• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    MOLECULES THAT BIND TO THE ANTIGEN, ITS PRODUCTION PROCESSES, AS WELL AS THE PHARMACEUTICAL COMPOSITION THAT INCLUDES THEM. An objective of the present invention is to provide processes to facilitate antigen capture mediated by molecules that bind to the antigen, facilitate the reduction of antigen concentration in plasma, increase the number of antigens to which a single molecule binds, improve pharmacokinetics of molecules that bind to the antigen and/or that molecules that bind to the antigen and/or that are, enhanced for the facilitated capture of antigens by the cells, capable of facilitating the reduction of the concentration of antigens in the plasma, capable of binding repeatedly to antigens and with improved pharmacokinetics, pharmaceutical compositions comprising such molecule and processes for the production of what was described above. The present inventors have found that antigen capture by cells is facilitated by antibodies that have binding activity to human FcRn at plasma pH and lower antigen binding activity at early endosomal pH; such antibodies can increase the number of antigens to which they bind; the reduction of antigen in plasma can be facilitated by administering such an antibody; and antibody pharmacokinetics can be improved through the use of these antibodies.
    公开号:BR112012024710A2
    申请号:R112012024710-7
    申请日:2011-03-30
    公开日:2021-04-27
    发明作者:Tomoyuki Igawa；Shinya Ishii；Atsuhiko Maeda；Tadashi NAKAI
    申请人:Chugai Seiyaku Kabushiki Kaisha；
    IPC主号:
    专利说明:

    [20] [20] the antigen-binding molecule of any one of [1] to [18], whose human FcRn binding domain comprises at least one amino acid selected from: 25 Met at amino acid position 237; Ala at amino acid position 238; Lys at amino acid position 239; Ile at amino acid position 248; Ala, Phe, Ile, Met, Gln, Ser, Val, Trp or Tyr at amino acid position 250; Phe, Trp or Tyr at amino acid position 252; Thr at amino acid position 254;
    [21] [21] the antigen-binding molecule of any one of [18] to [20], where the original IgG is selected from an IgG obtained from a non-human animal;
    [22] [22] the antigen-binding molecule of any one of [18] 15 to [20], where the original IgG is a human IgG;
    [23] [23] the antigen-binding molecule of any one of [1] through [22] that has antagonist activity;
    [24] [24] the antigen-binding molecule from [1] to [23], which binds with a membrane antigen or a soluble antigen; [25] the antigen-binding molecule of any one of [1] to [24], wherein the antigen-binding domain comprises an artificial ligand that binds with a receptor;
    [26] [26] the antigen-binding molecule of any one of [1] to [24], wherein the antigen-binding domain comprises an artificial receptor that binds with a ligand;
    [27] [27] the antigen-binding molecule of any one of [1] through [24], which is an antibody;
    [28] [28] the antigen-binding molecule of [27], wherein the antibody is selected from a chimeric antibody, a humanized antibody, or a human antibody;
    [29] [29] a pharmaceutical composition comprising any one of the antigen-binding molecule of [1] through [28];
    325; an amino acid substitution of Val for Ile at position 332; an amino acid substitution of Leu for Lys at position 334; 5 an amino acid substitution of His for Lys at position 360; an amino acid substitution of Ala for Asp at position 376; an amino acid substitution of Ala for Glu at position 380; an amino acid substitution of Ala for Glu at position 382; 10 an amino acid substitution of Ala for Asn or Ser at position 384; an amino acid substitution of Asp or His for Gly at position 385; an amino acid substitution of Pro for Gln at position 386; 15 an amino acid substitution of Glu for Pro at position 387; an amino acid substitution of Ala or Ser for Asn at position 389; an amino acid substitution of Ala for Ser at position 424; an amino acid substitution of Ala, Asp, Phe, Gly, His, Ile, 20 Lys, Leu, Asn, Pro, Gln, Ser, Thr, Val, Trp or Tyr for Met at position 428; an amino acid substitution of Lys for His at position 433; an amino acid substitution of Ala, Phe, His, Ser, Trp or Tyr for Asn at position 434; and an amino acid substitution of His or Phe for Tyr at position 436 (EU numbering) in the Fc domain of the original IgG.
    Meanwhile, the number of amino acids that will be changed is not particularly limited; and it is possible to change amino acids only at a single site or at two or more sites.
