Melanocortin-1 receptor-specific peptides for cytokine storm and inflammation therapy
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Publication Number
US-11286280-B2
Publication Date
2022-03-29
Expiration Date
Abstract
Methods preventing, ameliorating or treating cytokine storm or inflammatory disease, indications, conditions and syndromes by administration of a therapeutically effective amount of a melanocortin-1 receptor-specific cyclic peptide or pharmaceutically acceptable salt thereof.
Core Innovation
The invention relates to a method of treating cytokine storm by determining a human patient is in need of treating cytokine storm and administering a therapeutically effective amount of a melanocortin-1 receptor (MCR-1) agonist cyclic peptide or a pharmaceutically acceptable salt thereof. The administered peptide has an EC50 value at MCR-1 of less than about 1 nM, and the disclosed results indicate strong selectivity for MCR-1 over MCR-4.
The invention relates to structure-identified melanocortin-1 receptor agonist cyclic peptides, including SEQ ID NO:5, 6, and 10-35, and pharmaceutically acceptable salts thereof. The peptides are characterized by in vitro potency and selectivity, including MCR-1 Ki and EC50 values and MC-4/MCR-4 Ki values measured for selectivity assessment.
The reported examples include cAMP signaling in HBL cells, with cAMP HBL EC50 values and cAMP maximal efficacy values, supporting potent functional agonism. The described treatment framework further includes administration and formulation modalities such as subcutaneous injection, with an upper subcutaneous dosing limit of no more than about 50 μg/kg body weight.
Claims Coverage
The claim coverage centers on one independent method claim for treating cytokine storm using an MCR-1 agonist cyclic peptide with an MCR-1 EC50 below about 1 nM. The claims are further refined by stronger potency, quantitative MCR-1 versus MCR-4 Ki selectivity, specific SEQ ID peptide identity, and subcutaneous administration constraints.
Treating cytokine storm with an MCR-1 agonist cyclic peptide
Determining a human patient is in need of treating cytokine storm and administering a therapeutically effective amount of a melanocortin-1 receptor (MCR-1) agonist cyclic peptide or pharmaceutically acceptable salt thereof having an EC50 value at MCR-1 of less than about 1 nM.
Tighter MCR-1 potency threshold
The method uses an MCR-1 agonist cyclic peptide or pharmaceutically acceptable salt with an EC50 value at MCR-1 of less than about 0.1 nM.
MCR-1 selectivity over MCR-4 by Ki comparison
The peptide has a Ki at MCR-1 that is at least 100 times lower than its Ki at melanocortin-4 receptor (MCR-4).
Selected peptide identity by SEQ ID number
The MCR-1 agonist cyclic peptide or pharmaceutically acceptable salt is selected from SEQ ID NO:5 or SEQ ID NO:6.
Subcutaneous injection administration
The MCR-1 agonist cyclic peptide or pharmaceutically acceptable salt is administered via subcutaneous injection.
Upper subcutaneous dosing limit
The subcutaneous injection administers no more than about 50 μg/kg body weight.
The claims are directed to cytokine storm treatment with an MCR-1 agonist cyclic peptide meeting a low MCR-1 EC50 threshold, with optional narrowing by stronger potency, MCR-1/MCR-4 selectivity, SEQ ID identity, and subcutaneous dosing limits.
Stated Advantages
Potent functional agonists are supported by very low MCR-1 Ki/EC50 values and strong MCR-1 versus MCR-4 selectivity.
Strong MCR-1 selectivity over MCR-4 is demonstrated by markedly higher MCR-4 Ki values relative to MCR-1 Ki.
MCR-1-mediated cAMP signaling in HBL cells is demonstrated, with cAMP HBL Emax values reported.
Some variants achieve near-maximal efficacy, often approximately 97% to 109%.
Documented Applications
Treating cytokine storm in a human patient by administering an MCR-1 agonist cyclic peptide or pharmaceutically acceptable salt thereof.
Treating a broad range of inflammatory and inflammatory-related diseases, including arthritis and inflammatory bowel disease (IBD).
Treating inflammatory-related conditions described as COPD/asthma.
Treating transplant-related inflammatory syndromes, including graft-versus-host disease.
Treating fibrotic/sclerotic conditions, including systemic sclerosis and lung fibrosis.
Treating ischemia-related diseases, including ischemia-reperfusion injury.
Treating circulatory shock.
Treating melanoma/cancers where MCR-1 is expressed.
Targeted imaging and cytotoxic therapy contexts associated with MCR-1 expression.
Combination therapy with anti-inflammatory agents and PDE inhibitors.
Potential pulmonary (inhalation) delivery is described.
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