Anti-ApoE antibodies and polynucleotides thereof

Patent metadata

Field	Value
Publication number	US-12384834-B2
Application number	US-202017614008-A
Country	US
Kind code	B2
Filing date	May 28, 2020
Priority date	May 28, 2019
Publication date	Aug 12, 2025
Grant date	Aug 12, 2025

Abstract

Methods and compositions for preventing or treating cognitive decline associated with dementia and/or mild cognitive impairment and/or neurodegeneration using antibodies, peptides, fusion proteins, or genome editing systems that modulate HSPG/heparin binding affinities of ApoE.

First claim

What is claimed is:

1. An isolated antibody or antigen binding domain thereof that binds to Apolipoprotein E (ApoE), wherein the antibody or antigen binding domain thereof comprises a heavy chain variable region (VH) comprising a VHCDR1, a VHCDR2, and a VHCDR3; and a light chain variable region (VL) comprising a VLCDR1, a VLCDR2, and a VLCDR3, wherein the VHCDR1, the VHCDR2, the VHCDR3, the VLCDR1, the VLCDR2, and the VLCDR3 comprise the amino acid sequences of SEQ ID NOs: 17, 18, 19, 14, 15, and 16, respectively.

2. The antibody or antigen binding domain thereof of claim 1 , wherein the antibody or antigen binding domain thereof binds to an epitope that comprises or consists of the amino acid sequence TEELRVRLASHLRK (SEQ ID NO:3).

3. The antibody or antigen binding domain thereof of claim 1 , wherein the antibody or antigen binding domain thereof binds to one or more HSPG-binding sites of ApoE2, ApoE3, or ApoE4.

4. The antibody or antigen binding domain thereof of claim 1 , wherein the antibody or antigen binding domain thereof does not bind to a mutant ApoE protein comprising the amino acid sequence TEELRVSLASHLRK (SEQ ID NO: 2).

5. The antibody or antigen binding domain thereof of claim 4 , wherein the antibody or antigen binding domain thereof binds to an epitope that comprises or consists of the amino acid sequence TEELRVRLASHLRK (SEQ ID NO:3).

6. The antibody or antigen binding domain thereof of claim 1 , wherein the antibody or antigen binding domain thereof competes with and/or binds a same epitope as a reference anti-ApoE antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH and VL of the reference antibody comprise: (i) the amino acid sequence of SEQ ID NO: 13 and the amino acid sequence of SEQ ID NO:12, respectively; (ii) the amino acid sequence of SEQ ID NO:22 and the amino acid sequence of SEQ ID NO:23, respectively; (iii) the amino acid sequence of SEQ ID NO:33 and the amino acid sequence of SEQ ID NO:32, respectively; or (iv) the amino acid sequence of SEQ ID NO:43 and the amino acid sequence of SEQ ID NO:42, respectively.

7. The antibody or antigen binding domain thereof of claim 1 , wherein the antibody or antigen binding domain thereof comprises a mouse IgG1, IgG2a, IgG2b, IgG2c, or IgG3 heavy chain constant region.

8. The antibody or antigen binding domain thereof of claim 1 , wherein the antibody or antigen binding domain thereof is an antibody and comprises a human IgG1, IgG2, IgG3, or IgG4 heavy chain constant region.

9. The antibody or antigen binding domain thereof of claim 1 , wherein the antibody or antigen binding domain thereof comprises a human kappa or human lambda light chain constant region.

10. The antibody or antigen binding domain thereof of claim 1 , wherein the antibody is a whole antibody, a monoclonal antibody, a humanized antibody, or a chimeric antibody, and wherein the antigen-binding domain is a Fv, a scFv, an sc(Fv)2, an Fab, or an F(ab′)2.

11. The antibody or antigen binding domain thereof of claim 1 , further comprising one or more of: a half-life extending moiety, a blood-brain barrier penetrating moiety, or a detectable label.

12. A pharmaceutical composition comprising the antibody or antigen binding domain thereof of claim 1 .

13. An anti-ApoE antibody or antigen binding domain thereof comprising a VH comprising VHCDR1, VHCDR2, and VHCDR3, and a VL comprising VLCDR1, VLCDR2, and VLCDR3, wherein the VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3 comprise the amino acid sequences of SEQ ID NOS: 17, 18, 19, 14, 15, and 16, respectively.