    Combinations of two or more amino acid changes include, for example, those shown in Table 3. Meanwhile, the 30 combinations of changes that can potentiate binding to human FcRn in the acidic pH range when compared to the original human IgG are shown in Tables 4-1 through 4-5. When combinations of appropriate alterations that can also potentiate binding to human FcRn in the neutral pH range are selected from the alterations described above, these are applicable to the present invention.
    Furthermore, combinations of alterations that can potentiate the binding of Fv4-IgG1 to human FcRn 5 under neutral conditions are shown in Tables 6-1 and 6-2. The symbol "^" in the Tables shows an amino acid insertion after the number indicated in the EU numbering.
    For example, ^281S means that S is entered between positions 281 and 282 in EU numbering.
    Table 1 Position Amino Acid Change
    10 an amino acid substitution of His for Lys at position 360; an amino acid substitution of Ala for Asp at position 376; an amino acid substitution of Ala for Glu at position 380; 5 an amino acid substitution of Ala for Glu at position 382; an amino acid substitution of Ala for Asn or Ser at position 384; an amino acid substitution of Asp or His for Gly at position 385; 10 an amino acid substitution of Pro for Gln at position 386; an amino acid substitution of Glu for Pro at position 387; an amino acid substitution of Ala or Ser for Asn at position 389; an amino acid substitution of Ala for Ser at position 424; 15 an amino acid substitution of Ala, Asp, Phe, Gly, His, Ile, Lys, Leu, Asn, Pro, Gln, Ser, Thr, Val, Trp or Tyr for Met at position 428; an amino acid substitution of Lys for His at position 433; an amino acid substitution of Ala, Phe, His, Ser, Trp or Tyr for Asn at position 434; 20 and an amino acid substitution of His or Phe for Tyr at position 436 in EU numbering.
    The number of amino acids that will be changed is not particularly limited; it is possible to change an amino acid only at a single site or two or more sites.
    Combinations of two or more amino acid changes include, for example, those shown in Tables 3, 4-1 through 4-5, 6-1, 6-2 and 9. of human FcRn binding in the acidic and neutral pH ranges include, for example, human FcRn binding domains that comprise at least one amino acid selected from: Met at amino acid position 237; Ala at amino acid position 238;
    Lys at amino acid position 239; Ile at amino acid position 248; Ala, Phe, Ile, Met, Gln, Ser, Val, Trp or Tyr at amino acid position 250; 5 Phe, Trp or Tyr at amino acid position 252; Thr at amino acid position 254; Glu at amino acid position 255; Asp, Glu or Gln at amino acid position 256; Ala, Gly, Ile, Leu, Met, Asn, Ser, Thr or Val at amino acid position 257; His at amino acid position 258; Ala at amino acid position 265; Phe at amino acid position 270; Ala or Glu at amino acid position 286; 15 His at amino acid position 289; Ala at amino acid position 297; Gly at amino acid position 298; Ala at amino acid position 303; Ala at amino acid position 305; 20 Ala, Asp, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Val, Trp or Tyr at amino acid position 307; Ala, Phe, Ile, Leu, Met, Pro, Gln or Thr at amino acid position 308; Ala, Asp, Glu, Pro or Arg at amino acid position 309; 25 Ala, His or Ile at amino acid position 311; Ala or His at amino acid position 312; Lys or Arg at amino acid position 314; Ala or His at amino acid position 315; Ala at amino acid position 317; 30 Gly at amino acid position 325; Val at amino acid position 332; Read at amino acid position 334;
    His at amino acid position 360; Ala at amino acid position 376; Ala at amino acid position 380; Ala at amino acid position 382; 5 Ala at amino acid position 384; Asp or His at amino acid position 385; Pro at amino acid position 386; Glu at amino acid position 387; Ala or Ser at amino acid position 389; 10 Ala at amino acid position 424; Ala, Asp, Phe, Gly, His, Ile, Lys, Leu, Asn, Pro, Gln, Ser, Thr, Val, Trp or Tyr at amino acid position 428; Lys at amino acid position 433; Ala, Phe, His, Ser, Trp or Tyr at amino acid position 434; 15 and His or Phe at amino acid position 436 (EU numbering) in the Fc domain of the original IgG.
