IP Library Granted Patent US 12,527,835
Granted Patent B2
US 12,527,835 · App. 17/282,028 · Granted Jan 20, 2026

Brevican-binding peptides for brain tumor imaging

Inventors: Choi-Fong Cho (Boston, MA); Sean Edward Lawler (Scituate, MA); Mariano Sebastian Viapiano (Newton, MA)
Assignee: The Brigham and Women's Hospital, Inc.
A61K38/12A61K47/64A61K49/14A61P35/00C07K7/04C07K7/64
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Quick Facts
Patent No.
US 12,527,835
App. No.
17/282,028
Granted
Jan 20, 2026
Kind
B2
Abstract

Provided herein are compositions comprising peptides that bind specifically to BΔg (deglycosylated brevican), and methods of use thereof to deliver therapeutic and diagnostic agents to brevican-expressing cells, e.g., cancerous cells, e.g., brain cancer cells, e.g., glioblastoma cells.

Claims (36)

1 . An isolated peptide that binds to deglycosylated brevican (BΔg), wherein the peptide comprises a sequence of one of SEQ ID NOs: 6-9, or a variant thereof that is at least 80% identical to a sequence of one of SEQ ID NOs: 6-9, wherein the variant retains the ability to bind BΔg, and wherein the peptide is no more than 40 amino acids long.

2 . The isolated peptide of claim 1 , wherein the peptide comprises TKWGHVNK (SEQ ID NO:6) or a variant thereof.

3 . The isolated peptide of claim 1 , wherein the peptide is modified.

4 . The isolated peptide of claim 3 , wherein one or more of the amino acids in the peptide sequence are D-amino acid enantiomers.

5 . The isolated peptide of claim 3 , wherein the peptide is cyclized.

6 . The isolated peptide of claim 3 , wherein the peptide is biotinylated at the amino terminus and/or amidated at the carboxy terminus.

7 . The isolated peptide of claim 1 , wherein the peptide is linked to a payload.

8 . The isolated peptide of claim 7 , wherein the payload is selected from the group consisting of therapeutic agents and detectable agents.

9 . The isolated peptide of claim 7 , wherein the payload is selected from the group consisting of antibodies, peptides, oligonucleotides, and microbubbles.

10 . The isolated peptide of claim 8 , wherein the therapeutic agent comprises a cytotoxin, radioactive ion, or chemotherapeutic agent.

11 . The isolated peptide of claim 8 , wherein the detectable agent comprises a fluorophore, radioactive ion, or contrast agent.

12 . The isolated peptide of claim 8 , wherein the detectable agent comprises a nanoparticle.

13 . The isolated peptide of claim 12 , wherein the nanoparticle comprises an iron oxide nanoparticle; peptide-coated nanoparticle; gold nanoparticle; superparamagnetic iron oxide nanoparticle micelle; liposome; or polymeric micelle.

14 . A composition comprising the isolated peptide of claim 1 .

15 . An isolated peptide that binds to deglycosylated brevican (BΔg), wherein the peptide comprises a sequence of SEQ ID NO: 7 or 8, or a variant thereof that is at least 80% identical to a sequence of SEQ ID NO: 7 or 8, wherein the variant retains the ability to bind BΔg, and wherein the peptide is no more than 20 amino acids long.

16 . An isolated peptide that binds to deglycosylated brevican (BΔg), wherein the peptide comprises a sequence of SEQ ID NOs: 6 or 9, or a variant thereof that is at least 95% identical to a sequence of SEQ ID NOs: 6 or 9 or has up to one amino acid difference from the sequence of one of SEQ ID NOs: 6 or 9, wherein the variant retains the ability to bind BΔg.

17 . The isolated peptide of claim 16 , which is no more than 40 amino acids long.

18 . The isolated peptide of claim 17 , which is no more than 20 amino acids long.

19 . The isolated peptide of claim 16 , wherein the peptide comprises a variant that is at least 95% identical to SEQ ID NO:6 or has up to one amino acid difference from SEQ ID NO:6.

20 . The isolated peptide of claim 19 , wherein the peptide is modified.

21 . The isolated peptide of claim 20 , wherein one or more of the amino acids in the peptide sequence are D-amino acid enantiomers.

22 . The isolated peptide of claim 20 , wherein the peptide is cyclized.

23 . The isolated peptide of claim 20 , wherein the peptide is biotinylated at the amino terminus and/or amidated at the carboxy terminus.

24 . The isolated peptide of claim 19 , wherein the peptide is linked to a payload.

