Human Interferon Molecules and Their Uses

Abstract

Modified human interferon polypeptides and uses thereof are provided.

1 . A hIFN polypeptide comprising one or more non-naturally encoded amino acids having at least one modulated biological activity. 
     
     
         2 . The hIFN polypeptide of  claim 1 , wherein the hIFN polypeptide comprises one or more post-translational modifications. 
     
     
         3 . The hIFN polypeptide of  claim 1 , wherein the polypeptide is linked to a linker, polymer, or biologically active molecule. 
     
     
         4 . The hIFN polypeptide of  claim 3 , wherein the polypeptide is linked to a water soluble polymer. 
     
     
         5 . The hIFN polypeptide of  claim 1 , wherein the polypeptide is linked to a bifunctional polymer, bifunctional linker, or at least one additional hIFN polypeptide. 
     
     
         6 . The hIFN polypeptide of  claim 5 , wherein the bifunctional linker or polymer is linked to a second polypeptide. 
     
     
         7 . The hIFN polypeptide of  claim 6 , wherein the second polypeptide is a hIFN polypeptide. 
     
     
         8 . The hIFN polypeptide of  claim 4 , wherein the water soluble polymer comprises a poly(ethylene glycol) moiety. 
     
     
         9 . The hIFN polypeptide of  claim 4 , wherein said water soluble polymer is linked to a non-naturally encoded amino acid present in said hIFN polypeptide. 
     
     
         10 . The hIFN polypeptide of  claim 1 , wherein the non-naturally encoded amino acid is substituted at a position selected from the group consisting of residues 1-9, 10-21, 22-39, 40-75, 76-77, 78-100, 101-110, 111-132, 133-136, 137-155, 156-165 from SEQ ID NO: 2. 
     
     
         11 . The hIFN polypeptide of  claim 1 , wherein the non-naturally encoded amino acid is substituted at a position selected from the group consisting of residues before position 1 (i.e., at the N-terminus), 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, or 166 (i.e. at the carboxyl terminus), and any combination thereof from SEQ ID NO: 2. 
     
     
         12 . The hIFN polypeptide of  claim 11 , wherein the non-naturally encoded amino acid is substituted at a position selected from the group consisting of residues 100, 106, 107, 108, 111, 113, 114, and any combination thereof from SEQ ID NO: 2. 
     
     
         13 . The hIFN polypeptide of  claim 11 , wherein the non-naturally encoded amino acid is substituted at a position selected from the group consisting of residues 41, 45, 46, 48, 49, and any combination thereof from SEQ ID NO: 2. 
     
     
         14 . The hIFN polypeptide of  claim 11 , wherein the non-naturally encoded amino acid is substituted at a position selected from the group consisting of residues 61, 64, 65, 101, 103, 110, 117, 120, 121, 149, and any combination thereof from SEQ ID NO: 2. 
     
     
         15 . The hIFN polypeptide of  claim 11 , wherein the non-naturally encoded amino acid is substituted at a position selected from the group consisting of residues 6, 9, 12, 13, 16, 96, 156, 159, 160, 161, 162, and any combination thereof, from SEQ ID NO: 2. 
     
     
         16 . The hIFN polypeptide of  claim 11 , wherein the non-naturally encoded amino acid is substituted at a position selected from the group consisting of residues 2, 3, 4, 5, 7, 8, 16, 19, 20, 40, 42, 50, 51, 58, 68, 69, 70, 71, 73, 97, 105, 109, 112, 118, 148, 149, 152, 153, 158, 163, 164, 165, and any combination thereof from SEQ ID NO: 2. 
     
     
         17 . The hIFN polypeptide of  claim 4 , wherein the non-naturally encoded amino acid is substituted at a position selected from the group consisting of residues before position 1 (i.e., at the N-terminus), 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, or 166 (i.e. at the carboxyl terminus), and any combination thereof from SEQ ID NO: 2. 
     