    An amino acid at one site or amino acids at two or more sites can have these amino acids.
    Combinations of amino acids at two or more positions include, for example, those shown in Tables 3, 20 4-1 through 4-5, 6-1, 6-2 and 9. Alternatively, in a preferred embodiment, the molecule that matches binds to antigen whose antigen-binding activity in the acidic pH range is less than that in the neutral pH range includes antigen-binding molecules in which at least one amino acid in the antigen-binding molecule is replaced by histidine or an unnatural amino acid or in which at least one histidine or an unnatural amino acid has been inserted.
    The site at which the histidine or unnatural amino acid mutation is introduced is not particularly limited and can be any site, as long as the antigen-binding activity in the acidic pH range is weaker than that in the pH range. neutral (the KD value (in the acidic pH range)/KD (in the neutral pH range) is higher or the KD value (in the acidic pH range)/KD (in the neutral pH range) is higher) when compared com before replacement.
    权利要求:
    Claims (57)
    [1]
    1. Antigen-binding molecule, characterized by the fact that it comprises an antigen-binding domain and a human FcRn-binding domain, which has a binding activity to human FcRn 5 in the neutral pH ranges, where the binding activity to human FcRn in the neutral pH range is stronger than 3.2 micromolar KD.
    [2]
    2. Antigen-binding molecule, characterized by the fact that it comprises an antigen-binding domain and a human FcRn-binding domain, which has a binding activity to human FcRn 10 in the neutral pH ranges, where the binding activity to human FcRn in the neutral pH range is 28 times stronger than that of an intact human IgG.
    [3]
    3. Antigen-binding molecule, characterized by the fact that it comprises an antigen-binding domain and a human FcRn-binding domain, which has a binding activity to human FcRn 15 in the neutral pH ranges, where the binding activity to human FcRn in the neutral pH range is stronger than KD 2.3 micromolar.
    [4]
    4. Antigen-binding molecule, characterized by the fact that it comprises an antigen-binding domain and a human FcRn-binding domain, which has a binding activity to human FcRn 20 in the neutral pH ranges, where the binding activity to human FcRn in the neutral pH range is 38 times stronger than that of an intact human IgG.
    [5]
    5. Antigen-binding molecule according to any one of claims 1 to 4, characterized in that the neutral pH range is pH 7.0 to 8.0. 25
    [6]
    6. Antigen-binding molecule, characterized in that it comprises an antigen-binding domain and a human FcRn-binding domain in which a concentration of total antigens in the plasma after administration of the antigen-binding molecule a non-human animal is less than a plasma total antigen concentration 30 after administration of a reference molecule that binds antigen to a non-human animal that comprises the same antigen-binding domain and Fc domain of human IgG intact as a binding domain Petition 870210031404, 04/06/2021, p. 15/31 ws/DOCS/SDA P189104/REPORT/15995203v1 to human FcRn.
    [7]
    7. Antigen-binding molecule, characterized by the fact that the concentration of antigens in plasma after administration of the antigen-binding molecule to a non-human animal is less than a concentration of total antigens in the plasma obtained. starting from the non-human animal to which the antigen-binding molecule is not administered.
    [8]
    8. Antigen-binding molecule, characterized by the fact that it comprises an antigen-binding domain and a human FcRn-binding domain in which a molar ratio of antigen/molecule 10 that binds to the (C) antigen of the antigen-binding molecule calculated as follows; C=A/B, is less than a molar ratio of antigen/antigen-binding molecule (C') of an antigen-binding reference molecule 15 comprising the same antigen-binding domain and the Fc domain of intact human IgG as a human FcRn binding domain calculated as follows; C'=A'/B', where; 20 A is a plasma concentration of total antigens after administration of the antigen-binding molecule to a non-human animal, B is a plasma concentration of an antigen-binding molecule after administration of the antigen-binding molecule a non-human animal, 25 A' is a plasma concentration of total antigens after administration of a reference molecule that binds to the non-human animal antigen, B' is a plasma concentration of a molecule that binds to the antigen after administration of a reference molecule that binds to the antigen to a non-human animal.
    [9]
    9. Antigen-binding molecule according to any one of claims 6 to 8, characterized in that the non-human animal is a transgenic mouse for human FcRn.
