# US 10,501,549 B2 · Methods of inhibiting pathological angiogenesis with doppel-targeting molecules

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- Number: US 10,501,549 B2
- Document ID: US10501549B2
- Status: Granted
- Kind: B2
- Application number: 15/450,272
- Filed: 2017-03-06
- Published: 2017-09-14
- Granted: 2019-12-10
- Earliest claimed: 2015-11-30
- Assignees: Seoul National University R&Db Foundation; University of Ulsan; Korea Institute of Science and Technology; Pharosgen
- Applicants: Seoul National University R&Db Foundation; University of Ulsan; Korea Institute of Science and Technology; Pharosgen
- Inventors: Youngro Byun; In San Kim; Ahmed Al-Hilal Taslim; Sang-Yoon Kim; Ye Ji Jang
- Web page: https://patentgrep.com/patent/US10501549B2

## CPC

- C07K 16/2872: {against prion molecules, e.g. CD230}
- A61K 47/55: the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
- A61K 47/554: {the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid}
- A61K 47/61: the organic macromolecular compound being a polysaccharide or a derivative thereof
- A61P 35/00: Antineoplastic agents
- C07K 16/30: from tumour cells
- C12N 15/113: Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)}
- C12Q 1/68: involving nucleic acids
- G01N 33/5759: {involving compounds localised on the membrane of tumour or cancer cells}
- G01N 33/6893: {related to diseases not provided for elsewhere}
- A01K 2217/075: inducing loss of function, i.e. knock out
- A01K 2227/105: Murine
- A61K 2039/505: {comprising antibodies}
- C07K 2317/70: characterized by effect upon binding to a cell or to an antigen
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C12N 2310/11: Antisense
- C12N 2310/3515: Lipophilic moiety, e.g. cholesterol
- G01N 2333/705: Assays involving receptors, cell surface antigens or cell surface determinants
- 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)
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- 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)
- A01K: ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS

## Abstract

Described herein are doppel-targeting molecules useful for inhibiting pathological angiogenesis and treating diseases and conditions associated with pathological angiogenesis, such as tumors, cancers, atherosclerosis, tuberculosis, asthma, pulmonary arterial hypertension (PAH), neoplasms and neoplasm-related conditions, and for detecting doppel expression in a subject. Related compositions and methods also are described.

## Claims

### Claim 1

An antibody that binds to doppel or a doppel-binding fragment thereof, comprising a heavy chain variable region and a light chain variable region, wherein:
(a) the heavy chain variable region comprises a CDRH1 comprising the amino acid sequence of SEQ ID NO: 31; a CDRH2 comprising the amino acid sequence of SEQ ID NO: 32; and a CDRH3 comprising the amino acid sequence of SEQ ID NO: 33; and the light chain variable region comprises a CDRL1 comprising the amino acid sequence of SEQ ID NO: 13; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 14; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 15;
(b) the heavy chain variable region comprises a CDRH1 comprising the amino acid sequence of SEQ ID NO: 34; a CDRH2 comprising the amino acid sequence of SEQ ID NO: 35; and a CDRH3 comprising the amino acid sequence of SEQ ID NO: 36; and the light chain variable region comprises a CDRL1 comprising the amino acid sequence of SEQ ID NO: 16; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 17; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 18;
(c) the heavy chain variable region comprises a CDRH1 comprising the amino acid sequence of SEQ ID NO: 37; a CDRH2 comprising the amino acid sequence of SEQ ID NO: 38; and a CDRH3 comprising the amino acid sequence of SEQ ID NO: 39; and the light chain variable region comprises a CDRL1 comprising the amino acid sequence of SEQ ID NO: 19; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 20; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 21;
(d) the heavy chain variable region comprises a CDRH1 comprising the amino acid sequence of SEQ ID NO: 40; a CDRH2 comprising the amino acid sequence of SEQ ID NO: 41; and a CDRH3 comprising the amino acid sequence of SEQ ID NO: 42; and the light chain variable region comprises a CDRL1 comprising the amino acid sequence of SEQ ID NO: 22; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 23; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 24; or
(e) the heavy chain variable region comprises a CDRH1 comprising the amino acid sequence of SEQ ID NO: 43; a CDRH2 comprising the amino acid sequence of SEQ ID NO: 44; and a CDRH3 comprising the amino acid sequence of SEQ ID NO: 45; and the light chain variable region comprising a CDRL1 comprising the amino acid sequence of SEQ ID NO: 25; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 26; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 27.

### Claim 2 (depends on 1)

The antibody or fragment thereof according to claim 1, wherein the antibody or fragment thereof is a monoclonal antibody.

### Claim 3 (depends on 1)

A pharmaceutical composition comprising an anti-doppel antibody or doppel-binding fragment thereof according to claim 1 and a pharmaceutically acceptable carrier or diluent.

