# US 12,110,327 B2 · Anti-TREM1 antibodies and methods of use thereof

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- Number: US 12,110,327 B2
- Document ID: US12110327B2
- Status: Granted
- Kind: B2
- Application number: 17/931,757
- Filed: 2022-09-13
- Published: 2023-04-20
- Granted: 2024-10-08
- Earliest claimed: 2016-03-04
- Assignees: Alector LLC
- Applicants: Alector LLC
- Inventors: Andrew Pincetic; Arnon Rosenthal; Helen Lam; Francesca Avogadri-Connors; Seung-Joo Lee
- Web page: https://patentgrep.com/patent/US12110327B2

## CPC

- C07K 16/2803: {against the immunoglobulin superfamily}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/10: for osteoporosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/28: 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
- A61P 27/02: Ophthalmic agents
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 31/04: Antibacterial agents
- A61P 31/18: for HIV
- A61P 33/06: Antimalarials
- A61P 33/14: Ectoparasiticides, e.g. scabicides
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/02: Immunomodulators
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61K 2039/505: {comprising antibodies}
- 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 2317/55: Fab or Fab'
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/74: Inducing cell proliferation
- C07K 2317/75: Agonist effect on antigen
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2317/77: Internalization into the cell
- C07K 2317/80: remaining in the (producing) cell, i.e. intracellular antibodies or intrabodies
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The present disclosure is generally directed to compositions that include antibodies, e.g., monoclonal, chimeric, humanized antibodies, antibody fragments, etc., that specifically bind a TREM1 protein, e.g., a mammalian TREM1 or human TREM1, 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 a TREM1 protein, comprising a heavy chain and a light chain, wherein the light chain comprises a hypervariable region L1 (HVR-L1) comprising the amino acid sequence of SEQ ID NO: 10, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 29, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 101, and wherein the heavy chain comprises an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 130, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 159, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 229.

### Claim 2 (depends on 1)

The isolated antibody of claim 1, wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 457.

### Claim 3 (depends on 1)

The isolated antibody of claim 1, wherein the antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 377.

### Claim 4 (depends on 1)

The isolated antibody of claim 1, wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 457 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 377.

### Claim 5 (depends on 1)

The isolated antibody of claim 1, wherein the antibody enhances one or more TREM1 activities induced by binding of one or more TREM1 ligands to the TREM1 protein, as compared to the one or more TREM1 activities induced by binding of the one or more TREM1 ligands to the TREM1 protein in the absence of the isolated antibody.

### Claim 6 (depends on 5)

The isolated antibody of claim 5, wherein the one or more TREM1 activities are selected from the group consisting of:
a) TREM1 binding to DAP12;
b) TREM1 phosphorylation;
c) DAP12 phosphorylation; and
d) induction of respiratory burst in immune cells.

### Claim 7 (depends on 5)

The isolated antibody of claim 5, wherein the antibody enhances TREM1-dependent gene transcription induced by binding of one or more TREM1 ligands to the TREM1 protein.

### Claim 8 (depends on 7)

The isolated antibody of claim 7, wherein the one or more TREM1 ligands are selected from PGLYRP1 and a natural ligand expressed on activated neutrophils.

### Claim 9 (depends on 1)

The isolated antibody of claim 1, wherein the antibody binds to the TREM1 IgV domain.

### Claim 10 (depends on 1)

The isolated antibody of claim 1, wherein the antibody binds to amino acids 83-90 and 191-201 of SEQ ID NO: 1.

### Claim 11 (depends on 1)

The isolated antibody of claim 1, wherein the antibody competes with one or more TREM1 ligands for binding to the TREM1 protein.

### Claim 12 (depends on 1)

The isolated antibody of claim 1, wherein the antibody enhances one or more TREM1 activities induced by binding of one or more TREM1 ligands to the TREM1 protein in vitro on dendritic cells, bone marrow-derived dendritic cells, monocytes, microglia, macrophages, neutrophils, NK cells, osteoclasts, Langerhans cells of skin, Kupffer cells, or cell lines, as compared to the one or more TREM1 activities induced by binding of the one or more TREM1 ligands to the TREM1 protein in the absence of the isolated antibody.