    [10]
    10. Antigen-binding molecule according to any one of claims 6 to 9, characterized in that the plasma antigen concentration is a long-term total antigen concentration in the plasma.
    [11]
    11. Antigen-binding molecule according to any one of claims 6 to 9, characterized in that the plasma antigen concentration is a short-term total antigen concentration in the plasma. 10
    [12]
    12. Antigen-binding molecule, characterized by the fact that it comprises an antigen-binding domain and a human FcRn-binding domain, which has a binding activity to human FcRn in the acidic and neutral pH ranges and a lower antigen-binding activity in the acidic pH range than in the neutral pH range, where the binding activity to human FcRn in the neutral pH range is stronger than that of an intact human IgG.
    [13]
    13. Antigen-binding molecule according to any one of claims 1 to 11, characterized in that the antigen-binding activity of the antigen-binding domain in the acidic pH range 20 is less than that in the pH range neutral.
    [14]
    Antigen-binding molecule according to claim 12 or 13, characterized in that the proportion of antigen-binding activity in the acidic pH range and the neutral pH range is at least 2 in value. of KD (in the acidic pH range) /KD (in the neutral pH range). 25
    [15]
    15.Antigen-binding molecule according to any one of claims 12 to 14, characterized in that it comprises an amino acid mutation of the antigen-binding domain, which comprises a substitution of histidine by at least one amino acid of the antigen-binding domain or the insertion of at least one histidine. 30
    [16]
    16. Antigen-binding molecule according to any one of claims 12 to 14, characterized in that the antigen-binding domain is obtained starting from the library of antigen-binding domains.
    [17]
    17. Antigen-binding molecule according to any one of claims 1 to 16, characterized in that it comprises as the human FcRn binding domain an Fc domain resulting from the replacement of a different amino acid by at least one amino acid in the Fc domain of the original IgG.
    [18]
    18. Antigen-binding molecule according to any one of claims 1 to 17, characterized in that the human FcRn binding domain is a human FcRn binding domain comprising an amino acid sequence with a substitution of an amino acid different by at least one amino acid selected from those at positions 237, 238, 239, 248, 250, 252, 254, 255, 256, 257, 258, 265, 270, 286, 289, 297, 298, 303, 305, 307, 308, 309, 311, 312, 314, 315, 317, 325, 332, 334, 360, 376, 380, 382, 384, 385, 386, 387, 389, 424, 428, 433, 15 434 and 436 (EU numbering) in the Fc domain of the original IgG.
    [19]
    19. Antigen-binding molecule according to any one of claims 1 to 18, characterized in that it comprises a human FcRn binding domain comprising the amino acid substitution in the Fc domain of the original IgG comprising at least 20 one amino acid substitution selected from: an amino acid substitution of Met by Gly at position 237; an amino acid substitution of Ala for Pro at position 238; an amino acid substitution of Lys for Ser at position 239; 25 an amino acid substitution of Ile for Lys at position 248; an amino acid substitution of Ala, Phe, Ile, Met, Gln, Ser, Val, Trp or Tyr for Thr at position 250; an amino acid substitution of Phe, Trp or Tyr for Met at position 252; 30 an amino acid substitution of Thr for Ser at position 254; an amino acid substitution of Glu for Arg at position 255; an amino acid substitution of Asp, Glu or Gln for Thr at position 256; an amino acid substitution of Ala, Gly, Ile, Leu, Met, Asn, Ser, Thr or Val for Pro at position 257; an amino acid substitution of His for Glu at position 258; 5 an amino acid substitution of Ala for Asp at position 265; an amino acid substitution of Phe for Asp at position 270; an amino acid substitution of Ala or Glu for Asn at position 286; an amino acid substitution of His for Thr at position 289; an amino acid substitution of Ala for Asn at position 297; an amino acid substitution of Gly for Ser at position 298; 15 an amino acid substitution of Ala for Val at position 303; an amino acid substitution of Ala for Val at position 305; an amino acid substitution of Ala, Asp, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Val, Trp or Tyr for Thr at position 307; 20 an amino acid substitution of Ala, Phe, Ile, Leu, Met, Pro, Gln or Thr for Val at position 308; an amino acid substitution of Ala, Asp, Glu, Pro or Arg for Leu or Val at position 309; an amino acid substitution of Ala, His or Ile for Gln at position 311; an amino acid substitution of Ala or His for Asp at position 312; an amino acid substitution of Lys or Arg for Leu at position 314; 30 an amino acid substitution of Ala or His for Asn at position 315; an amino acid substitution of Ala for Lys at position 317;