     
         18 . The hIFN polypeptide of  claim 17 , wherein the non-naturally encoded amino acid is substituted at a position selected from the group consisting of residues 6, 9, 12, 13, 16, 41, 45, 46, 48, 49, 61, 64, 65, 96, 100, 101, 103, 106, 107, 108, 110, 111, 113, 114, 117, 120, 121, 149, 156, 159, 160, 161 and 162, and any combination thereof, from SEQ ID NO: 2. 
     
     
         19 . The hIFN polypeptide of  claim 1 , wherein the hIFN polypeptide comprises one or more amino acid substitution, addition or deletion that modulates affinity of the hIFN polypeptide for a hIFN receptor. 
     
     
         20 . The hIFN polypeptide of  claim 1 , wherein the hIFN polypeptide comprises one or more amino acid substitution, addition or deletion that increases the stability or solubility of the hIFN polypeptide. 
     
     
         21 . The hIFN polypeptide of  claim 1 , wherein the hIFN polypeptide comprises one or more amino acid substitution, addition or deletion that increases the expression of the hIFN polypeptide in a recombinant host cell. 
     
     
         22 . The hIFN polypeptide of  claim 1 , wherein the hIFN polypeptide comprises one or more amino acid substitution, addition or deletion that increases protease resistance of the hIFN polypeptide. 
     
     
         23 . The hIFN polypeptide of  claim 1 , wherein the non-naturally encoded amino acid is reactive toward a linker, polymer, or biologically active molecule that is otherwise unreactive toward any of the 20 common amino acids in the polypeptide. 
     
     
         24 . The hIFN polypeptide of  claim 1 , wherein the non-naturally encoded amino acid comprises a carbonyl group, an aminooxy group, a hydrazine group, a hydrazide group, a semicarbazide group, an azide group, or an alkyne group. 
     
     
         25 . The hIFN polypeptide of  claim 24 , wherein the non-naturally encoded amino acid comprises a carbonyl group. 
     
     
         26 . The hIFN polypeptide of  claim 25 , wherein the non-naturally encoded amino acid . has the structure: 
       
         
           
           
               
               
           
         
       
       wherein n is 0-10; R 1  is an alkyl, aryl, substituted alkyl, or substituted aryl; R 2  is H, an alkyl, aryl, substituted alkyl, and substituted aryl; and R 3  is H, an amino acid, a polypeptide, or an amino terminus modification group, and R 4  is H, an amino acid, a polypeptide, or a carboxy terminus modification group. 
     
     
         27 . The hIFN polypeptide of  claim 24 , wherein the non-naturally encoded amino acid comprises an aminooxy group. 
     
     
         28 . The hIFN polypeptide of  claim 24 , wherein the non-naturally encoded amino acid comprises a hydrazide group. 
     
     
         29 . The hIFN polypeptide of  claim 24 , wherein the non-naturally encoded amino acid comprises a hydrazine group. 
     
     
         30 . The hIFN polypeptide of  claim 24 , wherein the non-naturally encoded amino acid residue comprises a semicarbazide group. 
     
     
         31 . The hIFN polypeptide of  claim 24 , wherein the non-naturally encoded amino acid residue comprises an azide group. 
     
     
         32 . The hIFN polypeptide of  claim 31 , wherein the non-naturally encoded amino acid has the structure: 
       
         
           
           
               
               
           
         
       
       wherein n is 0-10; R 1  is an alkyl, aryl, substituted alkyl, substituted aryl or not present; X is O, N, S or not present; m is 0-10; R 2  is H, an amino acid, a polypeptide, or an amino terminus modification group, and R 3  is H, an amino acid, a polypeptide, or a carboxy terminus modification group. 
     
     
         33 . The hIFN polypeptide of  claim 24 , wherein the non-naturally encoded amino acid comprises an alkyne group. 
     
