# US 2014/0193402 A1 · ANTI-PDGFR-beta ANTIBODIES AND USES THEREOF

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- Number: US 2014/0193402 A1
- Document ID: US20140193402A1
- Status: Published application
- Kind: A1
- Application number: 14/148,753
- Filed: 2014-01-07
- Published: 2014-07-10
- Earliest claimed: 2013-01-09
- Assignees: Regeneron Pharmaceuticals, Inc.
- Applicants: Regeneron Pharmaceuticals, Inc.
- Inventors: Stanley J. WIEGAND; Ivan B. LOBOV
- Web page: https://patentgrep.com/patent/US20140193402A1

## CPC

- C07K 16/2863: {against receptors for growth factors, growth regulators}
- A61K 38/179: {for growth factors; for growth regulators}
- A61K 39/39541: {against normal tissues, cells}
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- 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 13/08: of the prostate
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 27/00: Drugs for disorders of the senses
- A61P 27/02: Ophthalmic agents
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 35/00: Antineoplastic agents
- C07K 14/71: for growth factors; for growth regulators
- A61K 2039/505: {comprising antibodies}
- A61K 2039/507: {Comprising a combination of two or more separate antibodies}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- 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 2319/30: 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 2319/40: containing a tag for immunodetection, or an epitope for immunisation
- C07K 2319/73: containing coiled-coiled motif (leucine zippers)
- 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 invention provides antibodies that bind to platelet derived growth factor receptor beta (PDGFR-beta) and methods of using the same. According to certain embodiments of the invention, the antibodies are fully human antibodies that bind to human PDGFR-beta with high affinity. The antibodies of the invention are useful for the treatment of diseases and disorders associated with PDGFR-beta signaling and/or PDGFR-beta cellular expression, such as ocular diseases, fibrotic diseases, vascular diseases and cancer.

## Claims

### Claim 1

An isolated antibody or antigen-binding fragment thereof that specifically binds monomeric human platelet derived growth factor receptor beta (PDGFR-beta) with a binding dissociation equilibrium constant (KD) of less than about 30 nM as measured in a surface plasmon resonance assay at 37° C.

### Claim 2 (depends on 1)

The antibody or antigen-binding fragment of claim 1, wherein the antibody or antigen-binding fragment thereof specifically binds monomeric PDGFR-beta with a KD of less than about 10 nM as measured in a surface plasmon resonance assay at 37° C.

### Claim 3

An isolated antibody or antigen-binding fragment thereof that specifically binds dimeric human platelet derived growth factor receptor beta (PDGFR-beta) with a binding dissociation equilibrium constant (KD) of less than about 200 pM as measured in a surface plasmon resonance assay at 37° C.

### Claim 4 (depends on 1)

The isolated antibody or antigen-binding fragment of claim 1, wherein the antibody or antigen-binding fragment thereof blocks binding of at least one PDGF ligand to PDGFR-beta.

### Claim 5 (depends on 4)

The isolated antibody or antigen-binding fragment of claim 4, wherein the antibody or antigen-binding fragment thereof blocks PDGF-BB ligand binding to soluble monomeric PDGFR-beta with an IC50 value of less than about 300 pM as measured in an in vitro receptor/ligand binding assay at 25° C.

### Claim 6 (depends on 5)

The antibody or antigen-binding fragment of claim 5, wherein the antibody or antigen-binding fragment thereof blocks PDGF-BB ligand binding to soluble monomeric PDGFR-beta with an IC50 value of less than about 150 pM as measured in an in vitro receptor/ligand binding assay at 25° C.

### Claim 7 (depends on 1)

The antibody or antigen-binding fragment of claim 1, wherein the antibody or antigen-binding fragment thereof inhibits PDGF ligand-mediated activation of PDGFR-beta signaling in cells that express PDGFR-beta.

### Claim 8 (depends on 1)

An antibody or antigen-binding fragment of claim 1, wherein the antibody or antigen-binding fragment thereof specifically interacts with one or more amino acids within Ig domain 2 of the extracellular domain of PDGFR-beta (within amino acids 97 through 178 of SEQ ID NO:337).

