Engineered Anti-PDL1 with IFNα Targets Both Immunoinhibitory and Activating Signals in the Liver to Break HBV Immune Tolerance

Overview

Journal Gut

Specialty Gastroenterology

Date 2022 Oct 31

PMID 36316098

Authors

Chao-Yang Meng

Shiyu Sun

Yong Liang

Hairong Xu

Chao Zhang

Min Zhang

Fu-Sheng Wang

Yang-Xin Fu

Hua Peng

Affiliations

Soon will be listed here.

Abstract

Objective: The purpose of this study is to develop an anti-PDL1-based interferon (IFN) fusion protein to overcome the chronic hepatitis B virus (HBV)-induced immune tolerance, and combine this immunotherapy with a HBV vaccine to achieve the functional cure of chronic hepatitis B (CHB) infection.

Design: We designed an anti-PDL1-IFNα heterodimeric fusion protein, in which one arm was derived from anti-PDL1 antibody and the other arm was IFNα, to allow targeted delivery of IFNα into the liver by anti-PDL1 antibody. The effect of the anti-PDL1-IFNα heterodimer on overcoming hepatitis B surface antigen (HBsAg) vaccine resistance was evaluated in chronic HBV carrier mice.

Results: The anti-PDL1-IFNα heterodimer preferentially targeted the liver and resulted in viral suppression, the PD1/PDL1 immune checkpoint blockade and dendritic cell activation/antigen presentation to activate HBsAg-specific T cells, thus breaking immune tolerance in chronic HBV carrier mice. When an HBsAg vaccine was administered soon after anti-PDL1-IFNα heterodimer treatment, we observed strong anti-HBsAg antibody and HBsAg-specific T cell responses for efficient HBsAg clearance in chronic HBV carrier mice that received the combination treatment but not in those that received either single treatment.

Conclusions: Targeting the liver with an engineered anti-PDL1-IFNα heterodimer can break HBV-induced immune tolerance to an HBsAg vaccine, offering a promising translatable therapeutic strategy for the functional cure of CHB.

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References

Xu D, Wang X, Shen X, Gong G, Ren H, Guo L . Results of a phase III clinical trial with an HBsAg-HBIG immunogenic complex therapeutic vaccine for chronic hepatitis B patients: experiences and findings. J Hepatol. 2013; 59(3):450-6. DOI: 10.1016/j.jhep.2013.05.003. View

Zhu D, Liu L, Yang D, Fu S, Bian Y, Sun Z . Clearing Persistent Extracellular Antigen of Hepatitis B Virus: An Immunomodulatory Strategy To Reverse Tolerance for an Effective Therapeutic Vaccination. J Immunol. 2016; 196(7):3079-87. PMC: 4824405. DOI: 10.4049/jimmunol.1502061. View

Chen L . Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol. 2004; 4(5):336-47. DOI: 10.1038/nri1349. View

Dion S, Bourgine M, Godon O, Levillayer F, Michel M . Adeno-associated virus-mediated gene transfer leads to persistent hepatitis B virus replication in mice expressing HLA-A2 and HLA-DR1 molecules. J Virol. 2013; 87(10):5554-63. PMC: 3648192. DOI: 10.1128/JVI.03134-12. View

Jacobi F, Wild K, Smits M, Zoldan K, Csernalabics B, Flecken T . OX40 stimulation and PD-L1 blockade synergistically augment HBV-specific CD4 T cells in patients with HBeAg-negative infection. J Hepatol. 2019; 70(6):1103-1113. DOI: 10.1016/j.jhep.2019.02.016. View

Thimme R, Wieland S, Steiger C, Ghrayeb J, Reimann K, Purcell R . CD8(+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J Virol. 2002; 77(1):68-76. PMC: 140637. DOI: 10.1128/jvi.77.1.68-76.2003. View

