Immune Modulation for HBV Cure

Transcription

1 Immune Modulation for HBV Cure Ulrike Protzer Institute of Virology echnische Universität München / Helmholtz Zentrum München echnische Universität München

2 How can hepatitis B be cured? 1. killing of infected hepatoctyes 2. loss of cccdna by cell division 3. degradation of nuclear cccdna Entry blocker NAP sirna Immune herapy Nucleos(t)ide analogues Capsid Assemby inhibitors Interferons LR agonists sirna Directly acting antivirals control, but do not eliminate HBV and a significant HCC risk remains

3 Direct viral inhibition Immune herapy herapeutic strategy Example Mechanism of action Phase Viral entry inhibitor Myrcludex B IIa argets NCP receptor to inhibit viral Cyclophilin-Inhibitors preclinical/ii infection Oxysterols preclinical ARC-520 II/III RNA inferference (RNAi) Antisense oligonucleotide II RNA molecules inhibiting gene ISIS-HBVRX I expression and release of new ALN-HBV preclinical virions KM-HBV I NUC B 1000 I cccdna silencing HDAC inhibitors inhibit cccdna transcription preclinical Interferon α/γ, Ltα/β APOBEC3A/B mediated cccdna preclinical degradation cccdna degradation HBV specific ALENs targeted disruption of cccdna preclinical Disubstituted sulfonamides (DSS) inhibits conversion of rcdna to cccdna preclinical enofovir alafenamide fumarate (GS-7340) III New nucleoside analogues AGX-1009 DNA polymerase (R) inhibition I Besifovir (LB80380) III Lagociclovir valactate (MIV-210) II HAP (e.g. BAY / GLS-4) I/II Capsid assembly modifiers Phenylpropenamide (A-130) Inhibits HBV replication by causing preclinical Isothiafludine (W28F) destabilization of viral nucleocapsid II NVR-1221 IIa Nucleic acid polymers REP 9AC Inhibits release of HBsAg (restores immune responses?) II Immune modulators PegInterferon-Lambda Cytokines with immunomodulating IIb LR-7/8 agonists (e.g. GS-9620 / RG-7795) and antiviral effcts III armogen based (GS-4774) II herapeutic vaccines G1050 (ransgene) I Induce and stimulate CD4+ and CD8+ ABX203 (Abivax) IIb/III -cell response DNA vaccine (e.g. INO-1800) I HB-Vac Activated-DCs II Exhausted cells PD-1/PD-L1 blockade Blockade of cell inhibitory signal, IIa CLA-4 Ab "checkpoint" inhibitor Antibody therapy bispecific antibodies: S-BiMAb MHC-independent cell activation preclinical Adoptive -cell therapy S-CAR -cells preclinical engineered -cells HBV-specific CRs preclinical

4 herapeutic strategy Example Mechanism of action Phase Immune herapy Immune modulators herapeutic vaccines Activate exhausted cells Antibody therapy Adoptive -cell therapy PegInterferon-Lambda Cytokines with immunomodulating and antiviral IIb LR-7/8 agonists (e.g. GS-9620 / RG- effcts 7795) III armogen based (GS-4774) II G1050 (ransgene) I Induce and stimulate CD4+ and CD8+ -cell ABX203 (Abivax) IIb/III response DNA vaccine (e.g. INO-1800) I HB-Vac Activated-DCs II PD-1/PD-L1 blockade Blockade of cell inhibitory signal, "checkpoint" IIa CLA-4 Ab inhibitor anti-s / anti-pres antibodies Fc-dependent immune activation preclinical bispecific antibodies: S-BiMAb MHC-independent cell activation preclinical S-CAR -cells preclinical engineered -cells HBV-specific CRs preclinical

5 Options for Anti-HBV Immune herapy Immune stimulatory molecules cytokines: interferons, lymphotoxins, IL-2, IL-12, IL-6. pattern recognition receptor agonists: LR-7, LR-8, LR-9, Rig-I check-point inhibitors: anti-pd1, anti-pdl-1, anti-cla4 Antibody mediated therapy -cell redirection antigen-specific, targeted approaches herapeutic vaccine

6 Immune stimulatory / modulatory molecules cytokines: Interferons: IFN-α, IFN-β, IFN-γ, IFN-λ Interleukins: IL-2, IL-12, IL-6. pattern recognition receptor agonists: LR-7, LR-8, LR-9, Rig-I activator check-point inhibitors: anti-pd1, anti-pdl-1, anti-cla4 diverse: granulocyte-macrophage colony stimulating factor (GM-CSF) levamisole, thymus humoral factor-gamma 2, alpha galactosylceramide, propagermanium, thymosin-alpha 1

7 Innate immune activators currently in clinical development GS 9620 LR-7 agonist Gilead Sciences Phase II RO (RG7795, ANA773) LR-7 agonist Roche Phase II Inarigivir (SB9200) RIG -1 and NOD2 agonist Spring Bank Pharmaceuticals, USA Phase II GS9688 LR-8 agonist Gilead Sciences Phase I

8 LR-7 agonists Lanford RE, Guerra B, Chavez D et al.: GS-9620, an oral agonist of oll-like receptor-7, induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees. Gastroenterology 2013;144: , 17 e1-10 Janssen, H. et al: Safety, Efficacy and Pharmacodynamics of Vesatolimod (GS-9620) in Virally-Suppressed Patients with Chronic Hepatitis B. Journal of Hepatology, online November 2017 In a Phase 2 study, vesatolimod, an oral, once-weekly, experimental immune-activating drug for the treatment of hepatitis B virus (HBV), is safe and well-tolerated in chronic HBV patients who are virally suppressed on oral antiviral treatment. Despite demonstrating ontarget biomarker responses in patients, however, no significant declines in hepatitis B surface antigen were observed.