     
         34 . The hIFN polypeptide of  claim 33 , wherein the non-naturally encoded amino acid has the structure: 
       
         
           
           
               
               
           
         
       
       wherein n is 0-10; R 1  is an alkyl, aryl, substituted alkyl, or substituted aryl; X is O, N, S or not present; m is 0-10, R 2  is H, an amino acid, a polypeptide, or an amino terminus modification group, and R 3  is H, an amino acid, a polypeptide, or a carboxy terminus modification group. 
     
     
         35 . The hIFN polypeptide of  claim 4 , wherein the water soluble polymer has a molecular weight of between about 0.1 kDa and about 100 kDa. 
     
     
         36 . The hIFN polypeptide of  claim 35 , wherein the water soluble polymer has a molecular weight of between about 0.1 kDa and about 50 kDa. 
     
     
         37 . The hIFN polypeptide of  claim 4 , which is made by reacting a hIFN polypeptide comprising a carbonyl-containing amino acid with a water soluble polymer comprising an aminooxy, hydrazine, hydrazide or semicarbazide group. 
     
     
         38 . The hIFN polypeptide of  claim 37 , wherein the aminooxy, hydrazine, hydrazide or semicarbazide group is linked to the water soluble polymer through an amide linkage. 
     
     
         39 . The hIFN polypeptide of  claim 4 , which is made by reacting a water soluble polymer comprising a carbonyl group with a polypeptide comprising a non-naturally encoded amino acid that comprises an aminooxy, a hydrazine, a hydrazide or a semicarbazide group. 
     
     
         40 . The hIFN polypeptide of  claim 4 , which is made by reacting a hIFN polypeptide comprising an alkyne-containing amino acid with a water soluble polymer comprising an azide moiety. 
     
     
         41 . The hIFN polypeptide of  claim 4 , which is made by reacting a hIFN polypeptide comprising an azide-containing amino acid with a water soluble polymer comprising an alkyne moiety. 
     
     
         42 . The hIFN polypeptide of  claim 24 , wherein the azide or alkyne group is linked to a water soluble polymer through an amide linkage. 
     
     
         43 . The hIFN polypeptide of  claim 4 , wherein the water soluble polymer is a branched or multiarmed polymer. 
     
     
         44 . The hIFN polypeptide of  claim 43 , wherein each branch of the branched polymer has a molecular weight of between about 1 kDa and about 100 kDa. 
     
     
         45 . The hIFN polypeptide of  claim 1 , wherein the polypeptide is a hIFN antagonist. 
     
     
         46 . The hIFN polypeptide of  claim 45 , wherein the non-naturally encoded amino acid is substituted at a position selected from the group consisting of residues 2, 3, 4, 5, 7, 8, 16, 19, 20, 40, 42, 50, 51, 58, 68, 69, 70, 71, 73, 97, 105, 109, 112, 118, 148, 149, 152, 153, 158, 163, 164, 165, and any combination thereof from SEQ ID NO: 2. 
     
     
         47 . The hIFN polypeptide of  claim 45 , wherein the non-naturally encoded amino acid is substituted at a position selected from the group consisting of residues 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 33, 34, 35, 74, 77, 78, 79, 80, 82, 83, 85, 86, 89, 90, 93, 94, 124, 125, 127, 128, 129, 131, 132, 133, 134, 135, 136, 137, and any combination thereof from SEQ ID NO: 2. 
     
     
         48 . The hIFN polypeptide of  claim 45 , wherein the polypeptide comprises one or more post-translational modification, linker, polymer, or biologically active molecule. 
     
     
         49 . The hIFN polypeptide of  claim 48 , wherein the polymer comprises a moiety selected from a group consisting of a water soluble polymer and poly(ethylene glycol). 
     
     
         50 . The hIFN polypeptide according to  claim 45 , wherein the non-naturally encoded amino acid is present within the receptor-binding region of the hIFN polypeptide. 
     
