# US 9,518,122 B2 · Endoglin antibodies

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- Number: US 9,518,122 B2
- Document ID: US9518122B2
- Status: Granted
- Kind: B2
- Application number: 14/838,006
- Filed: 2015-08-27
- Published: 2016-01-14
- Granted: 2016-12-13
- Earliest claimed: 2009-09-30
- Assignees: Tracon Pharmaceuticals, Inc.
- Applicants: Tracon Pharmaceuticals, Inc.
- Inventors: Charles Theuer; Maximiliano Vasquez
- Web page: https://patentgrep.com/patent/US9518122B2

## CPC

- C07K 16/30: from tumour cells
- A61K 31/282: Platinum compounds
- A61K 31/337: having four-membered rings, e.g. taxol
- A61K 31/4045: Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/69: Boron compounds
- A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)}
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- 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 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- 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 13/12: of the kidneys
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 27/02: Ophthalmic agents
- 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 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- C07K 16/2863: {against receptors for growth factors, growth regulators}
- C07K 16/2896: {against molecules with a "CD"-designation, not provided for elsewhere}
- C07K 16/3015: {Breast}
- C07K 16/3038: {Kidney, bladder}
- C07K 16/3046: {Stomach, Intestines}
- C07K 16/3061: {Blood cells}
- C07K 16/3069: {Reproductive system, e.g. ovaria, uterus, testes, prostate}
- G01N 33/5759: {involving compounds localised on the membrane of tumour or cancer cells}
- G01N 33/57595: {involving intracellular compounds}
- G01N 33/6872: {Intracellular protein regulatory factors and their receptors, e.g. including ion channels}
- 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 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/732: Antibody-dependent cellular cytotoxicity [ADCC]
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- G01N 2333/70596: Molecules with a "CD"-designation not provided for elsewhere in G01N2333/705
- G01N 2333/71: for growth factors; for growth regulators
- G01N 2800/16: Ophthalmology
- G01N 2800/164: Retinal disorders, e.g. retinopathy
- 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 application relates to compositions of humanized and humanized/deimmunized anti-endoglin antibodies and antigen-binding fragments thereof. One aspect relates to antibodies having one or more modifications in at least one amino acid residue of at least one of the framework regions of the variable heavy chain, the variable light chain or both. Another aspect relates to antibodies which bind endoglin and inhibit angiogenesis. Another aspect relates to the deimmunization of humanized antibodies to reduce immunogenicity. Another aspect relates to the use of humanized and humanized/deimmunized antibodies which bind endoglin for the detection, diagnosis or treatment of a disease or condition associated with endoglin, angiogenesis or a combination thereof.

## Claims

### Claim 1

A method of treating an ocular condition that is choroidal neovascularization (CNV), diabetic nephropathy, non-diabetic retinopathy, sub-retinal neovascularization, proliferative vitreoretinopathy, or a neovascular glaucoma in a subject in need thereof, comprising administering to the subject a composition comprising an antibody or antigen-binding fragment thereof, that binds endoglin, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence set forth as SEQ ID NO: 89 and a light chain variable region having an amino acid sequence set forth as SEQ ID NO: 93.

### Claim 2 (depends on 1)

The method of claim 1, wherein the ocular condition is choroidal neovascularization.

### Claim 3 (depends on 1)

The method of claim 1, wherein the ocular condition is diabetic nephropathy.

### Claim 4 (depends on 1)

The method of claim 1, wherein the ocular condition is non-diabetic retinopathy.

### Claim 5 (depends on 1)

The method of claim 1, wherein the ocular condition is sub-retinal neovascularization.

### Claim 6 (depends on 1)

The method of claim 1, wherein the ocular condition is proliferative vitreoretinopathy.

### Claim 7 (depends on 1)

The method of claim 1, wherein the ocular condition is a neovascular glaucoma.

