METHOD FOR ALTERING PLASMA RETENTION AND IMMUNOGENICITY OF ANTIGEN-BINDING MOLECULE
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Abstract
The present invention demonstrated that the modification of the Fc region of an antigen-binding molecule into an Fc region that does not form in a neutral pH range a heterotetramer complex containing two molecules of FcRn and an active Fcγ receptor improved the pharmacokinetics of the antigen-binding molecule and reduced the immune response to the antigen-binding molecule. The present invention also revealed methods for producing antigen-binding molecules having the properties described above, and successfully demonstrated that pharmaceutical compositions containing as an active ingredient such an antigen-binding molecule or an antigen-binding molecule produced by a production method of the present invention have excellent features over conventional antigen-binding molecules in that when administered, they exhibit improved pharmacokinetics and reduced in vivo immune response.
58 Citations
88 Claims
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1-44. -44. (canceled)
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45. A method for improving pharmacokinetics and/or reducing immunogenicity of an antigen-binding molecule, the method comprising:
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identifying a first antigen-binding molecule comprising (a) an antigen-binding domain whose antigen-binding activity varies depending on pH or on calcium ion concentration, and (b) an Fc region that has FcRn-binding activity at pH 7.4; producing a second antigen-binding molecule that is identical to the first antigen-binding molecule except for at least one amino acid mutation in the Fc region, wherein the ability of the second antigen-binding molecule to form a heterocomplex with two molecules of FcRn and one molecule of activating Fcγ
receptor at pH 7.4 is reduced compared to the ability of the first antigen-binding molecule to form such a heterocomplex at pH 7.4; andconducting one or more assays to confirm that the second antigen-binding molecule has one or more of the following properties; (1) increased plasma retention compared to the first antigen-binding molecule, (2) decreased plasma clearance compared to the first antigen-binding molecule, (3) decreased immunogenicity compared to the first antigen-binding molecule. - View Dependent Claims (46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64)
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65. An antigen-binding molecule comprising:
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an antigen-binding domain whose antigen-binding activity varies depending on pH or on calcium ion concentration; and an Fc region that has FcRn-binding activity at pH 7.4, wherein the Fc region comprises one or more of the following amino acids (all positions by EU numbering); Ala at position 234; Ala, Lys, or Arg at position 235; Arg at position 236; Lys or Arg at position 237; Lys or Arg at position 238; Lys or Arg at position 239; Phe at position 270; Ala at position 297; Gly at position 298; Gly at position 325; Arg at position 328; Lys or Arg at position 329. - View Dependent Claims (66, 67, 68, 69, 70, 71, 72, 82, 83, 84, 85, 86, 87, 88)
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73. An antigen-binding molecule comprising:
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an antigen-binding domain whose antigen-binding activity varies depending on pH or on calcium ion concentration; and an Fc region comprising two polypeptides, wherein one of the two polypeptides of the Fc region has FcRn-binding activity at pH 7.4 and the other does not have FcRn-binding activity at pH 7.4. - View Dependent Claims (74, 75, 76, 77, 78, 79, 80, 81)
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Specification