COMBINATION THERAPY FOR TREATING HEPATITIS B VIRUS INFECTION

FIELD OF THE INVENTION

[0001] The present invention relates to methods for treating hepatitis B virus (HBV) infection in a subject.

BACKGROUND

[0002] HBV infects more than 300 million people worldwide and is a common cause of liver disease and liver cancer. (Liang (2009) Hepatology 49:Sl3.)

HBV is a small DNA virus with unusual features similar to retroviruses, which replicates through an RNA intermediate (pregenomic RNA) and can integrate into the host genome. The unique features of the HBV replication cycle confer a distinct ability of the virus to persist in infected cells. HBV infection leads to a wide spectrum of liver disease ranging from acute (including fulminant hepatic failure) to chronic hepatitis, cirrhosis and hepatocellular carcinoma. Acute HBV infection can be either asymptomatic or present with symptomatic acute hepatitis. 90-95% of children and 5%— 10% of adults infected with HBV are unable to clear the virus and become chronically infected. Many chronically infected persons have mild liver disease with little or no long-term morbidity or mortality. Other individuals with chronic HBV infection develop active disease, which can progress to cirrhosis and liver cancer. These patients require careful monitoring and warrant therapeutic intervention.

[0003] Novel methods for treating HBV infection by modulating HBV infection in a cell are needed. In particular, methods for effectively disrupting HBV viral load of HBV-infected cells, reducing transcription of covalently closed circular

HBV DNA in HBV-infected cells, and/or reducing the amount of pre-genomic HBV RNA in HBV-infected cells are needed.

SUMMARY OF THE INVENTION

[0004] The present invention is based on the discovery of novel methods for treating HBV infection in a subject using a combination of a tumor necrosis factor receptor superfamily (TNFRSF) agonist (e.g., an agonistic antibody directed against a member of the TNFRSF, a soluble TNFRSF agonist including but not limited to its natural ligand) or a functional fragment thereof, and an interferon (IFN) agent or a functional fragment thereof. The novel methods described herein are useful for reducing transcription of covalently closed circular DNA (cccDNA) into pre-genomic RNA (pgRNA) in an HBV-infected cell, which in turn reduces HBV protein production by the HBV-infected cell, and ultimately reduces viral load of the HBV-infected cell.

[0005] In one aspect, a combination of a tumor necrosis factor receptor superfamily (TNFRSF) agonist or a functional fragment thereof and an interferon (IFN) agent or a functional fragment thereof, for use for treating a HBV infection is provided.

[0006] In a particular embodiment, the TNFRSF agonist or a functional fragment thereof is selected from the group consisting of a lymphotoxin alpha 3 receptor agonist, a lymphotoxin beta receptor agonist, a herpesvirus entry mediator agonist, a tumor necrosis factor-like receptor weak inducer of apoptosis agonist, a cluster of differentiation factor 40 agonist, a CD27 agonist, a CD30 agonist, a 4-1 BB agonist, a receptor activator of nuclear factor KB agonist, a Troy agonist, and a 0X40 receptor agonist, or functional fragments thereof.

[0007] In a particular embodiment, the TNFRSF agonist or a functional fragment thereof is selected from the group consisting of CD40L, LTa3, LIGHT and TWEAK, or functional fragments thereof. In a particular embodiment, the TNFRSF

agonist or a functional fragment thereof is selected from the group consisting of CD40L, LIGHT and TWEAK, or functional fragments thereof.

[0008] In a particular embodiment, the TNFRSF agonist or a functional fragment thereof is a CD40 agonist or a functional fragment thereof selected from the group consisting of a CD40 ligand (CD40F) or a functional fragment thereof, an agonistic anti-CD40 antibody, a functional fragment thereof or antigen-binding fragment thereof, and a fusion protein comprising a CD40 ligand or a functional fragment thereof. In a particular embodiment, the CD40F is hexameric CD40F or trimeric CD40F.

[0009] In a particular embodiment, the TNFRSF agonist or a functional fragment thereof is a polypeptide or a functional fragment thereof, an antibody or a functional fragment thereof, or an antigen-binding fragment thereof.

[0010] In a particular embodiment, the TNFRSF agonist or a functional fragment thereof is provided as a fusion protein comprising said TNFRSF agonist or a functional fragment thereof.

[0011] In a particular embodiment, the IFN agent or a functional fragment thereof is selected from the group consisting of a Type I IFN agent, a Type II IFN agent and a Type III IFN agent, or functional fragments thereof.

[0012] In a particular embodiment, the IFN agent or a functional fragment thereof is IFNa, KNb, IFNy or IFN/., or functional fragments thereof. In a particular embodiment, the IFN agent or a functional fragment thereof is PTNb or IFNy or functional fragments thereof. In a particular embodiment, the IFN agent or a functional fragment thereof is PTNb, or a functional fragment thereof. In a particular embodiment, the IFN agent or a functional fragment thereof is IFNa, or a functional fragment thereof.

[0013] In a particular embodiment, the IFN agent or a functional fragment thereof is provided as a fusion protein comprising said IFN agent or a functional fragment thereof.

[0014] In a particular embodiment, the TNFRSF agonist or a functional fragment thereof and the IFN agent or a functional fragment thereof are provided as a bifunctional immunostimulatory fusion protein comprising the said TNFRSF agonist or a functional fragment thereof, the said IFN agent or a functional fragment thereof and a linker.

[0015] In a particular embodiment, the TNFRSF agonist or a functional fragment thereof and the IFN agent or a functional fragment thereof are comprised in a single pharmaceutical composition.

[0016] In a particular embodiment, the TNFRSF agonist or a functional fragment thereof and the IFN agent or a functional fragment thereof are comprised in distinct pharmaceutical compositions.

[0017] In another aspect, a pharmaceutical composition comprising: a TNFRSF agonist or a functional fragment thereof; and a Type II IFN agent, a functional fragment of a Type II IFN agent, a Type III IFN agent, or a functional fragment of a Type III IFN agent.

[0018] In another aspect, a method of treating an HBV infection and/or one or more HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist (e.g., an agonistic antibody directed against a member of the TNFRSF, a soluble TNFRSF agonist including but not limited to its natural ligand) or a functional fragment thereof, and an

IFN agent or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0019] In another aspect, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of:

(i) a TNFRSF agonist selected from the group consisting of a lymphotoxin alpha 3 (LTa3) receptor (TNFRSF 1 A, TNFRSF 1B, or TNFRSF 14) agonist (e.g. LTa3), a lymphotoxin beta (LTP) receptor (TNFRSF3) agonist (e.g., LIGHT or HGb), a herpesvirus entry mediator (HVEM or TNFRSF 14) agonist (e.g. LIGHT), a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF12A) agonist (e.g., TWEAK also known as TNFSF12), a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist (e.g. CD40L), a CD27 (TNFRSF7) agonist (e.g. CD70), a CD30 (TNFRSF8) agonist, a 4-1BB (CD 137, TNFRSF9) agonist, a receptor activator of nuclear factor KB (RANK, TNFRSF 1 1A) agonist, a Troy (TNFRSF 19) agonist, and a 0X40 receptor (TNFRSF4) agonist or a functional fragment thereof; and

(ii) an IFN agent or a functional fragment thereof,

to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0020] In another aspect, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of:

(i) a TNFRSF agonist selected from the group consisting of a lymphotoxin alpha 3 (LTa3) receptor (TNFRSF 1 A, TNFRSF 1B, or TNFRSF 14) agonist (e.g. LTa3), a lymphotoxin beta (LTP) receptor (TNFRSF3) agonist (e.g., LIGHT or LTP), a herpesvirus entry mediator (HVEM or TNFRSF 14) agonist (LIGHT), a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF12A) agonist (e.g., TWEAK also known as TNFSF12), a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist (CD40L), a CD27 (TNFRSF7) agonist (CD70), a CD30 (TNFRSF8) agonist, a 4-1BB (CD137, TNFRSF9) agonist, a receptor

activator of nuclear factor KB (RANK, TNFRSF1 1A) agonist, a Troy (TNFRSF19) agonist, and a 0X40 receptor (TNFRSF4) agonist or a functional fragment thereof; and

(ii) an IFN agent or a functional fragment thereof,

to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0021] In another aspect, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of:

(i) a TNFRSF agonist selected from the group consisting of a lymphotoxin alpha 3 (LTa3) receptor (TNFRSF 1 A, TNFRSF 1B, or TNFRSF 14) agonist (e.g. LTa3), a lymphotoxin beta (I/Gb) receptor (TNFRSF3) agonist (e.g., LIGHT or KGb), a herpesvirus entry mediator (HVEM or TNFRSF 14) agonist (e.g. LIGHT), a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF12A) agonist (e.g., TWEAK also known as TNFSF12), a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist (e.g. CD40L), a CD27 (TNFRSF7) agonist (e.g. CD70), a CD30 (TNFRSF8) agonist, a receptor activator of nuclear factor KB (RANK, TNFRSF 11 A) agonist, a Troy (TNFRSF 19) agonist, and a 0X40 receptor (TNFRSF4) agonist or a functional fragment thereof; and

(ii) an IFN agent or a functional fragment thereof,

to decrease one or more symptoms of HBV infection in the subject, is provided.

