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US 6,497,871 B1Granted
Recombiniant gamma interferons having enhanced stability and methods therefor
AssigneeGenentech, Inc.
InventorsPatrick W. Gray, Ernst H. Rinderknecht
Life of this patent
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Abstract
The present invention relates to novel, stable recombinant gamma interferons exhibiting in greater or less degree the antiviral and antiproliferative activity in humans and pH 2 labile properties characteristic of native human gamma interferon. The amino acid sequence of such an interferon comprises, from the N-terminus: X-Y-Asp . . . Thr 1 2 126 wherein X is a methionine residue or hydrogen and Y is a glutamine residue, or, where X is hydrogen, Y is either a glutamine or a pyroglutamate residue.
Claims41
A composition suitable for pharmaceutical administration comprising:
- a recombinant gamma interferon polypeptide consisting of the amino acid sequence, extending from the N-terminus:
- X-Y-ASP-PRO-TYR-VAL-LYS-GLU-ALA-GLU-ASN-LEU-LYS- 1 2 3 4 5 6 7 8 9 10 11 12 LYS-TYR-PHE-ASN-ALA-GLY-HIS-SER-ASP-VAL-ALA-ASP- 13 14 15 16 17 18 19 20 21 22 23 24 ASN-GLY-THR-LEU-PHE-LEU-GLY-ILE-LEU-LYS-ASN-TRP- 25 26 27 28 29 30 31 32 33 34 35 36 LYS-GLU-GLU-SER-ASP-ARG-LYS-ILE-MET-GLN-SER-GLN- 37 38 39 40 41 42 43 44 45 46 47 48 ILE-VAL-SER-PHE-TYR-PHE-LYS-LEU-PHE-LYS-ASN-PHE- 49 50 51 52 53 54 55 56 57 58 59 60 LYS-ASP-ASP-GLN-SER-ILE-GLN-LYS-SER-VAL-GLU-THR- 61 62 63 64 65 66 67 68 69 70 71 72 ILE-LYS-GLU-ASP-MET-ASN-VAL-LYS-PHE-PHE-ASN-SER- 73 74 75 76 77 78 79 80 81 82 83 84 ASN-LYS-LYS-LYS-ARG-ASP-ASP-PHE-GLU-LYS-LEU-THR- 85 86 87 88 89 90 91 92 93 94 95 96 ASN-TYR-SER-VAL-THR-ASP-LEU-ASN-VAL-GLN-ARG-LYS- 97 98 99 100 101 102 103 104 105 106 107 108 ALA-ILE-HIS-GLU-LEU-ILE-GLN-VAL-MET-ALA-GLU-LEU- 109 110 111 112 113 114 115 116 117 118 119 120 SER-PRO-ALA-ALA-LYS-THR-n 121 122 123 124 125 126
- wherein X-Y is MET-GLN, H-GLN or H-pyroglutamate, wherein n is an integral number of amino acids from 0 to 13, and wherein said recombinant polypeptide has anti-viral and anti-proliferative activity.
A recombinant polypeptide consisting of the amino acid sequence:
- X-Y-ASP-PRO-TYR-VAL-LYS-GLU-ALA-GLU-ASN-LEU-LYS- 1 2 3 4 5 6 7 8 9 10 11 12 LYS-TYR-PHE-ASN-ALA-GLY-HIS-SER-ASP-VAL-ALA-ASP- 13 14 15 16 17 18 19 20 21 22 23 24 ASN-GLY-THR-LEU-PHE-LEU-GLY-ILE-LEU-LYS-ASN-TRP- 25 26 27 28 29 30 31 32 33 34 35 36 LYS-GLU-GLU-SER-ASP-ARG-LYS-ILE-MET-GLN-SER-GLN- 37 38 39 40 41 42 43 44 45 46 47 48 ILE-VAL-SER-PHE-TYR-PHE-LYS-LEU-PHE-LYS-ASN-PHE- 49 50 51 52 53 54 55 56 57 58 59 60 LYS-ASP-ASP-GLN-SER-ILE-GLN-LYS-SER-VAL-GLU-THR- 61 62 63 64 65 66 67 68 69 70 71 72 ILE-LYS-GLU-ASP-MET-ASN-VAL-LYS-PHE-PHE-ASN-SER- 73 74 75 76 77 78 79 80 81 82 83 84 ASN-LYS-LYS-LYS-ARG-ASP-ASP-PHE-GLU-LYS-LEU-THR- 85 86 87 88 89 90 91 92 93 94 95 96 ASN-TYR-SER-VAL-THR-ASP-LEU-ASN-VAL-GLN-ARG-LYS- 97 98 99 100 101 102 103 104 105 106 107 108 ALA-ILE-HIS-GLU-LEU-ILE-GLN-VAL-MET-ALA-GLU-LEU- 109 110 111 112 113 114 115 116 117 118 119 120 SER-PRO-ALA-ALA-LYS-THR-GLY-LYS-ARG-LYS-ARG-SER- 121 122 123 124 125 126 127 128 129 130 131 132 GLN-MET-LEU-PHE-ARG-GLY-ARG 133 134 135 136 137 138 139
- wherein X-Y is MET-GLN, H-GLN or H-pyrolutamate;
- and which is acid sensitive, can be neutralized by immune interferon antiserum, in monomeric form has an amino acid molecular weight of about 17,000, and has anti-viral and anti-proliferative activity.