### Claim 8

A method of treating choroidal neovascularization (CNV) in a subject in need thereof, comprising administering to the subject a composition comprising an antibody or antigen-binding fragment thereof, that binds endoglin, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region having the amino acid sequence set forth as SEQ ID NO: 89 and a light chain variable region having the amino acid sequence set forth as SEQ ID NO: 93, wherein: said heavy chain variable region further comprises one or more modifications selected from the group consisting of a substitution of glycine (G) by alanine (A) or serine (S) at position 49; a substitution of alanine (A) by isoleucine (I) at position 51; a substitution of lysine (K) by arginine (R) or asparagine (Q) at position 54, a substitution of leucine (L) by valine (V) at position 81 utilizing the Kabat numbering system; and the light chain variable region further comprises one or more modifications selected from the group consisting of a substitution of methionine (M) by leucine (L) at position 4; a substitution of alanine (A) by valine (V) at position 19; a substitution of threonine (T) by serine (S) at position 22; a substitution of alanine (A) by isoleucine (I) at position 48; and a substitution of threonine (T) by serine (S) at position 51utilizing the Kabat numbering system.

### Claim 9 (depends on 8)

The method of claim 8, comprising a heavy chain variable region having an amino acid sequence set forth as SEQ ID NO: 88, 89, 90, 91 or 92; and a light chain variable region having an amino acid sequence set forth as SEQ ID NO: 93, 94, 95, 96, 97, 100, 102, or 103.

### Claim 10 (depends on 8)

The method of claim 8, wherein the ocular condition is choroidal neovascularization.

### Claim 11 (depends on 8)

The method of claim 8, wherein the ocular condition is diabetic nephropathy.

### Claim 12 (depends on 8)

The method of claim 8, wherein the ocular condition is non-diabetic retinopathy.

### Claim 13 (depends on 8)

The method of claim 8, wherein the ocular condition is sub-retinal neovascularization.

### Claim 14 (depends on 8)

The method of claim 8, wherein the ocular condition is proliferative vitreoretinopathy.

### Claim 15 (depends on 8)

The method of claim 8, wherein the ocular condition is a neovascular glaucoma.

### Claim 16

A method of treating a chronic inflammatory disease in a subject in need thereof, comprising administering to the subject a composition comprising an antibody or antigen-binding fragment thereof, that binds endoglin, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence set forth as SEQ ID NO: 89 and a light chain variable region having an amino acid sequence set forth as SEQ ID NO: 93.

### Claim 17 (depends on 16)

The method of claim 16, wherein the chronic inflammatory disease is an inflammatory bowel disease (IBD).

### Claim 18 (depends on 17)

The method of claim 17, wherein the inflammatory bowel disease is Crohn's disease.

### Claim 19 (depends on 17)

The method of claim 17, wherein the inflammatory bowel disease is ulcerative colitis.

### Claim 20

A method of treating a chronic inflammatory disease in a subject in need thereof, comprising administering to the subject a composition comprising an antibody or antigen-binding fragment thereof, that binds endoglin, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region having the amino acid sequence set forth as SEQ ID NO: 89 and a light chain variable region having the amino acid sequence set forth as SEQ ID NO: 93, wherein: said heavy chain variable region further comprises one or more modifications selected from the group consisting of a substitution of glycine (G) by alanine (A) or serine (S) at position 49; a substitution of alanine (A) by isoleucine (I) at position 51; a substitution of lysine (K) by arginine (R) or asparagine (Q) at position 54, a substitution of leucine (L) by valine (V) at position 81 utilizing the Kabat numbering system; and the light chain variable region further comprises one or more modifications selected from the group consisting of a substitution of methionine (M) by leucine (L) at position 4; a substitution of alanine (A) by valine (V) at position 19; a substitution of threonine (T) by serine (S) at position 22; a substitution of alanine (A) by isoleucine (I) at position 48; and a substitution of threonine (T) by serine (S) at position 51 utilizing the Kabat numbering system.

### Claim 21 (depends on 20)

The method of claim 20, comprising a heavy chain variable region having an amino acid sequence set forth as SEQ ID NO: 88, 89, 90, 91 or 92; and a light chain variable region having an amino acid sequence set forth as SEQ ID NO: 93, 94, 95, 96, 97, 100, 102, or 103.

### Claim 22 (depends on 20)

The method of claim 20, wherein the chronic inflammatory disease is an inflammatory bowel disease (IBD).

### Claim 23 (depends on 22)

The method of claim 22, wherein the inflammatory bowel disease is Crohn's disease.

### Claim 24 (depends on 22)

The method of claim 22, wherein the inflammatory bowel disease is ulcerative colitis.