According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0022] According to a particular embodiment, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of:

(i) a TNFRSF agonist selected from the group consisting of a lymphotoxin alpha 3 (LTa3) receptor (TNFRSF 1 A, TNFRSF 1B, or TNFRSF 14) agonist (e.g. LTa3), a lymphotoxin beta (LTP) receptor (TNFRSF3) agonist (e.g., LIGHT or HGb), a herpesvirus entry mediator (HVEM or TNFRSF 14) agonist (LIGHT), a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF12A) agonist (e.g., TWEAK also known as TNFSF12), a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist (CD40L), a CD27 (TNFRSF7) agonist (CD70), a CD30 (TNFRSF8) agonist, a receptor activator of nuclear factor KB (RANK, TNFRSF1 1A) agonist, a Troy (TNFRSF19) agonist, and a 0X40 receptor (TNFRSF4) agonist or a functional fragment thereof; and

(ii) an IFN agent or a functional fragment thereof,

to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0023] In another aspect, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist or a functional fragment thereof; and a Type I IFN, or a functional fragment of a Type I IFN, or a Type II IFN, or a functional fragment of a Type II IFN, or a Type III IFN, or a functional fragment of a Type III IFN, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a

medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0024] In another aspect, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist or a functional fragment thereof; and a Type I IFN, or a functional fragment of a Type I IFN, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0025] In another aspect, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist or a functional fragment thereof; and a Type II IFN, or a functional fragment of a Type II IFN, or a Type III IFN, or a functional fragment of a Type III

IFN, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0026] In another aspect, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist selected from the group consisting of LTa3 receptor agonist, tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12A) agonist, I/Gb receptor (TNFRSF3) agonist, herpesvirus entry mediator (HVEM or TNFRSF14) agonist and cluster of differentiation factor 40 (CD40, TNFRSF5) agonist or a functional fragment thereof; and an IFN agent or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided.

According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0027] In a particular embodiment, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist selected from the group consisting of LTa3 receptor agonist, tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12A) agonist, I/Gb receptor (TNFRSF3) agonist, and cluster of differentiation factor 40 (CD40,

TNFRSF5) agonist or a functional fragment thereof; and an IFN agent or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0028] In a particular embodiment, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist selected from the group consisting of LTa3 receptor agonist, tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12A) agonist, herpesvirus entry mediator (HVEM or TNFRSF 14) agonist and cluster of differentiation factor 40 (CD40, TNFRSF5) agonist or a functional fragment thereof; and an IFN agent or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating an

HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided

[0029] In a particular embodiment, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist selected from the group consisting of LTa3, TWEAK, LIGHT, and

CD40L or a functional fragment thereof; and an IFN agent or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0030] In another aspect, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist selected from the group consisting of LTa3 receptor agonist, tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12A) agonist, ETb receptor (TNFRSF3) agonist and herpes virus entry mediator (HVEM or TNFRSF 14) agonist or a functional fragment thereof; and an IFN agent or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0031] In a particular embodiment, method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist selected from the group consisting of LTa3 receptor agonist, tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12A) agonist, and ETb receptor (TNFRSF3) agonist or a functional fragment thereof; and an IFN agent or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0032] In a particular embodiment, method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist selected from the group consisting of LTa3 receptor agonist, tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12A) agonist, and herpes virus entry mediator (HVEM or TNFRSF 14) agonist or a functional fragment thereof; and an IFN agent or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0033] In a particular embodiment, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a

TNFRSF agonist selected from the group consisting of a LTa3 receptor agonist, I/Gb receptor (TNFRSF3) agonist, a herpes virus entry mediator (HVEM or TNFRSF 14) agonist and a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12A) agonist, or a functional fragment thereof; and an IFN agent or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV

infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0034] In a particular embodiment, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist selected from the group consisting of a LTa3 receptor agonist, I/Gb receptor (TNFRSF3) agonist, and a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12A) agonist, or a functional fragment thereof; and an IFN agent or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0035] In a particular embodiment, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist selected from the group consisting of a LTa3 receptor agonist, a herpes virus entry mediator (HVEM or TNFRSF 14) agonist and a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12A) agonist, or a functional fragment thereof; and an IFN agent or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0036] In a particular embodiment, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist selected from the group consisting of LTa3, TWEAK, and LIGHT or

a functional fragment thereof; and an IFN agent or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0037] In another aspect, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist selected from the group consisting of I/Gb receptor (TNFRSF3) agonist, a herpes virus entry mediator (HVEM or TNFRSF 14) agonist, a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12A) agonist and a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist or a functional fragment thereof; and an IFN agent or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0038] In a particular embodiment, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist selected from the group consisting of I/Gb receptor (TNFRSF3) agonist, a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12 A) agonist and a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist or a functional fragment thereof; and an IFN agent or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the

subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0039] In a particular embodiment, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a

TNFRSF agonist selected from the group consisting of a herpes virus entry mediator (HVEM or TNFRSF 14) agonist, a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12A) agonist and a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist or a functional fragment thereof; and an IFN agent or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0040] In a particular embodiment, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist selected from the group consisting of CD40L, TWEAK, and LIGHT or a functional fragment thereof; and an IFN agent or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided.

According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0041] In another aspect, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist or a functional fragment thereof, and an IFN agent or a functional fragment thereof, to decrease one or more

symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0042] In a particular embodiment, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of CD40L or a functional fragment thereof, and an IFN agent or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0043] In another aspect, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF12A) agonist, and in particular TWEAK, or a functional fragment thereof, and an IFN agent or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0044] In another aspect, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a LT receptor (TNFRSF3) agonist or herpesvirus entry mediator (HVEM or TNFRSF14) agonist, and in particular LIGHT, or a functional fragment thereof, and an IFN agent or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating an

HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0045] In a particular embodiment, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a I/Gb receptor (TNFRSF3) agonist and in particular LIGHT, or a functional fragment thereof, and an IFN agent or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0046] In a particular embodiment, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a herpesvirus entry mediator (HVEM or TNFRSF14) agonist, and in particular LIGHT, or a functional fragment thereof, and an IFN agent or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0047] In another aspect, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNa, PTNb, IFNy and IFN/. or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0048] In another aspect, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a

TNFRSF agonist or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNa and PTNb or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0049] In another aspect, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a

TNFRSF agonist or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNy and IFN/. or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0050] In another aspect, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist selected from the group consisting of LTa3 receptor agonist, a I/Gb receptor (TNFRSF3) agonist, a herpes virus entry mediator (HVEM or TNFRSF 14) agonist, a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12A) agonist and a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist, or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNa, PTNίb, IFNy and IFNk or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0051] In a particular embodiment, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist selected from the group consisting of LTa3 receptor agonist, a I/Gb receptor (TNFRSF3) agonist, a tumor necrosis factor like receptor weak inducer of apoptosis (TNFRSF12A) agonist and a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist, or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNa, PTNίb, IFNy and IFNk or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0052] In a particular embodiment, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to

the subject a combination of a TNFRSF agonist selected from the group consisting of LT ct3 receptor agonist, a herpes virus entry mediator (HVEM or TNFRSF 14) agonist, a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12 A) agonist and a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist, or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNa, PTNίb, IFNy and IFNk or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0053] According to a particular embodiment, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist selected from the group consisting of LTa3, TWEAK, LIGHT, and CD40L or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNa, PTNb, IFNy and IFNk or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0054] In another aspect, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist selected from the group consisting of a LTa3 receptor agonist, a ETb receptor (TNFRSF3) agonist, a herpes virus entry mediator (HVEM or TNFRSF 14) agonist and a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF12A) agonist or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNa and PTNίb or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0055] In a particular embodiment, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist selected from the group consisting of a LTa3 receptor agonist, a I/Gb receptor (TNFRSF3) agonist, and a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12A) agonist or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNa and TNb or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0056] In a particular embodiment, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist selected from the group consisting of a LTa3 receptor agonist, a herpes virus entry mediator (HVEM or TNFRSF 14) agonist and a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12A) agonist or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNa and TNb or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0057] In a particular embodiment, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist selected from the group consisting of LTa3, TWEAK, and LIGHT or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNa and KNb or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0058] In another aspect, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist selected from the group consisting of a ETb receptor (TNFRSF3) agonist, a herpes virus entry mediator (HVEM or TNFRSF 14) agonist, a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12 A) agonist and a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNa and KNb or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0059] In a particular embodiment, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist selected from the group consisting of a

I/Gb receptor (TNFRSF3) agonist, a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12A) agonist and a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNa and PTNίb or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0060] In a particular embodiment, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist selected from the group consisting of a herpes virus entry mediator (HVEM or TNFRSF 14) agonist, a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF12A) agonist and a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNa and PTNίb or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0061] In a particular embodiment, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist selected from the group consisting of TWEAK, LIGHT and CD40L or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNa and KNb or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0062] In another aspect, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist selected from the group consisting of a LTa3 receptor agonist, a ETb receptor (TNFRSF3) agonist, a herpes virus entry mediator

(HVEM or TNFRSF 14) agonist and a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12A) agonist or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNy and IFNk or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0063] In a particular embodiment, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist selected from the group consisting of a LTa3 receptor agonist, a ETb receptor (TNFRSF3) agonist, and a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12A) agonist or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNy and IFNk or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0064] In a particular embodiment, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist selected from the group consisting of a LTa3 receptor agonist, a herpes virus entry mediator (HVEM or TNFRSF 14) agonist and a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12A) agonist or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNy and IFNk or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0065] According to a particular embodiment, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist selected from the group consisting of LTa3, TWEAK, and LIGHT or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNy and IFNk or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV

infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0066] In another aspect, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist selected from the group consisting of a I/Gb receptor (TNFRSF3) agonist, a herpes virus entry mediator (HVEM or TNFRSF 14) agonist, a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12 A) agonist and a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist or a functional fragment thereof; and an IFN agent selected from the group consisting of

