Human TIMP-1 antibodies
AssigneeBayer Aktiengesellschaft
InventorsClark Pan, Andreas M. Knorr, Michael Schauer, Claudia Hirth-Dietrich, Sabine Kraft, Barbara Krebs
Life of this patent
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Abstract
Human antibodies that bind to TIMP-1 can be used as reagents to diagnose and treat disorders in which TIMP-1 is elevated, such as liver fibrosis, alcoholic liver disease, cardiac fibrosis, acute coronary syndrome, lupus nephritis, glomerulosclerotic renal disease, benign prostate hypertrophy, colon cancer, lung cancer, and idiopathic pulmonary fibrosis.
Claims78
A purified preparation of a human antibody, wherein the antibody:
- binds to a tissue inhibitor of metalloprotease-1 (TIMP-1);
- and neutralizes a matrix metalloprotease (MMP)-inhibiting activity of the TIMP-1.
A purified preparation of a human antibody which comprises a VHCDR3 region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS:1-43 and 360.
A purified preparation of a human antibody which comprises a VLCDR3 region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS:44-86 and 365-379.
A purified preparation of a human antibody which comprises a VHCDR3 and VLCDR3 amino acid sequence pair selected from the group consisting of SEQ ID NOS:
- 1 and 44, SEQ ID NOS:2 and 45, SEQ ID NO:3 and 46, SEQ ID NOS:4 and 47, SEQ ID NOS:5 and 48, SEQ ID NOS:6 and 49, SEQ ID NOS:7 and 50, SEQ ID NOS:3 and 44, SEQ ID NOS:3 and 45, SEQ ID NOS:3 and 47, SEQ ID NOS:3 and 48, SEQ ID NOS:3 and 49, SEQ ID NOS:3 and 50, SEQ ID NOS:7 and 44, SEQ ID NOS:7 and 45, SEQ ID NOS:7 and 47, SEQ ID NOS:7 and 48, SEQ ID NOS:8 and 51, SEQ ID NOS:9 and 52, SEQ ID NOS:10 and 53, SEQ ID NOS:
- 11 and 54, SEQ ID NOS:
- 12 and 55, SEQ ID NOS:
- 13 and 56, SEQ ID NOS:14 and 57, SEQ ID NOS:15 and 58, SEQ ID NOS:16 and 59, SEQ ID NOS:17 and 60, SEQ ID NOS:18 and 61, SEQ ID NOS:19 and 62, SEQ ID NOS:20 and 63, SEQ ID NOS:21 and 64, SEQ ID NOS:22 and 65, SEQ ID NOS:23 and 66, SEQ ID NOS:24 and 67, SEQ ID NOS:25 and 68, SEQ ID NOS:26 and 69, SEQ ID NOS:
- 27 and 70, SEQ ID NOS:28 and 71, SEQ ID NOS:29 and 72, SEQ ID NOS:30 and 73, SEQ ID NOS:31 and 74, SEQ ID NOS:32 and 75, SEQ ID NOS:33 and 76, SEQ ID NOS:34 and 77, SEQ ID NOS:35 and 78, SEQ ID NOS:36 and 79, SEQ ID NOS:37 and 80, SEQ ID NOS:38 and 81, SEQ ID NOS:39 and 82, SEQ ID NOS:40 and 83, SEQ ID NOS:41 and 84, SEQ ID NOS:42 and 85, SEQ ID NOS:43 and 86, SEQ ID NOS:3 and 48, SEQ ID NOS:360 and 48, SEQ ID NOS:3 and 365, SEQ ID NOS:16 and 59, SEQ ID NOS:18 and 61, SEQ ID NOS:34 and 77, SEQ ID NOS:34 and 379, SEQ ID NOS:18 and 376, SEQ ID NOS:18 and 377, and SEQ ID NOS:18 and 378.
A purified preparation of a human antibody comprising a VHCDR3 and VLCDR3 amino acid sequence pair selected from the group consisting of SEQ ID NOS:
- 1 and 44, SEQ ID NOS:2 and 45, SEQ ID NO:3 and 46, SEQ ID NOS:4 and 47, SEQ ID NOS:5 and 48, SEQ ID NOS:6 and 49, SEQ ID NOS:7 and 50, SEQ ID NOS:3 and 44, SEQ ID NOS:3 and 45, SEQ ID NOS:3 and 47, SEQ ID NOS:3 and 48, SEQ ID NOS:3 and 49, SEQ ID NOS:3 and 50, SEQ ID NOS:7 and 44, SEQ ID NOS:7 and 45, SEQ ID NOS:7 and 47, SEQ ID NOS:7 and 48, SEQ ID NOS:8 and 51, SEQ ID NOS:9 and 52, SEQ ID NOS:10 and 53, SEQ ID NOS:11 and 54, SEQ ID NOS:12 and 55, SEQ ID NOS:13 and 56, SEQ ID NOS:14 and 57, SEQ ID NOS:15 and 58, SEQ ID NOS:16 and 59, SEQ ID NOS:17 and 60, SEQ ID NOS:18 and 61, SEQ ID NOS:19 and 62, SEQ ID NOS:20 and 63, SEQ ID NOS:21 and 64, SEQ ID NOS:22 and 65, SEQ ID NOS:23 and 66, SEQ ID NOS:24 and 67, SEQ ID NOS:25 and 68, SEQ ID NOS:26 and 69, SEQ ID NOS:
- 27 and 70, SEQ ID NOS:28 and 71, SEQ ID NOS:29 and 72, SEQ ID NOS:30 and 73, SEQ ID NOS:31 and 74, SEQ ID NOS:32 and 75, SEQ ID NOS:33 and 76, SEQ ID NOS:34 and 77, SEQ ID NOS:35 and 78, SEQ ID NOS:36 and 79, SEQ ID NOS:37 and 80, SEQ ID NOS:38 and 81, SEQ ID NOS:39 and 82, SEQ ID NOS:40 and 83, SEQ ID NOS:41 and 84, SEQ ID NOS:42 and 85, SEQ ID NOS:43 and 86, SEQ ID NOS:3 and 48, SEQ ID NOS:360 and 48, SEQ ID NOS:3 and 365, SEQ ID NOS:16 and 59, SEQ ID NOS:18 and 61, SEQ ID NOS:34 and 77, SEQ ID NOS:34 and 379, SEQ ID NOS:18 and 376, SEQ ID NOS:18 and 377, and SEQ ID NOS:18 and 378.
