Interferon-associated antigen binding proteins and uses thereof

Abstract

The present invention relates to novel interferon-associated antigen binding proteins as well as nucleic acids, vectors and vector systems encoding such interferon-associated antigen binding proteins. The present invention also relates to compositions comprising such interferon-associated antigen binding proteins, nucleic acids, vectors and vector systems. The novel interferon-associated antigen binding proteins afford beneficial improvements over the current state of the art, for example in that they effectively disrupt viral replication and thereby reduce HBV viral load. Thus, the present invention also provides medical uses of such interferon-associated antigen binding proteins, nucleic acids, vectors, vector systems and compositions, e.g., in the treatment of hepatitis B virus (HBV) infection and/or for decreasing one or more symptoms of HBV infection in a subject. The present invention further provides host cells comprising such nucleic acids, vectors and vector systems as well as methods of making the interferon- associated antigen binding proteins according to the invention using said host cells.

1 - 18 . (canceled) 
     
     
         19 . A composition comprising an interferon-associated antigen binding protein comprising:
 (I) an agonistic anti-CD40 antibody or an agonistic antigen binding fragment thereof, and   (II) an Interferon (IFN) or a functional fragment thereof, wherein the IFN or functional fragment thereof does not include Interferon-α2a (INF-α2a) or a functional fragment thereof,
 wherein the agonistic anti-CD40 antibody, or the agonistic antigen binding fragment thereof, comprises a heavy chain and a light chain, 
 wherein the heavy chain comprises a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 56; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 57; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 58; and 
 wherein the light chain comprises a complementarity determining region 1 (CDRL1) comprising the amino acid sequence of SEQ ID NO: 52; a complementarity determining region 2 (CDRL2) comprising the amino acid sequence of SEQ ID NO: 53; and a complementarity determining region 3 (CDRL3) comprising the amino acid sequence of SEQ ID NO: 54. 
   
     
     
         20 . The composition of  claim 19 , wherein the heavy chain comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 55 and the light chain comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 51. 
     
     
         21 . The composition of  claim 19 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 6 and the light chain comprises the amino acid sequence of SEQ ID NO: 3. 
     
     
         22 . The composition of  claim 19 , wherein the agonistic anti-CD40 antibody, or the agonistic antigen binding fragment thereof, comprises a Fab region heavy chain comprising the amino acid sequence of SEQ ID NO: 12. 
     
     
         23 . The composition of  claim 19 , wherein the IFN or the functional fragment thereof is fused to the light chain of the agonistic anti-CD40 antibody or the agonistic antigen binding fragment thereof. 
     
     
         24 . The composition of  claim 19 , wherein the IFN or the functional fragment thereof is fused to a C-terminus of the light chain of the agonistic anti-CD40 antibody or the agonistic antigen binding fragment thereof. 
     
     
         25 . The composition of  claim 19 , wherein the IFN or the functional fragment thereof is fused to the heavy chain of the agonistic anti-CD40 antibody or the agonistic antigen binding fragment thereof. 
     
     
         26 . The composition of  claim 19 , wherein the IFN or the functional fragment thereof is fused to a C-terminus of the heavy chain of the agonistic anti-CD40 antibody or the agonistic antigen binding fragment thereof. 
     
     
         27 . The composition of  claim 19 , wherein the agonistic anti-CD40 antibody or the agonistic antigen binding fragment thereof is fused to the IFN or the functional fragment thereof via a linker. 
     
     
         28 . The composition of  claim 27 , wherein the linker comprises the amino acid sequence of SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 24, SEQ ID NO: 25 or SEQ ID NO: 26. 
     
     
         29 . The composition of  claim 27 , wherein the linker comprises the amino acid sequence of SEQ ID NO: 24, SEQ ID NO: 25 or SEQ ID NO: 26. 
     
     
         30 . The composition of  claim 19 , wherein the IFN or the functional fragment thereof is selected from the group consisting of a Type I IFN, a Type II IFN and a Type III IFN, or a functional fragment thereof. 
     
     
         31 . The composition of  claim 30 , wherein the Type I IFN or the functional fragment thereof is IFNβ or a functional fragment thereof. 
     
     
         32 . The composition of  claim 31 , wherein the IFNβ comprises the amino acid sequence of SEQ ID NO: 14 or an amino acid sequence having at least 90% identity to SEQ ID NO: 14. 
     
     
         33 . The composition of  claim 30 , wherein the Type III IFN or the functional fragment thereof is IFNλ or a functional fragment thereof. 
     
     
         34 . The composition of  claim 33 , wherein the IFNλ or the functional fragment thereof is IFNλ2 or a functional fragment thereof. 
     
     
         35 . The composition of  claim 34 , wherein the IFNλ2 comprises the amino acid sequence of SEQ ID NO: 18 or an amino acid sequence having at least 90% identity to SEQ ID NO: 18. 
     
     
         36 . The composition of  claim 19 , wherein the composition is a pharmaceutical composition. 
     
     
         37 . A method for treating hepatitis B virus (HBV) infection and/or reducing one or more symptoms of HBV infection in a subject comprising:
 administering an effective amount of the pharmaceutical composition of  claim 36 .   
     
     
         38 . The method of  claim 37 , wherein the one or more symptoms of HBV infection are associated with chronic inflammation of the liver, hepatocellular carcinoma, development of membranous glomerulonephritis, risk of death, acute necrotizing vasculitis, papular acrodermatitis of childhood, HBV-associated nephropathy, and/or immune-mediated hematological disorders. 
     
     
         39 . The method of  claim 37 , wherein the one or more symptoms of HBV infection are associated with acute viral hepatitis. 
     