IFNy and IFNk or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0067] In a particular embodiment, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist selected from the group consisting of a

I/Gb receptor (TNFRSF3) agonist, a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12 A) agonist and a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNy and IFNk or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a

medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0068] In a particular embodiment, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist selected from the group consisting of a herpes virus entry mediator (HVEM or TNFRSF 14) agonist, a tumor necrosis factor like receptor weak inducer of apoptosis (TNFRSF12A) agonist and a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNy and IFNk or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0069] In a particular embodiment, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist selected from the group consisting of TWEAK, LIGHT and CD40L or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNy and IFNk or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0070] In another aspect, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNa and IFN or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0071] According to a particular embodiment, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of CD40L or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNa and PTNίb or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0072] In another aspect, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF12A) agonist, and in particular TWEAK, or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNa and PTNίb or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0073] In another aspect, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a ίTb receptor (TNFRSF3) agonist, a herpesvirus entry mediator (HVEM or TNFRSF14) agonist, and in particular LIGHT, or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNa and PTNίb or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0074] In a particular embodiment, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a HGb receptor (TNFRSF3) agonist, and in particular LIGHT, or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNa and PTNίb or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0075] In a particular embodiment, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a herpesvirus entry mediator (HVEM or TNFRSF14) agonist, and in particular LIGHT, or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNa and PTNίb or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0076] In another aspect, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist or a functional fragment thereof; and an IFNk agent selected from the group consisting of IL-28 and IL-29 or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0077] In a particular embodiment, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject CD40L or a functional fragment thereof; and an IFNk agent selected from the group consisting of IL-28 and IL-29 or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0078] In another aspect, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF12A) agonist, and in particular TWEAK, or a functional fragment thereof; and an IRNl agent

selected from the group consisting of IL-28 and IL-29 or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0079] In another aspect, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a I/Gb receptor (TNFRSF3) agonist, a herpesvirus entry mediator (HVEM or

TNFRSF14) agonist, and in particular LIGHT, or a functional fragment thereof; and an IFN/. agent selected from the group consisting of IL-28 and IL-29 or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0080] In a particular embodiment, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a HGb receptor (TNFRSF3) agonist, and in particular LIGHT, or a functional fragment thereof; and an IFN/. agent selected from the group consisting of IL-28 and IL-29 or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0081] In a particular embodiment, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a herpesvirus entry mediator (HVEM or TNFRSF14) agonist, and in particular FIGHT, or a functional fragment thereof; and an IFN/. agent selected from the group consisting of IF-28 and IF-29 or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0082] In another aspect, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist or a functional fragment thereof; and IFNy or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0083] According to a particular embodiment, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of CD40F or a functional fragment thereof; and IFNy or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0084] In another aspect, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF12A) agonist, and in particular TWEAK, or a functional fragment thereof; and IFNy or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0085] In another aspect, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a ETb receptor (TNFRSF3) agonist, a herpesvirus entry mediator (HVEM or TNFRSF14) agonist, and in particular LIGHT, or a functional fragment thereof; and IFNy or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0086] In a particular embodiment, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a ETb receptor (TNFRSF3) agonist, and in particular LIGHT, or a functional fragment thereof; and IFNy or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided.

According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0087] In a particular embodiment, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a herpesvirus entry mediator (HVEM or TNFRSF14) agonist, and in particular FIGHT, or a functional fragment thereof; and IFNy or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0088] In another aspect, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a FTa3 receptor agonist or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNa and PTNίb or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0089] In a particular embodiment, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of FTa3 or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNa and PTNίb or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0090] In another aspect, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a LTa3 receptor agonist or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNy and IFN/. or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0091] In a particular embodiment, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of LTa3 or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNy and IFN/. or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0092] In another aspect, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a tumor necrosis factor-like receptor weak inducer of apoptosis

(TNFRSF12A) agonist or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNa and PTNίb or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0093] In a particular embodiment, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of TWEAK or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNa and PTNίb or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0094] In another aspect, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF12A) agonist or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNy and IFNk or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0095] In a particular embodiment, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of TWEAK or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNy and PTNίl or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0096] In another aspect, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a ETb receptor (TNFRSF3) agonist or a herpes virus entry mediator (HVEM or TNFRSF14) agonist or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNa and KNb or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0097] In a particular embodiment, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a ETb receptor (TNFRSF3) agonist or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNa and

KNb or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said

aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0098] In a particular embodiment, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a herpes virus entry mediator (HVEM or TNFRSF14) agonist or a functional fragment thereof; and an IFN agent selected from the group consisting of IFN a and PTNb or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[0099] In a particular embodiment, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of FIGHT or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNa and PTNb or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said embodiment, the said combination for use in the treatment of an

HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00100] In another aspect, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a ETb receptor (TNFRSF3) agonist or a herpes virus entry mediator (HVEM or TNFRSF14) agonist or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNy and IFN/. or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00101] In a particular embodiment, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a I/Gb receptor (TNFRSF3) agonist or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNy and

IFN/. or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating an

HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00102] In a particular embodiment, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of a herpes virus entry mediator (HVEM or TNFRSF14) agonist or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNy and IFN/. or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00103] In a particular embodiment, a method of treating HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a combination of LIGHT or a functional fragment thereof; and an IFN agent selected from the group consisting of IFNy and IFN/. or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided.

According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00104] In another aspect, method of treating an HBV infection and HBV-related symptoms in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a TNFRSF agonist or a functional fragment thereof, and administering to the subject a pharmaceutical composition comprising an IFN agent or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00105] In another aspect, a TNFRSF agonist or a functional fragment thereof for use in treating one or more symptoms of HBV infection in a subject, in combination with an IFN agent or a functional fragment thereof, is provided. According to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00106] In another aspect, an IFN agent or a functional fragment thereof for use in treating one or more symptoms of HBV infection in a subject, in

combination with a TNFRSF agonist or a functional fragment thereof, is provided. According to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00107] In another aspect, a combination of (i) at least one TNFRSF agonist or a functional fragment thereof; and (ii) at least one IFN agent or a functional fragment thereof, for use in the treatment of HBV infection, is provided. According to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00108] In another aspect, a combination of (i) at least one TNFRSF agonist selected from the group consisting of a LTa3 receptor agonist, a I/Gb (TNFRSF3) agonist, a herpes virus entry mediator (HVEM or TNFRSF 14) agonist, a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF12A) agonist and a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist or a functional fragment thereof; and (ii) an IFN agent selected from the group consisting of a Type I IFN, a Type II IFN, and a Type III IFN or a functional fragment thereof, for use in the treatment of HBV infection, is provided. According to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00109] In another aspect, a combination of (i) at least one TNFRSF agonist selected from the group consisting of a LTa3 receptor agonist, a I/Gb (TNFRSF3) agonist, a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF12A) agonist and a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist or a functional fragment thereof; and (ii) an IFN agent selected from the group consisting of a Type I IFN, a Type II IFN, and a Type III IFN or a functional fragment thereof, for use in the treatment of HBV infection, is provided. According to the said aspect, the use of the said combination for preparing a medicament for treating an

HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00110] In another aspect, a combination of (i) at least one TNFRSF agonist selected from the group consisting of a LTa3 receptor agonist, a herpes virus entry mediator (HVEM or TNFRSF 14) agonist, a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12 A) agonist and a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist or a functional fragment thereof; and (ii) an IFN agent selected from the group consisting of a Type I IFN, a Type II IFN, and a Type III IFN or a functional fragment thereof, for use in the treatment of HBV infection, is provided. According to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00111] In another aspect, a combination of (i) at least one TNFRSF agonist selected from the group consisting of LTa3, TWEAK, LIGHT, and CD40L or a functional fragment thereof; and (ii) an IFN agent selected from the group consisting of a Type I IFN, a Type II IFN, and a Type III IFN or a functional fragment thereof, for use in the treatment of HBV infection, is provided. According to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00112] In another aspect, a combination of (i) at least one TNFRSF agonist selected from the group consisting of a LTa3 receptor agonist, a ETb receptor (TNFRSF3) agonist, a herpes virus entry mediator (HVEM or TNFRSF 14) agonist, a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF12A) agonist and a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist or a functional fragment thereof; and (ii) an IFN agent selected from the group consisting of IFNa, PTNίb, IFNy, and IFNk or a functional fragment thereof, for use in the treatment of HBV infection, is provided. According to the said aspect, the use of the said

combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00113] In a particular embodiment, a combination of (i) at least one TNFRSF agonist selected from the group consisting of a LTa3 receptor agonist, a receptor I/Gb (TNFRSF3) agonist, a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12A) agonist and a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist or a functional fragment thereof; and (ii) an IFN agent selected from the group consisting of IFNa, PTNίb, IFNy, and IFNk or a functional fragment thereof, for use in the treatment of HBV infection, is provided. According to the said aspect, the use of the said combination for preparing a medicament for treating an

HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00114] In a particular embodiment, a combination of (i) at least one TNFRSF agonist selected from the group consisting of a LTa3 receptor agonist, a herpes virus entry mediator (HVEM or TNFRSF 14) agonist, a tumor necrosis factor like receptor weak inducer of apoptosis (TNFRSF12A) agonist and a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist or a functional fragment thereof; and (ii) an IFN agent selected from the group consisting of IFNa, PTNb, IFNy, and IFNk or a functional fragment thereof, for use in the treatment of HBV infection, is provided. According to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00115] In a particular embodiment, a combination of (i) at least one TNFRSF agonist selected from the group consisting of LTa3, TWEAK, LIGHT, and CD40L or a functional fragment thereof; and (ii) an IFN agent selected from the group consisting of IFNa, KNb, IFNy, and IFNk or a functional fragment thereof, for use in the treatment of HBV infection, is provided. According to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00116] In another aspect, a combination of (i) at least one TNFRSF agonist selected from the group consisting of a I/Gb receptor (TNFRSF3) agonist, a herpes virus entry mediator (HVEM or TNFRSF 14) agonist, a tumor necrosis factor like receptor weak inducer of apoptosis (TNFRSF12A) agonist and a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist or a functional fragment thereof; and (ii) an IFN agent selected from the group consisting of IFNa, PTNίb, IFNy, and IFNk or a functional fragment thereof, for use in the treatment of HBV infection, is provided. According to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00117] In a particular embodiment, a combination of (i) at least one TNFRSF agonist selected from the group consisting of a ίTb receptor (TNFRSF3) agonist, a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12 A) agonist and a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist or a functional fragment thereof; and (ii) an IFN agent selected from the group consisting of IFNa, PTNίb, IFNy, and IFNk or a functional fragment thereof, for use in the treatment of HBV infection, is provided. According to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00118] In a particular embodiment, a combination of (i) at least one TNFRSF agonist selected from the group consisting of a herpes virus entry mediator (HVEM or TNFRSF 14) agonist, a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12A) agonist and a cluster of differentiation factor 40 (CD40,

TNFRSF5) agonist or a functional fragment thereof; and (ii) an IFN agent selected from the group consisting of IFNa, PTNίb, IFNy, and IFNk or a functional fragment thereof, for use in the treatment of HBV infection, is provided. According to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00119] In a particular embodiment, a combination of (i) at least one TNFRSF agonist selected from the group consisting of TWEAK, LIGHT, and CD40L or a functional fragment thereof; and (ii) an IFN agent selected from the group consisting of IFNa, KNb, IFNy, and IFN/. or a functional fragment thereof, for use in the treatment of HBV infection, is provided. According to the said embodiment, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00120] In another aspect, a combination of (i) at least one TNFRSF agonist selected from the group consisting of a LTa3 receptor agonist, a receptor ETb (TNFRSF3) agonist, a herpes virus entry mediator (HVEM or TNFRSF 14) agonist and a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12A) agonist or a functional fragment thereof; and (ii) an IFN agent selected from the group consisting of IFNa and KNb or a functional fragment thereof, for use in the treatment of HBV infection, is provided. According to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00121] In a particular embodiment, a combination of (i) at least one

TNFRSF agonist selected from the group consisting of a LTa3 receptor agonist, a receptor ETb (TNFRSF3) agonist, and a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF12A) agonist or a functional fragment thereof; and (ii) an IFN agent selected from the group consisting of IFNa and KNb or a functional fragment thereof, for use in the treatment of HBV infection, is provided. According to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00122] In a particular embodiment, a combination of (i) at least one TNFRSF agonist selected from the group consisting of a LTa3 receptor agonist, a herpes virus entry mediator (HVEM or TNFRSF 14) agonist and a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12A) agonist or a functional fragment thereof; and (ii) an IFN agent selected from the group consisting of IFNa and

PTNίb or a functional fragment thereof, for use in the treatment of HBV infection, is provided. According to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided

[00123] In a particular embodiment, a combination of (i) at least one

TNFRSF agonist selected from the group consisting of LTa3, TWEAK, and LIGHT or a functional fragment thereof; and (ii) an IFN agent selected from the group consisting of IFNa and KNb or a functional fragment thereof, for use in the treatment of HBV infection, is provided. According to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00124] In another aspect, a combination of (i) at least one TNFRSF agonist selected from the group consisting of a ETb receptor (TNFRSF3) agonist, a herpes virus entry mediator (HVEM or TNFRSF 14) agonist, a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF12A) agonist and a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist or a functional fragment thereof; and (ii) an IFN agent selected from the group consisting of IFNa and KNb or a functional fragment thereof, for use in the treatment of HBV infection, is provided. According to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00125] In a particular embodiment, a combination of (i) at least one TNFRSF agonist selected from the group consisting of a ETb receptor (TNFRSF3) agonist, a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12 A) agonist and a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist or a functional fragment thereof; and (ii) an IFN agent selected from the group consisting of IFNa and IRNb or a functional fragment thereof, for use in the treatment of HBV infection, is provided. According to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00126] In a particular embodiment, a combination of (i) at least one TNFRSF agonist selected from the group consisting of a herpes virus entry mediator (HVEM or TNFRSF 14) agonist, a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12 A) agonist and a cluster of differentiation factor 40 (CD40,

TNFRSF5) agonist or a functional fragment thereof; and (ii) an IFN agent selected from the group consisting of IFNa and PTNίb or a functional fragment thereof, for use in the treatment of HBV infection, is provided. According to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00127] In a particular embodiment, a combination of (i) at least one TNFRSF agonist selected from the group consisting of TWEAK, LIGHT and CD40L or a functional fragment thereof; and (ii) an IFN agent selected from the group consisting of IFNa and KNb or a functional fragment thereof, for use in the treatment of HBV infection, is provided. According to the said embodiment, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00128] In another aspect, a combination of (i) at least one TNFRSF agonist selected from the group consisting of LTa3 receptor agonist, a ETb receptor (TNFRSF3) agonist, a herpes virus entry mediator (HVEM or TNFRSF 14) agonist and a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12A) agonist or a functional fragment thereof; and (ii) an IFN agent selected from the group consisting of IFNy and IFNk or a functional fragment thereof, for use in the treatment of HBV infection, is provided. According to the said aspect, the use of the said

combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00129] In a particular embodiment, a combination of (i) at least one TNFRSF agonist selected from the group consisting of LTa3 receptor agonist, a I/Gb receptor (TNFRSF3) agonist, and a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12 A) agonist or a functional fragment thereof; and (ii) an IFN agent selected from the group consisting of IFNy and IFNk or a functional fragment thereof, for use in the treatment of HBV infection, is provided. According to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00130] In a particular embodiment, a combination of (i) at least one TNFRSF agonist selected from the group consisting of LTa3 receptor agonist, a herpes virus entry mediator (HVEM or TNFRSF 14) agonist and a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12A) agonist or a functional fragment thereof; and (ii) an IFN agent selected from the group consisting of IFNy and IFNk or a functional fragment thereof, for use in the treatment of HBV infection, is provided. According to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00131] In a particular embodiment, a combination of (i) at least one TNFRSF agonist selected from the group consisting of LTa3, TWEAK, and LIGHT or a functional fragment thereof; and (ii) an IFN agent selected from the group consisting of IFNy and IRNl or a functional fragment thereof, for use in the treatment of HBV infection, is provided. According to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00132] In another aspect, a combination of (i) at least one TNFRSF agonist selected from the group consisting of a I.Tb receptor (TNFRSF3) agonist, a herpes virus entry mediator (HVEM or TNFRSF 14) agonist, a tumor necrosis factor like receptor weak inducer of apoptosis (TNFRSF12A) agonist and a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist or a functional fragment thereof; and (ii) an IFN agent selected from the group consisting of IFNy and IFNk or a functional fragment thereof, for use in the treatment of HBV infection, is provided. According to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00133] In a particular embodiment, combination of (i) at least one TNFRSF agonist selected from the group consisting of a ETb receptor (TNFRSF3) agonist, a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12 A) agonist and a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist or a functional fragment thereof; and (ii) an IFN agent selected from the group consisting of

IFNy and IFNk or a functional fragment thereof, for use in the treatment of HBV infection, is provided. According to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00134] In a particular embodiment, combination of (i) at least one

TNFRSF agonist selected from the group consisting of a herpes virus entry mediator (HVEM or TNFRSF 14) agonist, a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12A) agonist and a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist or a functional fragment thereof; and (ii) an IFN agent selected from the group consisting of IFNy and IFNk or a functional fragment thereof, for use in the treatment of HBV infection, is provided. According to the said aspect, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00135] In a particular embodiment, a combination of (i) at least one TNFRSF agonist selected from the group consisting of TWEAK, LIGHT and CD40L or a functional fragment thereof; and (ii) an IFN agent selected from the group consisting of IFNy and IFN/. or a functional fragment thereof, for use in the treatment of HBV infection, is provided. According to the said embodiment, the use of the said combination for preparing a medicament for treating an HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00136] In another aspect, a combination of (i) at least one TNFRSF agonist or a functional fragment thereof, and (ii) at least an IFN agent or a functional fragment thereof, for use in the treatment of HBV infection by reducing the amount of pre-genomic HBV RNA in an HBV-infected cell, is provided. According to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00137] In another aspect, a method of treating a HBV infection in a subject in need thereof, comprising administering to the subject a combination of a TNFRSF agonist and an IFN agent or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided.

[00138] In an embodiment of any one of the aspects of the invention or in combination with any other embodiment of the invention, transcription of covalently closed circular (ccc) DNA to generate pregenomic (pg) RNA is inhibited in infected cells of the subject.

