Anti-mpl antibody
AssigneeChugai Seiyaku Kabushiki Kaisha
InventorsHiroyuki Tsunoda, Kiyotaka Nakano, Tetsuro Orita, Masayuki Tsuchiya, Yuichi Hirata
Life of this patent
Estimating the term…
Abstract
Anti-human Mpl antibodies were isolated and purified, and then anti-human Mpl diabodies and anti-human Mpl sc(Fv)2 were purified using genetic engineering techniques. Furthermore, the present inventors succeeded in humanizing anti-human Mpl sc(Fv)2. The diabodies and sc(Fv)2 were assayed for TPO-like agonistic activity, and were found to have activities higher than those of anti-human Mpl antibodies, or activities equivalent to or higher than those of naturally-occurring human TPO ligand.
Claims38
An antibody comprising a single-chain polypeptide having binding activity against TPO receptor (Mpl), wherein said antibody comprises two heavy chain variable regions and two light chain variable regions.
A chimeric antibody that binds to Mpl.
An antibody that binds to soluble Mpl.
An antibody that binds to human Mpl and monkey Mpl.
An antibody having agonistic activity against human Mpl and monkey Mpl.
An antibody whose binding activity to soluble Mpl is KD=10−6 M or lower.
An antibody whose binding activity to soluble Mpl is KD=10−7 M or lower.
An antibody whose TPO agonistic activity is EC50=100 nM or lower.
An antibody whose TPO agonistic activity is EC50=30 nM or lower.
An antibody whose TPO agonistic activity is EC50=10 nM or lower.
An antibody which comprises a heavy chain variable region, wherein said heavy chain variable regions comprises CDR1, CDR2 and CDR3 consisting of an amino acid sequence of any one of:
- [1]SEQ ID NOs:
- 3, 4, and 5
- [2] SEQ ID NOs:
- 6, 7, and 8
- [3] SEQ ID NOs:
- 9, 10, and 11
- [4] SEQ ID NOs:
- 15, 16, and 17
- [5] SEQ ID NOs:
- 18, 19, and 20
- [6] SEQ ID NOs:
- 21, 22, and 23
- [7] SEQ ID NOs:
- 24, 25, and 26
- [8] SEQ ID NOs:
- 27, 28, and 29
- [9] SEQ ID NOs:
- 30, 31, and 32
- [10] SEQ ID NOs:
- 33, 34, and 35
- [11] SEQ ID NOs:
- 36, 37, and 38
- [12] SEQ ID NOs:
- 39, 40, and 41
- [13] SEQ ID NOs:
- 42, 43, and 44
- [14] SEQ ID NOs:
- 48, 49, and 50
- [15] SEQ ID NOs:
- 51, 52, and 53
- [16] SEQ ID NOs:
- 54, 55, and 56
- [17] SEQ ID NOs:
- 57, 58, and 59.
An antibody which comprises a light chain variable region, wherein said light chain variable region comprises CDR1, CDR2 and CDR3 consisting of an amino acid sequence of any one of:
- [1] SEQ ID NOs:
- 60, 61, and 62
- [2] SEQ ID NOs:
- 63, 64, and 65
- [3] SEQ ID NOs:
- 78, 79, and 80
- [4] SEQ ID NOs:
- 84, 85, and 86
- [5] SEQ ID NOs:
- 93, 94, and 95
- [6] SEQ ID NOs:
- 96, 97, and 98
- [7] SEQ ID NOs:
- 102, 103, and 104
- [8] SEQ ID NOs:
- 108, 109, and 110
- [9] SEQ ID NOs:
- 111, 112, and 113
- [10] SEQ ID NOs:
- 114, 115, and 116.
An antibody that comprises a heavy chain variable region and a light chain variable region of any one of:
- [1] a heavy chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences consisting of SEQ ID NOs:
- 3, 4, and 5, and a light chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences consisting of SEQ ID NOs:
- 60, 61, and 62;
- [2] a heavy chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences consisting of SEQ ID NOs:
- 6, 7, and 8, and a light chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences consisting of SEQ ID NOs:
- 63, 64, and 65;
- [3] a heavy chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences consisting of SEQ ID NOs:
- 9, 10, and 11, and a light chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences consisting of SEQ ID NOs:
- 63, 64, and 65;
- [4] a heavy chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences consisting of SEQ ID NOs:
- 15, 16, and 17, and a light chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences consisting of SEQ ID NOs:
- 63, 64, and 65;
- [5] a heavy chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences consisting of SEQ ID NOs:
- 18, 19, and 20, and a light chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences consisting of SEQ ID NOs:
- 63, 64, and 65;
- [6] a heavy chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences consisting of SEQ ID NOs:
- 21, 22, and 23, and a light chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences consisting of SEQ ID NOs:
- 78, 79, and 80;
- [7] a heavy chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences consisting of SEQ ID NOs:
- 24, 25, and 26, and a light chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences consisting of SEQ ID NOs:
- 63, 64, and 65;
- [8] a heavy chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences consisting of SEQ ID NOs:
- 27, 28, and 29, and a light chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences consisting of SEQ ID NOs:
- 84, 85, and 86;
- [9] a heavy chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences consisting of SEQ ID NOs:
- 30, 31, and 32, and a light chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequence consisting of SEQ ID NOs:
- 63, 64, and 65;
- [10] a heavy chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences consisting of SEQ ID NOs:
- 33, 34, and 35, and a light chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences consisting of SEQ ID NOs:
- 63, 64, and 65;
- [11] a heavy chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences consisting of SEQ ID NOs:
- 36, 37, and 38, and a light chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences consisting of SEQ ID NOs:
- 93, 94, and 95;
- [12] a heavy chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences consisting of SEQ ID NOs:
- 39, 40, and 41, and a light chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences consisting of SEQ ID NOs:
- 96, 97, and 98;
- [13] a heavy chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences consisting of SEQ ID NOs:
- 42, 43, and 44, and a light chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences consisting of SEQ ID NOs:
- 78, 79, and 80;
- [14] a heavy chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences consisting of SEQ ID NOs:
- 45, 46, and 47, and a light chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences consisting of SEQ ID NOs:
- 102, 103, and 104;
- [15] a heavy chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences consisting of SEQ ID NOs:
- 48, 49, and 50, and a light chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences consisting of SEQ ID NOs:
- 63, 64, and 65;
- [16] a heavy chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences consisting of SEQ ID NOs:
- 51, 52, and 53, and a light chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences consisting of SEQ ID NOs:
- 108, 109, and 110,
- [17] a heavy chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences consisting of SEQ ID NOs:
- 54, 55, and 56, and a light chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences consisting of SEQ ID NOs:
- 111, 112, and 113;
- [18] a heavy chain variable region that comprises CDR1, CDR2, and CDR3 comprising the amino acid sequences consisting of SEQ ID NOs:
- 57, 58, and 59, and a light chain variable region that comprises CDR1, CDR2, and CDR3 each comprising the amino acid sequences consisting of SEQ ID NOs:
- 114, 115, and 116.