    an amino acid substitution of Gly for Asn at position 325; an amino acid substitution of Val for Ile at position 332; an amino acid substitution of Leu for Lys at position 5 334; an amino acid substitution of His for Lys at position 360; an amino acid substitution of Ala for Asp at position 376; an amino acid substitution of Ala for Glu at position 380; 10 an amino acid substitution of Ala for Glu at position 382; an amino acid substitution of Ala for Asn or Ser at position 384; an amino acid substitution of Asp or His for Gly at position 385; 15 an amino acid substitution of Pro for Gln at position 386; an amino acid substitution of Glu for Pro at position 387; an amino acid substitution of Ala or Ser for Asn at position 389; an amino acid substitution of Ala for Ser at position 424; 20 an amino acid substitution of Ala, Asp, Phe, Gly, His, Ile, Lys, Leu, Asn, Pro, Gln, Ser, Thr, Val, Trp or Tyr for Met at position 428; an amino acid substitution of Lys for His at position 433; an amino acid substitution of Ala, Phe, His, Ser, Trp or Tyr for Asn at position 434; 25 and an amino acid substitution of His or Phe for Tyr at position 436 in EU numbering.
    [20]
    20. Antigen-binding molecule according to any one of claims 1 to 18, characterized in that the human FcRn binding domain comprises at least one amino acid selected from: Met at amino acid position 237; Ala at amino acid position 238;
    Lys at amino acid position 239; Ile at amino acid position 248; Ala, Phe, Ile, Met, Gln, Ser, Val, Trp or Tyr at amino acid position 250; 5 Phe, Trp or Tyr as an amino acid position 252; Thr at amino acid position 254; Glu at amino acid position 255; Asp, Glu or Gln at amino acid position 256; Ala, Gly, Ile, Leu, Met, Asn, Ser, Thr or Val at amino acid position 257; His at amino acid position 258; Ala at amino acid position 265; Phe at amino acid position 270; Ala or Glu at amino acid position 286; 15 His at amino acid position 289; Ala at amino acid position 297; Gly at amino acid position 298; Ala at amino acid position 303; Ala at amino acid position 305; 20 Ala, Asp, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Val, Trp or Tyr at amino acid position 307; Ala, Phe, Ile, Leu, Met, Pro, Gln or Thr at amino acid position 308; Ala, Asp, Glu, Pro or Arg at amino acid position 309; 25 Ala, His or Ile at amino acid position 311; Ala or His at amino acid position 312; Lys or Arg at amino acid position 314; Ala or His at amino acid position 315; Ala at amino acid position 317; 30 Gly at amino acid position 325; Val at amino acid position 332; Read at amino acid position 334;
    His at amino acid position 360; Ala at amino acid position 376; Ala at amino acid position 380; Ala at amino acid position 382; 5 Ala at amino acid position 384; Asp or His at amino acid position 385; Pro at amino acid position 386; Glu at amino acid position 387; Ala or Ser at amino acid position 389; 10 Ala at amino acid position 424; Ala, Asp, Phe, Gly, His, Ile, Lys, Leu, Asn, Pro, Gln, Ser, Thr, Val, Trp or Tyr at amino acid position 428; Lys at amino acid position 433; Ala, Phe, His, Ser, Trp or Tyr at amino acid position 434; 15 and His or Phe as an amino acid at position 436 (EU numbering) in the Fc domain of the original IgG.
    [21]
    21. Antigen-binding molecule according to any one of claims 18 to 20, characterized in that the original IgG is selected from an IgG obtained from a non-human animal. 20
    [22]
    22. Antigen-binding molecule according to any one of claims 18 to 20, characterized in that the original IgG is a human IgG.
    [23]
    23. An antigen-binding molecule according to any one of claims 1 to 22, characterized in that it has an antagonistic activity.
    [24]
    24. Antigen-binding molecule according to any one of claims 1 to 23, characterized in that it binds with a membrane antigen or a soluble antigen.
    [25]
    25.Antigen-binding molecule according to any one of claims 1 to 24, characterized in that the antigen-binding domain comprises an artificial ligand that binds with a receptor.