[00139] In an embodiment of any one of the aspects of the invention or in combination with any other embodiment of the invention, the combination of the TNFRSF agonist and the IFN agent or functional fragment thereof synergistically inhibits transcription ofpgRNA in infected cells of the subject.

[00140] In an embodiment of any one of the aspects of the invention or in combination with any other embodiment of the invention, hepatitis B e-antigen (HBeAg) release from HBV-infected cells in the subject is inhibited.

[00141] In an embodiment of any one of the aspects of the invention or in combination with any other embodiment of the invention, the combination of the TNFRSF agonist and the IFN agent or functional fragment thereof synergistically inhibits HBeAg release from infected cells.

[00142] In an embodiment of any one of the aspects of the invention or in combination with any other embodiment of the invention, the combination of the TNFRSF agonist and the IFN agent or functional fragment thereof stimulates the IFN pathway in the subject.

[00143] In an embodiment of any one of the aspects of the invention, an IFN pathway biomarker level is increased in the subject, wherein said biomarker is selected from the group consisting of C-X-C motif chemokine 9 (CXCL9), C-X-C motif chemokine 10 (CXCL10) and C-X-C motif chemokine 1 1 (CXCL1 1).

[00144] In a particular embodiment, the combination of the TNFRSF agonist and the IFN agent or functional fragment thereof synergistically increases the IFN pathway biomarker level in the subject.

[00145] In an embodiment of any one of the aspects of the invention, the biomarker is C-X-C motif chemokine 10 (CXCL10).

[00146] In a particular embodiment, the combination of the TNFRSF agonist and the IFN agent or functional fragment thereof synergistically increases the CXCL10 biomarker level in the subject.

[00147] In an embodiment of any one of the aspects of the invention, the combination of the TNFRSF agonist and the IFN agent or functional fragment thereof synergistically stimulates CXCL10 release in the subject.

[00148] In an embodiment of any one of the aspects of the invention, the infected cells are hepatocytes.

[00149] In an embodiment of any one of the aspects of the invention, the TNFRSF agonist is selected from the group consisting of a LTa3 receptor (TNFRSF 1 A, TNFRSF 1B, or TNFRSF 14) agonist (e.g. LTa3), a ITGb receptor (TNFRSF3) agonist (e.g., LIGHT or LTB), a herpesvirus entry mediator (HVEM or TNFRSF14) agonist (e.g. LIGHT), a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF12A) agonist (e.g., TWEAK also known as TNFSF12), a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist (e.g. CD40L), a CD27 (TNFRSF7) agonist (e.g. CD70), a CD30 (TNFRSF8) agonist, a 4-1BB (CD 137, TNFRSF9) agonist, a receptor activator of nuclear factor KB (RANK, TNFRSF11A) agonist, a Troy (TNFRSF19) agonist, and a 0X40 receptor (TNFRSF4) agonist.

[00150] In an embodiment of any one of the aspects of the invention, the TNFRSF agonist is selected from the group consisting of a lymphotoxin alpha 3 (LTa3) receptor (TNFRSF1A, TNFRSF1B, or TNFRSF14) agonist, a lymphotoxin beta KGb receptor (TNFRSF3) agonist (e.g., LIGHT or LTB), a herpesvirus entry mediator (HVEM or TNFRSF 14) agonist (LIGHT), a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF 12A) agonist (e.g., TWEAK also known as TNFSF12), a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist (CD40L), a CD27 (TNFRSF7) agonist, a CD30 (TNFRSF8) agonist, a 4-1BB (CD137, TNFRSF9) agonist, a receptor activator of nuclear factor KB (RANK, TNFRSF11A) agonist, a Troy (TNFRSF 19) agonist, and a 0X40 receptor (TNFRSF4) agonist.

[00151] In an embodiment of any one of the aspects of the invention, the TNFRSF agonist is selected from the group consisting of a lymphotoxin alpha 3 (LTa3) receptor (TNFRSF 1 A, TNFRSF 1B, or TNFRSF 14) agonist (e.g. LTa3), a lymphotoxin beta ETb receptor (TNFRSF3) agonist (e.g., LIGHT or LTB), a herpesvirus entry mediator (HVEM or TNFRSF14) agonist (e.g. LIGHT), a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF12A) agonist (e.g., TWEAK also known as TNFSF12), a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist (e.g. CD40L), a CD27 (TNFRSF7) agonist (e.g. CD70), a CD30 (TNFRSF8) agonist, a receptor activator of nuclear factor KB (RANK, TNFRSF 1 1 A) agonist, a Troy (TNFRSF 19) agonist, and a 0X40 receptor (TNFRSF4) agonist.

[00152] In an embodiment of any one of the aspects of the invention, the TNFRSF agonist is selected from the group consisting of a lymphotoxin alpha 3 (LTa3) receptor (TNFRSF1A, TNFRSF1B, or TNFRSF14) agonist, a lymphotoxin beta KGb receptor (TNFRSF3) agonist (e.g., LIGHT or LTB), a herpesvirus entry mediator (HVEM or TNFRSF 14) agonist (LIGHT), a tumor necrosis factor-like

receptor weak inducer of apoptosis (TNFRSF12A) agonist (e.g., TWEAK also known as TNFSF12), a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist (CD40L), a CD27 (TNFRSF7) agonist, a CD30 (TNFRSF8) agonist, a receptor activator of nuclear factor KB (RANK, TNFRSF1 1A) agonist, a Troy (TNFRSF19) agonist, and a 0X40 receptor (TNFRSF4) agonist.

[00153] The TNFRSF agonist or functional fragment thereof according to the invention may be provided as a fusion protein comprising said TNFRSF agonist or a functional fragment thereof.

[00154] In an embodiment of any one of the aspects of the invention, the TNFRSF agonist is a CD40 agonist selected from the group consisting of a CD40 ligand (CD40L), or a functional fragment thereof, an agonistic anti-CD40 antibody or antigen-binding fragment thereof, and a fusion protein comprising a CD40 ligand, or a functional fragment thereof.

[00155] In an embodiment of any one of the aspects of the invention, the TNFRSF agonist comprises or consists of TWEAK, or a functional fragment thereof.

In particular, the TNFRSF agonist is a fusion protein comprising TWEAK or a functional fragment thereof.

[00156] In an embodiment of any one of the aspects of the invention, the TNFRSF agonist comprises or consists of LIGHT, or a functional fragment thereof. In particular, the TNFRSF agonist is a fusion protein comprising LIGHT or a functional fragment thereof.

[00157] In an embodiment of any one of the aspects of the invention, the TNFRSF agonist comprises or consists of CD40L, or a functional fragment thereof. In particular, the TNFRSF agonist is a fusion protein comprising CD40L or a functional fragment thereof.

[00158] In an embodiment of any one of the aspects of the invention, the CD40L is hexameric CD40L or trimeric CD40L.

[00159] In an embodiment of any one of the aspects of the invention, the fusion protein is a bifunctional immunostimulatory fusion protein comprising a

TNFRSF agonist or a functional fragment thereof, an IFN agent or a functional fragment thereof and a linker.

[00160] According to a particular embodiment, the TNFRSF agonist or a functional fragment thereof and the IFN agent or a functional fragment thereof are provided as a bifunctional immunostimulatory fusion protein comprising the said

TNFRSF agonist or a functional fragment thereof, an IFN agent or a functional fragment thereof and a linker.

[00161] In an embodiment of any one of the aspects of the invention, the IFN agent or functional fragment thereof is selected from the group consisting of a Type I IFN, a Type II IFN and a Type III IFN.

[00162] In an embodiment of any one of the aspects of the invention, the IFN agent or functional fragment thereof is IFNa, IFNp, I FNy or IFNk.

[00163] In an embodiment of any one of the aspects of the invention, the IFN agent or functional fragment thereof is IFNP or I FNy.

[00164] According to a particular embodiment, the IFN agent or functional fragment thereof is provided as a fusion protein comprising said IFN agent or functional fragment thereof.

[00165] In an embodiment of any one of the aspects of the invention, the IFN agent or functional fragment thereof is IFNp. In particular, IFNP is provided as a fusion protein comprising IFNp or a functional fragment thereof.

[00166] In an embodiment of any one of the aspects of the invention, the IFN agent or functional fragment thereof is IFNa. In particular, IFNa is provided as a fusion protein comprising IFNa or a functional fragment thereof.

[00167] In an embodiment of any one of the aspects of the invention, the IFN agent or functional fragment thereof is IFNk. In particular, IFNk is provided as a fusion protein comprising IFNk or a functional fragment thereof.

[00168] In an embodiment of any one of the aspects of the invention, the IFN agent or functional fragment thereof is IFNy. In particular, IFNy is provided as a fusion protein comprising IFNy or a functional fragment thereof.

[00169] In an embodiment of any one of the aspects of the invention, the IFN agent is provided as a fusion protein.

[00170] In an embodiment of any one of the aspects of the invention, the fusion protein is a bifunctional immunostimulatory fusion protein.

[00171] In an embodiment of any one of the aspects of the invention, the bifunctional immunostimulatory fusion protein further comprises a TNFRSF agonist or functional fragment thereof.

[00172] In an embodiment of any one of the aspects of the invention, the TNFRSF agonist or functional fragment thereof is selected from the group consisting of CD40L, LTa3, LIGHT and/or TWEAK.

[00173] In an embodiment of any one of the aspects of the invention, the TNFRSF agonist or functional fragment thereof is selected from the group consisting of CD40L, LIGHT and/or TWEAK.