Liu L, Hou J, Xu Y, Qin L, Liu W, Zhang H . PD-L1 upregulation by IFN-α/γ-mediated Stat1 suppresses anti-HBV T cell response. PLoS One. 2020; 15(7):e0228302. PMC: 7337294. DOI: 10.1371/journal.pone.0228302. View

Salimzadeh L, Bert N, Dutertre C, Gill U, Newell E, Frey C . PD-1 blockade partially recovers dysfunctional virus-specific B cells in chronic hepatitis B infection. J Clin Invest. 2018; 128(10):4573-4587. PMC: 6159957. DOI: 10.1172/JCI121957. View

Sadler A, Williams B . Interferon-inducible antiviral effectors. Nat Rev Immunol. 2008; 8(7):559-68. PMC: 2522268. DOI: 10.1038/nri2314. View

10.

Sarin S, Kumar M, Lau G, Abbas Z, Chan H, Chen C . Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int. 2015; 10(1):1-98. PMC: 4722087. DOI: 10.1007/s12072-015-9675-4. View

11.

Bertoletti A, Gehring A . Therapeutic vaccination and novel strategies to treat chronic HBV infection. Expert Rev Gastroenterol Hepatol. 2009; 3(5):561-9. DOI: 10.1586/egh.09.48. View

12.

Yang X, Zhang X, Fu M, Weichselbaum R, Gajewski T, Guo Y . Targeting the tumor microenvironment with interferon-β bridges innate and adaptive immune responses. Cancer Cell. 2014; 25(1):37-48. PMC: 3927846. DOI: 10.1016/j.ccr.2013.12.004. View

13.

Brahmer J, Tykodi S, Chow L, Hwu W, Topalian S, Hwu P . Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012; 366(26):2455-65. PMC: 3563263. DOI: 10.1056/NEJMoa1200694. View

14.

Zhang X, Zhou Y, Chen C, Fang W, Cai X, Zhang X . Hepatitis B virus reactivation in cancer patients with positive Hepatitis B surface antigen undergoing PD-1 inhibition. J Immunother Cancer. 2019; 7(1):322. PMC: 6873745. DOI: 10.1186/s40425-019-0808-5. View

15.

Terrault N, Bzowej N, Chang K, Hwang J, Jonas M, Murad M . AASLD guidelines for treatment of chronic hepatitis B. Hepatology. 2015; 63(1):261-83. PMC: 5987259. DOI: 10.1002/hep.28156. View

16.

Muhlbauer M, Fleck M, Schutz C, Weiss T, Froh M, Blank C . PD-L1 is induced in hepatocytes by viral infection and by interferon-alpha and -gamma and mediates T cell apoptosis. J Hepatol. 2006; 45(4):520-8. DOI: 10.1016/j.jhep.2006.05.007. View

17.

El-Khoueiry A, Sangro B, Yau T, Crocenzi T, Kudo M, Hsu C . Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017; 389(10088):2492-2502. PMC: 7539326. DOI: 10.1016/S0140-6736(17)31046-2. View

18.

Li F, Wei H, Wei H, Gao Y, Xu L, Yin W . Blocking the natural killer cell inhibitory receptor NKG2A increases activity of human natural killer cells and clears hepatitis B virus infection in mice. Gastroenterology. 2012; 144(2):392-401. DOI: 10.1053/j.gastro.2012.10.039. View

19.

Raeber M, Rosalia R, Schmid D, Karakus U, Boyman O . Interleukin-2 signals converge in a lymphoid-dendritic cell pathway that promotes anticancer immunity. Sci Transl Med. 2020; 12(561). DOI: 10.1126/scitranslmed.aba5464. View

20.

Vandepapeliere P, Lau G, Leroux-Roels G, Horsmans Y, Gane E, Tawandee T . Therapeutic vaccination of chronic hepatitis B patients with virus suppression by antiviral therapy: a randomized, controlled study of co-administration of HBsAg/AS02 candidate vaccine and lamivudine. Vaccine. 2007; 25(51):8585-97. DOI: 10.1016/j.vaccine.2007.09.072. View