    [26]
    26. Antigen-binding molecule according to any one of claims 1 to 24, characterized in that the antigen-binding domain comprises an artificial receptor that binds with a ligand. 5
    [27]
    27. Antigen-binding molecule according to any one of claims 1 to 24, characterized in that it is an antibody.
    [28]
    28. Antigen-binding molecule according to claim 27, characterized in that the antibody is selected from a chimeric antibody, a humanized antibody or a human antibody.
    [29]
    29. Pharmaceutical composition, characterized in that it comprises any one of the molecule that binds to the antigen as defined in any one of claims 1 to 28.
    [30]
    30. Process to facilitate the capture of antigens mediated by the 15 molecule that binds to the antigen by a cell, characterized by the fact that it is through the increase of its binding activity to human FcRn in the neutral pH range, in which the molecule that antigen-binding comprises an antigen-binding domain and a human FcRn-binding domain and has a human FcRn-binding activity in the acidic pH range. 20
    [31]
    31. Process to facilitate the capture of antigens mediated by the molecule that binds to the antigen by a cell, characterized by the fact that it is through the increase of its binding activity to human FcRn in the neutral pH range and the reduction of its activity of antigen binding in the acidic pH range to less than that in the neutral pH range, wherein the antigen-binding molecule comprises an antigen-binding domain and a human FcRn-binding domain and has binding activity to Human FcRn in the acidic pH range.
    [32]
    32. Process to increase the number of antigens to which a single antigen-binding molecule can bind, characterized by the fact that it is through increasing its binding activity to human FcRn in the neutral pH range, in that the antigen-binding molecule comprises an antigen-binding domain and an antigen-binding domain.
    Human FcRn and has a binding activity to human FcRn in the acidic pH range.
    [33]
    33. Process to increase the number of antigens to which a single antigen-binding molecule can bind, characterized by the fact that it is by increasing its binding activity to human FcRn in the neutral pH range and reducing its antigen-binding activity in the acidic pH range to less than that in the neutral pH range, where the antigen-binding molecule comprises an antigen-binding domain and a human FcRn-binding domain and it has a binding activity to human FcRn in the acidic pH range.
    [34]
    34. Process to increase the capacity of an antigen-binding molecule to eliminate an antigen from the plasma, characterized by the fact that it is through the increase of its binding activity to human FcRn in the neutral pH range, where the An antigen binding molecule 15 comprises an antigen binding domain and a human FcRn binding domain and has human FcRn binding activity in the acidic pH range.
    [35]
    35. Process to increase the ability of an antigen-binding molecule to eliminate an antigen from the plasma, characterized by the fact that it is through the increase of its binding activity to human FcRn in the neutral pH range and the reduction from its antigen-binding activity in the acidic pH range to less than that in the neutral pH range, where the antigen-binding molecule comprises an antigen-binding domain and a human FcRn-binding domain and has a binding activity to human FcRn in the acidic pH range.
    [36]
    36. Process to improve the pharmacokinetics of an antigen-binding molecule, characterized by the fact that it is through the increase of its binding activity to human FcRn in the neutral pH range, in which the molecule that binds to the antigen comprises an antigen binding domain and a human FcRn binding domain and has human FcRn binding activity in the acidic pH range.
    [37]
    37. Process to improve the pharmacokinetics of an antigen-binding molecule, characterized by the fact that it is through the increase of its binding activity to human FcRn in the neutral pH range and the reduction of its binding activity to the antigen in the acidic pH range to less than that in the neutral pH range, where the antigen-binding molecule comprises an antigen-binding domain and a human FcRn-binding domain and has human FcRn-binding activity. not in the acidic pH range.
    [38]
    38. Process to facilitate the intracellular dissociation of an antigen bound to a molecule that binds to the antigen outside the cell of the molecule that binds to the antigen, characterized by the fact that it is through the increase of its binding activity to human FcRn in the neutral pH range and reducing its antigen-binding activity in the acidic pH range to less than that in the neutral pH range, where the antigen-binding molecule comprises an antigen-binding domain and a human FcRn binding domain 15 and has a human FcRn binding activity in the acidic pH range.
