Anti-tmem106b antibodies and methods of use thereof

Patent metadata

Field	Value
Publication number	US-2020339680-A1
Application number	US-201816959081-A
Country	US
Kind code	A1
Filing date	Dec 21, 2018
Priority date	Dec 29, 2017
Publication date	Oct 29, 2020
Grant date	—

Abstract

The present disclosure is generally directed to compositions that include antibodies, e.g., monoclonal antibodies, antibody fragments, etc., that specifically bind a TMEM106B polypeptide, e.g., a mammalian TMEM106B or human TMEM106B, and use of such compositions in preventing, reducing risk, or treating an individual in need thereof.

First claim

What is claimed is:

1 . An isolated antibody that binds to human TMEM106B, wherein the antibody decreases cell surface levels of TMEM106B or decreases intracellular levels of TMEM106B.

2 . An isolated antibody that binds to human TMEM106B, wherein the antibody binds to one or more amino acids within the amino acid sequence NITNNNYYSVEVENI (SEQ ID NO:324), TIIGPLDMKQI (SEQ ID NO:325), VTCPTCQGTGRIPRG (SEQ ID NO:326), (ALIPYSDQRLR (SEQ ID NO:327), (KRTIYLNITNT (SEQ ID NO:328), YQYVDCGRNTT (SEQ ID NO:329), (LSHLPLHSSKEDAYD (SEQ ID NO:332), (NYYSVE (SEQ ID NO:334), (VIAEEM (SEQ ID NO:335), (IKVHNIVLMMQVTVT; SEQ ID NO:336), (IGVKSAYVSYDVQKR; SEQ ID NO:337), (QLGQSEYLNVLQPQQ (SEQ ID NO:338), (VIAEEMSYMYD (SEQ ID NO:340), (NITNNNYYSVE (SEQ ID NO:341), (NIVLMMQVTV (SEQ ID NO:342), (VTCPTCQGTGR (SEQ ID NO:343), (YLNITNTLNIT (SEQ ID NO:344), (NIVLMM (SEQ ID NO:345), (VSYDVQKRTIYLN (SEQ ID NO:346), (TVPTVIAEEMSYMYD (SEQ ID NO:347), (EFTGRDSVTCP (SEQ ID NO:348), or (CQGTGRIPRGQE (SEQ ID NO:349) of human TMEM106B.

3 . An isolated anti-TMEM106B antibody, wherein the anti-TMEM106B antibody comprises at least one, two, three, four, five, or six HVRs of an antibody selected from the group consisting of: TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-36, TM-37, TM-38, TM-39, TM-40, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52, and TM-53.

4 . An isolated antibody that binds to human TMEM106B, wherein the antibody comprises a heavy chain variable region and a light chain variable region,
wherein the heavy chain variable region comprises:
an HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 3-35;
an HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 36-78; and
an HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 79-120; and
wherein the light chain variable region comprises:
an HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 121-160;
an HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 161-185; and
an HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 186-224.

5 . The antibody of any one of claims 1 - 4 , wherein the heavy chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 225-268.

6 . The antibody of any one of claims 1 - 5 , wherein the light chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 269-314.

7 . An isolated antibody that binds to human TMEM106B, wherein the antibody competes with one or more of the antibodies of any one of claims 1 - 6 for binding to human TMEM106B.

8 . An isolated antibody that binds to human TMEM106B, wherein the antibody binds essentially the same or overlapping TMEM106B epitope as the antibody of any one of claims 1 - 7 .

9 . The antibody of any one of claims 1 - 8 , wherein the antibody reduces or inhibits the interaction or binding of TMEM106B and at least one TMEM106B ligand or binding partner.

10 . The antibody of claim 9 , wherein the TMEM106B ligand or binding partner is selected from the group consisting of progranulin, TMEM106A, TMTM106C, clathrin heavy chain, 1 subunit of adipocyte protein 2, CHMP2B, microtubule-associated protein 6, lysosomal-associated membrane protein 1, and vacuolar-ATPase accessory protein 1.

11 . The antibody of any one of claims 1 - 10 , wherein the antibody reduces or inhibits proteolysis of TMEM106B.

