# US 12,595,306 B2 · TREM2 stabilizing antibodies

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- Number: US 12,595,306 B2
- Document ID: US12595306B2
- Status: Granted
- Kind: B2
- Application number: 18/999,104
- Filed: 2024-12-23
- Published: 2025-05-01
- Granted: 2026-04-07
- Earliest claimed: 2018-10-15
- Assignees: Novartis AG
- Applicants: Novartis AG
- Inventors: Verena Brand; Dominik Feuerbach; Fabrizio Gasparini; Nathalie George; Eveline Schaadt; Derya Shimshek; Honnappa Srinivas; Markus Waldhuber; Rainer Wilcken
- Web page: https://patentgrep.com/patent/US12595306B2

## CPC

- C07K 16/2803: {against the immunoglobulin superfamily}
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- 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
- C12N 7/00: Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof (preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00)
- C12N 15/70: Vectors or expression systems specially adapted for E. coli
- A61K 2039/505: {comprising antibodies}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- C07K 2317/55: Fab or Fab'
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/75: Agonist effect on antigen
- C07K 2317/77: Internalization into the cell
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C07K 2317/94: Stability, e.g. half-life, pH, temperature or enzyme-resistance
- C07K 2319/21: containing a His-tag
- C12N 2750/14143: viral genome or elements thereof as genetic vector
- 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)
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

The present invention provides antibodies that bind to and stabilize human Triggering Receptor Expressed on Myeloid cells 2 (TREM2) protein and methods of using these antibodies.

## Claims

### Claim 1

An anti-TREM2 antibody or antigen-binding fragment thereof comprising three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), wherein (i) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 7, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 5, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 6, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 17, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 18, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 19, as defined by the Kabat numbering system; (ii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 8, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 9, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 6, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 20, the LCDR2 comprises the amino acid sequence of RAS and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 22, as defined by the Chothia numbering system; (iii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 10, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 11, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 12, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 23, the LCDR2 comprises the amino acid sequence of RAS, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 19, as defined by the IMGT numbering system; or (iv) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 4, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 5, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 6, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 17, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 18, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 19, as defined by the Combined numbering system.

### Claim 2 (depends on 1)

The anti-TREM2 antibody or antigen-binding fragment of claim 1, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region that is at least 95% identical to the amino acid sequence of SEQ ID NO: 13, and a light chain variable region that is at least 95% identical to the amino acid sequence of SEQ ID NO: 24.

### Claim 3

An anti-TREM2 antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 13, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 24.

### Claim 4 (depends on 1)

The anti-TREM2 antibody or antigen-binding fragment of claim 1, wherein the antibody or antigen-binding fragment comprises a human IgG heavy chain constant region.

### Claim 5 (depends on 1)

The anti-TREM2 antibody or antigen-binding fragment of claim 1, wherein the antibody or antigen-binding fragment comprises a human IgG1 heavy chain constant region.

### Claim 6 (depends on 1)

The anti-TREM2 antibody or antigen-binding fragment of claim 1, wherein the antibody or antigen-binding fragment comprises a modified Fc domain that has reduced antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) activity compared to the parental antibody.

### Claim 7 (depends on 1)

The anti-TREM2 antibody or antigen-binding fragment of claim 1, wherein the antibody or antigen-binding fragment comprises a human Ig kappa light chain constant region.

### Claim 8 (depends on 1)

The anti-TREM2 antibody or antigen-binding fragment of claim 1, wherein the antibody or antigen-binding fragment comprises a heavy chain that is at least 95% identical to the amino acid sequence of SEQ ID NO: 37, and a light chain that is at least 95% identical to the amino acid sequence of SEQ ID NO: 26.

### Claim 9

An anti-TREM2 antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 37, and a light chain comprising the amino acid sequence of SEQ ID NO: 26.

### Claim 10 (depends on 1)

A method of treating a neuroinflammatory or neurodegenerative disease in a human subject, comprising administering to the human subject a therapeutically effective amount of the antibody or antigen-binding fragment of claim 1.

