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- 2022-12-28
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438
Investigational Treatment Combining TG1050,
an HBV-Specific Immunotherapeutic, with
Direct Acting Antivirals or Immunomodulators,
Improves Sustained Antiviral Effects and
Immune Responses in HBV-Persistent Mice
Roland Kratzer1, Karine Lélu1, Alexei Evlachev1, Marie
Baldazza1, Doris Schmitt2, Nathalie Silvestre2, Benoit
Sansas3, Antoine F Carpentier4,5,6, Claire Banissi4,6, Abigail
Liebow Liebow7, Stuart Milstein7, Laura Sepp-Lorenzino7,
Yunfu Chen8, Qingyun Ren8, Li Jing8, Genevieve Inchauspe1
and Perrine Martin1, (1)Dept. of Infectious Diseases,
Lyon, France, Transgene SA, (2)Smart Virus Lab, Illkirch
Graffenstaden, France, Transgene SA, (3)Smart Data Lab,
Illkirch Graffenstaden, France, Transgene SA, (4)Laboratoire
De Recherches Biochirurgicales, Université Paris Descartes,
Hôpital Européen Georges Pompidou, Paris, France, (5)
Université Paris Diderot, Sorbonne Paris Cité, Paris, France,
(6)Hôpital Saint-Louis, Assistance Publique-Hôpitaux De
Paris (AP-HP), Paris, France, (7)Alnylam Pharmaceuticals,
Cambridge, MA 02142, USA, (8)The State Key Laboratory of
Anti-Infection Drug Development, HEC Pharma Group, Dong
Guan 523871, China
Background: Therapies for chronic hepatitis B virus (HBV)
infection rarely achieve functional cure. Novel direct-acting
antivirals (DAA), immunomodulators (IM) and therapeutic
vaccines are under development. Combination therapies
appear to be required to achieve functional cure. We explored
4 combination therapies to potentiate or complete the activity
of TG1050, a therapeutic vaccine based on an adenovirus
encoding a polyprotein comprising HBV Pol, Core and
domains of HBsAg, in phase 1 clinical trial (NCT02428400).
We associated TG1050 with an IM (TLR9 agonist CpG-
28, Oligovax or myeloid derived suppressor cell inhibitor
sildenafil) to boost or restore host immunity or with a DAA
(siRNA-HBV or capsid inhibitor HEC73045, HEC Pharma)
to lower HBsAg burdens, hence lower host tolerance, or
inhibit capsid formation. Methods: Combinations associating
TG1050 and DAA or IM were assessed in AAV-HBV infected
mice. Viral parameters in blood (HBV-DNA by qPCR and
HBsAg by ELISA), anti-HBc and anti-HBs antibodies (ELISA)
were monitored. HBV-RNA (by RT-qPCR) and liver function
(ALT) were studied in selected experiments. T cell immunity
was analyzed at the end of experiments (IFNγ-ELISpot
assays or IFNγ/IL-2/TNFa ICS). Results: TG1050+CpG-28
combination led to a sustained 1.6 log decrease in viremia
and 1.3 log decrease in circulating HBsAg levels 84 days post
1st treatment (means). Polymerase-specific T cell responses
in mice treated by TG1050+CpG-28 were correlated with
viral parameter decreases and moderate ALT elevation.
TG1050+sildenafil combination led to strong and sustained
off-treatment antiviral effects (73 days post 1st treatment): 0.8
log decrease in viremia, 1.1 log decrease in circulating HBsAg
levels and 0.7 log decrease in HBV-RNA. No beneficial effect
was seen, neither on maximum HBV DNA decrease (mean 2.7
log) nor on maximum HBsAg decrease (mean 2.9 log) when
TG1050 was combined with siRNA-HBV but the rebound of
circulating HBsAg and HBV DNA levels after therapy arrest
was significantly delayed. TG1050+HEC73045 combination
had no additive effect on viral parameters but increased
significantly anti-HBc antibodies induced by TG1050.
No combination effect was observed when TG1050 was
associated with NUC. Conclusion: Under our experimental
conditions we obtained proof-of-concept data in favor of
beneficial antiviral effects when TG1050 is combined with
three compounds: siRNA, MDSC inhibitor or TLR9 agonist,
paving the way to clinical investigation. |
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