# US 2019/0315845 A1 · Humanized anti-complement factor c1q antibodies and uses thereof

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- Number: US 2019/0315845 A1
- Document ID: US20190315845A1
- Status: Published application
- Kind: A1
- Application number: 16/415,278
- Filed: 2019-05-17
- Published: 2019-10-17
- Earliest claimed: 2014-11-05
- Assignees: Annexon, Inc.
- Applicants: Annexon, Inc.
- Inventors: Arnon Rosenthal; Michael Leviten
- Web page: https://patentgrep.com/patent/US20190315845A1

## CPC

- C07K 16/18: against material from animals or humans
- A61K 49/0002: {General or multifunctional contrast agents, e.g. chelated agents}
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/06: Antianaemics
- 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 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 21/02: Muscle relaxants, e.g. for tetanus or cramps
- A61P 21/04: for myasthenia gravis
- 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 27/04: Artificial tears; Irrigation solutions
- 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 35/00: Antineoplastic agents
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- G01N 33/564: for pre-existing immune complex or autoimmune disease {, i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9}
- G01N 33/6893: {related to diseases not provided for elsewhere}
- G01N 33/6896: {Neurological disorders, e.g. Alzheimer's disease}
- A61K 2039/505: {comprising antibodies}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- 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 2317/52: Constant or Fc region; Isotype
- 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 2317/94: Stability, e.g. half-life, pH, temperature or enzyme-resistance
- G01N 2333/4716: Complement proteins, e.g. anaphylatoxin, C3a, C5a
- 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
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

The present disclosure is directed to humanized anti-C1q antibodies and methods of using them.

## Claims

### Claim at position 1

1-29. (canceled)

### Claim 30

An anti-C1q antibody Fab fragment, wherein the antibody Fab fragment comprises:
a) a heavy chain variable domain, and the heavy chain variable domain comprises an amino acid sequence selected from SEQ ID NOs: 1-4, or an amino acid sequence with at least about 95% homology to the amino acid sequence selected from SEQ ID NOs: 1-4 and wherein the heavy chain variable domain comprises an HVR-H1 having the amino acid sequence of SEQ ID NO: 23, an HVR-H2 having the amino acid sequence of SEQ ID NO: 24, and an HVR-H3 having the amino acid sequence of SEQ ID NO: 25; and/or
b) a light chain variable domain, and the light chain variable domain comprises an amino acid sequence selected from SEQ ID NOs: 5-8, or an amino acid sequence with at least about 95% homology to the amino acid sequence selected from SEQ ID NOs: 5-8 and wherein the light chain variable domain comprises an HVR-L1 having the amino acid sequence of SEQ ID NO: 30, an HVR-L2 having the amino acid sequence of SEQ ID NO: 31, and an HVR-L3 having the amino acid sequence of SEQ ID NO: 32.

### Claim 31 (depends on 30)

The antibody Fab fragment of claim 30, wherein the antibody comprises a human heavy chain constant region, wherein the human heavy chain constant region is a human IgG4 heavy chain constant region.

### Claim 32 (depends on 30)

The antibody Fab fragment of claim 30, wherein the antibody binds specifically to rat C1q, to both human C1q and mouse C1q, or to human C1q, mouse C1q, and rat C1q.

### Claim 33 (depends on 30)

The antibody Fab fragment of claim 30, wherein the antibody has a dissociation constant (KD) for human C1q that ranges from less than about 10 μM to less than about 5 μM; wherein the antibody has dissociation constant (KD) for mouse C1q that ranges from less than about 125 nM to less than about 5 μM.

### Claim 34 (depends on 30)

The antibody Fab fragment of claim 30, wherein the antibody specifically binds to and inhibits a biological activity of C1q.

### Claim 35 (depends on 34)

The antibody Fab fragment of claim 34, wherein the biological activity is (1) C1q binding to an autoantibody, (2) C1q binding to C1r, (3) C1q binding to C1s, (4) C1q binding to phosphatidylserine, (5) C1q binding to pentraxin-3, (6) C1q binding to C-reactive protein (CRP), (7) C1q binding to globular C1q receptor (gC1qR), (8) C1q binding to complement receptor 1 (CR1), (9) C1q binding to beta-amyloid, or (10) C1q binding to calreticulin.

