Methods of inhibiting pathological angiogenesis with doppel-targeting molecules

Patent metadata

Field	Value
Publication number	US-10501549-B2
Application number	US-201715450272-A
Country	US
Kind code	B2
Filing date	Mar 6, 2017
Priority date	Nov 30, 2015
Publication date	Dec 10, 2019
Grant date	Dec 10, 2019

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.

First claim

What is claimed is:

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.

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

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

4. 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.

5. 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.

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

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.

17. The ant

Assignees

• Seoul Nat Univ R&Db Foundation
• Univ Of Ulsan
• Korea Inst Sci & Tech
• Pharosgen

Inventors

• Byun Youngro
• Kim In San
• Taslim Ahmed Al-Hilal
• Kim Sang-Yoon
• Jang Ye Ji

Classifications

• G01N33/5759

  involving compounds localised on the membrane of tumour or cancer cells · CPC title

• C07K16/2872 Primary

  against prion molecules, e.g. CD230 · CPC title

• G01N33/6893

  related to diseases not provided for elsewhere · CPC title

• C12N2310/11

  Antisense · CPC title

• G01N2333/705

  Assays involving receptors, cell surface antigens or cell surface determinants · CPC title