Agent for promoting angiogenesis and methods and uses thereof
Inventors
Dumont, Daniel • Van Slyke, Paul • Tumelty, David • Sokoll, Kenneth • Moss, Jason
Assignees
Vasomune Therapeutics Inc • Sunnybrook Research Institute
Publication Number
US-11384130-B2
Publication Date
2022-07-12
Expiration Date
2038-01-11
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Abstract
The present disclosure relates to compounds of Formula (I) which are multimeric forms of a monomeric binding peptide linearly bonded to PEG moieties to form the multimers. The multimeric forms stimulate angiogenesis and promote wound healing. The disclosure also includes pharmaceutical compositions comprising the multimers, including compositions suitable for topical or systemic administration.
Core Innovation
The invention relates to novel compounds of Formula (I), which comprise multimeric forms of monomeric binding peptides linearly bonded to polyethylene glycol (PEG) moieties, forming tetrameric, trimeric, or dimeric conjugates. These compounds act as Tie2 receptor agonists by mimicking the actions of angiopoietin-1 (Ang1), promoting Tie2 receptor phosphorylation and downstream signaling including MAPK, AKT and eNOS activation. They stimulate endothelial cell migration, release of matrix metalloproteinase-2 (MMP2), protect endothelial cells from apoptosis, induce angiogenesis in vivo, promote wound healing, and decrease vascular leak.
The compounds are chemically distinct from the parental vasculotide (VT), with an improved structure that avoids labile ring formations by employing a linear sulfane linker (Mpa-Br). This design yields a single product with enhanced stability and improved binding affinity to Tie2 across multiple species, showing activation of Tie2 at lower concentrations and a broader effective dose range than existing vasculotide compounds.
The problem addressed is the lack of effective, stable, and well-characterized Tie2 receptor agonists that can therapeutically modulate the angiopoietin/Tie2 signaling axis. While vasculotide mimics Ang1, it contains mixtures of reactive ring structures that preclude optimal stability and therapeutic application. Moreover, there are limited treatments addressing vascular leak, impaired wound healing, influenza-induced lung injury, and allergic diseases mediated by Tie2 pathways. The invention provides new compounds that overcome these limitations with improved activity and pharmacokinetics, enabling diverse therapeutic uses including treatment of diabetic wounds, lung injury from influenza, allergic diseases, and angiogenesis-related conditions.
Claims Coverage
The patent includes 26 claims with one main independent claim directed to the compound of formula (I) and other independent claims directed to pharmaceutical compositions, methods of making, and therapeutic methods.
Novel compound of formula (I) with defined peptide and linker components
The compound is a multimeric PEG-peptide conjugate according to formula (I), wherein the number of PEG units (n) is about 25 to 100, with each X and Y independently or simultaneously (C1-C20)-alkylene or (C2-C20)-alkenylene optionally substituted, and R represents a Tie2 binding peptide (T7, GA3, T4, T6, or T8) or retro-inverso peptide thereof, with specific embodiments where R is the T7 peptide (SEQ ID NO:1).
Pharmaceutical compositions comprising the compound
Compositions include the compound of formula (I) with a pharmaceutically acceptable carrier suitable for inhalation and/or topical, systemic, oral, intranasal, or parenteral administration.
Combination compositions including antiviral agents
Compositions comprising the compound of formula (I) together with antiviral agents such as amantadine, rimantadine, zanamivir, peramivir, viramidine, ribavirin, or oseltamivir.
Biomaterials incorporated with the compound
Biomaterials such as Matrigel, skin substitutes, or cross-linked glycosaminoglycan hydrogels containing the compound of formula (I).
Method of synthesizing the compound
A method including reaction of a Tie2 binding peptide (T7, GA3, T4, T6, or T8 or retro-inverso peptides) with thiol compounds and subsequent reaction with PEG-tetramers containing suitable leaving groups (halo, tosylate, mesylate) and protecting groups (trityl), wherein the halo is preferably bromo.
Method of stimulating angiogenesis
Administering the compound of formula (I) at a site in a subject needing angiogenesis stimulation.
Method of decreasing vascular permeability
Administering the compound of formula (I) at sites of leaky vessels in subjects.
Method of protecting endothelial cells
Administering the compound of formula (I) to subjects needing endothelial cell protection.
Method of stimulating wound healing
Administering the compound of formula (I) to subjects to stimulate wound healing, including diabetic ulcers and wounds such as decubitus ulcers, pressure ulcers, surgical incisions, traumatic injuries, burns, and skin grafts.
Method of treating diseases associated with eosinophil and basophil expansion
Treating atopic dermatitis, asthma, allergic rhinitis, leukemia of eosinophil/basophil origin, inflammatory bowel disease, or parasitic infections by inhibiting CFU-G cell expansion via administration of the compound.
Method of treating influenza and related pneumonia
Treating primary viral pneumonia or bacterial pneumonia occurring simultaneously or after influenza infection by administering the compound, optionally concurrently or sequentially with antiviral agents including amantadine, rimantadine, zanamivir, peramivir, viramidine, ribavirin, or oseltamivir.
The independent claims cover the novel chemical structure of the compound of formula (I) with specific peptide and linker configurations, pharmaceutical compositions including combination therapies, methods of synthesis using defined chemical reactions, and therapeutic uses including angiogenesis stimulation, vascular stabilization, endothelial protection, wound healing, treatment of eosinophil/basophil-mediated diseases, and treatment of influenza and influenza-related bacterial pneumonia.
Stated Advantages
The compounds exhibit improved activity over parental vasculotide, including increased magnitude of Tie2 receptor activation and broader effective dose range at lower concentrations.
The compounds demonstrate greater stability by eliminating labile ring structures susceptible to rearrangement present in parental vasculotide.
Improved binding affinity, including lower dissociation constants to human and animal Tie2 receptors, enhancing therapeutic efficacy.
The compounds reduce vascular leak following inflammatory challenges such as histamine-induced vascular leakage.
They provide efficacy in improving morbidity and mortality in influenza infection at doses significantly lower than parental vasculotide.
No observed drug accumulation during repeated dosing and favorable pharmacokinetics including longer half-life compared to parental vasculotide.
Documented Applications
Stimulating angiogenesis to promote vascularization in regenerative tissues and treat ischemic conditions.
Treating wounds including diabetic ulcers, decubitus ulcers, pressure ulcers, surgical incisions, burns, traumatic tissue injuries, and skin grafts by promoting wound healing.
Decreasing vascular permeability and leakage in conditions like stroke, macular degeneration, macular edema, lymph edema, breakdown of the blood-retinal and blood-brain barriers, bacterial-induced vascular leak, and tumor vasculature normalization.
Protecting endothelial cells in diseases including kidney injury and fibrosis, stroke, vascular dementia, macular degeneration, lung injury, and diabetic complications.
Treating allergic diseases and responses including atopic dermatitis, asthma, allergic rhinitis, by inhibiting expansion of CFU-G cells and reducing eosinophils and basophils.
Treating influenza infection and associated bacterial superinfections, including primary viral pneumonia and pneumonia following influenza, improving survival and reducing lung endothelial leak.
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