[00174] In an embodiment of any one of the aspects of the invention, the TNFRSF agonist is a polypeptide, an antibody, or an antigen-binding fragment thereof.

[00175] In an embodiment of any one of the aspects of the invention, the TNFRSF polypeptide, antibody or antigen-binding fragment thereof is provided directly to the subject.

[00176] In an embodiment of any one of the aspects of the invention, the TNFRSF polypeptide, antibody or antigen-binding fragment thereof is provided as a bifunctional immunostimulatory fusion protein.

[00177] In an embodiment of any one of the aspects of the invention, the TNFRSF polypeptide, antibody or antigen-binding fragment thereof is expressed from a polynucleotide provided to the subject.

[00178] In an embodiment of any one of the aspects of the invention, the

IFN agent or functional fragment thereof is provided directly to the subject.

[00179] In an embodiment of any one of the aspects of the invention, the IFN agent or functional fragment thereof is provided as a bifunctional immunostimulatory fusion protein.

[00180] In an embodiment of any one of the aspects of the invention, the IFN agent or functional fragment thereof is expressed from a polynucleotide provided to the subject.

[00181] In another aspect, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject with a combination of: (i) a lymphotoxin alpha 3 (LTa3) receptor (TNFRSF1A, TNFRSF1B, or TNFRSF14) agonist, a lymphotoxin beta (LTp ) receptor (TNFRSF3) agonist (e.g., LIGHT or HGb), a herpesvirus entry mediator (HVEM or TNFRSF14) agonist (LIGHT), a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF12A) agonist (e.g., TWEAK, also known as TNFSF12), a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist (CD40L), a CD27 (TNFRSF7) agonist (CD70), a CD30 (TNFRSF8) agonist, a 4-1BB (CD137, TNFRSF9) agonist, a receptor activator of nuclear factor KB (RANK, TNFRSF1 1A) agonist, a Troy (TNFRSF19) agonist, and a 0X40 receptor (TNFRSF4) agonist; and (ii) an IFN agent or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided.

[00182] In another aspect, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of: a TNFRSF agonist; and a Type I IFN, or a functional fragment of a Type I IFN to decrease one or more symptoms of HBV infection in the subject, is provided.

[00183] In another aspect, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of: a TNFRSF agonist; and a Type II IFN, a functional fragment of a Type II IFN, a Type III IFN, or a functional fragment of a Type III IFN, to decrease one or more symptoms of HBV infection in the subject, is provided.

[00184] In another aspect, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of: LTa3, LIGHT and/or TWEAK; and an IFN agent or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided.

[00185] In another aspect, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of: CD40L; and an IFN agent or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided.

[00186] In another aspect, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of: a TNFRSF agonist; and IFNa or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided.

[00187] In another aspect, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of:

LTa3, LIGHT and/or TWEAK; and IFNa or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided.

[00188] In another aspect, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of: CD40L; and IFNa or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided.

[00189] In another aspect, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of: a TNFRSF agonist; and KNb or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided.

[00190] In another aspect, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of: LTa3, LIGHT and/or TWEAK; and KNb or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided.

[00191] In another aspect, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of: CD40L; and KNb or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided.

[00192] In another aspect, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of: a TNFRSF agonist; and IFNy or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided.

[00193] In another aspect, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of: LTa3, LIGHT and/or TWEAK; and IFNy or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided.

[00194] In another aspect, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of:

CD40L; and IFNy or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided.

[00195] In another aspect, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of: a TNFRSF agonist; and IFNA or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided.

[00196] In another aspect, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of: LTa3, LIGHT and/or TWEAK; and IFNA or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided.

[00197] In another aspect, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of: CD40L; and IFNA or a functional fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided.

[00198] In another aspect of the invention, a method of treating an HBV infection in a subject in need thereof, comprising: administering to the subject a pharmaceutical composition comprising a TNFRSF agonist; and administering to the subject a pharmaceutical composition comprising an IFN agent or a functional

fragment thereof, to decrease one or more symptoms of HBV infection in the subject, is provided.

[00199] In an embodiment of any one of the aspects of the invention, the pharmaceutical compositions are administered sequentially.

[00200] In an embodiment of any one of the aspects of the invention, the pharmaceutical compositions are administered concomitantly.

[00201] In an embodiment of any one of the aspects of the invention, the TNFRSF agonist and IFN agent or functional fragment thereof are administered in a single pharmaceutical composition.

[00202] In an embodiment of any one of the aspects of the invention, the TNFRSF agonist and IFN agent or functional fragment thereof are comprised in distinct pharmaceutical compositions.

[00203] In another aspect of the invention, a TNFRSF agonist for use in treating one or more symptoms of HBV infection in a subject, in combination with an IFN agent or a functional fragment thereof, is provided.

[00204] In another aspect of the invention, an IFN agent or a functional fragment thereof for use in treating one or more symptoms of HBV infection in a subject, in combination with a TNFRSF agonist, is provided.

[00205] In another aspect of the invention, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist and IFNa or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00206] In a particular embodiment, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of CD40L and IFNa or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00207] In another aspect of the invention, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist and IFNp or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00208] In a particular embodiment, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of CD40L and IFNp or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00209] In another aspect of the invention, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist and INFy or a functional fragment thereof to decrease one or more symptoms of HBV

infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00210] In a particular embodiment, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist and IL28 or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00211] In a particular embodiment, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of CD40L and IL28 or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00212] In a particular embodiment, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a cluster of differentiation factor 40 (CD40, TNFRSF5) agonist and IL29 or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV

infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00213] In a particular embodiment, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of CD40L and IL29 or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00214] In another aspect of the invention, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a LTa3 receptor agonist and IFNa or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00215] In a particular embodiment, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of LTa3 and IFNa or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00216] In another aspect of the invention, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF12A) agonist and IFNa or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00217] In a particular embodiment, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of TWEAK and IFNa or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00218] In another aspect of the invention, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a ETb receptor (TNFRSF3) agonist or a herpesvirus entry mediator (HVEM or TNFRSF14) agonist and IFNa or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00219] In a particular embodiment, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a HGb receptor (TNFRSF3) agonist and IFNa or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00220] In particular embodiment, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a herpesvirus entry mediator (HVEM or TNFRSF14) agonist and IFNa or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00221] In a particular embodiment, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of LIGHT and IFNa or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00222] In another aspect of the invention, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a LTa3 receptor agonist and Iϊ b or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00223] In a particular embodiment, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of LTa3 and KNb or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00224] In another aspect of the invention, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF12A) agonist and IFNP or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00225] In a particular embodiment, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of TWEAK and IFNP or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00226] In another aspect of the invention, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a I/Gb receptor (TNFRSF3) agonist or a herpes virus entry mediator (HVEM or TNFRSF14) agonist and PTNίb or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00227] In a particular embodiment, method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a I/Gb receptor (TNFRSF3) agonist and PTNίb or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00228] In a particular embodiment, method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a herpes virus entry mediator (HVEM or TNFRSF14) agonist and PTNίb or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00229] In a particular embodiment, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of LIGHT and IFNp or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00230] In another aspect of the invention, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a LTa3 receptor agonist and IFNy or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00231] In a particular embodiment, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of LTa3 and IFNy or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00232] In another aspect of the invention, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a tumor necrosis factor-like receptor weak inducer of apoptosis (TNFRSF12A) agonist and IFNy or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00233] In a particular embodiment, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of TWEAK and IFNy or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00234] In another aspect of the invention, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a ETb receptor (TNFRSF3) agonist or a herpes virus entry mediator (HVEM or TNFRSF14) agonist and IFNy or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00235] In a particular embodiment, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a ίTb receptor (TNFRSF3) agonist and IFNy or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00236] In a particular embodiment, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of a herpes virus entry mediator (HVEM or TNFRSF14) agonist and IFNy or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided

[00237] In a particular embodiment, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of LIGHT and IFNy or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, provided. According to the said embodiment, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said embodiment, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00238] In another aspect of the invention, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of Ig-TWEAK and IFNP or a functional fragment thereof to decrease one

or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00239] In another aspect of the invention, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of Ig-CD40L and PTNίb or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00240] In another aspect of the invention, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of Ig-LTa3 and IFNp or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00241] In another aspect of the invention, a method of treating HBV infection in a subject in need thereof, comprising administering to the subject a combination of Ig-LIGHT and IFNp or a functional fragment thereof to decrease one or more symptoms of HBV infection in the subject, is provided. According to the said aspect, the said combination for use in the treatment of an HBV infection, and/or decreasing one or more symptoms of HBV infection in the subject, is provided. Still according to the said aspect, the use of the said combination for preparing a medicament for treating a HBV infection, and/or for decreasing one or more symptoms of HBV infection in the subject, is provided.

[00242] In another aspect of the invention, a pharmaceutical composition comprising: a TNFRSF agonist; and a Type II IFN, a functional fragment of a Type II IFN, a Type III IFN, or a functional fragment of a Type III IFN, is provided.

[00243] In another aspect of the invention, a pharmaceutical composition comprising: a TNFRSF agonist; and a Type I IFN, or a functional fragment of a Type I IFN, is provided.

[00244] In another aspect of the invention, a pharmaceutical composition comprising: LTa3, LIGHT and/or TWEAK; and an IFN agent or a functional fragment thereof, is provided.