A purified preparation of a human antibody which comprises a heavy chain and a light chain amino acid pair selected from the group consisting of SEQ ID NOS:
- 140 and 97, SEQ ID NOS:141 and 98, SEQ ID NOS:142 and 99, SEQ ID NOS:143 and 100, SEQ ID NOS:144 and 101, SEQ ID NOS:145 and 102, SEQ ID NOS:146 and 103, SEQ ID NOS:142 and 97, SEQ ID NOS:142 and 98, SEQ ID NOS:142 and 100, SEQ ID NOS:142 and 101, SEQ ID NOS:142 and 102, SEQ ID NOS:142 and 103, SEQ ID NOS:146 and 97, SEQ ID NOS:146 and 98, SEQ ID NO:146 and 100, SEQ ID NOS:146 and 101, SEQ ID NOS:148 and 104, SEQ ID NOS:148 and 105, SEQ ID NOS:149 and 106, SEQ ID NOS:150 and 107, SEQ ID NOS:
- 151 and 108, SEQ ID NOS:
- 152 and 109, SEQ ID NOS:
- 153 and 110, SEQ ID NOS:154 and 111, SEQ ID NOS:155 and 112, SEQ ID NOS:156 and 113, SEQ ID NOS:157 and 114, SEQ ID NOS:158 and 115, SEQ ID NOS:159 and 116, SEQ ID NOS:160 and 117, SEQ ID NOS:161 and 118, SEQ ID NOS:162 and 119, SEQ ID NOS:163 and 120, SEQ ID NOS:164 and 121, SEQ ID NOS:165 and 122, SEQ ID NOS:166 and 123, SEQ ID NOS:167 and 124, SEQ ID NOS:168 and 125, SEQ ID NOS:169 and 126, SEQ ID NOS:170 and 127, SEQ ID NOS:171 and 128, SEQ ID NOS:172 and 129, SEQ ID NOS:173 and 130, SEQ ID NOS:174 and 131, SEQ ID NOS:175 and 132, SEQ ID NOS:176 and 133, SEQ ID NOS:177 and 134, SEQ ID NOS:178 and 135, SEQ ID NOS:179 and 136, SEQ ID NOS:180 and 137, SEQ ID NOS:181 and 138, and SEQ ID NOS:182 and 139.
A pharmaceutical composition comprising:
- a human antibody which (1) binds to a TIMP-1 and (2) neutralizes an MMP-inhibiting activity of the TIMP-1;
- and
- a pharmaceutically acceptable carrier.
A purified polynucleotide which encodes a human antibody comprising a VHCDR3 region which comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:1-43 and 360, wherein the human antibody (1) binds to a TIMP-1 and (2) neutralizes an MMP-inhibiting activity of the TIMP-1.
The purified polynucleotide of claim 31 wherein the VHCDR3 region is encoded by a nucleotide sequence selected from the group consisting of SEQ ID NOS:227-269.
A purified polynucleotide which encodes a human antibody comprising a VLCDR3 region which comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:44-86 and 365-379, wherein the human antibody (1) binds to a TIMP-1 and (2) neutralizes an MMP-inhibiting activity of the TIMP-1.
The method of claim 55 wherein the expression vector comprises a polynucleotide sequence selected from the group consisting of SEQ ID NOS:
- 183-357.
A method of decreasing an MMP-inhibiting activity of a TIMP-1, comprising the step of:
- contacting the TIMP-1 with a human antibody that binds to the TIMP-1, whereby the MMP-inhibiting activity of the TIMP-1 is decreased relative to MMP-inhibiting activity of the TIMP-1 in the absence of the antibody.
A method of ameliorating symptoms of a disorder in which TIMP-1 is elevated, comprising the step of:
- administering to a patient having the disorder an effective amount of a human antibody which neutralizes an MMP-inhibiting activity of the TIMP-1, whereby symptoms of the disorder are ameliorated.
A method of detecting a TIMP-1 in a test preparation, comprising the steps of:
- contacting the test preparation with a human antibody that specifically binds to the TIMP-1;
- and
- assaying the test preparation for the presence of an antibody-TIMP-1 complex.
A method to aid in diagnosing a disorder in which a TIMP-1 level is elevated, comprising the steps of:
- contacting a sample from a patient suspected of having the disorder with a human antibody that binds to TIMP-1;
- and
- assaying for the presence of an antibody-TIMP-1 complex, whereby detection of an amount of the complex which is greater than an amount of the complex in a normal sample identifies the patient as likely to have the disorder.
Dependencies are inferred from the claim text.