     
         51 . The hIFN polypeptide according to  claim 45 , wherein the polypeptide prevents dimerization of the hIFN receptor. 
     
     
         52 . The hIFN polypeptide of  claim 1 , wherein the non-naturally encoded amino acid comprises a saccharide moiety. 
     
     
         53 . The hIFN polypeptide of  claim 3 , wherein the linker, polymer, or biologically active molecule is linked to the polypeptide via a saccharide moiety. 
     
     
         54 . An isolated nucleic acid comprising a polynucleotide that hybridizes under stringent conditions to SEQ ID NO:21 or SEQ ID NO:22, wherein the polynucleotide comprises at least one selector codon. 
     
     
         55 . The isolated nucleic acid of  claim 54 , wherein the selector codon is selected from the group consisting of an amber codon, ochre codon, opal codon, a unique codon, a rare codon, and a four-base codon. 
     
     
         56 . A method of making the hIFN polypeptide of  claim 3 , the method comprising contacting an isolated hIFN polypeptide comprising a non-naturally encoded amino acid with a linker, polymer, or biologically active molecule comprising a moiety that reacts with the non-naturally encoded amino acid. 
     
     
         57 . The method of  claim 56 , wherein the polymer comprises a moiety selected from a group consisting of a water soluble polymer and a poly(ethylene glycol). 
     
     
         58 . The method of  claim 56 , wherein the non-naturally encoded amino acid comprises a carbonyl group, an aminooxy group, a hydrazide group, a hydrazine group, a semicarbazide group, an azide group, or an alkyne group. 
     
     
         59 . The method of  claim 56 , wherein the non-naturally encoded amino acid comprises a carbonyl moiety and the linker, polymer, or biologically active molecule comprises an aminooxy, a hydrazine, a hydrazide or a semicarbazide moiety. 
     
     
         60 . The method of  claim 59 , wherein the aminooxy, hydrazine, hydrazide or semicarbazide moiety is linked to the linker, polymer, or biologically active molecule through an amide linkage. 
     
     
         61 . The method of  claim 56 , wherein the non-naturally encoded amino acid comprises an alkyne moiety and the linker, polymer, or biologically active molecule comprises an azide moiety. 
     
     
         62 . The method of  claim 56 , wherein the non-naturally encoded amino acid comprises an azide moiety and the linker, polymer, or biologically active molecule comprises an alkyne moiety. 
     
     
         63 . The method of  claim 58 , wherein the azide or alkyne moiety is linked to a linker, polymer, or biologically active molecule through an amide linkage. 
     
     
         64 . The method of  claim 57 , wherein the poly(ethylene glycol) moiety has an average molecular weight of between about 0.1 kDa and about 100 kDa. 
     
     
         65 . The method of  claim 57 , wherein the poly(ethylene glycol) moiety is a branched or multiarmed polymer. 
     
     
         66 . A composition comprising the hIFN polypeptide of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         67 . The composition of  claim 66 , wherein the non-naturally encoded amino acid is linked to a water soluble polymer. 
     
     
         68 . A method of treating a patient having a disorder modulated by hIFN comprising administering to the patient a therapeutically-effective amount of the composition of  claim 66 . 
     
     
         69 . A cell comprising the nucleic acid of  claim 54 . 
     
     
         70 . The cell of  claim 69 , wherein the cell comprises an orthogonal tRNA synthetase or an orthogonal tRNA. 
     
     
         71 . A method of making a hIFN polypeptide comprising a non-naturally encoded amino acid, the method comprising, culturing cells comprising a polynucleotide or polynucleotides encoding a hIFN polypeptide and comprising a selector codon, an orthogonal RNA synthetase and an orthogonal tRNA under conditions to permit expression of the hIFN polypeptide comprising a non-naturally encoded amino acid; and purifying the hIFN polypeptide. 
     
     
         72 . A method of increasing serum half-life or circulation time of a hIFN polypeptide, the method comprising substituting one or more non-naturally encoded amino acids for any one or more naturally occurring amino acids in the hIFN polypeptide. 
     
