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CA-3114669-C - HUMANISED ANTI-N-TRUNCATED AMYLOID BETA MONOCLONAL ANTIBODY

CA3114669CCA 3114669 CCA3114669 CCA 3114669CCA-3114669-C

Abstract

The present invention relates to humanised antibodies that bind amyloid peptides, which antibodies comprise mutations in the heavy chain and/or light chain variable domains, which mutations improve the binding activity. The antibodies may be useful in the treatment of Alzheimer's disease (AD).

Inventors

  • Thomas Bayer
  • Preeti Bakrania
  • Sarah Davies
  • ALEX BROWN
  • Chido MPAMHANGA
  • David Matthews
  • Mark Carr
  • Gareth HALL

Assignees

  • GEORG-AUGUST-UNIVERSITAT GOTTINGEN STIFTUNG OFFENTLICHEN RECHTS, UNIVERS
  • LIFEARC

Dates

Publication Date
20260505
Application Date
20191002
Priority Date
20181004

Claims (14)

  1. 61 WE CLAIM: 1. An antibody comprising a heavy chain variable domain and a light chain variable domain, wherein a) the heavy chain variable domain (VH domain) comprises the following amino acid sequence of SEQ ID NO:2 QVQLQESGPG LVKPSETLSL TCTVSGFSLS SYGIHWIRQP PGKGLEWIGV MWSGGITX1X6Y X2X3X4X5SRVTIS RDTSKNQVSL KLSSVTAADT AVYYCARGSR YALDYWGQGT LVTVSS wherein X1 is D or N; X2 is A, or P; X3 is A or S; X4 is F or L; X5 is I or K; and X6 is F or Y, and b) the light chain variable domain (VK domain) comprises the following amino acid sequence of SEQ ID NO:6 DIQMTQSPSS LSASVGDRVT ITCRASQDIS NYLNWYQQKP GKAPKLLIYY TSRLHSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQQ GX7TLPPTFGG GTKLEIK wherein X7 is N or H.
  2. 2. An antibody according to claim 1 wherein the antibody binds amyloid peptides AβpE3-42 and Aβ4-42 and does not bind amyloid peptide Aβ1-42.
  3. 3. An antibody according to any one of claims 1 to 2, wherein the heavy chain variable domain comprises SEQ ID NO: 3.
  4. 4. An antibody according to any one of claims 1 to 2, wherein the heavy chain variable domain comprises SEQ ID NO: 4.
  5. 5. An antibody according to any one of claims 1 to 2, wherein the heavy chain variable domain comprises SEQ ID NO: 5.
  6. 6. An antibody according to any one of claims 1 to 5, wherein the light chain variable domain comprises SEQ ID NO: 7.
  7. 7. An antibody according to any one of claims 1 to 5, wherein the light chain variable domain comprises SEQ ID NO: 8. 62
  8. 8. An antibody according to any one of claims 1 to 2 comprising the VH domain of SEQ ID NO: 3 and the VK domain of SEQ ID NO: 7.
  9. 9. An antibody according to any one of claims 1 to 2 comprising the VH domain of SEQ ID NO: 4 and the VK domain of SEQ ID NO: 7.
  10. 10. An antibody according to any one of claims 1 to 2 comprising the VH domain of SEQ ID NO: 5 and the VK domain of SEQ ID NO: 8.
  11. 11. An antibody according to any one of claims 1 to 2 comprising the VH domain of SEQ ID NO: 5 and the VK domain of SEQ ID NO: 7.
  12. 12. A pharmaceutical composition comprising an antibody according to any one of claims 1 to 11 with a pharmaceutically acceptable carrier.
  13. 13. Use of an antibody according to any one of claims 1 to 11 or the pharmaceutical composition of claim 12, for treatment of a human or animal body.
  14. 14. Use of an antibody according to any one of claims 1 to 11 or the pharmaceutical composition of claim 12, for treatment of Alzheimer’s disease.