25 . The isolated peptide of claim 24 , wherein the payload is selected from the group consisting of therapeutic agents and detectable agents.

26 . The isolated peptide of claim 24 , wherein the payload is selected from the group consisting of antibodies, peptides, oligonucleotides, and microbubbles.

27 . The isolated peptide of claim 25 , wherein the therapeutic agent comprises a cytotoxin, radioactive ion, or chemotherapeutic agent.

28 . The isolated peptide of claim 25 , wherein the detectable agent comprises a fluorophore, radioactive ion, or contrast agent.

29 . The isolated peptide of claim 25 , wherein the detectable agent comprises a nanoparticle.

30 . The isolated peptide of claim 29 , wherein the nanoparticle comprises an iron oxide nanoparticle; peptide-coated nanoparticle; gold nanoparticle; superparamagnetic iron oxide nanoparticle micelle; liposome; or polymeric micelle.

31 . The isolated peptide of claim 19 , which is no more than 40 amino acids long.

32 . The isolated peptide of claim 31 , which is no more than 20 amino acids long.

33 . A composition comprising the isolated peptide of claim 19 .

34 . The isolated peptide of claim 4 , wherein all the amino acids in the peptide sequence are D-amino acid enantiomers.

35 . The isolated peptide of claim 21 , wherein all the amino acids in the peptide sequence are D-amino acid enantiomers.

36 . A composition comprising the isolated peptide of claim 35 .

