# US 11,440,957 B2 · Anti-TMEM106B antibodies and methods of use thereof

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- Number: US 11,440,957 B2
- Document ID: US11440957B2
- Status: Granted
- Kind: B2
- Application number: 16/959,081
- Filed: 2018-12-21
- Published: 2020-10-29
- Granted: 2022-09-13
- Earliest claimed: 2017-12-29
- Assignees: Alector LLC
- Applicants: Alector LLC
- Inventors: Arnon Rosenthal; Eric Brown; Tina Schwabe; Angie Yee; Herve Rhinn
- Web page: https://patentgrep.com/patent/US11440957B2

## CPC

- C07K 16/18: against material from animals or humans
- C07K 16/28: against receptors, cell surface antigens or cell surface determinants
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- C07K 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## 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.

## Claims

### Claim 1

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 and light chain variable region comprise-:
(a) an HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs:4, 37, 80, 122, 162, and 187, respectively;
(b) an HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs:5, 38, 81, 123, 163, and 188, respectively;
(c) an HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs: 11, 44, 87, 123, 169, and 188, respectively;
(d) an HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs:12, 45, 88, 129, 170, and 194, respectively;
(e) an HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs:13, 46, 89, 130, 171, and 195, respectively;
(f) an HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs:14, 47, 90, 131, 170, and 196, respectively;
(g) an HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs:15, 48, 91, 132, 172, and 197, respectively;
(h) an HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs:6, 53, 96, 136, 175, and 201, respectively;
(i) an HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs:14, 54, 97, 137, 176, and 202, respectively;
(j) an HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs:19, 55, 98, 138, 169, and 203, respectively;
(k) an HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs:11, 58, 101, 138, 169, and 207, respectively;
(l) an HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs:14, 64, 107, 146, 161, and 202, respectively;
(m) an HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs:25, 67, 110, 149, 161, and 196, respectively;
(n) an HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs:26, 68, 111, 150, 181, and 214, respectively;
(o) an HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs:27, 69, 112, 151, 181, and 215, respectively;
(p) an HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs:29, 71, 111, 153, 181, and 214, respectively;
(q) an HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs:33, 75, 117, 156, 161, and 220, respectively;
(r) an HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs:9, 42, 85, 127, 167, and 192, respectively;
(s) an HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs:7, 40, 83, 125, 165, and 190, respectively;
(t) an HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs:9, 60, 103, 143, 167, and 192, respectively;
(u) an HVR-H1, HVR-H2, HVR-H3, HVR-11, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs:21, 61, 104, 144, 169, and 209, respectively;
(v) an HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs:16, 50, 93, 134, 172, and 199, respectively;
(w) an HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs:13, 46, 89, 141, 171, and 206, respectively; or
(x) an HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 comprising the amino acid sequences of SEQ ID NOs:22, 62, 105, 145, 161, and 210, respectively.

### Claim 2 (depends on 1)

The antibody of claim 1, wherein the heavy chain variable region and light chain variable region comprise the amino acid sequences of:
(a) SEQ ID NOs: 226 and 270, respectively,
(b) SEQ ID NOs: 227 and 271, respectively;
(c) SEQ ID NOs: 233 and 277, respectively;
(d) SEQ ID NOs: 234 and 278, respectively;
(e) SEQ ID NOs: 235 and 279, respectively;
(f) SEQ ID NOs: 236 and 280, respectively;
(g) SEQ ID NOs: 237 and 281, respectively;
(h) SEQ ID NOs: 242 and 286, respectively;
(i) SEQ ID NOs: 243 and 287, respectively,
(j) SEQ ID NOs: 244 and 289, respectively;
(k) SEQ ID NOs: 247 and 293, respectively;
(l) SEQ ID NOs: 253 and 299, respectively;
(m) SEQ ID NOs: 256 and 302, respectively;
(n) SEQ ID NOs: 257 and 303, respectively;
(o) SEQ ID NOs: 258 and 304, respectively;
(p) SEQ ID NOs: 260 and 306, respectively;
(q) SEQ ID NOs: 264 and 310, respectively;
(r) SEQ ID NOs: 231 and 275, respectively;
(s) SEQ ID NOs: 229 and 273, respectively;
(t) SEQ ID NOs: 249 and 295, respectively;
(u) SEQ ID NOs: 250 and 296, respectively;
(v) SEQ ID NOs: 239 and 283, respectively;
(w) SEQ ID NOs: 235 and 292, respectively; or
(x) SEQ ID NOs: 251 and 297, respectively.