### Claim 13 (depends on 1)

The isolated antibody of claim 1, wherein the antibody decreases levels of TREM1 on one or more cells.

### Claim 14 (depends on 13)

The isolated antibody of claim 13, wherein the antibody decreases levels of TREM1 in vitro on dendritic cells, bone marrow-derived dendritic cells, monocytes, microglia, macrophages, neutrophils, NK cells, osteoclasts, Langerhans cells of skin, Kupffer cells, or cell lines.

### Claim 15 (depends on 1)

The isolated antibody of claim 1, wherein the antibody is an IgG1, IgG2, IgG3, or IgG4 isotype.

### Claim 16 (depends on 15)

The isolated antibody of claim 15, wherein the antibody binds an inhibitory Fc receptor.

### Claim 17 (depends on 16)

The isolated antibody of claim 16, wherein the inhibitory Fc receptor is inhibitory Fc-gamma receptor IIB (FcyIIB).

### Claim 18 (depends on 15)

The isolated antibody of claim 15, wherein the isolated antibody is a human IgG1 isotype.

### Claim 19 (depends on 18)

The isolated antibody of claim 18, wherein the isolated antibody comprises one or more amino acid substitutions in the Fc region selected from N297A, D265A, D270A, L234A, L235A, G237A, C226S, C229S, E233P, L234V, L234F, L235E, P331S, S267E, L328F, A330L, M252Y, S254T, T256E, L328E, P238D, S267E, L328F, E233D, G237D, H268D, P271G, A330R, and any combination thereof, or comprises a G236 deletion in the Fc region, wherein the numbering of the residues is according to EU numbering.

### Claim 20 (depends on 15)

The isolated antibody of claim 15, wherein the isolated antibody:
(a) has a hybrid IgG1/IgG2 isotype comprising a human IgG1 constant region modified to replace the IgG1 heavy chain constant domain 1 (CH1) and hinge region with the human IgG2 CHI and hinge region, optionally wherein the IgG2 isotype CH1 and hinge region comprises the amino acid sequence of ASTKGPSVFP LAPCSRSTSE STAALGCL VK DYFPEPVTVS WNSGAL TSGVHTFPA VLQSS GL YSLSSVVT VPSSNFGTQT YTCNVDHKPS NTKVDKTVERKCCVECPPCP (SEQ ID NO: 476), and optionally wherein the antibody Fc region comprises a S267E amino acid substitution, a L328F amino acid substitution, or both, and/or a N297A or N297Q amino acid substitution, wherein the numbering of the residues is according to EU numbering;
(b) has an IgG2 isotype and comprises one or more amino acid substitutions in the Fc region selected from P238S, V234A, G237A, H268A, H268Q, V309L, A330S, P331S, C214S, C232S, C233S, S267E, L328F, M252Y, S254T, T256E, H268E, N297A, N297Q, A330L, and any combination thereof, wherein the numbering of the residues is according to EU numbering;
(c) has a human IgG4 isotype and comprises one or more amino acid substitutions in the Fc region selected from L235A, G237A, S228P, L236E, S267E, E318A, L328F, M252Y, S254T, T256E, E233P, F234V, L234A/F234A, S228P, S241P, L248E, T394D, N297A, N297Q, L235E, and any combination thereof, wherein the numbering of the residues is according to EU numbering; or
(d) has a hybrid IgG2/4 isotype, and optionally wherein the antibody comprises an amino acid sequence comprising amino acids 118 to 260 of human IgG2 and amino acids 261 to 447 of human IgG4, wherein the numbering of the residues is according to EU numbering.

### Claim 21 (depends on 1)

An isolated antibody that binds to TREM1 produced by the method comprising culturing a host cell comprising a vector comprising a nucleic acid sequence encoding the antibody of claim 1 so that the antibody is produced.

### Claim 22 (depends on 1)

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