    [39]
    39. Process to facilitate extracellular release of the antigen-free form of an antigen-binding molecule captured by a cell in an antigen-bound form, characterized by the fact that it is 20 by increasing its binding activity to human FcRn in the neutral pH range and the reduction of its antigen-binding activity in the acidic pH range to less than that in the neutral pH range, where the antigen-binding molecule comprises an antigen-binding domain and a domain binding to human FcRn and has a binding activity to human FcRn in the acidic pH range.
    [40]
    40. Process to reduce the concentration of total antigens in plasma or free in plasma, characterized by the fact that it is through the increase of its binding activity to human FcRn in the neutral pH range, in which the molecule that binds to the antigen comprises an antigen binding domain and a human FcRn binding domain and has human FcRn binding activity in the acidic pH range.
    [41]
    41. Process to reduce the concentration of total plasma or free antigens in plasma, characterized by the fact that it is through the increase of its binding activity to human FcRn in the neutral pH range and the reduction of its binding activity to the antigen in the acidic pH range to less than that in the neutral pH range, wherein the antigen-binding molecule comprises an antigen-binding domain and a human FcRn-binding domain and has a human FcRn-binding activity - not in the acidic pH range.
    [42]
    42. Process according to any one of claims 30 to 41, characterized in that the acidic pH range is pH 5.5 to 6.5 10 and the neutral pH range is pH 7.0 to 8.0.
    [43]
    43. Process according to any one of claims 30 to 41, characterized in that the increase in binding activity to human FcRn in the neutral pH range is an increase through the replacement of a different amino acid by at least one amino acid in the domain Fc 15 of the original IgG from the human FcRn binding domain.
    [44]
    44. Process according to any one of claims 30 to 41, characterized in that the increase in binding activity to human FcRn in the neutral pH range is an increase through the replacement of a different amino acid by at least one amino acid selected 20 of those at positions 237, 238, 239, 248, 250, 252, 254, 255, 256, 257, 258, 265, 270, 286, 289, 297, 298, 303, 305, 307, 308, 309, 311 , 312, 314, 315, 317, 325, 332, 334, 360, 376, 380, 382, 384, 385, 386, 387, 389, 424, 428, 433, 434 and 436 (EU numbering) in the Fc domain of Original IgG from the human FcRn binding domain. 25
    [45]
    45. Process according to any one of claims 31, 33, 35, 37 to 39 and 41, characterized in that the antigen-binding activity of the molecule that binds to the antigen in the acidic pH range is reduced until less than that in the neutral pH range by replacing histidine with at least one amino acid of the antigen-binding molecule or inserting at least one histidine.
    [46]
    46. Process according to any one of claims 31, 33, 35, 37 to 39 and 41, characterized in that the alloy domain
    Antigen binding is obtained from the library of antigen binding domains.
    [47]
    47. Process according to any one of claims 31, 33, 35, 37 to 39 and 41, characterized in that the decrease in the antigen-binding activity is represented by an increase in the KD value (in the range of acidic pH) /KD (in the neutral pH range) which is a ratio of antigen-binding activity in the acidic pH range and the neutral pH range, relative to before the substitution or insertion of histidine.
    [48]
    48. Process for the production of a molecule that binds to the antigen, characterized by the fact that it comprises the steps of: (a) selection of a molecule that binds to the antigen that has the strongest human FcRn binding activity in the range pH neutral than 3.2 micromolar KD obtained by altering at least one amino acid in the human FcRn binding domain of an antigen-binding molecule; (b) obtaining a gene encoding an antigen-binding molecule in which a human FcRn-binding domain and an antigen-binding domain prepared in (a) are linked; and (c) production of an antigen-binding molecule using the gene prepared in (b).