[00245] In another aspect of the invention, a pharmaceutical composition comprising: a TNFRSF agonist; and IFNa or a functional fragment thereof, is provided.

[00246] In another aspect of the invention, a pharmaceutical composition comprising: LTa3, LIGHT and/or TWEAK; and IFNa or a functional fragment thereof, is provided.

[00247] In another aspect of the invention, a pharmaceutical composition comprising: a CD40L; and IFNa or a functional fragment thereof, is provided.

[00248] In another aspect of the invention, a pharmaceutical composition comprising: a TNFRSF agonist; and KNb or a functional fragment thereof, is provided.

[00249] In another aspect of the invention, a pharmaceutical composition comprising: LTa3, LIGHT and/or TWEAK; and KNb or a functional fragment thereof, is provided.

[00250] In another aspect of the invention, a pharmaceutical composition comprising: a CD40L; and KNb or a functional fragment thereof, is provided.

[00251] In another aspect of the invention, a pharmaceutical composition comprising: a TNFRSF agonist; and IFNy or a functional fragment thereof, is provided.

[00252] In another aspect of the invention, a pharmaceutical composition comprising: LTa3, LIGHT and/or TWEAK; and IFNy or a functional fragment thereof, is provided.

[00253] In another aspect of the invention, a pharmaceutical composition comprising: a CD40L; and IFNy or a functional fragment thereof, is provided.

[00254] In another aspect of the invention, a pharmaceutical composition comprising: a TNFRSF agonist; and IFNA or a functional fragment thereof, is provided.

[00255] In another aspect of the invention, a pharmaceutical composition comprising: LTa3, LIGHT and/or TWEAK; and IFNA or a functional fragment thereof, is provided.

[00256] In another aspect of the invention, a pharmaceutical composition comprising: a CD40L; and IFNA or a functional fragment thereof, is provided.

BRIEF DESCRIPTION OF THE DRAWINGS

[00257] The foregoing and other features and advantages of the present invention will be more fully understood from the following detailed description of illustrative embodiments taken in conjunction with the accompanying drawings.

[00258] Fig. 1A - Fig. IB graphically depict the synergistic reduction of hepatitis B e-antigen (HBeAg) release using a combination of interferon beta ( I FN b ) and cluster of differentiation 40 ligand (CD40L) or a combination of interferon alpha (IFNa) and cluster of differentiation 40 ligand (CD40L) in hepatitis B virus (HBV)-infected primary human hepatocytes. Primary human hepatocytes were assayed at 8 days post-infection, and were treated with IFNa, IFNP and/or CD40L at day 2 and day 6. IFNa, 1000 U; IFNp, 100 U; CD40L, 150 ng/mL. Fig. 1A schematically depicts

the timeline of the experiment. Fig. IB graphically shows levels of Hbe Ag with different agents.

[00259] Fig. 2A - Fig. 2B show the effect of IPNίb and CD40L on the transcription of the closed circular DNA (cccDNA) into pregenomic RNA (pgRNA) in HBV-infected primary hepatocytes. Fig. 2 A schematically depicts the outline of the assay. Fig. 2B graphically shows that short-term stimulation was sufficient to greatly reduce pgRNA transcription.

Fig. 3A - Fig. 3B show the effects of IF P and CD40L on signaling pathways.

[00260] Fig. 3A graphically depicts CXCL10 release in the IFN pathway, demonstrating that a combination of IPNίb and CD40L synergistically enhance the IFN pathway. Fig. 3B graphically depicts IL8 release in the inflammatory pathway, demonstrating that IPNίb and CD40L do not synergistically enhance the inflammatory pathway.

[00261] Fig. 4 A - Fig. 4B show the effects of different IFN types on CXCL10 release. Fig. 4A graphically depicts the effects of different TNF family members in combination with different IFN types. Fig. 4B graphically depicts the synergistic effect of costimulation of hepatocytes with CD40L and Type III interferons (IL28 and IL29).

[00262] Fig. 5 graphically depicts synergistic effects mediated by various CD40 agonists in combination with IPNίb on CXCL10 release. Specifically,

Fig. 5 shows the effects of hexameric CD40L (hCD40L), trimeric CD40L (tCD40L) and anti-CD40 agonistic antibody (a-CD40) on CXCL10 release.

[00263] Fig. 6A - Fig. 6B graphically depict the potency of the synergistic effects of CD40L in combination with PTNίb. Fig. 6A shows the effects of CD40L in combination with IFNp on CXCL10 release; Hash marked boxes represent saturated points. Fig. 6B shows the effect of CD40L in combination with IFNp on IL8 release.

[00264] Fig. 7A - Fig. 7F graphically depict synergistic effects of CD40L in combination with IPNίb, as measured by transcriptomic analysis at select time points. It is expressed in Fragments Per Kilobase Of Exon Per Million Fragments Mapped (FPKM). Fig. 7A shows the effects of CD40L in combination with IPNίb on CXCL10 mRNA expression. Fig. 7B shows the effects of CD40L in combination with

PTNίb on CXCL8/IL8 mRNA expression. Fig. 7C shows the effects of CD40L in combination with PTNίb on CXCL9 mRNA expression. Fig. 7D shows the effects of CD40L in combination with IFNP on mRNA CXCL1 1 expression. Fig. 7E shows the effects of CD40L in combination with IPNίb on CXCL3 mRNA expression. Fig. 7F shows the effects of CD40L in combination with IFNP on CCL20 mRNA expression.

[00265] Fig. 8 graphically depicts synergistic effects of CD40L in combination with IFNp on CXCL10 release from primary human hepatocytes. CXCL10 release was assayed at day 3 and day 7 after stimulation of primary human hepatocytes (PHHs) infected or not by HBV.

[00266] Fig. 9A - Fig. 9B graphically depict synergistic effects of Ig- Tweak (Fig. 9 A) and Ig -LIGHT (Fig. 9B) in combination with PTNίb on CXCL10 release in hepatocytes (HepaRG cells). Fig. 9C - Fig. 9D graphically depict the functional effect of Ig-Tweak (Fig. 9C) and Ig-LIGHT (Fig. 9D) on NFkB pathway in A549 cells. Fig. 9E - Fig. 9F graphically depict the boost of IFNb-induced antiviral effect by Ig-Tweak (Fig. 9E) and Ig-LIGHT (Fig. 9F) in combination with IFNb

(Interferon beta) on primary hepatocytes infected by HBV. NS: Non stimulated; NT: Non treated.

[00267] Fig. 10A - Fig. 10B graphically depict the effect of three Duokine molecules on activating the CD40L-mediated NFKB pathway (Fig. 10A) and the Type I IFN-mediated JAK/STAT pathway reporter assay (Fig. 10B). The

Duokines include an IFNP-IgGl Fc-CD40L fusion (IFNb-Ig-CD40L), an IPNίb-CD40L fusion with a simple linker (IFNb-CD40L), and an PTNίb -Leucine Zipper (LZ)-CD40L fusion (IFNb-LZ-CD40L).

[00268] Fig. 11A - Fig. 11B graphically depict the effect of the Duokine molecules on CXCL10 release from hepatocytes (hepaRG cells). Fig. 11A shows the effects of three different Duokine molecules alone on CXCL10 release. Fig. 11B shows the effect of a Duokine in combination with an anti-CD40L antagonistic antibody.

[00269] Fig. 12 graphically depicts the effect of Duokine molecules on CXCL10 release from hepatocytes (HepaRG cells). The Duokine is IFNP-IgGl Fc-Tweak fusion (IFNb-Ig-Tweak). Vvide: empty vector.

[00270] Fig. 13 graphically depicts the effect of Duokine molecules on CXCL10 release from hepatocytes. The Duokines include IFNP-IgGl Fc-Light fusion

(IFNb-Ig -Light), and an IFNP -Leucine Zipper (LZ)-Light fusion (IFNb-LZ-Light). Vvide: empty vector.

[00271] Fig. 14A - Fig. 14B graphically depict persistence of viremia and viral antigens at various time points up to 49 days post-injection of an adeno-associated virus (AAV)/HBV in mice. Fig. 14A shows serum HBV DNA levels. Fig.

14B shows serum HBV antigen levels.

[00272] Fig. 15 depicts cccDNA formation in an AAV/HBV model.

[00273] Fig. 16 graphically depicts the synergistic effects of mCD40L in combination with mIFNp on CXCL10 release in vivo murine model.“MIX-mCD40L”: mIFNb and mCD40L combination.

[00274] Fig. 17A graphically depicts the activity of recombinant murine mlFNb-Fc-mlgGl on the interferon pathway using IFN-reporter raw-dual cells. Fig. 17B graphically depicts the activity of recombinant murine Fc-mIgGl-mCD40L on CD40-induced NFkB pathway in HEK-CD40 reporter cells. Fig. 17C graphically depicts the ELISA dosage of mlFNb-Fc-mlgGl in the serum of mice administrated with 0,84irg of the recombinant protein. Fig. 17D graphically depicts the dosage of Fc-mIgGl-mCD40L in the serum sampled at different times after administration of mice with 30irg of the recombinant protein. [00275] Fig. 18 depicts antiviral activities of a murine fusion protein comprising interferon beta (mlFNb-Fc-mlgGl) and a murine fusion protein comprising CD40L (Fc-mIgGl-mCD40L) alone or in combination in the AAV/HBV-transduced mouse model. Shown are study design and study groups (Fig· 18A) and viral parameters at each sampling time. Peripheral blood viral protein

HBe-Ag (Fig. 18B), viremia: peripheral blood HBV DNA level (Fig. 18C) and liver HBV DNA level (Fig. 18D) are expressed as individual values with mean +/- sem. Liver HBV pgR A (Fig. 18E) is expressed as fold change individual data with Geometric mean.

