Cells/ML Days post-transfection GTU ィ Control 7 Segregation/Partioning Function GTU DNA/nuclear compartment binding protein () GTU plasmid Conventional plasmid 8

5 as a Transcription Activator Pol II transcription machinery 9 GTU Induced Comparative Expression VEGF165 expression Luciferase activity ng/ml of VEGF days 5 days relative luc activity days 5 days 5 days GTU -VEGF165 GTU EGFP-luc pcmvvegf165 pngvlegfp-luc pngvlhuvegf165 pcmvegfp-luc 1

6 GTU Expression Enhancement in Mouse Muscle at 72h FVB strain 1,E+7 1,E+6 rlu 1,E+5 median 1,E+4 1,E+3 GTU6CMV regular CMV 11 K14 epi-gtu Expression Enhancement in Swine Skin at 48h 2,E+7 1,5E+7 rlu 1,E+7 mean 5,E+6,E+ GTU6K14 knockout control K14 regular 12

7 in vivo imaging of GTU Luc expression after ID+EP: PhotonImager II GTU-RB-EGFP-luc Counts R1 R2 R3 CMV-eGFP-Luc DNA Counts R1 R D Days D8 8 7 D Days D3 D D2 D3 1 1 X1 1 counts X1 1 counts Properties of GTU Vectors dependent enhancement of antigen expression makes GTU superior to conventional vectors in expression of antigen Therefore requiring lower amount of DNA to get adequate expression of the antigen dependent segregation/partitioning of the vector has effect in proliferating cells Auxotrophic selection marker, based on arad gene is used in GTU plasmids for production in E.Coli 14

8 Preclinical Studies in Non-Human Primates 15 Investigational Vaccine CMV 1 BS arad MultiHIV-B GTU-MultiHIV-B 883 bps BPV1 RSV LTR REV NEF TAT GAG EPITOPES 16

9 Preclinical Immunogenicity Studies in Non-Human Primates Intradermal (i.d.) injections of macaques: Classical i.d. with needle i.d. + in vivo electroporation DNA vaccinations 4 12 Weeks 1 mg DNA per vaccination and per animal split in 1 injection sites in the back skin, on the basis of 1 µl at 1 mg/ml per injection site 17 T Cell Responses to Four HIV Antigens TAT, REV, NEF, GAG 4 3 TAT 4 Controls MultiHIV MultiHIV EP 2 1 Controls MultiHIV MultiHIV EP REV NEF GAG IFN-γ SFC/million PBMC Control M ultihiv M ultihiv EP Weeks 18

10 Conclusions from NHP Studies AuxoGTU -MultiHIV B and MultiSIV plasmids are immunogenic AuxoGTU Induces long lasting HIV or SIV specific T-cells (> 3 years) Induces polyfunctional (IFNg + IL-2) T-cells Immunogenicity is strongly dependent on the delivery method Electroproration: Increases level and localisation of plasmid expression in skin Increases level of T-cell response Augment the breath of epitope recognition Significant decrease of PVL in the id+ep group during primary infection 19 GTU -MultiHIV B Clade DNA Vaccine, a Randomized Placebo-Controlled Phase II Trial in Untreated HIVinfected Individuals 2

11 Protocol Outline Study design Randomised, single-blinded, placebo-controlled Study population HIV subtype C infected, 18-4 yrs CD4 > 35 cells/mm 3 Viral load > 5 copies/ml No AIDS defining illness No history of ARV therapy Sample size 4 vaccine and 2 placebo Route of administration Biojector IM (1mg) ID (.5mg) for first three immunizations Boosts IM (2mg) and ID (1mg) Immunization schedule, 1, 3 months Boosts at 19 and 2 months Primary endpoints Safety : post vaccination & AE Immunogenicity: IFN-γ ELISPOT Cross-clade IFN-γ ELISPOT ICS Secondary endpoint Clinical effects CD4, CD3, CD8 Viral load Study Duration Q1/26-Q1/29 21 Enrollment Characteristics Age (yrs) Plasma Viral load copies/ml CD4 cells/µl Mean Range

12 Average Changes (Overall Weeks 1-18) Plasma Viral Load Comparison Estimate P-value FIT vs. Placebo ID: FIT vs. Placebo IM: FIT vs. Placebo CD4 Cell Counts Comparison Estimate P-value FIT vs. Placebo ID: FIT vs. Placebo IM: FIT vs. Placebo Conclusions GTU is anovel DNA vaccine vector Capacity for extended maintenance, segregation/partitioning and activated expression of genes of interest Preclinical confirmitian of superiority for induction of polyfunctional, persistent T-cell immune response lasting more than 3 years Use of the GTU-based vaccine in treatment naive HIV-1 infected patients resulted in a significant decrease in the viral load of.5 log and increase of the CD4+ cells by 72 FIT Biotech has completed 5 clinical HIV vaccine trials with superior safety and tolerability profile FIT Biotech continues HIV1 therapeutic and preventive clinical trial program in collaboration with international partners in USA and Europe 24