12 . The antibody of any one of claims 1 - 11 , wherein the antibody increases TGFbeta expression.

13 . The antibody of any one of claims 1 - 12 , wherein the antibody reduces TDP-43 inclusions.

14 . The antibody of any one of claims 1 - 13 , wherein the antibody reduces decline in cognitive and behavioral function, and improves cognitive and behavioral function.

15 . The antibody of any one of claims 1 - 14 , wherein the antibody is a monoclonal antibody.

16 . The antibody of any one of claims 1 - 15 , wherein the antibody is of the IgG class, the IgM class, or the IgA class.

17 . The antibody of claim 16 , wherein the antibody is of the IgG class and has an IgG1, IgG2, or IgG4 isotype.

18 . The antibody of any one of claims 1 - 17 , wherein the antibody is an antibody fragment.

19 . The antibody of claim 18 , wherein the fragment is a Fab, Fab′, Fab′-SH, F(ab′)2, Fv or scFv fragment.

20 . The antibody of any one of claims 1 - 19 , wherein the antibody further comprises:
(a) an antigen facilitating transport across the blood-brain-barrier; (b) an antigen facilitating transport across the blood-brain-barrier selected from the group consisting of transferrin receptor (TR), insulin receptor (HIR), insulin-like growth factor receptor (IGFR), low-density lipoprotein receptor related proteins 1 and 2 (LPR-1 and 2), diphtheria toxin receptor, CRM197, a llama single domain antibody, TMEM 30(A), a protein transduction domain, TAT, Syn-B, penetratin, a poly-arginine peptide, an angiopeptide, and ANG1005; (c) a disease-causing agent selected from the group consisting of disease-causing peptides or proteins or, disease-causing nucleic acids, wherein the disease-causing nucleic acids are antisense GGCCCC (G2C4) repeat-expansion RNA, the disease-causing proteins are selected from the group consisting of amyloid beta, oligomeric amyloid beta, amyloid beta plaques, amyloid precursor protein or fragments thereof, Tau, IAPP, alpha-synuclein, TDP-43, FUS protein, C9orf72 (chromosome 9 open reading frame 72) c9RAN protein, prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, ataxin 1, ataxin 2, ataxin 3, ataxin 7, ataxin 8, ataxin 10, Lewy body, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI, serum amyloid A, medin, prolactin, transthyretin, lysozyme, beta 2 microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin light chain AL, S-IBM protein, Repeat-associated non-ATG (RAN) translation products, DiPeptide repeat (DPR) peptides, glycine-alanine (GA) repeat peptides, glycine-proline (GP) repeat peptides, glycine-arginine (GR) repeat peptides, proline-alanine (PA) repeat peptides, ubiquitin, and proline-arginine (PR) repeat peptides; (d) ligands and/or proteins expressed on immune cells, wherein the ligands and/or proteins selected from the group consisting of CD40, OX40, ICOS, CD28, CD137/4-1BB, CD27, GITR, PD-L1, CTLA-4, PD-L2, PD-1, B7-H3, B7-H4, HVEM, BTLA, KIR, GAL9, TIM3, A2AR, LAG-3, and phosphatidylserine; and (e) a protein, lipid, polysaccharide, or glycolipid expressed on one or more tumor cells.

21 . An isolated nucleic acid comprising a nucleic acid sequence encoding the antibody of any one of the preceding claims.

22 . A vector comprising the nucleic acid of claim 21 .

23 . An isolated host cell comprising the vector of claim 22 .

24 . A method of producing an antibody that binds to human TMEM106B, comprising culturing the cell of claim 23 so that the antibody is produced.

25 . The method of claim 24 , further comprising recovering the antibody produced by the cell.

26

Assignees

• Alector Llc

Inventors

• Rosenthal Arnon
• Brown Eric
• Schwabe Tina
• Yee Angie
• Rhinn Herve

Classifications

• A61K2039/505

  comprising antibodies · CPC title

• C07K2317/56

  variable (Fv) region, i.e. VH and/or VL · CPC title

• C07K2317/34

  Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues · CPC title

• 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

• A61P25/00

  Drugs for disorders of the nervous system · CPC title