### Claim 4 (depends on 1)

The antibody or doppel-binding fragment thereof according to claim 1, wherein the heavy chain variable region comprises a CDRH1 comprising the amino acid sequence of SEQ ID NO: 34; a CDRH2 comprising the amino acid sequence of SEQ ID NO: 35; and a CDRH3 comprising the amino acid sequence of SEQ ID NO: 36; and the light chain variable region comprises a CDRL1 comprising the amino acid sequence of SEQ ID NO: 16; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 17; and a CDRL3comprising the amino acid sequence of SEQ ID NO: 18.

### Claim 5 (depends on 4)

The antibody or fragment thereof according to claim 4, wherein the heavy chain variable region comprises an amino acid sequence selected from SEQ ID NO: 56 or a sequence at least 90% identical thereto; and the light chain variable region comprises an amino acid sequence selected from SEQ ID NO: 50 or a sequence at least 90% identical thereto.

### Claim 6 (depends on 4)

The doppel-binding antibody fragment according to claim 4, wherein the doppel-binding antibody fragment binds to the dimeric form of doppel.

### Claim 7 (depends on 1)

The antibody or doppel-binding fragment thereof according to claim 1, wherein the heavy chain variable region comprises a CDRH1 comprising the amino acid sequence of SEQ ID NO: 37; a CDRH2 comprising the amino acid sequence of SEQ ID NO: 38; and a CDRH3 comprising the amino acid sequence of SEQ ID NO: 39; and the light chain variable region comprises a CDRL1 comprising the amino acid sequence of SEQ ID NO: 19; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 20; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 21.

### Claim 8 (depends on 7)

The antibody or fragment thereof according to claim 7, wherein the heavy chain variable region comprises an amino acid sequence selected from SEQ ID NO: 57 or a sequence at least 90% identical thereto; and the light chain variable region comprises an amino acid sequence selected from SEQ ID NO: 51 or a sequence at least 90% identical thereto.

### Claim 9 (depends on 7)

The doppel-binding antibody fragment according to claim 7, wherein the doppel-binding antibody fragment binds to non-glycosylated doppel with greater affinity than glycosylated doppel.

### Claim 10 (depends on 1)

The antibody or doppel-binding fragment thereof according to claim 1, wherein the heavy chain variable region comprises a CDRH1 comprising the amino acid sequence of SEQ ID NO: 40; a CDRH2 comprising the amino acid sequence of SEQ ID NO: 41; and a CDRH3 comprising the amino acid sequence of SEQ ID NO: 42; and the light chain variable region comprises a CDRL1 comprising the amino acid sequence of SEQ ID NO: 22; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 23; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 24.

### Claim 11 (depends on 10)

The antibody or fragment thereof according to claim 10, wherein the heavy chain variable region comprises an amino acid sequence selected from SEQ ID NO: 58 or a sequence at least 90% identical thereto; and the light chain variable region comprises an amino acid sequence selected from SEQ ID NO: 52 or a sequence at least 90% identical thereto.

### Claim 12 (depends on 10)

The doppel-binding antibody fragment according to claim 10, wherein the doppel-binding antibody fragment binds to non-glycosylated doppel with greater affinity than glycosylated doppel.

### Claim 13 (depends on 1)

The antibody or doppel-binding fragment thereof according to claim 1, wherein the heavy chain variable region comprises a CDRH1 comprising the amino acid sequence of SEQ ID NO: 43; a CDRH2 comprising the amino acid sequence of SEQ ID NO: 44; and a CDRH3 comprising the amino acid sequence of SEQ ID NO: 45; and the light chain variable region comprising a CDRL1 comprising the amino acid sequence of SEQ ID NO: 25; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 26; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 27.

### Claim 14 (depends on 13)

The antibody or fragment thereof according to claim 13, wherein the heavy chain variable region comprises an amino acid sequence selected from SEQ ID NO: 59 or a sequence at least 90% identical thereto; and the light chain variable region comprises an amino acid sequence selected from SEQ ID NO: 53 or a sequence at least 90% identical thereto.

### Claim 15 (depends on 13)

The doppel-binding antibody fragment according to claim 13, wherein the doppel-binding antibody fragment specifically binds to SEQ ID NO: 12 or SEQ ID NO: 61.

### Claim 16 (depends on 1)

The antibody or doppel-binding fragment thereof according to claim 1, wherein the heavy chain variable region comprises a CDRH1 comprising the amino acid sequence of SEQ ID NO: 31; a CDRH2 comprising the amino acid sequence of SEQ ID NO: 32; and a CDRH3 comprising the amino acid sequence of SEQ ID NO: 33; and the light chain variable region comprises a CDRL1 comprising the amino acid sequence of SEQ ID NO: 13; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 14; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 15.

### Claim 17 (depends on 16)

The antibody or doppel-binding fragment thereof according to claim 16, wherein the heavy chain variable region comprises an amino acid sequence selected from SEQ ID NO: 55 or a sequence at least 90% identical thereto; and the light chain variable region comprises an amino acid sequence selected from SEQ ID NO: 49 or a sequence at least 90% identical thereto.

### Claim 18 (depends on 16)

The doppel-binding antibody fragment according to claim 16, wherein the-doppel-binding antibody fragment specifically binds to SEQ ID NO: 11.