     
         40 . The method of  claim 39 , wherein the one or more symptoms of HBV infection associated with acute viral hepatitis comprise a loss of appetite, nausea, vomiting, body aches, dark urine, jaundice, fulminant hepatic failure, low-grade fever, stomach pain, and/or bloated stomach. 
     
     
         41 . The method of  claim 37 , wherein the subject is a human. 
     
     
         42 . The method of  claim 37 , wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 55 and the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 51. 
     
     
         43 . The method of  claim 37 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 6 and the light chain comprises the amino acid of SEQ ID NO: 3. 
     
     
         44 . The method of  claim 37 , wherein the agonistic anti-CD40 antibody, or the agonistic antigen binding fragment thereof, comprises a Fab region heavy chain comprising the amino acid sequence of SEQ ID NO: 12. 
     
     
         45 . The method of  claim 37 , wherein the agonistic anti-CD40 antibody or the agonistic antigen binding fragment thereof is fused to the IFN or the functional fragment thereof via a linker. 
     
     
         46 . The method of  claim 45 , wherein the linker comprises the amino acid sequence of SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 24, SEQ ID NO: 25, or SEQ ID NO: 26. 
     
     
         47 . The method of  claim 37 , wherein the IFN or the functional fragment thereof is selected from the group consisting of a Type I IFN, a Type II IFN, and a Type III IFN, or a functional fragment thereof. 
     
     
         48 . The method of  claim 47 , wherein the Type I IFN or the functional fragment thereof is IFNβ or a functional fragment thereof. 
     
     
         49 . The method of  claim 48 , wherein the IFNβ comprises the amino acid sequence of SEQ ID NO: 14 or an amino acid sequence having at least 90% identity to SEQ ID NO: 14. 
     
     
         50 . The method of  claim 47 , wherein the Type III IFN or the functional fragment thereof is IFNλ or a functional fragment thereof. 
     
     
         51 . The method of  claim 50 , wherein the IFNλ or the functional fragment thereof is IFNλ2 or a functional fragment thereof. 
     
     
         52 . The method of  claim 51 , wherein the IFNλ2 comprises the amino acid sequence of SEQ ID NO: 18 or an amino acid sequence having at least 90% identity to SEQ ID NO: 18. 
     
     
         53 . A nucleic acid encoding an interferon-associated antigen binding protein, wherein the interferon-associated antigen binding protein comprises:
 (I) an agonistic anti-CD40 antibody or an agonistic antigen binding fragment thereof, and   (II) an Interferon (IFN) or a functional fragment thereof, wherein the IFN or functional fragment thereof does not include Interferon-α2a (IFN-α2a) or a functional fragment thereof,
 wherein the agonistic anti-CD40 antibody, or the agonistic antigen binding fragment thereof, comprises a heavy chain and a light chain, 
 wherein the heavy chain comprises a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 56; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 57; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 58; and 
 wherein the light chain comprises a complementarity determining region 1 (CDRL1) comprising the amino acid sequence of SEQ ID NO: 52; a complementarity determining region 2 (CDRL2) comprising the amino acid sequence of SEQ ID NO: 53; and a complementarity determining region 3 (CDRL3) comprising the amino acid sequence of SEQ ID NO: 54. 
   
     
     
         54 . A vector comprising the nucleic acid according to  claim 53 . 
     
     
         55 . A vector system comprising:
 (I) a first vector comprising a nucleic acid encoding an Interferon (IFN), or a functional fragment thereof, fused to a light chain of an agonistic anti-CD40 antibody, or an agonistic antigen binding fragment thereof, wherein the IFN or functional fragment thereof does not include Interferon-α2a (IFN-a2a) or a functional fragment thereof, and wherein the light chain of the agonistic anti-CD40 antibody or agonistic antigen-binding fragment thereof comprises a complementarity determining region 1 (CDRL1) comprising the amino acid sequence of SEQ ID NO: 52; a complementarity determining region 2 (CDRL2) comprising the amino acid sequence of SEQ ID NO: 53; and a complementarity determining region 3 (CDRL3) comprising the amino acid sequence of SEQ ID NO: 54 and
 a second vector comprising a nucleic acid encoding a heavy chain of an agonistic anti-CD40 antibody, or agonistic antigen binding fragment thereof, wherein the heavy chain of the agonistic anti-CD40 antibody or agonistic antigen-binding fragment thereof comprises a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 56; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 57; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 58; or 
   (II) a first vector comprising a nucleic acid encoding an IFN, or a functional fragment thereof, fused to a heavy chain of an agonistic anti-CD40 antibody, or an agonistic antigen binding fragment thereof, wherein the IFN or functional fragment thereof does not include Interferon-α2a (IFNα2a) or a functional fragment thereof, and wherein the heavy chain of the agonistic anti-CD40 antibody or agonistic antigen-binding fragment thereof comprises a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 56; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 57; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 58 and
 a second vector comprising a nucleic acid encoding a light chain of an agonistic anti-CD40 antibody, or agonistic antigen binding fragment thereof, wherein the light chain of the agonistic anti-CD40 antibody or agonistic antigen-binding fragment thereof comprises a complementarity determining region 1 (CDRL1) comprising the amino acid sequence of SEQ ID NO: 52; a complementarity determining region 2 (CDRL2) comprising the amino acid sequence of SEQ ID NO: 53; and a complementarity determining region 3 (CDRL3) comprising the amino acid sequence of SEQ ID NO: 54. 
   
     
     
         56 . An isolated host cell comprising the nucleic acid according to  claim 53 . 
     
     
         57 . An isolated host cell comprising the vector according to  claim 54 . 
     
     
         58 . An isolated host cell comprising the vector system according to  claim 55 .