IP Library › Granted Patent US 12,202,881
Granted Patent B2
US 12,202,881 · App. 18/295,068 · Granted Jan 21, 2025

Integrin binding peptides and uses thereof

Inventor: Jai Prakash (Enschede, NL)
Assignees: Jai Prakash; Universiteit Twente
C07K14/70546A61K47/60A61K47/62A61K49/0045A61K49/0056A61P1/16C07K7/06C07K7/08C07K14/78A61K38/00C07K2319/00
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Quick Facts
Patent No.
US 12,202,881
App. No.
18/295,068
Granted
Jan 21, 2025
Kind
B2
Abstract

The disclosure relates to integrin binding peptides, pharmaceutical compositions comprising the peptides and to uses thereof as therapeutic, diagnostic, imaging and targeting agents.

Claims (30)

1. An integrin alpha 5 (ITGA5) binding peptide consisting of 7 to 16 amino acids and comprising an amino acid sequence, wherein:

the amino acid sequence is selected from the group consisting of RYYRITY (SEQ ID NO:8), TTVRYYRITYGE (SEQ ID NO:7), YYRITYGETGGN (SEQ ID NO:56), RAYRITY (SEQ ID NO: 62), RYYRATY (SEQ ID NO:64), AYYRITY (SEQ ID NO: 61), RYYAITY (SEQ ID NO: 63), RYYRITA (SEQ ID NO: 65), and RYYRITYC (SEQ ID NO: 11), and wherein the peptide is in the form of a pharmaceutically acceptable salt.

2. The peptide of claim 1 , wherein the ITGA5 binding peptide consists of an amino acid sequence selected from the group consisting of RYYRITY (SEQ ID NO:8), RAYRITY (SEQ ID NO: 62), RYYRATY (SEQ ID NO:64), AYYRITY (SEQ ID NO: 61), RYYAITY (SEQ ID NO: 63), RYYRITA (SEQ ID NO: 65), RYYRITYC (SEQ ID NO:11), TTVRYYRITYGE (SEQ ID NO:7), and YYRITYGETGGN (SEQ ID NO:56).

3. The peptide of claim 1 , wherein the peptide has a5ß1 integrin and/or ITGA5 inhibiting activity.

4. The peptide of claim 1 , wherein the peptide has an additional C-terminal cysteine.

5. An integrin alpha (ITGA5) binding peptide consisting of 7 to 16 amino acids and comprising an amino acid sequence, wherein the amino acid sequence is selected from the group consisting of RYYRITY (SEQ ID NO:8), TTVRYYRITYGE (SEQ ID NO:7), YYRITYGETGGN (SEQ ID NO:56), RAYRITY (SEQ ID NO: 62), RYYRATY (SEQ ID NO:64), AYYRITY (SEQ ID NO: 61), RYYAITY (SEQ ID NO: 63), RYYRITA (SEQ ID NO: 65), and RYYRITYC (SEQ ID NO:11), wherein the peptide is in the form of a pharmaceutically acceptable salt, which is a cyclic or bicyclic peptide.

6. The peptide of claim 1 , wherein the ITGA5 binding peptide consists of 7 to 16 amino acids.

7. A dimeric peptide comprising at least two integrin alpha 5 (ITGA5) binding peptides consisting of 7 to 16 amino acids and each ITGA5 binding peptide comprising an amino acid sequence, wherein the amino acid sequence is selected from the group consisting of RYYRITY (SEQ ID NO:8), TTVRYYRITYGE (SEQ ID NO:7), YYRITYGETGGN (SEQ ID NO:56), RAYRITY (SEQ ID NO: 62), RYYRATY (SEQ ID NO: 64), AYYRITY (SEQ ID NO: 61), RYYAITY (SEQ ID NO: 63), RYYRITA (SEQ ID NO: 65), and RYYRITYC (SEQ ID NO:11), wherein the dimeric peptide is in the form of a pharmaceutically acceptable salt.

8. The dimeric peptide of claim 7 , wherein each of the two peptides of the dimeric peptide comprises a cysteine residue.

9. The dimeric peptide of claim 7 , which is a cyclic or bicyclic dimeric peptide.

10. A compound comprising the peptide of claim 1 .

11. The compound of claim 10 , further comprising at least one further moiety.

12. The compound of claim 11 , wherein the at least one further moiety comprises a label, a linker, a N-terminal modification, a C-terminal modification, and/or an internal modification.