Assignments (2)
CONFIRMATORY LICENSE Recorded Sep 13, 2024
From: BRIGHAM AND WOMEN'S HOSPITAL
To: UNITED STATES GOVERNMENT
Reel/Frame 068967/0369 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 28, 2021
From: CHO, CHOI-FONG; LAWLER, SEAN EDWARD; VIAPIANO, MARIANO SEBASTIAN
To: THE BRIGHAM AND WOMEN'S HOSPITAL, INC.
Reel/Frame 057950/0625 →
Continuity (2)
Provisional Application 62739845 · Oct 1, 2018
Related Publication 20210353708A1 · Nov 18, 2021
References Cited (62)
US 7820436B2 · Mori · 2010 [cited by examiner]
US 20050227322A1 · Lindquist · 2005 [cited by examiner]
US 20070061916A1 · Kovalic · 2007 [cited by examiner]
US 20110296543A1 · Chang · 2011 [cited by examiner]
US 20160302425A1 · DiDonato et al. · 2016 [cited by applicant]
US 20170015757A1 · Viapiano et al. · 2017 [cited by applicant]
WO WO2007056536 · 2007 [cited by applicant]
Chang et al., Seq Id No. 87861 from US 2011/0296543. 2011. [cited by examiner]
Mori et al., Seq Id No. 133 from U.S. Pat. No. 7,820,436. 2010. [cited by examiner]
Amadei et al., “A fast, reproducible and low-cost method for sequence deconvolution of ‘on-bead’peptides via ‘on-target’ maldi-TOF/TOF mass spectrometry,” Journal of Mass Spectrometry, Mar. 2010, 45(3):241-51. [cited by applicant]
Chen et al., “Modern methods for delivery of drugs across the blood-brain barrier,” Advanced Drug Delivery Reviews, May 15, 2012, 64(7):640-65. [cited by applicant]
Cho et al., “Blood-brain-barrier spheroids as an in vitro screening platform for brain-penetrating agents,” Nature Communications, Jun. 6, 2017, 8(1), 14 pages. [cited by applicant]
Cho et al., “DDIS-19. Novel Peptide Homing to Glioma-Specific Isoform of Brevican Selectively Targets Malignant Brain Tumors,” Neuro-Oncology, Nov. 2017, 19(Suppl 6):vi62, 2 pages (abstract only). [cited by applicant]
Cho et al., “Design of a microfluidic chip for magnetic-activated sorting of one-bead-one-compound libraries,” ACS Combinatorial Science, Jun. 13, 2016, 18(6):271-8. [cited by applicant]
Cho et al., “Discovery of novel integrin ligands from combinatorial libraries using a multiplex “beads on a bead” approach,” Nano Letters, Nov. 14, 2012, 12(11):5957-65. [cited by applicant]
Cho et al., “Exth-51. Brevican-Specific Peptides for the Development of Next-Generation Targeted Theranostics for Malignant Gliomas,” Neurooncology, Nov. 2016, 18(Supp 6), 1 page (abstract only). [cited by applicant]
Cho et al., “High-throughput screening of one-bead-one-compound peptide libraries using intact cells,” ACS Combinatorial Science, Aug. 12, 2013, 15(8):393, 25 pages. [cited by applicant]
Cho et al., “Viral nanoparticles decorated with novel EGFL7 ligands enable intravital imaging of tumor neovasculature,” Nanoscale, Aug. 2017, 9(33):12096-109. [cited by applicant]
Dhermain et al., “Advanced MRI and PET imaging for assessment of treatment response in patients with gliomas,” The Lancet Neurology, Sep. 1, 2010, 9(9):906-20. [cited by applicant]
Dwyer et al., “Brevican knockdown reduces late-stage glioma tumor aggressiveness,” Journal of Neuro-Oncology, Oct. 2014, 120(1):63-72. [cited by applicant]
Fadzen et al., “Perfluoroarene-based peptide macrocycles to enhance penetration across the blood-brain barrier,” Journal of the American Chemical Society, Nov. 8, 2017, 139(44):15628-31. [cited by applicant]
Garcia-Carbonero et al., “Current perspectives on the clinical experience, pharmacology, and continued development of the camptothecins,” Clinical Cancer Research, Mar. 1, 2002, 8(3):641-61. [cited by applicant]
GenBank: ADG12460.1, “signal transduction histidine kinase [Caulobacter segnis ATCC 21756],” dated Jan. 28, 2014, 2 pages. [cited by applicant]
Giannini et al., “Patient tumor EGFR and PDGFRA gene amplifications retained in an invasive intracranial xenograft model of glioblastoma multiforme,” Neuro-oncology, Apr. 1, 2005, 7(2):164-76. [cited by applicant]
Hayashi-Takanaka et al., “Evaluation of chemical fluorescent dyes as a protein conjugation partner for live cell imaging, ” PloS one, Sep. 3, 2014, 9(9):e106271, 11 pages. [cited by applicant]
Henne et al., “Synthesis and activity of a folate peptide camptothecin prodrug,” Bioorganic & Medicinal Chemistry Letters, Oct. 15, 2006, 16(20):5350-5. [cited by applicant]
Holland, “Glioblastoma multiforme: the terminator,” Proceedings of the National Academy of Sciences, Jun. 6, 2000, 97(12):6242-4. [cited by applicant]
Hu et al., “The proteoglycan brevican binds to fibronectin after proteolytic cleavage and promotes glioma cell motility,” Journal of Biological Chemistry, Sep. 5, 2008, 283(36):24848-59. [cited by applicant]
Jaworski et al., “BEHAB (brain enriched hyaluronan binding) is expressed in surgical samples of glioma and in intracranial grafts of invasive glioma cell lines,” Cancer Research, May 15, 1996, 56(10):2293-8. [cited by applicant]
Jaworski et al., “BEHAB, a new member of the proteoglycan tandem repeat family of hyaluronan-binding proteins that is restricted to the brain,” The Journal of Cell Biology, Apr. 15, 1994, 125(2):495-509. [cited by applicant]
Johnson et al., “Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma,” Science, Jan. 10, 2014, 343(6167):189-93. [cited by applicant]