9 Rig-I activator SB9200 (Inarigivir) Small molecule nucleic acid hybrid Orally bioavailable prodrug HBeAg ACHIEVE rial Safe, but clinical efficacy needs to be proven HBeAg+

10 cell response determines course of Hepatitis B Immune response strong antibody and effector cell response self-limiting infection therapeutic vaccination cells are scarce, no neutralizing antibodies chronic infection

11 Vaccine Name Proteins/ coding sequences Vaccine type/ Composition Results available Sponsor Development Stage Clinical rial Reference No. Reference herapeutic vaccine trials in chronic Hepatitis B but: no heterologous prime-boost HB-110 HB-100 ppdpsc18 HBsAg,, HBcAg, human IL-12 pgx10 S +pgx10 S1/S2/X +pgx10 core +pgx10 Pol +pgx10 hil-12n222l 3 Plasmid based DNA vaccine 5 Plasmid based DNA vaccine 4 antigens + human IL-12 DNA vaccine adjuvanted with particle mediated epidermal delivery INO-1800 HbsAg, HBcAg DNA plasmid Recruiting HB02 VAC- ADN HB pres/s pcmv-s2.s DNA vaccine; CMV promoter, plasmid vector CVI-HBV-002 HbsAg DNA+ L-pampo Recruiting heravax (DV- 601) HBsAg, HBcAg Protein + adjuvant Study completed, results not reported Study completed, results not reported Well tolerated; No change in relapse rate in HBV treated patients or decrease in virological breakthrough Well tolerated; anti-viral response observed in all patients Genexine Phase I NC NC NC PowderMed Phase I NC Inovio Pharmaceuticals Phase I NC ANRS Phase I/II NC CHA Vaccine Phase I/II Institute Co., Ltd. Dynavax echnologies Corp. Phase Ib NC NC Hepcell M IC31 adjuvanted peptide Recruiting Altimmune, Inc. Phase I NC HBsAg/HBcAg HBsAg, HBcAg protein Research GS-4774 εpa-44 Multi-peptide vaccine Phase II naïve group ongoing; no significant viral decrease in treatmentexperience patients Some seroconversion observed in all groups, no statistical analysis Chongqing Jaichen Biotechnology, Phase II NC NC NC NC NC ABX 203 HBsAg, HBcAg HBsAg, HBcAg Ongoing ABIVAX S.A. Phase II/III NC psg2.hbs/ MVA.HBs Fusion protein HBsAg, HBcAg, HBxAg HBsAg, HBcAg Protein + amogen cell stimulator Protein prime- viral vector boost Adjuvanted protein primeviral vector boost Well tolerated, but did not control HBV infection Gilead Oxxon herapeutics Phase II Phase IIa ISRCN Research Kim et al., Exp Mol Med. 40: Yang et al., Gene herapy. 13: Mancini Bourgine et al., Vaccine 24: US US US Li et al., 2015, Vaccine. 33: Gaggar et al., Vaccine. 32: Cavenaugh et al., PLoS ONE 6: e Backes, 2016, Vaccine Kosinska, Bauer & Protzer, Current Opinion in Virology 2017

12 hervacb strategy: heterologous prime - boost HBsAg anti-hbs reduce viremia/ inflammation Induce neutralizing antibodies, prime cell responses cell control Buchmann et al. Vaccine 2013; Backes et al Vaccine 2016

13 Adoptive cell therapy in hepatitis B infection with HBV acute hepatitis B effective cell response expansion re-infusion cell isolation chronic hepatitis B (>250 million worldwide, WHO 2017) very weak cell response virus clearance / functional cure receptor expression genetic modification virus persistence

14 Adoptive cell therapy Chimeric antigen receptor (CAR) cell receptor (CR) spacer single chain antibody fragment CD3ζ signaling CD28 signaling HBV S protein CD3ζ constant region variable region processed peptide in an MHC complex HBV-infected hepatocytes Bohne et al, Gastroenterology 2008 Krebs et al., Gastroenterology 2013 Gehring et al, J Hepatology 2010 Kah et al, JCI 2017 Wisskirchen et al., PLOS One 2017 Wisskirchen, Kah et al., submitted

15 Summary HBV is able to avoid and to escape immune responses Antivirals control but do not eliminate HBV immune activation may be necessary to clear the virus Immune modulatory therapy seems to be safe however, efficacy needs to be proven (except IFN!) HBV Cure Immune therapy activating CD8 cells checkpoint inhibitors (cave: cells are scarce...!) therapeutic vaccination cell redirection

16 HBV has a complicated life cycle From: Ko, Michler & Protzer, Current Opinion Virology 2017