13. A compound comprising an integrin alpha 5 (ITGA5) binding peptide consisting of 7 to 16 amino acids and comprising an amino acid sequence, wherein the amino acid sequence is selected from the group consisting of RYYRITY (SEQ ID NO:8), TTVRYYRITYGE (SEQ ID NO:7), YYRITYGETGGN (SEQ ID NO:56), RAYRITY (SEQ ID NO: 62), RYYRATY (SEQ ID NO:64), AYYRITY (SEQ ID NO: 61), RYYAITY (SEQ ID NO: 63), RYYRITA (SEQ ID NO: 65), and RYYRITYC (SEQ ID NO:11), wherein the peptide is optionally in the form of a pharmaceutically acceptable salt, wherein the compound comprises the peptide coupled to or encapsulated into a carrier selected from the group consisting of nanoparticles, microparticles, nanocapsules, nanocomplexes, polyplexes, carbon nanotubes, quantum dots, microcapsules, liposomes, microspheres, hydrogels, polymers, micelles, dendrimers, lipid complexes, serum albumin, antibodies, antibody fragments, cyclodextrins, and dextran.

14. A pharmaceutical composition comprising:

the peptide of claim 1 , and

at least one pharmaceutically acceptable carrier, diluent, and/or excipient.

15. A method for treating a subject having fibrosis or a fibrosis-related disorder, an inflammatory disease or cancer, wherein the cancer expresses integrin alpha 5 (ITGA5), the method comprising:

administering to the subject a therapeutically effective amount of an integrin alpha 5 (ITGA5) binding peptide consisting of 7 to 16 amino acids and comprising an amino acid sequence,

wherein the amino acid sequence is selected from the group consisting of RYYRITY (SEQ ID NO: 8), RAYRITY (SEQ ID NO: 62), RYYRATY (SEQ ID NO:64), AYYRITY (SEQ ID NO: 61), RYYAITY (SEQ ID NO: 63), RYYRITA (SEQ ID NO: 65), RYYRITYC (SEQ ID NO:11), TTVRYYRITYGE (SEQ ID NO:7), and YYRITYGETGGN (SEQ ID NO: 56),

or a pharmaceutically acceptable salt of the ITGA5 binding peptide,

or a therapeutically effective amount of a dimeric peptide comprising at least two of the ITGA5 binding peptide,

or a therapeutically effective amount of a compound comprising the ITGA5 binding peptide.

16. A method of imaging a tissue expressing integrin alpha 5 (ITGA5), the method comprising contacting the tissue with an integrin alpha 5 (ITGA5) binding peptide consisting of 7 to 16 amino acids,

wherein the ITGA5 binding peptide comprises a peptide selected from the group consisting of RYYRITY (SEQ ID NO:8), RAYRITY (SEQ ID NO: 62), RYYRATY (SEQ ID NO:64), AYYRITY (SEQ ID NO: 61), RYYAITY (SEQ ID NO: 63), RYYRITA (SEQ ID NO: 65), RYYRITYC (SEQ ID NO:11), TTVRYYRITYGE (SEQ ID NO:7), and YYRITYGETGGN (SEQ ID NO:56), and an imaging label.

17. The method according to claim 16 , wherein the tissue expresses a5ß1 integrin.

18. An integrin alpha 5 (ITGA5) binding peptide, wherein the ITGA5 binding peptide consists of an amino acid sequence selected from the group consisting of RYYRITY (SEQ ID NO:8), RAYRITY (SEQ ID NO: 62), RYYRATY (SEQ ID NO:64), AYYRITY (SEQ ID NO: 61), RYYAITY (SEQ ID NO: 63), RYYRITA (SEQ ID NO: 65), RYYRITYC (SEQ ID NO:11), TTVRYYRITYGE (SEQ ID NO:7), YYRITYGETGGN (SEQ ID NO:56), and any one of SEQ ID NO: 8, SEQ ID NO:62, SEQ ID NO:64, SEQ ID NO:61, SEQ ID NO:63, SEQ ID NO: 65, SEQ ID NO: 11, SEQ ID NO:7, and SEQ ID NO:56 having an additional amino acid positioned N-terminally and/or C-terminally on said amino acid sequence, and wherein the peptide is in the form of a pharmaceutically acceptable salt.

19. An integrin alpha 5 (ITGA5) binding peptide, wherein the ITGA5 binding peptide consists of 7 to 16 amino acids and comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 11, SEQ ID NO:61, SEQ ID NO: 62, SEQ ID NO: 63, and SEQ ID NO: 65, and wherein the peptide is in the form of a pharmaceutically acceptable salt.