### Claim 9 (depends on 1)

The antibody or antigen-binding fragment of claim 1, wherein the antibody or antigen-binding fragment thereof competes for binding to PDGFR-beta with a reference antibody comprising an HCVR/LCVR sequence pair selected from the group consisting of SEQ ID NOs: 2/10, 18/26, 34/42, 50/58, 66/74, 82/90, 98/106, 114/122, 130/138, 146/154, 162/170, 178/186, 194/202, 210/218, 226/234, 242/250, 258/266, 274/282, 290/298, 306/314, and 322/330.

### Claim 10 (depends on 1)

The antibody or antigen-binding fragment of claim 1, wherein the antibody or antigen-binding fragment thereof binds to the same epitope on PDGFR-beta as a reference antibody comprising an HCVR/LCVR sequence pair selected from the group consisting of SEQ ID NOs: 2/10, 18/26, 34/42, 50/58, 66/74, 82/90, 98/106, 114/122, 130/138, 146/154, 162/170, 178/186, 194/202, 210/218, 226/234, 242/250, 258/266, 274/282, 290/298, 306/314, and 322/330.

### Claim 11

An isolated antibody or antigen-binding fragment thereof that specifically binds human platelet derived growth factor receptor beta (PDGFR-beta), wherein the antibody or antigen-binding fragment comprises: (a) the complementarity determining regions (CDRs) of a heavy chain variable region (HCVR) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 18, 34, 50, 66, 82, 98, 114, 130, 146, 162, 178, 194, 210, 226, 242, 258, 274, 290, 306, and 322; and (b) the CDRs of a light chain variable region (LCVR) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 26, 42, 58, 74, 90, 106, 122, 138, 154, 170, 186, 202, 218, 234, 250, 266, 282, 298, 314, and 330.

### Claim 12 (depends on 11)

The isolated antibody or antigen-binding fragment of claim 11, wherein the antibody or antigen-binding fragment comprises the heavy and light chain CDRs of a HCVR/LCVR amino acid sequence pair selected from the group consisting of: SEQ ID NOs: 2/10, 18/26, 34/42, 50/58, 66/74, 82/90, 98/106, 114/122, 130/138, 146/154, 162/170, 178/186, 194/202, 210/218, 226/234, 242/250, 258/266, 274/282, 290/298, 306/314, and 322/330.

### Claim 13 (depends on 12)

The isolated antibody or antigen-binding fragment of claim 12, wherein the antibody or antigen-binding fragment comprises HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 domains, respectively, selected from the group consisting of: SEQ ID NOs: 4-6-8-12-14-16; 20-22-24-28-30-32; 36-38-40-44-46-48; 52-54-56-60-62-64; 68-70-72-76-78-80; 84-86-88-92-94-96; 100-102-104-108-110-112; 116-118-120-124-126-128; 132-134-136-140-142-144; 148-150-152-156-158-160; 164-166-168-172-174-176; 180-182-184-188-190-192; 196-198-200-204-206-208; 212-214-216-220-222-224; 228-230-232-236-238-240; 244-246-248-252-254-256; 260-262-264-268-270-272; 276-278-280-284-286-288; 292-294-296-300-302-304; 308-310-312-316-318-320; and 324-326-328-332-334-336.

### Claim 14

An isolated antibody or antigen-binding fragment thereof that specifically binds human platelet derived growth factor receptor beta (PDGFR-beta), wherein the antibody or antigen-binding fragment comprises: (a) a heavy chain variable region (HCVR) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 18, 34, 50, 66, 82, 98, 114, 130, 146, 162, 178, 194, 210, 226, 242, 258, 274, 290, 306, and 322; and (b) a light chain variable region (LCVR) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 26, 42, 58, 74, 90, 106, 122, 138, 154, 170, 186, 202, 218, 234, 250, 266, 282, 298, 314, and 330.

### Claim 15 (depends on 14)

The isolated antibody or antigen-binding fragment of claim 14, wherein the antibody or antigen-binding fragment comprises a HCVR/LCVR amino acid sequence pair selected from the group consisting of: SEQ ID NOs: 2/10, 18/26, 34/42, 50/58, 66/74, 82/90, 98/106, 114/122, 130/138, 146/154, 162/170, 178/186, 194/202, 210/218, 226/234, 242/250, 258/266, 274/282, 290/298, 306/314, and 322/330.