    [49]
    49. Process for the production of a molecule that binds to the antigen, characterized by the fact that it comprises the steps of: (a) selection of a molecule that binds to the antigen that has the strongest human FcRn binding activity in the range of neutral pH of 25 than before the change of at least one amino acid in the human FcRn-binding domain of an antigen-binding molecule that has human FcRn-binding activity in the acidic pH range; (b) alteration of at least one amino acid in the antigen-binding domain of an antigen-binding molecule and selection of an antigen-binding molecule that has the strongest antigen-binding activity in the range of neutral pH than in the acidic pH range; (c) obtaining a gene encoding an antigen-binding molecule in which a human FcRn-binding domain and an antigen-binding domain prepared in (a) and (b) are linked; and (d) production of an antigen-binding molecule using the gene prepared in (c). 5
    [50]
    50. Process for the production of a molecule that binds to the antigen, characterized by the fact that it comprises the steps of: (a) selection of a molecule that binds to the antigen that has the strongest human FcRn binding activity in the range of neutral pH than before the change of at least one amino acid in the human FcRn-binding domain 10 of an antigen-binding molecule that has human FcRn-binding activity in the acidic pH range; (b) selection of an antigen-binding molecule that has stronger antigen-binding activity in the neutral pH range than in the acidic pH range; (c) obtaining a gene encoding an antigen-binding molecule in which a human FcRn-binding domain and an antigen-binding domain prepared in (a) and (b) are linked; and (d) production of an antigen-binding molecule using the gene prepared in (c). 20
    [51]
    51. Antigen-binding molecule, characterized in that it is obtained through the production process as defined in any one of claims 48 to 50.
    [52]
    52. Process for the verification of a molecule that binds to the antigen, characterized by the fact that it comprises the steps of: 25 (a) selection of a molecule that binds to the antigen that has binding activity to the strongest human FcRn in the range pH neutral than 3.2 micromolar KD obtained by altering at least one amino acid in the human FcRn binding domain of an antigen-binding molecule; (b) obtaining a gene encoding an antigen-binding molecule in which a human FcRn-binding domain and an antigen-binding domain prepared in (a) are linked; and
    (c) production of an antigen-binding molecule using the gene prepared in (b).
    [53]
    53. Process for the verification of a molecule that binds to the antigen, characterized by the fact that it comprises the steps of: 5 (a) selection of a molecule that binds to the antigen that has the strongest human FcRn binding activity in the range pH neutral than before the change of at least one amino acid in the human FcRn-binding domain of an antigen-binding molecule that has human FcRn-binding activity in the acidic pH range; 10 (b) alteration of at least one amino acid in the antigen-binding domain of an antigen-binding molecule and selection of an antigen-binding molecule that has the strongest antigen-binding activity in the range of neutral pH than in the acidic pH range; (c) obtaining a gene encoding an antigen-binding molecule in which a human FcRn-binding domain and an antigen-binding domain prepared in (a) and (b) are linked; and (d) production of an antigen-binding molecule using the gene prepared in (c).
    [54]
    54. Process for the verification of a molecule that binds to the antigen, characterized by the fact that it comprises the steps of: (a) selection of a molecule that binds to the antigen that has the strongest human FcRn binding activity in the range pH neutral than before changing at least one amino acid in the human FcRn-binding domain of an antigen-binding molecule that has human FcRn-binding activity in the acidic pH range; (b) selection of an antigen-binding molecule that has stronger antigen-binding activity in the neutral pH range than in the acidic pH range; (c) obtaining a gene encoding an antigen binding molecule in which a human FcRn binding domain and an antigen binding domain prepared in (a) and (b) are linked; and (d) production of an antigen-binding molecule using the gene prepared in (c).
    [55]
    55. Process according to any one of claims 30 to 54, characterized in that the antigen-binding domain comprises an artificial ligand that binds with a receptor. 5
    [56]
    56. Process according to any one of claims 30 to 54, characterized in that the antigen-binding domain comprises an artificial receptor that binds with a ligand.
    [57]
    57. Process according to any one of claims 30 to 54, characterized in that the molecule that binds to the antigen is an antibody.
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    法律状态:
    2021-05-11| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2021-06-01| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI N? 10196/2001, QUE MODIFICOU A LEI N? 9279/96, A CONCESS?O DA PATENTE EST? CONDICIONADA ? ANU?NCIA PR?VIA DA ANVISA. CONSIDERANDO A APROVA??O DOS TERMOS DO PARECER N? 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL N? 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVID?NCIAS CAB?VEIS. |
    2021-07-06| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|
    2021-07-13| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2021-11-03| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|
    优先权:
    申请号 | 申请日 | 专利标题
    JP2010079667|2010-03-30|
    JP2010-079667|2010-03-30|
    JP2010250830|2010-11-09|
    JP2010-250830|2010-11-09|
    PCT/JP2011/001888|WO2011122011A2|2010-03-30|2011-03-30|Antibodies with modified affinity to fcrn that promote antigen clearance|
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