Therapeutic fusion protein

Patent metadata

Field	Value
Publication number	US-2016168253-A1
Application number	US-201414907173-A
Country	US
Kind code	A1
Filing date	Jul 30, 2014
Priority date	Aug 2, 2013
Publication date	Jun 16, 2016
Grant date	—

Abstract

The invention relates to a fusion protein comprising an antibody directed to Aβ, a monovalent binding entity which binds to a blood brain barrier receptor and a neprilysin.

First claim

1 . A fusion protein comprising, an antibody directed to Aβ, a monovalent binding entity which binds to a blood brain barrier receptor and a neprilysin moiety.

2 . The fusion protein of claim 1 , wherein the blood brain receptor is selected from the group consisting of the transferrin receptor, insulin receptor, insulin-like growth factor receptor, low density lipoprotein receptor-related protein 8, low density lipoprotein receptor-related protein 1 and heparin-binding epidermal growth factor-like growth factor.

3 . The fusion protein of claim 1 , wherein the monovalent binding entity is a blood brain barrier ligand or a monovalent antibody fragment.

4 . The fusion protein of claim 1 , comprising:
the antibody directed to Aβ comprising two heavy and two light chains, the monovalent binding entity which binds to a blood brain receptor coupled to a C-terminal part of the first heavy chain of the antibody directed against Aβ by a first linker and the neprilysin moiety coupled to a C-terminal part of the second heavy chain of the antibody directed against Aβ by a second linker.

5 . The fusion protein of claim 4 , wherein the monovalent binding entity which binds to a blood brain receptor is coupled to the C-terminal end of the Fc part of the first heavy chain of the full length antibody directed against Aβ by a first linker and
the neprilysin moiety is coupled to the C-terminal end of the Fc part of the second heavy chain of the full length antibody directed against Aβ by a second linker.

6 . The fusion protein of claim 5 , wherein the first and second linker are a peptide or a chemical linker.

7 . The fusion protein of claim 1 , wherein the monovalent binding entity which binds to a blood brain barrier receptor is a scFab directed to the transferrin receptor.

8 . The fusion protein of claim 1 , wherein the antibody directed to Aβ comprises (a) H-CDR1 comprising the amino acid sequence of Seq. Id. No. 5, (b) H-CDR2 comprising the amino acid sequence of Seq. Id. No. 6, (c) H-CDR3 comprising the amino acid sequence of Seq. Id. No. 7, (d) L-CDR1 comprising the amino acid sequence of Seq. Id. No. 8, (e) L-CDR2 comprising the amino acid sequence of Seq. Id. No. 9 and (f) L-CDR3 comprising the amino acid sequence of Seq. Id. No. 10.

9 . The fusion protein of claim 1 , wherein the antibody directed to Aβ comprises a V H domain comprising the amino acid sequence of Seq. Id. No. 3 and a V L domain comprising the amino acid sequence of Seq. Id. No. 4.

10 . The fusion protein of claim 4 , wherein one of the heavy chains of the antibody directed to Aβ comprises a first dimerization module and the second heavy chain of the antibody directed to Aβ comprises a second dimerization module allowing heterodimerization of the two heavy chains.

11 . The fusion protein of claim 10 , wherein the first dimerization module comprises knobs and the second dimerization module comprises holes according to the knobs into holes strategy.

12 . The fusion protein of claim 1 , comprising one monovalent binding entity which binds to a blood brain barrier receptor.

13 . An isolated nucleic acid encoding the fusion protein of claim 1 .

14 . A host cell comprising the nucleic acid of claim 13 .

15 . A pharmaceutical formulation, comprising the fusion protein of claim 1 and a pharmaceutical carrier.

16 - 17 . (canceled)

18 . The fusion protein of claim 3 , wherein the monovalent binding entity is a blood brain barrier ligand or a monovalent antibody fragment selected from the group consisting of scFv, Fv, scFab, Fab and VHH.

19 . The fusion protein of claim 6 , wherein the first and second linker are a peptide linker.

20 . The fusion protein of claim 12 , wherein the monovalent binding entity which binds to a blood brain barrier receptor is scFab directed to the transferrin receptor.

Assignees

• Hoffmann La Roche
• Hoffmann La Roche

Inventors

• Bohrmann Bernd
• Freskgard Per-Ola
• Knoetgen Hendrik
• Niewoehner Jens

Classifications

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• C07K2319/74

  containing a fusion for binding to a cell surface receptor · CPC title

• C07K2317/60

  characterized by non-natural combinations of immunoglobulin fragments · CPC title

• C12Y304/24011

  Neprilysin (3.4.24.11), i.e. enkephalinase or neutral endopeptidase 24.11 · CPC title

• C07K2319/50

  containing protease site · CPC title