EPHA3 and multi-valent targeting of tumors

Patent metadata

Field	Value
Publication number	US-10752667-B2
Application number	US-201815958608-A
Country	US
Kind code	B2
Filing date	Apr 20, 2018
Priority date	Nov 11, 2013
Publication date	Aug 25, 2020
Grant date	Aug 25, 2020

Abstract

Provided herein is a construct comprising, in combination: an EphA3, EphA2 and/or EphB2 binding ligand; and at least one effector molecule. In some embodiments, the at least one effector molecule comprises a therapeutic agent, a nanoparticle, a detectable group, a lipid, or a liposome. In some embodiments, the construct is a fusion protein and/or a covalent conjugate. Further provided is a construct comprising, in combination: a ligand that binds to EphA2, EphA3 and/or EphB2; a ligand that binds to IL-13Rα2; and at least one effector molecule. Also provided are methods of use thereof for treating cancer.

First claim

That which is claimed is:

1. A method of treating cancer in a subject in need thereof, comprising administering to said subject in a treatment effective amount:
a construct comprising, in combination:
a ligand that binds to all three of EphA2, EphA3, and EphB2;
a ligand that binds to IL-13Ra2; and
at least one effector molecule, wherein said at least one effector molecule comprises a therapeutic agent,
wherein said construct is a fusion protein and/or a covalent conjugate,
wherein said construct has a first end and a second end, said first end comprising said ligand that binds to all three of EphA2, EphA3 and EphB2; and said second end comprising said ligand that binds to IL-13Ra2, and
wherein said construct comprises a linker between said first end and said second end.

2. The method of claim 1 , wherein said ligand that binds to all three of EphA2, EphA3, and EphB2 is a monomer or dimer of eA5, a mutant of eA5, or an EphA2, EphA3 and EphB2 binding fragment thereof.

3. The method of claim 2 , wherein said eA5, mutant of eA5, or EphA2, EphA3 and EphB2 binding fragment thereof is glycosylated.

4. The method of claim 1 , wherein said at least one effector molecule comprises a diphtheria toxin or a Pseudomonas exotoxin A.

5. The method of claim 1 , wherein said construct further comprises:
a cytosol localization element covalently coupled between said ligand that binds to all three of EphA2, EphA3, and EphB2 and said at least one effector molecule; and
a subcellular compartment localization signal element covalently coupled between said ligand that binds to all three of EphA2, EphA3, and EphB2 and said at least one effector molecule.

6. The method of claim 5 , wherein said subcellular compartment localization signal element is a nuclear localization element or a lysosomal localization element.

7. The method of claim 1 , wherein said cancer is breast cancer, bladder cancer, pancreatic cancer, colorectal cancer, head and neck cancer, thyroid cancer, prostate cancer, melanoma, or glioma.

8. The method of claim 1 , wherein said cancer is glioblastoma, prostate cancer or melanoma.

9. The method of claim 1 , wherein said cancer is glioblastoma.

10. The method of claim 1 , wherein said at least one effector molecule comprises a chemotherapeutic agent.

11. The method of claim 10 , wherein said chemotherapeutic agent comprises an anthracycline.

12. The method of claim 11 , wherein the anthracycline comprises doxorubicin or a 4′-O-benzylated analog thereof.

13. The method of claim 1 , wherein said construct is a covalent conjugate of two or more fusion proteins.

14. The method of claim 1 , wherein said linker between said first end and said second end is a protein linker.

15. The method of claim 14 , wherein said protein linker comprises an ADCC and/or CDC activating domain.

16. The method of claim 14 , wherein said protein linker comprises an Fc fragment of human IgGl.

17. The method of claim 1 , wherein said ligand that binds to all three of EphA2, EphA3 and EphB2 is a monomer or dimer of: a mutant of eA5.

18. The method of claim 17 , wherein the mutant of eA5 comprises a G-H loop mutant.

19. The method of claim 17 , wherein the mutant of eA5 comprises a P123A, S125A and/or G127A mutation.

20. The method of claim 1 , wherein said ligand that binds to IL-13Rα2 is IL-13, a mutant of IL13, or an IL13-Rα2 binding fragment thereof.

Assignees

• Univ Wake Forest Health Sciences

Inventors

• Debinski Waldemar
• Tome Carla Lema
• Ferluga Sara
• Sonawane Poonam S

Classifications

• G01N33/5759

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

• C07K14/5437 Primary

  IL-13 · CPC title

• C07K14/52

  Cytokines; Lymphokines; Interferons · CPC title

• C07K2319/33

  fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title