N-terminal epitopes in amyloid beta and conformationally-selective antibodies thereto

Patent metadata

Field	Value
Publication number	US-10772969-B2
Application number	US-201615774805-A
Country	US
Kind code	B2
Filing date	Nov 9, 2016
Priority date	Nov 9, 2015
Publication date	Sep 15, 2020
Grant date	Sep 15, 2020

Abstract

The disclosure pertains to N-terminal epitopes identified in A-beta, including conformational epitopes, antibodies thereto and methods of making and using immunogens and antibodies specific thereto.

First claim

The invention claimed is:

1. An isolated antibody that specifically binds to an amyloid-beta (A-beta) peptide having a sequence of HDSG (SEQ ID NO:1) or a related epitope sequence in A-beta the antibody comprising a light chain variable region and a heavy chain variable region, the heavy chain variable region comprising complementarity determining regions CDR-H1, CDR-H2 and CDR-H3, the light chain variable region comprising complementarity determining regions CDR-L1, CDR-L2 and CDR-L3 and with the amino acid sequences of said CDRs comprising the sequences:

(SEQ ID NO: 17)

CDR-H1 GYTFTSYW

(SEQ ID NO: 18)

CDR-H2 IDPSDSQT

(SEQ ID NO: 19)

CDR-H3 SRGGY

(SEQ ID NO: 20)

CDR-L1 QDINNY

(SEQ ID NO: 21)

CDR-L2 YTS

(SEQ ID NO: 22)

CDR-L3 LQYDNLWT.

2. The antibody of claim 1 , wherein the antibody is a conformation specific and/or selective antibody that specifically or selectively binds to HDSG (SEQ ID NO:1) or a related epitope peptide presented in a cyclic compound, preferably a cyclic peptide having a sequence as set forth in SEQ ID NO: 2, 12, 28 or 29.

3. The antibody of claim 1 , wherein the antibody is a monoclonal antibody and/or wherein the antibody is a humanized antibody.

4. The antibody of claim 1 , wherein the antibody is an antibody binding fragment selected from Fab, Fab′, F(ab′)2, scFv, dsFv, ds-scFv, dimers, nanobodies, minibodies, diabodies, and multimers thereof.

5. The antibody of claim 1 , wherein the light chain variable region and the heavy chain variable region are fused.

6. The antibody of claim 1 , wherein the heavy chain variable region comprises:
A. i) an amino acid sequence as set forth in SEQ ID NO: 24;
ii) an amino acid sequence with at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% sequence identity to SEQ ID NO: 24, wherein the CDR sequences are as set forth in SEQ ID NO: 17, 18 and 19, or
iii) a conservatively substituted amino acid sequence of A. i), and/or

wherein the antibody comprises a light chain variable region comprising:
B. i) an amino acid sequence as set forth in SEQ ID NO: 26,
ii) an amino acid sequence with at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% sequence identity to SEQ ID NO: 26, wherein the CDR sequences are as set forth in SEQ ID NO: 20, 21 and 22, or
iii) a conservatively substituted amino acid sequence of B. i).

7. The isolated antibody of claim 6 , wherein the heavy chain variable region amino acid sequence is encoded by a nucleotide sequence as set forth in SEQ ID NO: 23 or a codon degenerate or optimized version thereof; and/or the antibody comprises a light chain variable region amino acid sequence encoded by a nucleotide sequence as set out in SEQ ID NO: 25 or a codon degenerate or optimized version thereof.

8. The isolated antibody of claim 2 , wherein the antibody selectively binds A-beta oligomer over A-beta monomer and/or A-beta fibril.

9. The isolated antibody of claim 8 , wherein the antibody is at least 2 fold and more selective for A-beta oligomer over A-beta monomer and/or A-beta fibril.

10. An immunoconjugate comprising the antibody of claim 1 and a detectable label or cytotoxic agent, optionally wherein the detectable label comprises a positron emitting radionuclide.

11. A composition comprising the antibody of claim 1 , or an immunoconjugate comprising said antibody, optionally with a diluent.

12. A cell expressing an antibody of claim 1 , optionally wherein the cell is a hybridoma.

13. A kit comprising the antibody of claim 1 or an immunoconjugate comprising said antibody or a cell expressing said antibody.

14. A method of determining if a biological sample comprises A-beta, the method comprising:
a. contacting the biological sample with an antibody of claim 1 or an immunoconjugate comprising said antibody; and
b. detecting the presence of any antibody complex.

15. A method of measuring a level of A-beta in a subject, the method comprising:
administering to a subject at risk of, suspected of having, or having Alzheimer's Disease (AD), an immunoconjugate comprising the antibody of claim 1 , wherein the antibody is conjugated to a detectable label; and
detecting the label, optionally wherein the label is a positron emitting radionuclide.

16. A method of inhibiting A-beta oligomer propagation, the method comprising contacting a cell or tissue expressing A-beta with an effective amount of the A-beta specific antibody of claim 1 , or an immunoconjugate comprising said antibody, to inhibit A-beta aggregation and/or oligomer propagation.

17. A method of treating AD or other disease characterized by A-beta amyloid pathology, the method comprising administering to a subject in need thereof an effective amount of the antibody of claim 1 or a pharmaceutical composition comprising said antibody.

Assignees

• Univ British Columbia

Inventors

• Cashman Neil R
• Plotkin Steven S

Classifications

• C07K16/18 Primary

  against material from animals or humans · CPC title

• C07K5/10

  Tetrapeptides · CPC title

• C07K5/1024

  with the first amino acid being heterocyclic · CPC title

• C07K5/1021

  with the first amino acid being acidic · CPC title

• C07K7/06

  having 5 to 11 amino acids · CPC title