### Claim 36 (depends on 34)

The antibody Fab fragment of claim 34, wherein the biological activity is (1) activation of the classical complement activation pathway, (2) activation of antibody and complement dependent cytotoxicity, (3) CH50 hemolysis, (4) synapse loss, (5) B-cell antibody production, (6) dendritic cell maturation, (7) T-cell proliferation, (8) cytokine production (9) microglia activation, (10) Arthus reaction, (11) phagocytosis of synapses or nerve endings, or (12) activation of complement receptor 3 (CR3/C3) expressing cells.

### Claim 37 (depends on 36)

The antibody Fab fragment of claim 36, wherein CH50 hemolysis comprises human, mouse, and/or rat CH50 hemolysis.

### Claim 38 (depends on 37)

The antibody Fab fragment of claim 37, wherein the antibody is capable of neutralizing from at least about 50%, to at least about 90% of CH50 hemolysis.

### Claim 39 (depends on 30)

A pharmaceutical composition comprising the antibody Fab fragment of claim 30 and a pharmaceutically acceptable carrier.

### Claim 40 (depends on 30)

A kit comprising an antibody Fab fragment of claim 30, and a package insert comprising instructions for using the antibody Fab fragment to treat a disease associated with complement activation in an individual in need of such treatment.

### Claim 41

A anti-C1q antibody Fab fragment, the antibody Fab fragment comprising a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 3, and wherein the light chain variable domain comprises an amino acid sequence of SEQ ID NO: 7.

### Claim 42 (depends on 41)

The antibody Fab fragment of claim 41, wherein the antibody comprises a human heavy chain constant region, wherein the human heavy chain constant region is a human IgG4 heavy chain constant region.

### Claim 43 (depends on 41)

The antibody Fab fragment of claim 41, wherein the antibody binds specifically to rat C1q, to both human C1q and mouse C1q, or to human C1q, mouse C1q, and rat C1q.

### Claim 44 (depends on 41)

The antibody Fab fragment of claim 41, wherein the antibody has a dissociation constant (KD) for human C1q that ranges from less than about 10 μM to less than about 5 μM; wherein the antibody has dissociation constant (KD) for mouse C1q that ranges from less than about 125 nM to less than about 5 μM.

### Claim 45 (depends on 41)

The antibody Fab fragment of claim 41, wherein the antibody specifically binds to and inhibits a biological activity of C1q.

### Claim 46 (depends on 45)

The antibody Fab fragment of claim 45, wherein the biological activity is (1) C1q binding to an autoantibody, (2) C1q binding to C1r, (3) C1q binding to C1s, (4) C1q binding to phosphatidylserine, (5) C1q binding to pentraxin-3, (6) C1q binding to C-reactive protein (CRP), (7) C1q binding to globular C1q receptor (gC1qR), (8) C1q binding to complement receptor 1 (CR1), (9) C1q binding to beta-amyloid, or (10) C1q binding to calreticulin.

### Claim 47 (depends on 45)

The antibody Fab fragment of claim 45, wherein the biological activity is (1) activation of the classical complement activation pathway, (2) activation of antibody and complement dependent cytotoxicity, (3) CH50 hemolysis, (4) synapse loss, (5) B-cell antibody production, (6) dendritic cell maturation, (7) T-cell proliferation, (8) cytokine production (9) microglia activation, (10) Arthus reaction, (11) phagocytosis of synapses or nerve endings, or (12) activation of complement receptor 3 (CR3/C3) expressing cells.

### Claim 48 (depends on 47)

The antibody Fab fragment of claim 47, wherein CH50 hemolysis comprises human, mouse, and/or rat CH50 hemolysis.

### Claim 49 (depends on 48)

The antibody Fab fragment of claim 48, wherein the antibody is capable of neutralizing from at least about 50%, to at least about 90% of CH50 hemolysis.

### Claim 50 (depends on 41)

A pharmaceutical composition comprising the antibody Fab fragment of claim 41 and a pharmaceutically acceptable carrier.

### Claim 51 (depends on 41)

A kit comprising an antibody Fab fragment of claim 41, and a package insert comprising instructions for using the antibody Fab fragment to treat a disease associated with complement activation in an individual in need of such treatment.