Description

HUMANISED ANTI-N-TRUNCATED AMYLOID BETA MONOCLONAL ANTIBODY Field The present invention relates to humanised antibodies that bind amyloid peptides. Background 5 The murine anti-amyloid beta (Af3) antibody NT4X-167 was initially raised against Af34-40 amyloid peptide and is reported to bind specifically to the N-truncated amyloid peptides Af3pE3-42 and Af34-42 but not to amyloid peptide Af31-42 (Antonios et al Acta Neuropathol. Commun. (2013) 6 1 56). Passive immunization using NT4X-167 has been shown to be therapeutically beneficial in Alzheimer mouse models (Antonios et al Scientific Reports 5 17338; 2015). Humanised versions of NT4X-167 would be useful for clinical applications, for example in the treatment of Alzheimer's disease (AD). Summary 15 The present inventors have unexpectedly discovered that the binding activity of humanised versions of the NT4X-167 antibody is improved by mutation of certain residues within the heavy chain and/or light chain variable domains. This may be useful for example in development candidate molecules for clinical use. 20 A first aspect of the invention provides an anti-Af3 antibody comprising a heavy chain variable domain and a light chain variable domain, wherein a) the heavy chain variable domain (VH domain) comprises SEQ ID NO:2 with four or fewer additional alterations, such as substitutions, in the framework regions, and b) the light chain variable domain (VK domain) comprises SEQ ID NO:6, optionally 25 with up to four or fewer additional alterations, such as substitutions, in the framework regions. The anti-Af3 antibody may specifically bind N-terminal truncated amyloid peptides (Af3pE3-x or Af34-x). For example, the anti-Af3 antibody may specifically bind to one or more, preferably all, of Af3pE3-38, Af3pE3-40, Af3pE3-14, Af3pE3-42, Af34-38, Af34-40, Af34-14 and Af34-42. The anti-Af3 antibody may display no specific binding to full-length amyloid peptides or amyloid peptides without N terminal truncations (Af31-x), such as Af31-42, Af31-38, Af31-40 or Af31-14. 2 Preferably, the heavy chain variable domain (VH domain) of the anti-Af3 antibody comprises SEQ ID NO: 3, SEQ ID NO: 4 or SEQ ID NO: 5. 5 Preferably, the light chain variable domain (VL domain) of the anti-Af3 antibody comprises SEQ ID NO: 7 or SEQ ID NO: 8. A second aspect described herein provides a pharmaceutical composition comprising an antibody of the first aspect and a pharmaceutically acceptable carrier. A third aspect described herein provides a nucleic acid encoding an antibody of the first aspect or a heavy chain variable domain and/or light chain variable domain thereof. A fourth aspect described herein provides a vector comprising a nucleic acid of the third aspect. A fifth aspect described herein provides a host cell comprising a nucleic acid of the third aspect or a vector of the fourth aspect. A sixth aspect described herein provides a method for making an antibody according to the first 20 aspect the method comprising expressing, in a host cell culture, a vector according to the fourth aspect to produce said antibody; and recovering the antibody from the cell culture. A seventh aspect described herein provides a method of treatment of Alzheimer's Disease by administering, to an individual in need of treatment, an effective amount of an antibody according 25 to the first aspect or the pharmaceutical composition according to the second aspect. An eighth aspect described herein provides an antibody according to the first aspect or the pharmaceutical composition according to the second aspect, for use in a method of treatment of the human or animal body. A ninth aspect described herein provides an antibody according to the first aspect or the pharmaceutical composition according to the second aspect, for use in a method of treatment of Alzheimer's disease in an individual. 3 These and other aspects and embodiments described herein are described in more detail below. Brief Description of the Figures 5 Figure 1 shows the binding of murine NT4X-167 antibody to amyloid peptides. Figure 2 shows the binding of murine and chimeric NT4X-167 antibody to PSL amyloid peptides Figure 3 shows the binding of murine, humanized and chimeric NT4X-167 to Ar3pE3-42 amyloid 10 peptides: Initial Versions Figure 4 shows the binding of humanized variants to AJ31-42. Figure 5 shows the binding of humanized variants to AJ3pE3-42. Figure 6 shows the binding of the second round of humanized NT4X-167 antibodies to AJ3pE3-42 peptide: HC to HR Versions in combination with RKA Figure 7 shows the binding of the second round of humanized NT4X-167 antibodies to AJ3pE3-42 20 peptide by ELISA. Figure 8 shows the binding of the third round of humanized NT4X-167 antibodies to AJ3pE3-42 peptide: HS to HY Versions in combination with RKA 25 Figure 9 shows binding of the fifth round of humanized NT4X-167 antibodies to AJ3pE3-42 peptide: rcNT4XS6A, rcNT4XS7A, rcNT4XS8A Versions in combination with RKA Figure 10 shows the thermal stabil