14. The antibody or antigen binding domain thereof of claim 13 , wherein the VH comprises the amino acid sequence that is at least 80% identical to the amino acid sequences of SEQ ID NO: 22 and comprises VHCDR1, VHCDR2 and VHCDR3 having the amino acid sequences of SEQ ID NOs: 17, 18 and 19, respectively; and the VL comprises the amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO:23 and comprises VLCDR1, VLCDR2 and VLCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15 and 16, respectively.

15. The antibody of claim 14 , wherein the VH comprises the amino acid sequence with at least 90% sequence identity to the amino acid sequences of SEQ ID NO: 22 and comprises VHCDR1, VHCDR2 and VHCDR3 having the amino acid sequences of SEQ ID NOs: 17, 18 and 19, respectively; and the VL comprises the amino acid sequence with at least 90% sequence identity to the amino acid sequence of SEQ ID NO:23 and comprises VLCDR1, VLCDR2 and VLCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15 and 16, respectively.

16. The antibody or antigen binding domain thereof of claim 13 , wherein (i) the VH comprises the amino acid sequence with at least 80% sequence identity to amino acids 20-139 of the amino acid sequence of SEQ ID NO: 22 and comprises VHCDR1, VHCDR2 and VHCDR3 having the amino acid sequences of SEQ ID NOs: 17, 18 and 19, respectively; and (ii) the VL comprise the amino acid sequence with at least 80% sequence identity to amino acids 21-131 of the amino acid sequence of SEQ ID NO: 23 and comprises VLCDR1, VLCDR2, and VLCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15 and 16, respectively.

17. The antibody or antigen binding domain thereof of claim 16 , wherein (i) the VH comprises the amino acid sequence with at least 90% sequence identity to amino acids 20-139 of the amino acid sequence of SEQ ID NO: 22 and comprises VHCDR1, VHCDR2 and VHCDR3 having the amino acid sequences of SEQ ID NOs: 17, 18 and 19, respectively; and (ii) the VL comprise the amino acid sequence with at least 90% sequence identity to amino acids 21-131 of the amino acid sequence of SEQ ID NO: 23 and comprises VLCDR1, VLCDR2, and VLCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15 and 16, respectively.

18. The antibody or antigen binding domain thereof of claim 17 , wherein (i) the VH comprises the amino acid sequence with at least 95% sequence identity to amino acids 20-139 of the amino acid sequence of SEQ ID NO: 22 and comprises VHCDR1, VHCDR2 and VHCDR3 having the amino acid sequences of SEQ ID NOs: 17, 18 and 19, respectively; and (ii) the VL comprise the amino acid sequence with at least 95% sequence identity to amino acids 21-131 of the amino acid sequence of SEQ ID NO: 23 and comprises VLCDR1, VLCDR2 and VLCDR3 having the amino acid sequences of SEQ ID NOs: 14, 15 and 16, respectively.

19. The antibody or antigen binding domain thereof of claim 18 , wherein (i) the VH comprises the amino acid sequence of amino acids 20-139 of the amino acid sequence of SEQ ID NO: 22, and (ii) the VL comprise the amino acid sequence of amino acids 21-131 of the amino acid sequence of SEQ ID NO: 23.

20. An isolated polynucleotide or polynucleotides encoding the antibody or antigen binding domain thereof of claim 1 .

21. A vector or vectors comprising the polynucleotide or polynucleotides of claim 20 .

22. An isolated host cell comprising the vector or vectors of claim 21 .

Assignees

• Massachusetts Gen Hospital
• Banner Health
• Schepens Eye Res Inst

Inventors

• Quiroz Yakeel T
• Arboleda-Velasquez Joseph F
• Reiman Eric
• Lopera Francisco

Classifications

• A61K2039/505

  comprising antibodies · CPC title

• C07K2317/31

  multispecific · CPC title

• G01N2800/168

  Glaucoma · CPC title

• G01N2800/164

  Retinal disorders, e.g. retinopathy · CPC title

• G01N2800/28

  Neurological disorders · CPC title