[00276] Fig. 19A - Fig. 19C graphically depict the functional activity of the fusion protein IFNa-huIgGl-huCD40L on HEK-Blue-CD40 cells (Fig. 19A), HEK-Blue-IFNa/b cells (Fig. 19B) and on HBV infection (Hbe release) of primary hepatocytes (Fig. 19C). IF a: Interferon alpha.

DETAILED DESCRIPTION

[00277] The present invention is based in part on the discovery of a combination therapy that synergistically inhibits transcription of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) into pregenomic RNA (pgRNA) in HBV-infected cells, synergistically inhibits release of hepatitis B e-antigen (HBeAg) from HBV-infected cells, and synergistically enhances the IFN pathway in uninfected and HBV infected hepatocytes, in particular in uninfected and HBV infected primary human hepatocytes. Combination therapies comprising administering a TNFRSF agonist (e.g., an agonistic antibody directed against a member of the TNFRSF, a soluble TNFRSF agonist including but not limited to its natural ligand) or a functional fragment thereof and an interferon (IFN) agent or a functional fragment thereof to an

HBV-infected cell, or subject infected with HBV, are provided.

[00278] The disclosure may be more readily understood in the light of the selected terms defined below.

[00279] As used herein, a“TNFRSF agonist” refers to a compound (e.g., a protein, a fusion protein, a polypeptide, an antibody, an antigen-binding fragment of an antibody or the like) that activates a TNFRSF. For example, a TNFRSF agonist may be an agonistic antibody directed against a member of the TNFRSF, a soluble TNFRSF agonist including but not limited to its natural ligand or a functional fragment of thereof.

[00280] As used herein, the term“antibody” refers to immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, as well as multimers thereof (e.g., IgM). Each heavy chain comprises a heavy chain variable region (abbreviated VH or VH) and a heavy chain constant region (CH or CH). The heavy chain constant region comprises three domains, CH1 , CH2 and CH3. Each light chain comprises a light chain variable region (abbreviated VL) and a light chain constant region (CL or CL). The light chain constant region comprises one domain (CL1). The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1 , CDR1 , FR2, CDR2, FR3, CDR3, FR4.

[00281] As used herein, the term “ligand” refers to any substance capable of binding, or of being bound, to another substance. A ligand may be a peptide, a polypeptide, a protein, an aptamer, a polysaccharide, a sugar molecule, a carbohydrate, a lipid, an oligonucleotide, a polynucleotide, a synthetic molecule, an inorganic molecule, an organic molecule, and any combination thereof.

[00282] As used herein, the term “functional fragment” refers to a fragment of a substance that retains one or more functional activities of the original substance. For example, a functional fragment of a TNFRSF agonist refers to a fragment of a TNFRSF agonist that retains a function of the TNFRSF agonist as described herein, e.g., it activates a target TNFRSF. A functional fragment of an interferon refers to a fragment of an interferon that retains an IFN function as described herein, e.g., it mediates IFN pathway signaling.

[00283] As used herein, “hepatitis B virus” or“HBV” refers to the double stranded DNA virus that causes hepatitis B, which belongs to a family of closely related DNA viruses called the Hepadnaviruses. Hepadnaviruses have a strong preference for infecting liver cells, but small amounts of hepadnaviral DNA can be found in kidney, pancreas, and mononuclear cells. However, infection at these sites is not linked to extra hepatic disease.

[00284] The HBV virion, i.e., the Dane particle, consists of an outer lipid envelope and an icosahedral nucleocapsid core composed of protein. The nucleocapsid encloses the viral DNA and a DNA polymerase that has reverse transcriptase activity similar to retroviruses. The outer envelope contains embedded proteins which are involved in viral binding of, and entry into, susceptible cells. The virus is one of the smallest enveloped animal viruses with a virion diameter of 42 nm, but pleomorphic forms exist, including filamentous and spherical bodies lacking a core. These particles are not infectious and are composed of the lipid and protein that forms part of the surface of the virion, which is called the surface antigen (HBsAg), and is produced in excess during the life cycle of the virus. HBV comprises HBsAg, HBcAg (and its splice variant HBeAg), DNA polymerase and Hbx. HBV is one of a few known non-retroviral viruses which employ reverse transcription as a part of its replication process.

[00285] The HBV nucleocapsid contains a relatively small and partially duplex 3.2 kb circular DNA, viral polymerase and core protein. The genome has only four long open reading frames. The pre-S-S (pre-surface-surface) region of the genome encodes the three viral surface antigens by differential initiation of translation at each of three in-frame initiation codons.

[00286] The most abundant protein of HBV is the 24 kD S protein (which is known as HBsAg). The pre-C-C (pre-core-core) region encodes HBcAg (HBV core Antigen) and HBeAg (HBV e Antigen). HBeAg is not required for viral

replication and plays no role in viral assembly. The P-coding region is specific for the viral polymerase, a multifunctional enzyme involved in DNA synthesis and RNA encapsidation. The X open reading frame encodes the viral X protein (HBx), which modulates host-cell signal transduction and can directly and indirectly affect host and viral gene expression.

CLAIMS

1. A combination of a tumor necrosis factor receptor superfamily (TNFRSF) agonist or a functional fragment thereof and an interferon (IFN) agent or a functional fragment thereof, for use for treating a HBV infection.

2. The combination for its use according to claim 1 , wherein the TNFRSF agonist or a functional fragment thereof is selected from the group consisting of a lymphotoxin alpha 3 receptor agonist, a lymphotoxin beta receptor agonist, a herpesvirus entry mediator agonist, a tumor necrosis factor-like receptor weak inducer of apoptosis agonist, a cluster of differentiation factor 40 agonist, a CD27 agonist, a CD30 agonist, a 4-1BB agonist, a receptor activator of nuclear factor KB agonist, a Troy agonist, and a 0X40 receptor agonist, or functional fragments thereof.

3. The combination for its use according to claim 1 or 2, wherein the TNFRSF agonist or a functional fragment thereof is selected from the group consisting of CD40L, LTa3, LIGHT and TWEAK, or functional fragments thereof.

4. The combination for its use according to any one of claims 1 to 3, wherein the TNFRSF agonist or a functional fragment thereof is selected from the group consisting of

CD40L, LIGHT and TWEAK, or functional fragments thereof.

5. The combination for its use according to any one of claims 1 to 4, wherein the TNFRSF agonist or a functional fragment thereof is a CD40 agonist or a functional fragment thereof selected from the group consisting of a CD40 ligand (CD40L) or a functional fragment thereof, an agonistic anti-CD40 antibody, a functional fragment thereof or antigen-binding fragment thereof, and a fusion protein comprising a CD40 ligand or a functional fragment thereof.

6. The combination for its use according to claim 5, wherein the CD40L is hexameric CD40L or trimeric CD40L.

7. The combination for its use according to any one of claims 1 to 6, wherein the TNFRSF agonist or a functional fragment thereof is a polypeptide or a functional fragment thereof, an antibody or a functional fragment thereof, or an antigen-binding fragment thereof.

8. The combination for its use according to any one of claims 1 to 7, wherein the TNFRSF agonist or a functional fragment thereof is provided as a fusion protein comprising said TNFRSF agonist or a functional fragment thereof.

9. The combination for its use according to any one of claims 1 to 8, wherein the IFN agent or a functional fragment thereof is selected from the group consisting of a Type I IFN agent, a Type II IFN agent and a Type III IFN agent, or functional fragments thereof.

10. The combination for its use according to any one of claims 1 to 9, wherein the IFN agent or a functional fragment thereof is IFNa, PTNίb, IFNy or IFN/., or functional fragments thereof.

1 1.The combination for its use according to any one of claims 1 to 10, wherein the

IFN agent or a functional fragment thereof is PTNίb or IFNy, or functional fragments thereof.

12. The combination for its use according to any one of claims 1 to 1 1 , wherein the IFN agent or a functional fragment thereof is PTNίb, or a functional fragment thereof.

13. The combination for its use according to any one of claims 1 to 10, wherein the IFN agent or a functional fragment thereof is IFNa, or a functional fragment thereof.

14. The combination for its use according to any one of claims 1 to 13, wherein the IFN agent or a functional fragment thereof is provided as a fusion protein comprising said IFN agent or a functional fragment thereof.

15. The combination for its use according to any one of claims 1 to 14, wherein the

TNFRSF agonist or a functional fragment thereof and the IFN agent or a functional fragment thereof are provided as a bifunctional immunostimulatory fusion protein comprising the said TNFRSF agonist or a functional fragment thereof, the said IFN agent or a functional fragment thereof and a linker.

16. The combination for its use according to any one of claims 1 to 15, wherein the TNFRSF agonist or a functional fragment thereof and the IFN agent or a functional fragment thereof are comprised in a single pharmaceutical composition.

17. The combination for its use according to any one of claims 1 to 14, wherein the

TNFRSF agonist or a functional fragment thereof and the IFN agent or a functional fragment thereof are comprised in distinct pharmaceutical compositions.

18.A pharmaceutical composition comprising:

a TNFRSF agonist or a functional fragment thereof; and

a Type II IFN agent, a functional fragment of a Type II IFN agent, a Type III IFN agent, or a functional fragment of a Type III IFN agent.