An antibody that comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:
- 118.
An antibody that comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:
- 120.
An antibody that comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:
- 118 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:
- 120.
An antibody comprising the amino acid sequence of SEQ ID NO:
- 122 or 264.
An antibody that comprises a heavy chain variable region, wherein said heavy chain variable region comprises FR1, FR2, FR3, and FR4 consisting of amino acid sequences of any one of:
- [1] SEQ ID NOs:
- 230, 232, 234, and 236
- [2] SEQ ID NOs:
- 265, 267, 269, and 271
- [3] SEQ ID NOs:
- 279, 281, 283, and 285
- [4] SEQ ID NOs:
- 298, 299, 300, and 301
- [5] SEQ ID NOs:
- 298, 299, 306, and 301.
An antibody comprising a light chain variable region, wherein said light chain variable region comprises FR1, FR2, FR3, and FR4 consisting of amino acid sequences of any one of:
- [1] SEQ ID NOs:
- 239, 241, 243, and 245
- [2] SEQ ID NOs:
- 272, 274, 276, and 278
- [3] SEQ ID NOs:
- 302, 303, 304, and 305
- [4] SEQ ID NOs:
- 302, 307, 308, and 305.
An antibody that comprises a heavy chain variable region and a light chain variable region of any one of:
- [1] a heavy chain variable region which comprises FR1, FR2, FR3, and FR4 having the amino acid sequences consisting of SEQ ID NOs:
- 230, 232, 234, and 236, and a light chain variable region which comprises FR1, FR2, FR3, and FR4 having the amino acid sequences consisting of SEQ ID NOs:
- 239, 241, 243, and 245;
- [2] a heavy chain variable region which comprises FR1, FR2, FR3, and FR4 having the amino acid sequences consisting of SEQ ID NOs:
- 265, 267, 269, and 271, and a light chain variable region which comprises FR1, FR2, FR3, and FR4 having the amino acid sequences consisting of SEQ ID NOs:
- 272, 274, 276, and 278;
- [3] a heavy chain variable region which comprises FR1, FR2, FR3, and FR4 having the amino acid sequences consisting of SEQ ID NOs:
- 279, 281, 283, and 285, and a light chain variable region which comprises FR1, FR2, FR3, and FR4 having the amino acid sequences consisting of SEQ ID NOs:
- 272, 274, 276, and 278;
- [4] a heavy chain variable region which comprises FR1, FR2, FR3, and FR4 having the amino acid sequences consisting of SEQ ID NOs:
- 298, 299, 300, and 301, and a light chain variable region which comprises FR1, FR2, FR3, and FR4 having the amino acid sequences consisting of SEQ ID NOs:
- 302, 303, 304, and 305;
- [5] a heavy chain variable region which comprises FR1, FR2, FR3, and FR4 having the amino acid sequences consisting of SEQ ID NOs:
- 298, 299, 306, and 301, and a light chain variable region which comprises FR1, FR2, FR3, and FR4 having the amino acid sequences consisting of SEQ ID NOs:
- 302, 307, 308, and 305.
An antibody that comprises a heavy chain variable region, wherein said heavy chain variable region comprises the amino acid sequence of SEQ ID NO:
- 229, 256, 262, 289, or 295.
An antibody that comprises a light chain variable region, wherein said light chain variable region comprises the amino acid sequence of SEQ ID NO:
- 238, 258, 291, or 297.
An antibody that comprises a heavy chain variable region and a light chain variable region of any one of:
- [1] a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:
- 229, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:
- 238;
- [2] a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:
- 256, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:
- 258;
- [3] a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:
- 262, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:
- 258;
- [4] a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:
- 289, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:
- 291;
- [5] a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:
- 295, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:
- 297.
An antibody that comprises the amino acid sequence of SEQ ID NO:
- 2, 254, 260, 287, or 293.
An antibody that recognizes the region of amino acids 26 to 274 of human Mpl.
Dependencies are inferred from the claim text.