# US 10,308,718 B2 · Anti-sortilin antibodies and methods of use thereof

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- Number: US 10,308,718 B2
- Document ID: US10308718B2
- Status: Granted
- Kind: B2
- Application number: 15/867,609
- Filed: 2018-01-10
- Published: 2018-09-20
- Granted: 2019-06-04
- Earliest claimed: 2016-04-07
- Assignees: Alector LLC
- Applicants: Alector LLC
- Inventors: Arnon Rosenthal; Tina Schwabe; Michael Kurnellas; Robert Pejchal; Anthony B. Cooper
- Web page: https://patentgrep.com/patent/US10308718B2

## CPC

- C07K 16/2863: {against receptors for growth factors, growth regulators}
- A61K 31/7088: Compounds having three or more nucleosides or nucleotides
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 21/02: Muscle relaxants, e.g. for tetanus or cramps
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/08: Antiepileptics; Anticonvulsants
- 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 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 16/286: {against neuromediator receptors, e.g. serotonin receptor, dopamine receptor}
- C07K 2317/14: Specific host cells or culture conditions, e.g. components, pH or temperature
- C07K 2317/21: from primates, e.g. man
- C07K 2317/31: multispecific
- 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 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- C07K 2319/32: fusions with soluble part of a cell surface receptor, "decoy receptors"
- 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

## Abstract

The present disclosure is generally directed to compositions that include antibodies, e.g., monoclonal, chimeric, humanized antibodies, antibody fragments, etc., that specifically bind on or more epitopes within a Sortilin protein, e.g., human Sortilin or a mammalian Sortilin, and use of such compostions in preventing, reducing risk, or treating an individual in need thereof.

## Claims

### Claim 1

An isolated anti-Sortilin antibody, wherein the anti-Sortilin antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises:
(a) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 9;
(b) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 29; and
(c) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 55, and wherein the heavy chain variable domain comprises:
(a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 520;
(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 533; and
(c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 553.

### Claim 2 (depends on 1)

The anti-Sortilin antibody of claim 1, wherein the anti-Sortilin antibody is a human antibody, a bispecific antibody, a monoclonal antibody, a multivalent antibody, a conjugated antibody, or a chimeric antibody.

### Claim 3 (depends on 1)

The anti-Sortilin antibody of claim 1, wherein the anti-Sortilin antibody is a multivalent antibody recognizing a second antigen.

### Claim 4 (depends on 3)

The anti-Sortilin antibody of claim 3, wherein the second antigen is an antigen facilitating transport across the blood-brain-barrier.

### Claim 5 (depends on 4)

The anti-Sortilin antibody of claim 4, wherein the second antigen is 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, a protein transduction domain, penetratin, a poly-arginine peptide, and an angiopep peptide.

### Claim 6 (depends on 1)

The anti-Sortilin antibody of claim 1, wherein the anti-Sortilin antibody is an antibody fragment that binds to an epitope comprising amino acid residues on human Sortilin or a mammalian Sortilin protein.

### Claim 7 (depends on 6)

The anti-Sortilin antibody of claim 6, wherein the fragment is an Fab, Fab′, Fab′-SH, F(ab′)2, Fv, or scFv fragment.

### Claim 8 (depends on 1)

The anti-Sortilin antibody of claim 1, wherein the anti-Sortilin antibody has a human Fc IgG1 isotype.

### Claim 9 (depends on 1)

The anti-Sortilin antibody of claim 1, wherein the anti-Sortilin antibody has a human Fc IgG1 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: N297A, N297Q, D265A, L234A, L235A, C226S, C229S, P238S, E233P, L234V, P238A, A327Q, A327G, P329A, K322A, L234F, L235E, P331S, T394D, A330L, M252Y, S254T, T256E, and any combination thereof, wherein the numbering of the residues is according to EU numbering.

### Claim 10 (depends on 1)

The anti-Sortilin antibody of claim 1, wherein the anti-Sortilin antibody has a human Fc IgG1 isotype and comprises an amino acid substitution in the Fc region at residue position L234A and L235A, wherein the numbering of the residues is according to EU numbering.

### Claim 11 (depends on 1)

The anti-Sortilin antibody of claim 1, wherein the anti-Sortilin antibody has an IgG4 isotype.

### Claim 12 (depends on 11)

The anti-Sortilin antibody of claim 11, wherein the anti-Sortilin antibody has a human Fc IgG4 isotype and comprises an amino acid substitution in the Fc region at residue position S228P, F234A, and L235A, wherein the numbering of the residue position is according to EU numbering.

### Claim 13 (depends on 1)

The anti-Sortilin antibody of claim 1, wherein the anti-Sortilin antibody increases extracellular levels of Progranulin.

### Claim 14 (depends on 13)

The anti-Sortilin antibody of claim 13, wherein the anti-Sortilin antibody decreases cellular levels of Sortilin.

### Claim 15 (depends on 14)

The anti-Sortilin antibody of claim 14, wherein the antibody decreases cell surface levels of Sortilin, decreases total levels of Sortilin, or any combination thereof.

### Claim 16 (depends on 15)

The anti-Sortilin antibody of claim 15, wherein the anti-Sortilin antibody induces Sortilin degradation, Sortilin internalization, Sortilin down regulation, or any combination thereof.

### Claim 17 (depends on 1)

The anti-Sortilin antibody of claim 1, wherein the anti-Sortilin antibody further inhibits interaction between Sortilin and pro-nerve growth factor (pro-NGF).

### Claim 18 (depends on 1)

The anti-Sortilin antibody of claim 1, wherein the anti-Sortilin antibody binds specifically to human Sortilin, mouse Sortilin, or both human Sortilin and mouse Sortilin.

### Claim 19 (depends on 18)

The anti-Sortilin antibody of claim 18, wherein the anti-Sortilin antibody has a dissociation constant (KD) for human Sortilin, mouse Sortilin, or both, that ranges from about 100 nM to about 0.005 nM.

### Claim 20 (depends on 1)

The anti-Sortilin antibody of claim 1, wherein the anti-Sortilin antibody decreases expression of one or more pro-inflammatory mediators selected from the group consisting of IL-6, IL12p70, IL12p40, IL-1β, TNF-α, CXCL1, CCL2, CCL3, CCL4, and CCL5.

### Claim 21

An isolated anti-Sortilin antibody, wherein the anti-Sortilin antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 343 and a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 648.