Therapeutics for Biomarkers of - Virology Education...
Transcript of Therapeutics for Biomarkers of - Virology Education...
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• 30 faculty and labs dedicated to the pursuit of antivirals
• Focus upon chronic viral diseases (viral hepatitis / herpes simplex)
• Outreach services for chronic viral infection
Therapeutics for HBV, HCV, HCC;
Biomarkers of HCC & Fibrosis T. Block
J. ChangG. ChenJ ClementA. CuconatiY. DuA. EvansM. GoetzH. T GuoJ. T GuoD. HornP LamW. KinneyJ. KulpF. KlaessigX. LuB. Maryanoff
B. NefskyR. PhilipM. SofiaA. ReitzP. RomanoJ. VaccaK. ShailubhaiY. SuM. XuT Zhou
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Disclosures
Contravir: Board of Directors
Arbutus: Research Grants & Equity
Glycotest: Board of Directors
Your companies name: Here!
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Morphogenesis of hepatitis B virus as a therapeutic target
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HBsAg Essential viral protein (S neg virus in not viable)
Extra virological functions (?immuno evasion)
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Extra virological roles:
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Extra virological roles:Un masking: too much HBs, HBsAbs are made, but
complexed with HBs
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Eliminate HBs, and un mask, liberate, present HBsAbs
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HBsAb appearance after spontaneous or drug induced HBsAg loss occurs, but can take months to
yearsAp
pear
ance
of H
BsA
b
Years following loss of HBsAg
17-76% of those who loss HBsAg spontaneously (~0.1-2.0% per year, peaking age 50) develop detectable HBsAbs within two-ten years
Chu, C.-M. and Liaw, Y.-F. Antiviral Therapy, 2010
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TolerizationToo much HBs (S): exhaustion of T cells,
NPCs/APCs
SS
S
S
S
SS
SS
S
S
S
SS
SS
S S
S
SS
S
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HBs as an immunosuppressor
But, what’s the evidence that an anti-HBs agent would do more than just act as a direct acting antiviral?
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CircumstantialIts levels have negative predictive value
No decline in HBs after 12 weeks of IFN Rx is 90-100% predictive of ineffective Rx (Liaw, 2012; Mocauri, 2009; Rickborst, 2010)
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CircumstantialIts levels have positive predictive value
HBsAg pretreatment and early post treatment levels of HBsAg correlate with NUC long term response (Lee, Ahn, 2011; Shin, 2012)
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Less HBsAg, better outcome Spontaneous loss of HBsAg associated with greatly
reduced risk of liver cirrhosis and liver cancer
Chu, C.-M. and Liaw, Y.-F. Antiviral Therapy, 2010
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Experimental Evidence In vitro experiments show HBsAg suppresses the
function of monocytes, dendritic cells ( DCs) and natural killer (NK) cells by direct interaction
Op den Brouw et al. Immunology, ( 2009b), 1 26, 280-9; Woltman et al. PLoS One, (201 1), 6, e l 5324 & Shi et al. J Viral Hepat.
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Hepatitis B virus surface antigen (HBsAg) and hepatitis B virus (HBV) inhibit antigen presentation capacity of myeloid dendritic cells (mDC).