     
         73 . The hIFN polypeptide of  claim 1  wherein said polypeptide is chemically synthesized. 
     
     
         74 . The hIFN polypeptide of  claim 1 , wherein the polypeptide is ribosomally synthesized. 
     
     
         75 . A hIFN polypeptide comprising a non-naturally encoded amino acid , wherein the non-naturally encoded amino acid is substituted at a position selected from the group consisting of 23, 24, 25, 26, 27, 28, 30, 31, 32, 33, 128, 129, 131, 132, 133, 134, 135, 136, 137, 158, 159, 160, 161, 162, 163, 164, 165 of SEQ ID NO: 2 or the corresponding amino acids in SEQ ID NO: 1 or 3. 
     
     
         76 . The hIFN polypeptide of  claim 75 , wherein the non-naturally encoded amino acid comprises a carbonyl group, an aminooxy group, a hydrazide group, a hydrazine group, a semicarbazide group, an azide group, or an alkyne group. 
     
     
         77 . The hIFN polypeptide of  claim 75 , wherein the non-naturally encoded amino acid is coupled to a water soluble polymer. 
     
     
         78 . The hIFN polypeptide of  claim 75 , wherein the water soluble polymer is a poly(ethylene glycol) moiety having a molecular weight of between about 0.1 kDa and about 100 kDa. 
     
     
         79 . The hIFN polypeptide of  claim 78 , wherein the poly(ethylene glycol) moiety is a branched or multiarmed polymer. 
     
     
         80 . The hIFN polypeptide of  claim 79 , wherein the poly(ethylene glycol) moiety has a molecular weight of between about 1 kDa and about 100 kDa. 
     
     
         81 . A composition comprising the hIFN polypeptide of  claim 75  and a pharmaceutically acceptable carrier. 
     
     
         82 . A hIFN polypeptide comprising one or more amino acid substitution, addition or deletion that increases the expression of the hIFN polypeptide in a recombinant host cell. 
     
     
         83 . A hIFN polypeptide comprising a water soluble polymer linked by a covalent bond to the hIFN polypeptide at a single amino acid. 
     
     
         84 . The hIFN polypeptide of  claim 83 , wherein the water soluble polymer comprises a poly(ethylene glycol) moiety. 
     
     
         85 . The hIFN polypeptide of  claim 83 , wherein the amino acid covalently linked to the water soluble polymer is a non-naturally encoded amino acid. 
     
     
         86 . The hIFN polypeptide of  claim 1  wherein said non-naturally encoded amino acid is linked to a poly(ethylene glycol) molecule. 
     
     
         87 . The hIFN polypeptide of  claim 1  comprising at least one linker, polymer, or biologically active molecule, wherein said linker, polymer, or biologically active molecule is attached to the polypeptide through a functional group of a non-naturally encoded amino acid ribosomally incorporated into the polypeptide. 
     
     
         88 . The hIFN polypeptide of  claim 87 , wherein said hIFN polypeptide is monoPEGylated. 
     
     
         89 . The hIFN polypeptide of  claim 1  comprising a linker, polymer or biologically active molecule that is attached to one or more non-naturally encoded amino acid wherein said non-naturally encoded amino acid is ribosomally incorporated into the polypeptide at pre-selected sites. 
     
     
         90 . The hIFN polypeptide of  claim 89 , wherein the hIFN polypeptide comprises one said linker, polymer, or biologically active molecule. 
     
     
         91 . The hIFN polypeptide of  claim 1 , wherein said hIFN polypeptide comprises one or more post-translational modification, linker, polymer, biologically active molecule, water soluble polymer, bifunctional polymer, bifunctional linker, additional hIFN polypeptide, second polypeptide, or poly(ethylene glycol) moiety, and wherein said hIFN polypeptide is selected from a group consisting of consensus IFN, IFNα, IFNβ, IFNε, IFNγ, IFNω, IFNτ, IFNα-1a, IFNα-1b, IFNα-2a, IFNα-2b, IFNβ-1a, IFNβ-1b, and IFNγ-1a. 
     