### Claim 3 (depends on 1)

The isolated antibody of claim 1, wherein the antibody decreases cell surface levels of TMEM106B or decreases intracellular levels of TMEM106B.

### Claim 4 (depends on 1)

The antibody of claim 1, wherein the antibody reduces or inhibits the interaction or binding of TMEM106B and at least one TMEM106B ligand or binding partner.

### Claim 5 (depends on 4)

The antibody of claim 4, wherein the TMEM106B ligand or binding partner is selected from the group consisting of progranulin, TMEM106A, TMEM106C, clathrin heavy chain, μ1 subunit of adipocyte protein 2, CHMP2B, microtubule-associated protein 6, lysosomal-associated membrane protein 1, and vacuolar-ATPase accessory protein 1.

### Claim 6 (depends on 1)

The antibody of claim 1, wherein the antibody reduces or inhibits proteolysis of TMEM106B.

### Claim 7 (depends on 1)

The antibody of claim 1, wherein the antibody increases TGFbeta expression.

### Claim 8 (depends on 1)

The antibody of claim 1, wherein the antibody reduces TDP-43 inclusions.

### Claim 9 (depends on 1)

The antibody of claim 1, wherein the antibody reduces decline in cognitive and behavioral function, and improves cognitive and behavioral function.

### Claim 10 (depends on 1)

The antibody of claim 1, wherein the antibody is a monoclonal antibody.

### Claim 11 (depends on 1)

The antibody of claim 1, wherein the antibody is of the IgG class, the IgM class, or the IgA class.

### Claim 12 (depends on 11)

The antibody of claim 11, wherein the antibody is of the IgG class and has an IgG1, IgG2, or IgG4 isotype.

### Claim 13 (depends on 1)

The antibody of claim 1, wherein the antibody is an antibody fragment.

### Claim 14 (depends on 13)

The antibody of claim 13, wherein the fragment is a Fab, Fab′, Fab′-SH, F(ab′)2, Fv or scFv fragment.

### Claim 15 (depends on 1)

The antibody of claim 1, wherein the antibody further comprises:
(a) 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;
(b) 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 A1, 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;
(c) 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.

### Claim 16 (depends on 1)

A pharmaceutical composition comprising the antibody of claim 1 and a pharmaceutically acceptable carrier.

### Claim 17 (depends on 1)

The isolated antibody of claim 1,
wherein the heavy chain variable region comprises:
an HVR-H1 comprising the amino acid sequence of SEQ ID NO:11;
an HVR-H2 comprising the amino acid sequence of SEQ ID NO:44; and
an HVR-H3 comprising the amino acid sequence of SEQ ID NO:87; and
wherein the light chain variable region comprises:
an HVR-L1 comprising the amino acid sequence of SEQ ID NO:123;
an HVR-L2 comprising the amino acid sequence of SEQ ID NO:169; and
an HVR-L3 comprising the amino acid sequence of SEQ ID NO:188.

### Claim 18 (depends on 17)

The antibody of claim 17, wherein the heavy chain variable region and light chain variable region comprise the amino acid sequences of SEQ ID NOs: 233 and 277, respectively.

### Claim 19 (depends on 18)

The antibody of claim 18, wherein the antibody is of the IgG class and has an IgG1 isotype.

### Claim 20 (depends on 17)

The antibody of claim 17, wherein the antibody further comprises an antigen facilitating transport across the blood-brain-barrier 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 land 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.

### Claim 21 (depends on 18)

The antibody of claim 18, wherein the antibody further comprises an antigen facilitating transport across the blood-brain-barrier 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.

