ApoC-II mimetic peptides
Inventors
Remaley, Alan Thomas • Ghosh, Soumitra Shanker • Devalaraja, Madhav N. • Lo, Chih-Hung • Sviridov, Denis O. • Wolska, Anna
Assignees
Novo Nordisk AS • US Department of Health and Human Services
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Publication Number
US-11136372-B2
Publication Date
2021-10-05
Expiration Date
2038-01-19
Abstract
The disclosure provides apolipoprotein C-II (apoC-II) mimetic peptides and methods for treating hypertriglyceridemia in a patient with an effective amount of an apoC-II mimetic peptide.
Core Innovation
The invention provides apolipoprotein C-II (apoC-II) mimetic peptides and methods for treating hypertriglyceridemia by administering an effective amount of such peptides. The apoC-II mimetic peptides are designed as multihelical peptides, typically bihelical, including a first amphipathic helical domain that binds to lipids or lipoprotein surfaces and a second helical domain that activates lipoprotein lipase (LPL). These peptides lower triglyceride levels both in vitro and in vivo, and can displace apoC-III from lipoprotein surfaces, which allows efficacy in disorders with diminished or absent LPL or elevated apoC-III.
The problem being addressed is that hypertriglyceridemia, defined by elevated serum triglycerides over 150 mg/dL, poses risks for cardiovascular disease and acute pancreatitis, but current treatments such as fibrates and omega-3 fatty acids have not clearly demonstrated efficacy in reducing these risks. Hypertriglyceridemia can arise from secondary causes like obesity, diabetes, pregnancy, alcohol use, and certain drugs, as well as from rare genetic defects in LPL or apoC-II.
The invention specifically addresses the need for new therapeutic agents to treat both common and genetically caused hypertriglyceridemia. The apoC-II mimetic peptides have been designed with modifications including elongations, truncations, mutations, and chemical modifications to improve lipid binding and LPL activation properties, resulting in peptides capable of enhancing triglyceride lipolysis, displacing apoC-III, and effectively reducing triglyceride levels in vivo, including in animal models of apoC-II deficiency and hypertriglyceridemia.
Claims Coverage
The patent claims include one independent composition claim directed to apoC-II mimetic peptides and several method and pharmaceutical composition claims, encompassing peptide structure, medical use, and production methods. There are five main inventive features extracted from independent claims.
ApoC-II mimetic peptide composition with specific domain structure and amino acid length
An isolated apoC-II mimetic peptide of no more than 50 amino acids, comprising from N-terminus to C-terminus a first amphipathic helical domain, a hinge region containing valine, and a second helical domain, excluding the peptide of SEQ ID NO: 56.
Sequence variation of apoC-II mimetic peptides based on SEQ ID NO: 9
Isolated apoC-II mimetic peptides comprising an amphipathic first helical domain, a hinge region, and a second helical domain, where the peptide sequence differs from SEQ ID NO: 9 by 0 to 4 residue substitutions or has at least 90% sequence identity to SEQ ID NO: 9.
Pharmaceutical compositions comprising apoC-II mimetic peptides suitable for injection
Pharmaceutical compositions comprising the apoC-II mimetic peptide of at least 90% sequence identity to SEQ ID NO: 9 and a pharmaceutically acceptable carrier, suitable for subcutaneous injection.
Methods of treating hypertriglyceridemia with apoC-II mimetic peptides or compositions
Methods of treating hypertriglyceridemia by administering to a patient an effective amount of the apoC-II mimetic peptide or pharmaceutical composition comprising the peptide, where the hypertriglyceridemia can be associated with obesity, diabetes mellitus, alcohol consumption, medication, LPL deficiency (including familial forms), apoC-II deficiency, elevated apoC-III, or varying pre-treatment triglyceride concentrations.
Methods of manufacturing the apoC-II mimetic peptides
Methods of making the apoC-II mimetic peptides by recombinant production or chemical synthesis.
The claims cover isolated apoC-II mimetic peptides characterized by specific amphipathic and activating helical domains within a defined amino acid length, pharmaceutical formulations, therapeutic methods targeting hypertriglyceridemia under various causes, and methods for producing such peptides.
Stated Advantages
The apoC-II mimetic peptides effectively lower triglyceride levels both in vitro and in vivo.
They can activate lipolysis by LPL and displace apoC-III from lipoproteins, enhancing triglyceride clearance even in conditions with LPL deficiency or elevated apoC-III.
Chemical modifications improve lipid binding affinity, cell permeability, and biological half-life.
The peptides demonstrate efficacy across various models of hypertriglyceridemia, including genetic and post-prandial conditions.
Documented Applications
Treatment of hypertriglyceridemia in patients, including those with obesity, diabetes mellitus, alcohol consumption, medication-induced triglyceride elevation, LPL deficiency, familial LPL deficiency, apoC-II deficiency, and elevated apoC-III levels.
Reduction of elevated triglyceride levels across a wide range of severities, including post-prandial hypertriglyceridemia.
Pharmaceutical compositions for administration by various routes, especially subcutaneous injection.
Use in animal models such as apoC-II knockout mice, apoC-III transgenic mice, and obese monkey models to reduce triglyceride and VLDL levels.
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