A composition suitable for pharmaceutical administration comprising:
- a recombinant modified gamma interferon polypeptide comprising a substitution, deletion, insertion or addition of a single amino acid in a gamma interferon consisting of the amino acid sequence:
- X-Y-ASP-PRO-TYR-VAL-LYS-GLU-ALA-GLU-ASN-LEU-LYS- 1 2 3 4 5 6 7 8 9 10 11 12 LYS-TYR-PHE-ASN-ALA-GLY-HIS-SER-ASP-VAL-ALA-ASP- 13 14 15 16 17 18 19 20 21 22 23 24 ASN-GLY-THR-LEU-PHE-LEU-GLY-ILE-LEU-LYS-ASN-TRP- 25 26 27 28 29 30 31 32 33 34 35 36 LYS-GLU-GLU-SER-ASP-ARG-LYS-ILE-MET-GLN-SER-GLN- 37 38 39 40 41 42 43 44 45 46 47 48 ILE-VAL-SER-PHE-TYR-PHE-LYS-LEU-PHE-LYS-ASN-PHE- 49 50 51 52 53 54 55 56 57 58 59 60 LYS-ASP-ASP-GLN-SER-ILE-GLN-LYS-SER-VAL-GLU-THR- 61 62 63 64 65 66 67 68 69 70 71 72 ILE-LYS-GLU-ASP-MET-ASN-VAL-LYS-PHE-PHE-ASN-SER- 73 74 75 76 77 78 79 80 81 82 83 84 ASN-LYS-LYS-LYS-ARG-ASP-ASP-PHE-GLU-LYS-LEU-THR- 85 86 87 88 89 90 91 92 93 94 95 96 ASN-TYR-SER-VAL-THR-ASP-LEU-ASN-VAL-GLN-ARG-LYS- 97 98 99 100 101 102 103 104 105 106 107 108 ALA-ILE-HIS-GLU-LEU-ILE-GLN-VAL-MET-ALA-GLU-LEU- 109 110 111 112 113 114 115 116 117 118 119 120 SER-PRO-ALA-ALA-LYS-THR-n 121 122 123 124 125 126
- wherein X-Y is MET-GLN, H-GLN or H-pyroglutamate, wherein n is an integral number of amino acid residues from 0 to 15, wherein said modified species is acid sensitive, can be neutralized by immune interferon antiserum, in monomeric form has an amino acid molecular weight of about 17,000, and has anti-viral and anti-proliferative activity.
A recombinant gamma interferon polypeptide consisting of the amino acid sequence, extending from the N-terminus:
- X-Y-ASP-PRO-TYR-VAL-LYS-GLU-ALA-GLU-ASN-LEU-LYS- 1 2 3 4 5 6 7 8 9 10 11 12 LYS-TYR-PHE-ASN-ALA-GLY-HIS-SER-ASP-VAL-ALA-ASP- 13 14 15 16 17 18 19 20 21 22 23 24 ASN-GLY-THR-LEU-PHE-LEU-GLY-ILE-LEU-LYS-ASN-TRP 31 32 33 34 29 30 31 32 33 34 35 36 LYS-GLU-GLU-SER-ASP-ARG-LYS-ILE-MET-GLN-SER-GLN- 37 38 39 40 41 42 43 44 45 46 47 48 ILE-VAL-SER-PHE-TYR-PHE-LYS-LEU-PHE-LYS-ASN-PHE- 49 50 51 52 53 54 55 56 57 58 59 60 LYS-ASP-ASP-GLN-SER-ILE-GLN-LYS-SER-VAL-GLU-THR- 61 62 63 64 65 66 67 68 59 70 71 72 ILE-LYS-GLU-ASP-MET-ASN-VAL-LYS-PHE-PHE-ASN-SER- 73 74 75 76 77 78 79 80 81 82 83 84 ASN-LYS-LYS-LYS-ARG-ASP-ASP-PHE-GLU-LYS-LEU-THR- 85 86 87 88 89 90 91 92 93 94 95 96 ASN-TYR-SER-VAL-THR-ASP-LEU-ASN-VAL-GLN-ARG-LYS- 97 98 99 100 101 102 103 104 105 106 107 108 ALA-ILE-HIS-GLU-LEU-ILE-GLN-VAL-MET-ALA-GLU-LEU- 109 110 111 112 113 114 115 116 117 118 119 120 SER-PRO-ALA-ALA-LYS-THR-Z 121 122 123 124 125 126
- wherein X-Y is MET-GLN, H-GLN or H-pyroglutamate, and Z consists of n amino acids, wherein n is an integer from 0 to 16.
The polypeptide of claim-74, wherein Z is
- GLY-LYS-ARG-LYS-ARG-SER-GLN-MET-LEU-PHE-ARG-GLY-ARG-ARG-ALA-SER.
Dependencies are inferred from the claim text.