Peptide inhibition of CCR3-mediated diseases or conditions
Inventors
Ackerman, Steven Jules • Laffey, Fan Gao • Hitchinson, Ben • Garnier, Boris • Gaponenko, Vadim • Tarasova, Nadya • Abdelkarim, Hazem
Assignees
University of Illinois System • US Department of Health and Human Services
Publication Number
US-10363286-B2
Publication Date
2019-07-30
Expiration Date
2036-02-12
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Abstract
A C—C chemokine receptor 3 (CCR3) peptide analog that exhibits biased antagonism by binding to and inhibiting ligand-mediated signaling and chemotaxis while promoting the internalization and degradation of CCR3 is provided as is a method of using the peptide analog to treat, prevent, or ameliorate one or more symptoms of an eosinophil- or CCR3-mediated disease or condition.
Core Innovation
This invention provides a C—C chemokine receptor 3 (CCR3) peptide analog that exhibits biased antagonism by binding to and inhibiting ligand-mediated signaling and chemotaxis while promoting the internalization and degradation of CCR3. The peptide analog is PEGylated, may be up to 30 or 50 amino acid residues in length, and can form nanoparticles that protect it from proteolytic degradation in aqueous medium. This innovation enables inhibition of CCR3 activity without causing receptor accumulation on the cell surface, thereby avoiding drug tolerance.
The problem being solved arises from the limitations of existing small molecule CCR3 antagonists, which are typically unbiased and inhibit both chemotaxis and receptor internalization. Such antagonists lead to receptor accumulation on the cell surface, reduced potency over time, and development of drug tolerance. Since CCR3 signaling is critical for eosinophil recruitment and activation implicated in allergic disorders such as asthma and eosinophilic esophagitis, more effective CCR3-targeted therapies that avoid these limitations are needed.
Claims Coverage
The patent includes multiple independent claims covering CCR3 peptide analogs with specific amino acid sequences and PEGylation, as well as compositions and delivery forms containing these analogs. The main inventive features encompass the peptide sequences, PEGylation ranges, pharmaceutical formulations, inhaler devices, and nanoparticle compositions.
CCR3 peptide analog with specified amino acid sequences and PEGylation
A CCR3 peptide analog comprising the amino acid sequences LLNLAISDLLFLVTLPFWIHY (SEQ ID NO:17) or LLFLVTLPFWIHYVRGHNWVFGH (SEQ ID NO:18), wherein the peptide analog is PEGylated and is up to 50 amino acid residues in length.
PEGylation specifying PEG unit range
The peptide analog includes between 5 and 50 polyethylene glycol units to enhance stability, solubility, and bioavailability.
Pharmaceutical compositions containing the CCR3 peptide analog
Pharmaceutical compositions comprising the CCR3 peptide analog and a pharmaceutically acceptable carrier suitable for various administration routes.
Delivery via metered dose inhaler
A metered dose inhaler comprising an aerosol canister with one or more propellants and the CCR3 peptide analog for pulmonary delivery.
Nanoparticle compositions of the CCR3 peptide analog
Nanoparticle compositions formed by self-assembly of the CCR3 peptide analog, protecting it and facilitating delivery.
Nanoparticle compositions combined with second therapeutic agents
Nanoparticle compositions that further include one or more additional therapeutic agents, such as steroids, antibacterials, or anti-inflammatory drugs.
The independent claims cover the CCR3 peptide analogs with particular sequences and PEGylation, their pharmaceutical formulations including nanoparticle forms, inhalation devices for delivery, and combinations with other therapeutics. The key inventive features are the specific peptide sequences with modifications that enable biased antagonism and improved stability/delivery.
Stated Advantages
The CCR3 peptide analog is a biased antagonist that inhibits CCR3 signaling and chemotaxis while promoting receptor internalization and degradation, thereby avoiding the drug tolerance typically seen with small molecule CCR3 antagonists that cause receptor accumulation.
The peptide analog forms nanoparticles in aqueous medium, protecting it from proteolytic degradation and enhancing stability, bioavailability, and tissue penetration.
Pharmaceutical compositions can be formulated for various delivery routes including inhalation, enabling targeted delivery to lungs or esophagus for treatment of eosinophil- or CCR3-mediated diseases.
Documented Applications
Treatment, prevention, or amelioration of one or more symptoms of eosinophil- or CCR3-mediated diseases or conditions such as asthma, eosinophilic esophagitis, allergic rhinitis, atopic dermatitis, eosinophilic gastrointestinal diseases, and other inflammatory, infectious, or immune-related disorders.
Use in aerosol formulations for inhalation via nebulization or metered dose inhalers to deliver the peptide to the lungs.
Administration to the esophagus via oral viscous formulations that coat the esophagus to treat eosinophilic esophagitis.
Combination therapy using nanoparticle formulations including CCR3 peptide analogs with additional therapeutic agents like steroids, antibacterials, antifungals, anticoagulants, and anti-inflammatory drugs.
Preclinical mouse models of eosinophilic asthma and eosinophilic esophagitis to inhibit eosinophil recruitment and associated inflammation.
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