### Claim 22 (depends on 17)

A pharmaceutical composition comprising the antibody of claim 17 and a pharmaceutically acceptable carrier.

### Claim 23 (depends on 18)

A pharmaceutical composition comprising the antibody of claim 18 and a pharmaceutically acceptable carrier.

### Claim 24 (depends on 19)

A pharmaceutical composition comprising the antibody of claim 19 and a pharmaceutically acceptable carrier.

### Claim 25 (depends on 21)

A pharmaceutical composition comprising the antibody of claim 21 and a pharmaceutically acceptable carrier.

### Claim 26 (depends on 1)

The isolated antibody of claim 1,
wherein the heavy chain variable region comprises:
an HVR-H1 comprising the amino acid sequence of SEQ ID NO:5;
an HVR-H2 comprising the amino acid sequence of SEQ ID NO:38; and
an HVR-H3 comprising the amino acid sequence of SEQ ID NO:81; and
wherein the light chain variable region comprises:
an HVR-L1 comprising the amino acid sequence of SEQ ID NO:123;
an HVR-L2 comprising the amino acid sequence of SEQ ID NO:163; and
an HVR-L3 comprising the amino acid sequence of SEQ ID NO:188.

### Claim 27 (depends on 26)

The antibody of claim 26, wherein the heavy chain variable region and light chain variable region comprise the amino acid sequences of SEQ ID NOs: 227 and 271, respectively.

### Claim 28 (depends on 27)

The antibody of claim 27, wherein the antibody is of the IgG class and has an IgG1 isotype.

### Claim 29 (depends on 26)

The antibody of claim 26, wherein the antibody further comprises 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 land 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.

### Claim 30 (depends on 27)

The antibody of claim 27, wherein the antibody further comprises 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 land 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.

### Claim 31 (depends on 26)

A pharmaceutical composition comprising the antibody of claim 26 and a pharmaceutically acceptable carrier.

### Claim 32 (depends on 27)

A pharmaceutical composition comprising the antibody of claim 27 and a pharmaceutically acceptable carrier.

### Claim 33 (depends on 28)

A pharmaceutical composition comprising the antibody of claim 28 and a pharmaceutically acceptable carrier.

### Claim 34 (depends on 29)

A pharmaceutical composition comprising the antibody of claim 29 and a pharmaceutically acceptable carrier.

### Claim 35 (depends on 1)

The isolated antibody of claim 1,
wherein the heavy chain variable region comprises:
an HVR-H1 comprising the amino acid sequence of SEQ ID NO:11;
an HVR-H2 comprising the amino acid sequence of SEQ ID NO:58; and
an HVR-H3 comprising the amino acid sequence of SEQ ID NO:101; and
wherein the light chain variable region comprises:
an HVR-L1 comprising the amino acid sequence of SEQ ID NO:138;
an HVR-L2 comprising the amino acid sequence of SEQ ID NO:169; and
an HVR-L3 comprising the amino acid sequence of SEQ ID NO:207.

### Claim 36 (depends on 35)

The antibody of claim 35, wherein the heavy chain variable region and light chain variable region comprise the amino acid sequences of SEQ ID NOs: 247 and 293, respectively.

### Claim 37 (depends on 36)

The antibody of claim 36, wherein the antibody is of the IgG class and has an IgG1 isotype.

### Claim 38 (depends on 35)

The antibody of claim 35, wherein the antibody further comprises 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 land 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.

### Claim 39 (depends on 36)

The antibody of claim 36, wherein the antibody further comprises 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 land 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.

### Claim 40 (depends on 35)

A pharmaceutical composition comprising the antibody of claim 35 and a pharmaceutically acceptable carrier.

### Claim 41 (depends on 36)

A pharmaceutical composition comprising the antibody of claim 36 and a pharmaceutically acceptable carrier.

### Claim 42 (depends on 37)

A pharmaceutical composition comprising the antibody of claim 37 and a pharmaceutically acceptable carrier.

### Claim 43 (depends on 38)

A pharmaceutical composition comprising the antibody of claim 38 and a pharmaceutically acceptable carrier.