     
         92 . The hIFN polypeptide of  claim 1 , wherein said hIFN polypeptide comprises one or more amino acid substitution, addition, or deletion that increases affinity of the hIFN polypeptide for a hIFN receptor, increases the stability or solubility of the hIFN polypeptide, increases the expression of the hIFN polypeptide in a recombinant host cell or synthesized in vitro, or increases protease resistance of the hIFN polypeptide, and wherein said hIFN polypeptide is selected from a group consisting of consensus IFN, IFNα, IFNβ, IFNε, IFNγ, IFNω, IFNτ, IFNα-1a, IFNα-1b, IFNα-2a, IFNα-2b, IFNβ-1a, IFNβ-1b, and IFNγ-1a. 
     
     
         93 . The hIFN polypeptide of  claim 1 , wherein the hIFN polypeptide comprises one or more amino acid substitution, addition, or deletion that modulates immunogenicity of the hIFN polypeptide. 
     
     
         94 . The hIFN polypeptide of  claim 1 , wherein the hIFN polypeptide comprises one or more amino acid substitution, addition, or deletion that modulates serum half-life or circulation time of the hIFN polypeptide. 
     
     
         95 . A method of modulating immunogenicity of a hIFN polypeptide, the method comprising substituting one or more non-naturally encoded amino acids for any one or more naturally occurring amino acids in the hIFN polypeptide. 
     
     
         96 . The hIFN polypeptide of  claim 1  wherein the non-naturally encoded amino acid is substituted at a position selected from the group consisting of residues: 31, 134, 34, 38, 129, 36, 122, 37, 121, 41, 125, 124, 149, 117, 39, 118, 120, 107, 108, 106, 100, 111, 113, 114, 41, 45, 46, 48, 49, 61, 64, 65, 101, 103, 102, 110, 117, 120, 121, 149, 96, 6, 9, 12, 13, 16, 68, 70, 109, 159, 161, 156, 160, 162, 24, 27, 78, 83, 85, 87, 89, 164, or any combination thereof (SEQ ID NO: 2). 
     
     
         97 . The hIFN polypeptide of  claim 1  wherein the non-naturally encoded amino acid is substituted at position 107 (SEQ ID NO: 2). 
     
     
         98 . The hIFN polypeptide of  claim 1 , wherein the hIFN polypeptide comprises one or more amino acid substitution, addition, or deletion that modulates interaction with opioid receptors. 
     
     
         99 . The hIFN polypeptide of  claim 98 , wherein said opioid receptor is the μ opioid receptor. 
     
     
         100 . The hIFN polypeptide of  claim 1 , wherein the hIFN polypeptide comprises one or more amino acid substitution, addition, or deletion that modulates 5-HT brain neurotransmission. 
     
     
         101 . The hIFN polypeptide of  claim 1 , wherein the hIFN polypeptide comprises one or more amino acid substitution, addition, or deletion that modulates induction of indoleamine 2,3-dioxygenase. 
     
     
         102 . The hIFN polypeptide of  claim 1  or  96 , wherein said hIFN has antiviral activity and reduced non-antiviral activity and side effects compared with hIFN. 
     
     
         103 . The hIFN polypeptide of  claim 1  further comprising one or more amino acid substitutions selected from the group consisting of G10E, M16R, R13E, T79R, K83Q, K83S, Y85L, T86S, E87S, Q90R, Q91E, N93Q, D94V, E96K, R120K, K121T, Q124R, R125G, L128R, R149Y, R149E, R149S, D77-D94 OF SEQ ID NO: 2 is replaced with HERALDQLLSSLWRELQV, and V105-D114 of SEQ ID NO: 2 is replaced with GQSAPLP.