mDC were activated in the presence of 1 μg/ml HBsAg or HBV particles (multiplicity of infection of 100) or the appropriate controls and cultured for 6 days with allogeneic T cells. (a) Representative experiment of the effect of serum derived-HBsAg on the T-cell stimulatory capacity of mDC, measured by [3H]thymidine incorporation in proliferating T cells (ratio mDC : T cells = 1 : 15
Op den Brouw et al, 2009, Immunology, 126:2, 280-289
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Zhu, D. , et al. J. Immunol. 2016, 196:3079-3087
Breaking immune tolerance in mice by neutralizing HBsAg
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WT
Weeks following inoculation of viral DNA
Poster 91 Lu Gao/Zhipeng Yan (Roche)AndSimilar findings from:Lin, Chen & Hwang, Abstract
HBsAg negative virus fail to establish chronic infections in C3H hydrodynamically infecetd mice (cccDNA established at simialr rates)
Intr
a-he
patic
DN
ASynthetic cccDNA
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Molecular basis of HBsAg morphogenesis
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VLDL
MTP
NEDD4 gAdaptin
Cuconatti et al 2013
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Therapeutic targeting of HBsAg
Protein folding inhibitors (Blumberg)
Small Molecule inhibitors (Arbutus, Roche)
Nucleic Acid Polymers (NAPs) (Replicor)
mAb
RNAi, cccDNA inhibitors
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IminosugarProtein Folding inhibitor (Editope)
Imino sugar cyclo hexyl aklyl DNJs
NPCs/APCs
SS
S
S
S
SS
SS
S
S
S
SS
SS
S
S
S
SS
KPSDGNCTC
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Editope: Therapeutic creation of a novel T cell epitope to by-pass immune tolerance
KPSDGNCTCKPSDGDCTC
N
Proteasome
ER
Cytoplasm
MHC-I
NNN N
ERAD
PNGase
Norton, P., et al. Hepatology, 2010
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Norton, Block et al, 2010, Hepatology
Only woodchucks treated with protein folding inhibitors generated D epitope lymphocytic reactivity
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Small molecule small molecule Blumberg/Arbutus Preclinical Prevents secretion
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Small Molecule Blumberg Lipovir, appears to prevent HBsAg interaction
with LDL morphogenesis system and inhibit HBsAg
Cuconatti et al
Cuconatti et al 2014
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Small Molecule, unreported mechanism
Roche (Human Trials)
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Replicor Nucleic Acid Polymers (NAPs)Unknown mechanism, but impressive human trials
Al-Mahtab M, Bazinet M, Vaillant A (2016) Safety and Efficacy of Nucleic Acid Polymers in Monotherapy and Combined with Immunotherapy in Treatment-Naive Bangladeshi Patients with HBeAg+ Chronic Hepatitis B Infection. PLoS ONE 11(6): e0156667. doi:10.1371/journal.pone.0156667http://journals.plos.org/plosone/article?id=info:doi/10.1371/journal.pone.0156667
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Mono therapy with REP 2139-Ca
Al-Mahtab M, Bazinet M, Vaillant A (2016) Safety and Efficacy of Nucleic Acid Polymers in Monotherapy and Combined with Immunotherapy in Treatment-Naive Bangladeshi Patients with HBeAg+ Chronic Hepatitis B Infection. PLoS ONE 11(6): e0156667. doi:10.1371/
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VLDL
MTP
NEDD4 gAdaptin
Current inhibitors of HBsAg
Cuconatti et al 2014
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Direct Acting inhibitors of HBsAg
Rep 2139, Rep2165
Nucleic acid polymers (NAPs)
Phase II Replicor
RG7834 Small Molecule
Phase I/II Roche
Blum /Arb Small Molecule
preclinical Arbutus
Blum Editope Small Molecule
preclinical Blumberg
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Conclusions HBsAg is an essential viral protein, so inhibitors of HBs
will be Direct Acting Antivirals
HBsAg appears to play a role in establishing and, or sustaining, chronicity Perhaps via immuno evasion Perhaps via non immune molecular mechanism
Thus: HBs inhibitors could have direct acting and immunoenhancing antiviral affects
Endpoints: Decline or loss of HBsAg;Gain of HBsAb; can be observed with people Rx with NUC
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AcknowledgementThe Baruch S. Blumberg Institute,Hepatitis B Foundation
Jinhong Chang lab:Fang Guo
Ju-Tao Guo lab:Xuesen ZhaoFei LiuPinghu Zhang
Timothy M. Block
Andy CuconatiYanming DuMichael XuMichael Goetz
Funding(US) National Institutes of
Health (NIAID, NCI)Baruch S Blumberg InstCommonwealth of PAOncore-Arbutus, Inc.
Andy CuconatiYanming DuMichael XuMichael Goetz
Ying Su LabSurbhi JainSelena Lin(Batbold Boldbataar)
Anand Mehta Lab (now at Drexel)