### Claim 11 (depends on 10)

The method of claim 10, wherein the disease is Alzheimer's disease, frontotemporal dementia, Parkinson's disease, Nasu-Hakola disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), anti-NMDA receptor encephalitis, autism, brain lupus (NP-SLE), chemo-induced peripheral neuropathy (CIPN), postherapeutic neuralgia, chronic inflammatory demyelinating polyneuropathy (CIDP), epilepsy, Guillain-Barre Syndrome (GBS), inclusion body myositis, lysosomal storage diseases, sphingomyelinlipidose (Niemann-Pick C), mucopolysaccharidose II/IIIB, metachromatic leukodystrophy, multifocal motor neuropathy, Myasthenia Gravis, Neuro-Behcet's Disease, neuromyelitis optica (NMO), optic neuritis, polymyositis, dermatomyositis, Rasmussen's encephalitis, Rett's Syndrome, stroke, transverse myelitis, traumatic brain injury, spinal cord injury, viral encephalitis, or bacterial meningitis.

### Claim 12 (depends on 10)

The method of claim 10, wherein the disease is Alzheimer's disease.

### Claim 13 (depends on 10)

The method of claim 10, wherein the disease is multiple sclerosis.

### Claim 14 (depends on 10)

The method of claim 10, wherein the disease is amyotrophic lateral sclerosis.

### Claim 15 (depends on 3)

A method of treating a neuroinflammatory or neurodegenerative disease in a human subject, comprising administering to the human subject a therapeutically effective amount of the antibody or antigen-binding fragment of claim 3.

### Claim 16 (depends on 15)

The method of claim 15, wherein the disease is Alzheimer's disease, frontotemporal dementia, Parkinson's disease, Nasu-Hakola disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), anti-NMDA receptor encephalitis, autism, brain lupus (NP-SLE), chemo-induced peripheral neuropathy (CIPN), postherapeutic neuralgia, chronic inflammatory demyelinating polyneuropathy (CIDP), epilepsy, Guillain-Barré Syndrome (GBS), inclusion body myositis, lysosomal storage diseases, sphingomyelinlipidose (Niemann-Pick C), mucopolysaccharidose II/IIIB, metachromatic leukodystrophy, multifocal motor neuropathy, Myasthenia Gravis, Neuro-Behcet's Disease, neuromyelitis optica (NMO), optic neuritis, polymyositis, dermatomyositis, Rasmussen's encephalitis, Rett's Syndrome, stroke, transverse myelitis, traumatic brain injury, spinal cord injury, viral encephalitis, or bacterial meningitis.

### Claim 17 (depends on 15)

The method of claim 15, wherein the disease is Alzheimer's disease.

### Claim 18 (depends on 15)

The method of claim 15, wherein the disease is multiple sclerosis.

### Claim 19 (depends on 15)

The method of claim 15, wherein the disease is amyotrophic lateral sclerosis.

### Claim 20 (depends on 9)

A method of treating a neuroinflammatory or neurodegenerative disease in a human subject, comprising administering to the human subject a therapeutically effective amount of the antibody or antigen-binding fragment of claim 9.

### Claim 21 (depends on 20)

The method of claim 20, wherein the disease is Alzheimer's disease, frontotemporal dementia, Parkinson's disease, Nasu-Hakola disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), anti-NMDA receptor encephalitis, autism, brain lupus (NP-SLE), chemo-induced peripheral neuropathy (CIPN), postherapeutic neuralgia, chronic inflammatory demyelinating polyneuropathy (CIDP), epilepsy, Guillain-Barre Syndrome (GBS), inclusion body myositis, lysosomal storage diseases, sphingomyelinlipidose (Niemann-Pick C), mucopolysaccharidose II/IIIB, metachromatic leukodystrophy, multifocal motor neuropathy, Myasthenia Gravis, Neuro-Behcet's Disease, neuromyelitis optica (NMO), optic neuritis, polymyositis, dermatomyositis, Rasmussen's encephalitis, Rett's Syndrome, stroke, transverse myelitis, traumatic brain injury, spinal cord injury, viral encephalitis, or bacterial meningitis.

### Claim 22 (depends on 20)

The method of claim 20, wherein the disease is Alzheimer's disease.

### Claim 23 (depends on 20)

The method of claim 20, wherein the disease is multiple sclerosis.

### Claim 24 (depends on 20)

The method of claim 20, wherein the disease is amyotrophic lateral sclerosis.