Kalepu et al., “Insoluble drug delivery strategies: review of recent advances and business prospects,” Acta Pharmaceutica Sinica B, Sep. 1, 2015, 5(5):442-53. [cited by applicant]
Kemper et al., “Modulation of the blood-brain barrier in oncology: therapeutic opportunities for the treatment of brain tumours?,” Cancer Treatment Reviews, Aug. 1, 2004, 30(5):415-23. [cited by applicant]
Ladner et al., “Phage display-derived peptides as therapeutic alternatives to antibodies,” Drug Discovery Today, Jun. 1, 2004, 9(12):525-9. [cited by applicant]
Lam et al., “A new type of synthetic peptide library for identifying ligand-binding activity,” Nature, Nov. 1991, 354(6348):82-4. [cited by applicant]
Leriche et al., “Cleavable linkers in chemical biology,” Bioorganic & Medicinal Chemistry, Jan. 15, 2012, 20(2):571-82. [cited by applicant]
Liskamp et al., “Bioactive macrocyclic peptides and peptide mimics,” Modern Supramolecular Chemistry: Strategies for Macrocycle Synthesis, Feb. 13, 2008, 1-27. [cited by applicant]
Löscher et al., “Drug resistance in brain diseases and the role of drug efflux transporters,” Nature Reviews Neuroscience, Aug. 2005, 6(8):591-602. [cited by applicant]
Louis, “Molecular pathology of malignant gliomas,” Annu. Rev. Pathol. Mech. Dis., Feb. 28, 2006. 1:97-117. [cited by applicant]
Lu et al., “The role of brevican in glioma: promoting tumor cell motility in vitro and in vivo,” BMC Cancer, Dec. 2012, 12(1):1-0, 10 pages. [cited by applicant]
McLendon et al., “Comprehensive genomic characterization defines human glioblastoma genes and core pathways,” Nature, Oct. 23, 2008, 455(7216):1061-8. [cited by applicant]
Mijalis et al., “A fully automated flow-based approach for accelerated peptide synthesis,” Nature Chemical Biology, Feb. 2017, 13(5):464, 5 pages. [cited by applicant]
Milton et al., “Total chemical synthesis of a D-enzyme: the enantiomers of HIV-1 protease show reciprocal chiral substrate specificity [corrected],” Science, Jun. 5, 1992, 256(5062):1445-8. [cited by applicant]
Morgan et al., “Dendrimer-encapsulated camptothecins: increased solubility, cellular uptake, and cellular retention affords enhanced anticancer activity in vitro,” Cancer Research, Dec. 15, 2006, 66(24):11913-21. [cited by applicant]
Motl et al., “Pharmacokinetic considerations in the treatment of CNS tumours,” Clinical Pharmacokinetics, Sep. 2006, 45(9):871-903. [cited by applicant]
Oberlies et al., “Camptothecin and taxol: historic achievements in natural products research,” Journal of Natural Products, Feb. 27, 2004, 67(2):129-35. [cited by applicant]
PCT International Preliminary Report on Patentability in International Appln. No. PCT/US2019/054064, dated Apr. 15, 2021, 7 pages. [cited by applicant]
PCT International Search Report and Written Opinion in International Appln. No. PCT/US2019/054064, dated Mar. 10, 2020, 11 pages. [cited by applicant]
Phillips et al., “Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis,” Cancer Cell, Mar. 1, 2006, 9(3):157-73. [cited by applicant]
Polivka et al., “Advances in experimental targeted therapy and immunotherapy for patients with glioblastoma multiforme,” Anticancer Research, Jan. 1, 2017, 37(1):21-33. [cited by applicant]
Raavé et al., “Chemotherapeutic drug delivery by tumoral extracellular matrix targeting,” Journal of Controlled Release, Mar. 28, 2018, 274:1, 22 pages. [cited by applicant]
Rudolf et al., “Chemical proteomics: ligation and cleavage of protein modifications,” Current Opinion in Chemical Biology, Feb. 1, 2013, 17(1):110-7. [cited by applicant]
Saito et al., “Drug delivery strategy utilizing conjugation via reversible disulfide linkages: role and site of cellular reducing activities,” Advanced Drug Delivery Reviews, Feb. 10, 2003, 55(2):199-215. [cited by applicant]
Simon et al., “Rapid flow-based peptide synthesis,” Chembiochem: a European Journal of Chemical Biology, Mar. 21, 2014, 15(5):713-20. [cited by applicant]
Stupp et al., “Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma,” New England Journal of Medicine, Mar. 10, 2005, 352(10):987-96. [cited by applicant]
Verhaak et al., “Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1,” Cancer Cell, Jan. 19, 2010, 17(1):98-110. [cited by applicant]
Viapiano et al., “A novel membrane-associated glycovariant of BEHAB/brevican is up-regulated during rat brain development and in a rat model of invasive glioma,” Journal of Biological Chemistry, Aug. 29, 2003, 278(35):3… [cited by applicant]
Viapiano et al., “BEHAB/brevican requires ADAMTS-mediated proteolytic cleavage to promote glioma invasion,” Journal of Neurooncology, Jul. 2008, 88(3):261-72. [cited by applicant]
Viapiano et al., “Novel tumor-specific isoforms of BEHAB/brevican identified in human malignant gliomas,” Cancer Research, Aug. 1, 2005, 65(15):6726-33. [cited by applicant]
Welch et al., “Potent D-peptide inhibitors of HIV-1 entry,” Proceedings of the National Academy of Sciences, Oct. 23, 2007, 104(43):16828-33. [cited by applicant]
Zhang et al., “Expression of a cleaved brain-specific extracellular matrix protein mediates glioma cell invasion in vivo,” Journal of Neuroscience, Apr. 1, 1998, 18(7):2370-6. [cited by applicant]
Zhang et al., “Peptides in cancer nanomedicine: drug carriers, targeting ligands and protease substrates,” Journal of Controlled Release, Apr. 10, 2012, 159(1):2-13. [cited by applicant]