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US-12624089-B2 - Antigen-binding molecule for promoting disappearance of antigen via FcγRIIB

US12624089B2US 12624089 B2US12624089 B2US 12624089B2US-12624089-B2

Abstract

The present invention provides antigen-binding molecules containing (i) an antigen-binding domain whose antigen-binding activity varies depending on ion concentration conditions, (ii) an FcγR-binding domain having Fcγ RIIb-selective binding activity, and (iii) an FcRn-binding domain having FcRn-binding activity under an acidic pH range condition, and methods of decreasing plasma antigen concentration as compared to before administering the molecule, which include the step of administering the molecule.

Inventors

  • Tomoyuki Igawa
  • Atsuhiko Maeda
  • Yuki Iwayanagi
  • Kenta Haraya
  • Hitoshi Katada
  • Shojiro Kadono
  • Futa Mimoto

Assignees

  • CHUGAI SEIYAKU KABUSHIKI KAISHA

Dates

Publication Date
20260512
Application Date
20220630
Priority Date
20120824

Claims (12)

  1. 1 . A pharmaceutical composition comprising an antibody comprising a heavy chain constant region comprising SEQ ID NO: 14 with at least the following substitutions: L234Y/P238D/A330K, wherein all position numbers are by EU numbering.
  2. 2 . The pharmaceutical composition of claim 1 , wherein the heavy chain constant region further comprises a V264I substitution, by EU numbering.
  3. 3 . The pharmaceutical composition of claim 1 , wherein the heavy chain constant region further comprises a K439E substitution, by EU numbering.
  4. 4 . The pharmaceutical composition of claim 2 , wherein the heavy chain constant region further comprises a K439E substitution, by EU numbering.
  5. 5 . The pharmaceutical composition of claim 1 , wherein the antibody further comprises a human or humanized heavy chain variable domain, a human or humanized light chain variable domain, and a human light chain constant region.
  6. 6 . The pharmaceutical composition of claim 2 , wherein the antibody further comprises a human or humanized heavy chain variable domain, a human or humanized light chain variable domain, and a human light chain constant region.
  7. 7 . A pharmaceutical composition comprising an antibody comprising a heavy chain constant region comprising SEQ ID NO: 14 with at least the following substitutions: L234Y/P238D/A330K, and with a deletion of the two carboxy-terminal amino acids, wherein all position numbers are by EU numbering.
  8. 8 . The pharmaceutical composition of claim 7 , wherein the heavy chain constant region further comprises a V264I substitution, by EU numbering.
  9. 9 . The pharmaceutical composition of claim 7 , wherein the heavy chain constant region further comprises a K439E substitution, by EU numbering.
  10. 10 . The pharmaceutical composition of claim 8 , wherein the heavy chain constant region further comprises a K439E substitution, by EU numbering.
  11. 11 . The pharmaceutical composition of claim 7 , wherein the antibody further comprises a human or humanized heavy chain variable domain, a human or humanized light chain variable domain, and a human light chain constant region.
  12. 12 . The pharmaceutical composition of claim 8 , wherein the antibody further comprises a human or humanized heavy chain variable domain, a human or humanized light chain variable domain, and a human light chain constant region.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a divisional application of U.S. application Ser. No. 14/379,825, filed on Aug. 20, 2014, which is the National Stage of International Application No. PCT/JP2013/054461, filed on Feb. 22, 2013, which claims the benefit of International Application No. PCT/JP2012/054624, filed on Feb. 24, 2012, and Japanese Application No. 2012-185866, filed on Aug. 24, 2012, and International Application No. PCT/JP2012/075092, filed on Sep. 28, 2012. The contents of the foregoing U.S. application are incorporated by reference. SEQUENCE LISTING This application contains a Sequence Listing that has been submitted electronically as an ASCII text file named SequenceListing.txt. The ASCII text file, created on Jun. 28, 2022, is 204 kilobytes in size. The material in the ASCII text file is hereby incorporated by reference in its entirety. TECHNICAL FIELD The present invention provides uses of antigen-binding molecules for eliminating antigens from plasma; methods for eliminating antigens from plasma, which comprise administering antigen-binding molecules; pharmaceutical compositions comprising antigen-binding molecules that are capable of eliminating antigens from plasma; and methods for producing antigen-binding molecules for eliminating antigens from plasma. BACKGROUND ART Antibodies are drawing attention as pharmaceuticals as they are highly stable in plasma and have few side effects. At present, a number of IgG-type therapeutic antibodies are available on the market and many therapeutic antibodies are currently under development (Non-patent Documents 1 and 2). Meanwhile, various technologies applicable to second-generation therapeutic antibodies have been reported, including those that enhance effector function, antigen-binding ability, pharmacokinetics, and stability, and those that reduce the risk of immunogenicity (Non-patent Document 3). In general, the requisite dose of a therapeutic antibody is very high. This, in turn, has led to problems, such as high production cost, as well as the difficulty in producing subcutaneous formulations. In theory, the dose of a therapeutic antibody may be reduced by improving antibody pharmacokinetics or improving the affinity between antibodies and antigens. Literature has reported methods for improving antibody pharmacokinetics using artificial substitution of amino acids in constant regions (Non-patent Documents 4 and 5). Similarly, affinity maturation has been reported as a technology for enhancing antigen-binding activity and/or antigen-neutralizing activity of an antibody (Non-patent Document 6). This technology enables enhancement of antigen-binding activity by introduction of amino acid mutations into the CDR region of a variable region or such. The enhancement of antigen-binding ability enables improvement of in vitro biological activity or reduction of dosage, and further enables improvement of in vivo efficacy (Non-patent Document 7). The antigen-neutralizing capacity of a single antibody molecule having neutralizing activity depends on its affinity. Therefore, the affinity of antibodies has been enhanced using various methods in order to neutralize antigens with a small amount of antibodies (Non-patent Document 6). Furthermore, if the affinity of the antibody to the antigen could be made infinite by covalent binding to the antigen, a single antibody molecule could neutralize one antigen molecule (a divalent antibody can neutralize two antigen molecules). However, the stoichiometric neutralization reaction of one antibody molecule against one antigen molecule (one divalent antibody against two antigens) is the limit of such methods, and thus it is impossible to completely neutralize antigen with an amount of antibody smaller than the amount of antigen. That is, antigen-neutralizing effect by enhancing affinity has a limit (Non-patent Document 8). To sustain the neutralization effect of a neutralizing antibody for a certain period, the antibody must be administered at a dose higher than the amount of antigens produced in the body during the same period. With just the improvement of antibody pharmacokinetics or affinity maturation technology described above, there is thus a limitation in the reduction of the required antibody dose. Accordingly, in order to sustain the antigen-neutralizing effect for a target period with an amount of antibody smaller than the amount of antigen, a single antibody must neutralize multiple antigens. An antigen-binding molecule that binds to an antigen in a pH- and/or metal ion concentration-dependent manner has recently been reported as a novel method for achieving the above objective (Patent Documents 1 and 2). The ion concentration-dependent antigen-binding molecules, which strongly bind to an antigen under neutral pH and/or high calcium ion concentration conditions in plasma and dissociate from the antigen under acidic pH and/or low calcium ion concentration conditions in the endosome, ca