20. The peptide of claim 19 , wherein the ITGA5 binding peptide consists of the amino acid sequence selected from the group consisting of SEQ ID NO: 11, SEQ ID NO:61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, and SEQ ID NO:65.

21. The peptide of claim 19 , wherein the ITGA5 binding peptide further comprises a C-terminal cysteine.

Priority Claims (1)
EP 15191256 · Oct 23, 2015 · regional
Continuity (2)
Continuation 15770105
Related Publication 20240025965A1 · Jan 25, 2024
References Cited (61)
US 4589881A · Pierschbacher et al. · 1986 [cited by applicant]
US 5536814A · Ruoslahti et al. · 1996 [cited by applicant]
US 6570065B1 · Kossmann et al. · 2003 [cited by applicant]
US 11634470B2 · Prakash · 2023 [cited by examiner]
US 20080070840A1 · Min et al. · 2008 [cited by applicant]
US 20100152063A1 · Cappuccilli et al. · 2010 [cited by applicant]
CN 1305495A · 2001 [cited by applicant]
JP 2005523682A · 2005 [cited by applicant]
JP 2013523179A · 2013 [cited by applicant]
WO 9514714A1 · 1995 [cited by applicant]
WO 9812226A1 · 1998 [cited by applicant]
WO 9958139A2 · 1999 [cited by applicant]
WO 9958552A2 · 1999 [cited by applicant]
WO 0064480A1 · 2000 [cited by applicant]
WO 2003027246A2 · 2003 [cited by applicant]
WO 2003031589A2 · 2003 [cited by applicant]
WO 2006036834A2 · 2006 [cited by applicant]
WO 2007071248A2 · 2007 [cited by applicant]
WO 2008021290A2 · 2008 [cited by applicant]
WO 2013040142A2 · 2013 [cited by applicant]
WO 2013067029A2 · 2013 [cited by applicant]
WO WO2013142229A1 · 2013 [cited by examiner]
WO 2014059213A1 · 2014 [cited by applicant]
WO WO2014120891A2 · 2014 [cited by examiner]
WO 2015103643A2 · 2015 [cited by applicant]
WO 2015193359A2 · 2015 [cited by applicant]
WO 2017069627A1 · 2017 [cited by applicant]
WO 2013185027A2 · 2020 [cited by applicant]
NCBI (Year: 2024). [cited by examiner]
UniProtKB/TrEMBL (Q59G22_Human (Year: 2020). [cited by examiner]
Sharma et al. The EMBO Journal vol. 18 No. 6 pp. 1468-1479, 1999. Crystal structure of a heparin- and integrin-binding segment of human fibronectin (Year: 1999). [cited by examiner]
Aina et al: “Canine malignant melanoma alpha-3 integrin binding peptides”, Veterinary Immunology and Immunopathology, Elsevier BV, Amsterdam, NL, vol. 143, No. 1, May 11, 2011 (Nov. 5, 2011), pp. 11-19. [cited by applicant]
Atherton et al. “Solid-Phase Peptide Synthesis: A Practical Approach” vol. 265, No. 1,2 FEBS Letters Jun. 1990 (Abstract Only). [cited by applicant]
Database UniProt [Online] Oct. 16, 2013 (Oct. 16, 2013), “SubName: Full=HAD super, subIIIB family protein {ECO:0000313:EMBL:EPP30409.1}; Flags: Fragment;”, XP002755039, retrieved from EBI accession No. UniProt: S7IPZ7 D… [cited by applicant]
Database UniProt [Online] Oct. 19, 2011 (Oct. 19, 2011), “SubName: Full=Hypothetical membrane protein {ECO:0000313:EMBL:AEK63686.1};”, XP002755038, retrieved from EBI accession No. UniProt:G0ADR3 Database accession No. … [cited by applicant]
Database UniProt [Online] Jun. 24, 2015 (Jun. 24, 2015), “SubName: Full=Uncharacterized protein {ECO:0000313:EMBL:JAH10272.1};”, XP002755037, retrieved from EBI accession No. UniProt:A0A0E9Q1A5 Database accession No. A0… [cited by applicant]
European Communication pursuant to Article 94(3) EPC for European Application No. 16794079, dated Feb. 24, 2023, 3 pages. [cited by applicant]
European Communication pursuant to Article 94(3) EPC for European Application No. 16794079, dated Jan. 14, 2020, 3 pages. [cited by applicant]
European Communication pursuant to Article 94(3) EPC for European Application No. 16794079, dated May 6, 2019, 4 pages. [cited by applicant]
