Conjugated fibronectin-binding peptides for use in tumor or fibrosis diagnosis and therapy

Patent metadata

Field	Value
Publication number	US-12559525-B2
Application number	US-202217938092-A
Country	US
Kind code	B2
Filing date	Oct 5, 2022
Priority date	Oct 5, 2021
Publication date	Feb 24, 2026
Grant date	Feb 24, 2026

Abstract

The present invention relates to fibronectin-binding peptides according to the sequence
FnI5BS-L1-FnI4BS-L2-FnI3BS-L3-FnI2BS

which are useful in tumor or fibrosis diagnosis and therapy. Instant peptides show improved fibronectin-binding and biodistribution properties compared to the prior art. Furthermore, instant peptides may be conjugated to a payload and are useful in the treatment and/or prevention of diseases associated with pathological fibronectin accumulation, including cancer and fibrosis. Instant peptides are also useful in diagnosis of diseases associated with pathological fibronectin accumulation, including cancer and fibrosis.

First claim

The invention claimed is:

1 . A fibronectin binding peptide comprising the sequence:
FnI5BS-L1-FnI4BS-L2-FnI3BS-L3-FnI2BS wherein: FnI5BS is a polypeptide sequence selected from

(SEQ ID NO.: 1)

Gln-Val-Thr-Thr-Gly-Ser-Asn,

(SEQ ID NO.: 2)

Gln-Val-Thr-Thr-Ala-Ser-Asn,

(SEQ ID NO.: 3)

Gln-Val-Thr-Thr-Val-Ser-Asn,

and

(SEQ ID NO.: 4)

Gln-Val-Thr-Thr-Ser-Ser-Asn;

FnI4BS is a polypeptide sequence selected from

(SEQ ID NO.: 5)

Val-Glu-Phe-Thr-Glu-Glu-Ser,

(SEQ ID NO.: 6)

Val-Glu-Phe-Ser-Glu-Glu-Ser,

(SEQ ID NO.: 7)

Val-Glu-Phe-Cys-Glu-Glu-Ser,

(SEQ ID NO.: 8)

Val-Glu-Phe-Asn-Glu-Glu-Ser,

and

(SEQ ID NO.: 9)

Val-Glu-Phe-Gln-Glu-Glu-Ser;

FnI3BS is a polypeptide of sequence Gly-Ile-Val-Thr-Gly-Ala-Val (SEQ ID NO.: 10);
FnI2BS is a polypeptide of sequence (His-Thr-Thr-Val-Glu-Asp-Thr (SEQ ID NO.: 11); and
L1, L2 and L3 are each a polypeptide sequence comprising 0, 1 or 2 amino acid residues.

2 . The fibronectin binding peptide of claim 1 , wherein
FnI5BS is a polypeptide of sequence according to SEQ ID NO.: 1; and/or FnI4BS is a polypeptide of sequence according to SEQ ID NO.: 5.

3 . The fibronectin binding peptide of claim 1 , wherein
L1 is a single amino acid residue Leu; and/or L2 is a single amino acid residue selected from the group consisting of Leu, Ile, Val, Ala and Met; and/or L3 is a dipeptide of sequence Ser-Asp.

4 . The fibronectin binding peptide of claim 1 , wherein
L1 is a single amino acid residue Leu; and L2 is a single amino acid residue Leu; and L3 is a dipeptide of sequence Ser-Asp.

5 . The fibronectin binding peptide of claim 1 , comprising a polypeptide sequence Gln-Val-Thr-Thr-Gly-Ser-Asn-Leu-Val-Glu-Phe-Thr-Glu-Glu-Ser-Leu-Gly-Ile-Val-Thr-Gly-Ala-Val-Ser-Asp-His-Thr-Thr-Val-Glu-Asp-Thr (SEQ ID NO: 12).

6 . The fibronectin binding peptide of claim 1 , characterized by binding to Fib1 (SEQ ID NO: 14) with a K D of 5.0 nM or tighter, as determined by using a fluorescence polarization assay.

7 . The fibronectin binding peptide of claim 1 , further conjugated to a payload, wherein the payload is directly conjugated to the N or C terminus of the said polypeptide sequence through an amide bond, or wherein the payload is conjugated to the N or C terminus of the polypeptide sequence via a linker.

8 . The fibronectin binding peptide of claim 7 , wherein the linker comprises a peptide moiety, a PEG moiety, a moiety derived from cadaverine or a C 1-12 alkylene moiety.

9 . The fibronectin binding peptide of claim 7 , wherein the payload is a biologically active molecule or an imaging agent.

10 . The fibronectin binding peptide of claim 9 , wherein the payload is a biologically active molecule.

11 . The fibronectin binding peptide of claim 10 , wherein the biologically active molecule is selected from the group consisting of cytostatic agent, cytotoxic agent, cytokine, transcription factor inhibitor, proteasome and protease inhibitor, apoptosis modulator, cell cycle modulator, angiogenesis inhibitor, hormone or hormone derivative, photodynamic therapy molecule, nano- and microparticle for thermoablation therapy, radionuclide, miRNA, siRNA and immunomodulatory antigen molecule.

12 . The fibronectin binding peptide of claim 11 , wherein the biologically active molecule is selected from the group consisting of Paclitaxel, Chlorambucil, Endostatin, Sunitinib, Interleukin-7, 177 Lu, and 111 In.

13 . The fibronectin binding peptide of claim 9 , wherein the payload is an imaging agent.

14 . The fibronectin binding peptide of claim 13 , wherein the imaging agent comprises a radionuclide, a fluorescent dye, a chemiluminescent agent, a bioluminescent agent, a spectrally resolvable inorganic fluorescent semiconductor nanocrystal, a metal nanoparticle, a nanocluster, a paramagnetic metal ion, an enzyme, a colorimetric label, biotin, dioxigenin, a hapten or a protein, or
wherein the imaging agent is selected from the group consisting of radionuclide, MRI active compound, ultrasound contrast agent, fluorophore, marker for PET and SPECT.

15 . The fibronectin binding peptide of claim 7 , wherein the payload comprises a radionuclide, selected from the group consisting of 67 Cu, 90 Y, 111 In, 131 I, 161 Tb, 169 Er and 177 Lu or selected from the group consisting of 44 Sc, 64 Cu, 67/68 Ga 99 Tc, and 111 In, wherein the payload is [ 111 In]In-NODAGA moiety.

16 . A pharmaceutical composition comprising the fibronectin binding peptide of claim 1 and a pharmaceutically acceptable carrier.

17 . A method of treatment of a disease associated with pathologic fibronectin accumulation, the method comprising the step of administering the therapeutically effective amount of the fibronectin binding peptide of claim 10 to the subject in need thereof.

18 . The method according to claim 17 , wherein the disease associated with pathologic fibronectin accumulation is selected from the group consisting of fibrosis, cancer, lymphedema, immune disease, autoimmune disease, and atherosclerosis.

19 . The method according to claim 18 , wherein the disease associated with pathologic fibronectin accumulation is the autoimmune di

Assignees

• Eth Zuerich
• Scherrer Inst Paul

Inventors

• Vogel Viola
• Chabria Mamta
• Valpreda Giulia
• Trachsel Belinda
• Behe Martin

Classifications

• G01N33/68

  involving proteins, peptides or amino acids {(involving lipoproteins G01N33/92)} · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• G01N2333/78

  Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG] · CPC title

• G01N33/6887

  from muscle, cartilage or connective tissue · CPC title