### Claim 16 (depends on 1)

A pharmaceutical composition comprising the antibody or antigen-binding fragment of claim 1, and a pharmaceutically acceptable carrier or diluent.

### Claim 17 (depends on 16)

A method for treating an eye disease, the method comprising administering the pharmaceutical composition of claim 16 to a subject afflicted with an eye disease.

### Claim 18 (depends on 17)

The method of claim 17, wherein the eye disease is selected from the group consisting of age-related macular degeneration (AMD), exudative AMD, diabetic retinopathy, central retinal vein occlusion (CRVO), iris neovascularization, neovascular glaucoma, post-surgical fibrosis in glaucoma, proliferative vitreoretinopathy (PVR), choroidal neovascularization, optic disc neovascularization, corneal neovascularization, retinal neovascularization, vitreal neovascularization, pannus, pterygium, macular edema, diabetic macular edema (DME), vascular retinopathy, retinal degeneration, uveitis, and inflammatory diseases of the eye.

### Claim 19 (depends on 1)

A pharmaceutical composition comprising the antibody or antigen-binding fragment of claim 1, a VEGF antagonist, and a pharmaceutically acceptable carrier or diluent.

### Claim 20 (depends on 19)

The pharmaceutical composition of claim 19, wherein the VEGF antagonist is a VEGF-inhibiting fusion protein or an anti-VEGF antibody or antigen binding fragment of an anti-VEGF antibody.

### Claim 21 (depends on 20)

The pharmaceutical composition of claim 20, wherein the VEGF antagonist is aflibercept, bevacizumab, or ranibizumab.

### Claim 22 (depends on 19)

A method for treating an eye disease, the method comprising administering the pharmaceutical composition of claim 19 to a subject afflicted with an eye disease.

### Claim 23 (depends on 22)

The method of claim 22, wherein the eye disease is selected from the group consisting of age-related macular degeneration (AMD), exudative AMD, diabetic retinopathy, central retinal vein occlusion (CRVO), iris neovascularization, neovascular glaucoma, post-surgical fibrosis in glaucoma, proliferative vitreoretinopathy (PVR), choroidal neovascularization, optic disc neovascularization, corneal neovascularization, retinal neovascularization, vitreal neovascularization, pannus, pterygium, macular edema, diabetic macular edema (DME), vascular retinopathy, retinal degeneration, uveitis, and inflammatory diseases of the eye.

### Claim 24 (depends on 1)

A method of treating age-related macular degeneration (AMD), the method comprising administering to a subject in need thereof: (i) the antibody or antigen-binding fragment of claim 1; and (ii) aflibercept.

### Claim 25 (depends on 24)

The method of claim 24, wherein the antibody or antigen-binding fragment thereof is administered to the subject prior to, concurrent with, or after administration of aflibercept to the subject.

### Claim 26 (depends on 24)

The method of claim 24, wherein the antibody or antigen-binding fragment thereof and aflibercept are administered to the subject together in a single formulation.

### Claim 27 (depends on 24)

The method of claim 24, wherein the antibody or antigen-binding fragment thereof and aflibercept are administered to the subject in separate dosage forms.

### Claim 28 (depends on 16)

A method for inhibiting tumor growth, the method comprising administering the pharmaceutical composition of claim 16 to a subject afflicted with a tumor.

### Claim 29 (depends on 28)

The method of claim 28, wherein the tumor is selected from the group consisting of a renal tumor, a pancreatic tumor, a head and neck tumor, a breast tumor, a prostate tumor, a colon tumor, a gastric tumor, and ovarian tumor, a lung tumor, and a skin tumor.

### Claim 30 (depends on 16)

A method for treating fibrosis, the method comprising administering the pharmaceutical composition of claim 16 to a subject afflicted with a fibrotic condition.

### Claim 31 (depends on 30)

The method of claim 30, wherein the fibrotic condition is pulmonary fibrosis, ocular fibrosis, skin fibrosis, kidney fibrosis, or liver fibrosis.