European Communication pursuant to Article 94(3) EPC for European Application No. 16794079, dated Sep. 28, 2020, 5 pages. [cited by applicant]
European Search Report and Search Opinion received for EP Application No. 16794079, dated on Sep. 1, 2021, 4 pages. [cited by applicant]
Intention to Grant for European Application No. 16794079, dated Sep. 23, 2022, 6 pages. [cited by applicant]
International Search Report for International Application No. PCT/NL2016/050725, mailed on Feb. 10, 2017, 5 pages. [cited by applicant]
International Written Opinion for International Application No. PCT/NL2016/050725, mailed on Feb. 10, 2017, 9 pages. [cited by applicant]
Japanese Notice of Reasons for Refusal for Japanese Application No. 2018-540362, mailed Sep. 23, 2020, 8 pages (English translation only). [cited by applicant]
Merrifield “Solid Phase Peptide Synthesis. I. the Synthesis of a Tetrapeptide” J. Am. Chem. Soc. 1963, 85, 14, 2149-2154, Publication Date:Jul. 1, 1963 https://doi.org/10.1021/ja00897a025 (Abstract Only). [cited by applicant]
Nagae et al. “Crystal structure of ?5?1 integrin ectodomain: Atomic details of the fibronectin receptor” J. Cell Biol. vol. 197 No. 1 131-140 www.jcb.org/cgi/doi/10.1083/jcb.201111077. [cited by applicant]
Navab et al., Prognostic gene-expression signature of carcinoma-associated fibroblasts in non-small cell lung cancer PNAS 2011, 108(17):7160-7165. [cited by applicant]
Neubauer et al. Selective Imaging of the Angiogenic Relevant Integrins a5β1 and avβ3, vol. 52, Issue 44, p. 11656-11659 (2013) Wiley. [cited by applicant]
Protocol Multiwell Peptide Microarrays of JPT Technologies, Berlin Germany; Manual (20 pages). [cited by applicant]
Rana et al. “A mixed-alpha, beta miniprotein stereochemically reprogrammed to high-binding affinity for acetylcholine” Biopolymers Nov. 2007; 87(4):231-43. https://doi.org/10.1002/bip.20829. [cited by applicant]
Rohrbacher et al. “Spontaneous head-to-tail cyclization of unprotected linear peptides with the KAHA ligation” Chem. Sci., 2015, 6, 4889-4896. [cited by applicant]
Sequence listing of WO 2013/142229 (Year: 2013). [cited by applicant]
Sharma et al. Crystal structure of a heparin-and integrin-binding segment of human fibronectin. 1999. The EMBO Journal vol. 18 No. 6 pp. 1468-1479, 1999 (Year: 1999). [cited by applicant]
Svendsen et al., “The a11β1 Integrin Has a Mechanistic Role in Control of Interstitial Fluid Pressure and Edema Formation in Inflammation” Arterioscler. Thromb. Vasc. Biol. 2009, 29(11):1864-1870. [cited by applicant]
Talior-Volodarsky et al., “a11 integrin stimulates myofibroblast differentiation in diabetic cardiomyopathy” Cardiovasc. Res. 2012, 96(2):265-275. [cited by applicant]
Tiger et al. “alpha11beta1 Integrin Is a Receptor for Interstitial Collagens Involved in Cell Migration and Collagen Reorganization on Mesenchymal Nonmuscle Cells” Dev. Biol. 2001, 237(1):116-129). [cited by applicant]
Tuin et al. “Structural and biological evaluation of some loloatin C analogues” Bioorganic & Medicinal Chemistry, vol. 17, Issue 17, 2009, pp. 6233-6240, ISSN 0968-0896, https://doi.org/10.1016/j.bmc.2009.07.049. [cited by applicant]
Uniprot sequence (Year: 2020). [cited by applicant]
Zhu et al., “Integrin _11 regulates IGF2 expression in fibroblasts to enhance tumorigenicity of human non-small-cell lung cancer cells” PNAS 2007, 104(28):11754-11759. [cited by applicant]
Biochemistry, 2010, vol. 49, pp. 1549-1555, Supporting Information (pp. 1-43). [cited by applicant]