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EP-3986555-B1 - METHODS FOR TREATING NEOINTIMAL HYPERPLASIA USING F11R/JAM-A INHIBITORS

EP3986555B1EP 3986555 B1EP3986555 B1EP 3986555B1EP-3986555-B1

Inventors

  • Salifu, Moro O.
  • BABINSKA, ANNA

Dates

Publication Date
20260506
Application Date
20200214

Claims (12)

  1. A composition for use in treating neointimal hyperplasia in a subject having an arterio-venous fistula or an arterio-venous graft, the composition comprising an inhibitor of cell adhesion molecule receptor/Junctional Adhesion Molecule-A (F11R/JAM-A), wherein the subject has chronic kidney disease or end stage renal disease and has undergone renal replacement therapy, and the inhibitor of F11R/JAM-A comprises a peptide selected from any one or more of an amino acid sequence of SEQ ID NO: 2, an amino acid sequence of SEQ ID NO: 3, an amino acid sequence of SEQ ID NO: 4, an amino acid sequence of SEQ ID NO: 5, an amino acid sequence of SEQ ID NO: 6, an amino acid sequence of SEQ ID NO: 7, an amino acid sequence of SEQ ID NO: 8, an amino acid sequence of SEQ ID NO: 9, an amino acid sequence of SEQ ID NO: 10, an amino acid sequence of SEQ ID NO: 11, an amino acid sequence of SEQ ID NO: 12, an amino acid sequence of SEQ ID NO: 13, an amino acid sequence of SEQ ID NO: 14, an amino acid sequence of SEQ ID NO: 15, an amino acid sequence of SEQ ID NO: 16, and an amino acid sequence of SEQ ID NO: 17.
  2. The composition for use of claim 1, wherein the subject has chronic kidney disease.
  3. The composition for use of claim 1, wherein the subject has undergone a procedure, and said procedure is selected from the group consisting of surgical revision and angioplasty.
  4. The composition for use of claim 1, wherein said renal replacement therapy comprises hemodialysis.
  5. The composition for use of claim 4, wherein said peptide is an amino acid sequence of SEQ ID NO: 3.
  6. The composition for use of claim 5, wherein the subject has chronic kidney disease.
  7. The composition for use of claim 5, wherein said subject has undergone surgical revision.
  8. The composition for use of claim 5, wherein said subject has undergone angioplasty.
  9. The composition for use of any one of claims 1 through 4, wherein said composition further comprises a pharmaceutically acceptable excipient.
  10. The composition for use of any one of claims 1 through 5, wherein said composition is administered parenterally, by intravenous injection, intra-arterial injection, intramuscular injection, intraperitoneally, topically, transdermally, subcutaneously, orally, or any combination thereof.
  11. The composition for use of claim 1, wherein said composition further comprises a polyethylene glycol tag.
  12. The composition for use of claim 5, wherein said composition further comprises a pharmaceutically acceptable excipient.

Description

This application claims benefit of U.S. Provisional Patent Application Serial No. 62/863,477, filed January 10, 2019. FIELD The present disclosure relates generally to compositions comprising F11R/JAM-A inhibitors for treating neointimal hyperplasia. BACKGROUND Neointimal hyperplasia is the proliferation and migration of smooth muscle cells from the media into the intima in response to vessel injury resulting in luminal narrowing. It is initiated by arterial wall damage induced mechanically and/or by shear stress resulting from high flow, pressure and/or turbulence. The damaged endothelium exposes ligands that attract platelets and recruitment of inflammatory cells and releases of cytokines that facilitate vascular smooth muscle cell proliferation and migration. Clinically, neointimal hyperplasia may be the primary underlying lesion in vaso-oclusive diseases such as stenosis observed in artero-venous fistulas and artero-venous grafts. Stenosis from neointimal hyperplasia is difficult to treat. Unlike soft atheromatous plaques, stenoses from neointimal hyperplasia are firm and require prolonged high inflation pressures to dilate with a balloon. The stenoses often recur and repeated dilatation causes repeated intimal injury which perpetuates the neointimal hyperplasia. A stent may be inserted to hold the stenosis open, however, such an approach presents drawbacks. For example, the stent itself will stimulate further neointimal hyperplasia. The intimal tissue may grow through the interstices of a bare stent and re-stenose the vessel. A covered stent may prevent this from happening but neointimal hyperplasia can still occur at the ends of the stent where there is heavy irritation of the vessel wall. There remains a need for effective methods of treating neointimal hyperplasia. Strategies are under investigation to reduce neointimal hyperplasia such as coating of angioplasty balloons, drug-eluting stents and intravascular brachytherapy, however anticoagulant therapy such as systemic low-dose low molecular weight heparin, and systemic low-dose warfarin or antiplatelet therapies have failed to reduce occurrence of neointimal hyperplasia. There remains a need to improve methods of treating neointimal hyperplasia. The present disclosure is directed to overcoming these and other deficiencies in the art. US 2009/274739 A1 discloses compositions containing an mTOR inhibitor, such as rapamycin or a rapamycin derivative, in combination with a PI3 kinase inhibitor and/or a leptin inhibitor, intraluminal devices configured to release such compositions, and methods for the treatment and/or prevention of intimal hyperplasia, vascular stenosis and/or restenosis comprising delivery of such compositions or intraluminal devices to subjects in need thereof. US 2009/202538 A1 discloses a cell adhesion molecule (CAM), designated F11 receptor (F11R) and its use to inhibit platelet aggregation and platelet adhesion for the treatment and prevention of cardiovascular disorders. Peptides derived from the extracellular domain of F11R and small molecules and peptidomimetics based on the structure of these peptides are disclosed, as well as inhibitory antibodies and functional fragments thereof. Salifu et al., 2007. "Relationship between the soluble F11 receptor and markers of inflammation in hemodialysis patients." Journal of investigative medicine: the official publication of the American Federation for Clinical Research 55,3: 115-9 discloses that the serum levels of the soluble released form of F11R is elevated in hemodialysis patients. US 2011/158943 A1 discloses interferon-α2b modified with Y-shaped branched polyethylene glycol (PEG) at a single Lys residue. The peglated IFN-α2b can be used for the preparation of a medicament for treating a disease, e.g. viral infections such as Hepatitis C. WO 2004/063327 A2 discloses a cell adhesion molecule (CAM), designated F11 receptor (F11R) determined to effect platelet aggregation, secretion, platelet spreading and cellular adhesion. F11R-antagonists and methods for the prevention and treatment of thrombosis, heart attacks, stroke and other clinical disorders involving thrombus formation are also disclosed. US 2012/035094 A1 discloses a compound including a peptidomimetic which interacts sterically with the binding site of a F11R molecule, known as peptide 4D. Babinska et al., 2014. "Development of new antiatherosclerotic and antithrombotic drugs utilizing F11 receptor (F11R/JAM-A) peptides." Biopolymers 102,4: 322-34 discloses peptides with enhanced resistance to proteolysis, based on the amino acid sequence of the F11 receptor molecule that were designed, prepared, and examined as potential candidates for the development of anti-atherosclerotic and anti-thrombotic therapeutic drugs. Babinska et al., 2019. "A peptide antagonist of F11R/JAM-A reduces plaque formation and prolongs survival in an animal model of atherosclerosis." Atherosclerosis 284: 92-101 discloses that peptide 4D significantl