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-11167012-B2
Publication Date
2021-11-09
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 includes specific amino acid sequences derived from the CCR3 second transmembrane domain and extracellular loop. It is PEGylated and can form nanoparticles that enhance stability and bioavailability.
The problem being solved relates to existing CCR3 antagonists, which are typically unbiased and inhibit both chemotaxis and receptor internalization. This leads to receptor accumulation on the cell surface and the development of drug tolerance, limiting their long-term effectiveness. Thus, there is a need for CCR3 antagonists that inhibit receptor signaling but still promote receptor internalization and degradation to avoid resistance.
Claims Coverage
The patent includes three claims focusing on methods of treating various diseases using specific CCR3 peptide analogs with defined characteristics and administration methods.
Use of PEGylated CCR3 peptide analogs for treating eosinophil- or CCR3-mediated diseases
Administering an effective amount of a pharmaceutical composition comprising a PEGylated CCR3 peptide analog having the amino acid sequence LLNLAISDLLFLVTLPFWIHY (SEQ ID NO:17) or LLFLVTLPFWIHYVRGHNWVFGH (SEQ ID NO:18), optionally in nanoparticle form or with a pharmaceutically acceptable carrier, to treat or ameliorate symptoms of diseases such as asthma, eosinophilic esophagitis, eosinophilic colitis, allergic rhinitis, atopic dermatitis, Crohn's disease, inflammatory bowel disease, or age-related macular degeneration.
Pulmonary delivery of the CCR3 peptide analog
Administration of the pharmaceutical composition to the lungs of the subject, specifically via nebulization, to effectively deliver the CCR3 peptide analog for treatment purposes.
The claims cover methods of treating various eosinophil- or CCR3-mediated diseases by administering PEGylated CCR3 peptide analogs, especially including delivery via nebulization to the lungs, highlighting both the peptide composition and its mode of administration as inventive features.
Stated Advantages
The CCR3 peptide analog exhibits biased antagonism by inhibiting receptor signaling and chemotaxis while promoting receptor internalization and degradation, which prevents receptor accumulation and drug tolerance.
The peptide analog self-assembles into nanoparticles that protect it from proteolytic degradation, increase stability and bioavailability, and facilitate effective delivery.
The peptide analog is effective in inhibiting eosinophil recruitment in vivo in models of eosinophilic esophagitis and allergic asthma, outperforming small molecule CCR3 antagonists.
The invention enables diverse administration routes including pulmonary (nebulization), oral viscous preparations for esophageal coating, and systemic delivery with optimized formulations.
Documented Applications
Treatment, prevention, or amelioration of one or more symptoms of eosinophil- or CCR3-mediated diseases or conditions including asthma, eosinophilic esophagitis, eosinophilic colitis, allergic rhinitis, atopic dermatitis, Crohn's disease, inflammatory bowel disease, and age-related macular degeneration.
In vivo inhibition of eosinophil recruitment in models of eosinophilic esophagitis and allergic asthma by administration of the CCR3 peptide analog or nanoparticle compositions.
Pulmonary delivery via nebulization for local treatment of lung-related eosinophilic or CCR3-mediated diseases.
Oral viscous preparation administration for coating the esophagus to treat eosinophilic esophagitis.
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