Targeted therapeutic agents comprising multivalent protein-biopolymer fusions

Patent metadata

Field	Value
Publication number	US-2018258157-A1
Application number	US-201615561799-A
Country	US
Kind code	A1
Filing date	Mar 25, 2016
Priority date	Mar 26, 2015
Publication date	Sep 13, 2018
Grant date	—

Abstract

Provided herein are fusion proteins including at least one binding polypeptide and at least one unstructured polypeptide. The fusion protein may further include at least one linker. Further provided are methods for determining the presence of a target in a sample, methods of treating a disease, methods of diagnosing a disease in a subject, and methods of determining the effectiveness of a treatment for a disease in a subject. The methods may include administering to the subject an effective amount of the fusion protein.

First claim

We claim:

1 - 35 . (canceled)

36 . A multivalent fusion protein comprising at least one Fibronectin type III (FnIII) domain and at least one elastin-like polypeptide (ELP), wherein the FnIII domain binds TNF-related apoptosis-inducing ligand receptor 2 (TRAILR-2), and comprises an amino acid sequence consisting of SEQ ID NO: 1.

37 . The multivalent fusion protein of claim 36 , wherein the at least one ELP comprises an amino acid sequence consisting of (VPGXG) n (SEQ ID NO: 19), wherein X is any amino acid except proline and n is an integer greater than or equal to 1.

38 . The multivalent fusion protein of claim 37 , wherein n is 60, 120, or 180.

39 . The multivalent fusion protein of claim 37 , wherein X is valine.

40 . (canceled)

41 . The multivalent fusion protein of claim 36 , wherein the multivalent fusion protein comprises a plurality of FnIII domains.

42 . The multivalent fusion protein of claim 41 , wherein the multivalent fusion protein comprises 2, 4, or 6 FnIII domains.

43 . The multivalent fusion protein of claim 41 , wherein the multivalent fusion protein further comprises a linker positioned between at least two adjacent FnIII domains.

44 . The multivalent fusion protein of claim 43 , wherein the linker comprises at least one glycine and at least one serine.

45 . The multivalent fusion protein of claim 44 , wherein the linker comprises an amino acid sequence consisting of SEQ ID NO: 3 ((Gly 4 Ser) 3 ).

46 . The multivalent fusion protein of claim 43 , wherein the linker comprises an amino acid sequence consisting of SEQ ID NO: 4.

47 . A method for treating a disease associated with TNF-related apoptosis-inducing ligand receptor 2 (TRAILR-2) in a subject in need thereof, the method comprising administering to the subject an effective amount of the multivalent fusion protein of claim 36 .

48 . The method of claim 47 , wherein the disease comprises cancer.

49 . The method of claim 48 , wherein the cancer comprises colorectal adenocarcinoma.

50 . The method of claim 47 , wherein the multivalent fusion protein is administered intravenously, intraarterially, or intraperitoneally to the subject.

51 . The method of claim 48 , wherein the multivalent fusion protein is administered intratumorally.

52 . The method of claim 47 , wherein the multivalent fusion protein forms a depot upon administration to the subject.

53 . The method of claim 47 , wherein the multivalent fusion protein is administered in a controlled release formulation.

54 - 65 . (canceled)

Assignees

• Univ Duke

Inventors

• Chilkoti Ashutosh
• Manzari Mandana
• Fevre Mareva

Classifications

• C07K2319/00

  Fusion polypeptide · CPC title

• A61P35/00

  Antineoplastic agents · 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

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title

• C07K2319/74

  containing a fusion for binding to a cell surface receptor · CPC title