Method for treating CD40-mediated diseases
Inventors
Subauste, Carlos • Subauste, Cecilia
Assignees
Case Western Reserve University
Publication Number
US-12319726-B2
Publication Date
2025-06-03
Expiration Date
2029-05-19
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Abstract
A cell-permeable polypeptide includes a membrane transduction domain and a polypeptide comprising an amino acid sequence substantially homologous to the amino acid sequence of the TRAF2,3 binding domain, the cell permeable peptide inhibiting binding of TRAF2 to the TRAF2,3 binding domain of CD40 to decrease or inhibit a CD-40 activity or signal transduction pathway associated with a CD40-mediated disease in cells of a subject.
Core Innovation
The invention provides compositions and methods for treating CD40-mediated diseases by inhibiting specific intracellular interactions within the CD40 signaling pathway. This is achieved through the use of a cell-permeable polypeptide that includes a membrane transduction domain and a polypeptide portion substantially homologous to the TRAF2,3 binding domain, or its retro-inverso equivalent, designed to competitively inhibit the binding of TRAF2 to the cytoplasmic portion of CD40. By blocking this interaction, the signal transduction pathway associated with CD40-mediated diseases in cells of a subject is disrupted.
The core problem addressed is that traditional approaches to block CD40-CD154 interactions, such as anti-CD154 monoclonal antibodies, led to adverse effects like platelet aggregation and thrombosis, making such approaches clinically unfeasible. Indiscriminate inhibition of the CD40 pathway also risks compromising immune responses against pathogens. Therefore, the invention seeks a selective therapeutic methodology that inhibits CD40-mediated pro-inflammatory activity without diminishing key aspects of host resistance.
The present method utilizes a cell-permeable polypeptide agent that inhibits TRAF2 binding to the TRAF2,3 binding site of CD40, without interfering with the binding of CD40 ligand (CD40L) to CD40. This enables inhibition of specific pro-inflammatory responses—such as the upregulation of VCAM-1 or ICAM-1, production of chemokines (e.g., MCP-1, CXCL1), tissue factor, metalloproteinases, nitric oxide, or prostaglandins—without inducing platelet aggregation or affecting the cell-mediated immune response. The agent is designed for administration to CD40-expressing cells and is adaptable for various delivery systems dependent on the target disease.
The invention further includes embodiments where the cell-permeable polypeptide is in retro-inverso format, thus providing increased resistance to proteolytic degradation and enhanced pharmaceutical properties. In addition, methods may combine this agent with a second agent, such as one inhibiting the activity or production of interleukin-1 (IL-1), to further control CD40-driven responses. These innovations enable precise modulation of pro-inflammatory signaling in a range of CD40-mediated inflammatory, autoimmune, and neurodegenerative diseases.
Claims Coverage
The patent contains one independent claim covering the main inventive composition, followed by dependent claims specifying peptide sequences, formats, and additional formulation details. The following outlines the inventive features claimed.
Cell-permeable polypeptide inhibiting TRAF2 binding to CD40
A cell-permeable polypeptide that competitively inhibits binding of TRAF2 to the TRAF2,3 binding domain of CD40 of cells. The polypeptide comprises a membrane transduction domain and a retro-inverso peptide of a CD40-TRAF2,3 blocking peptide, the peptide comprising an amino acid sequence at least 70% identical to SEQ ID NO: 10.
The claims specifically protect a composition based on a cell-permeable, retro-inverso CD40-TRAF2,3 blocking peptide with a defined sequence homology. Dependent claims provide coverage for variants of the peptide sequence, particular sequence listings, and pharmaceutical carriers.
Stated Advantages
The agent does not promote platelet aggregation or thrombosis in the subject.
The cell-mediated immune response of the subject is substantially unimpaired.
Selective inhibition of CD40-mediated pro-inflammatory responses while leaving host defense mechanisms largely intact.
Retro-inverso peptide format increases resistance to proteolytic degradation and extends the effective time as a pharmaceutical.
Documented Applications
Treatment of CD40-mediated inflammatory diseases, including atherosclerosis.
Treatment of neurodegenerative disorders, such as Alzheimer's disease, cerebral ischemia, multiple sclerosis, and amyotrophic lateral sclerosis.
Treatment of autoimmune diseases, including inflammatory bowel disease, systemic lupus erythematosus, and rheumatoid arthritis.
Treatment of diseases comprising malignant B-cells, such as B-cell lymphomas and leukemias.
Treatment of ischemia, including organ ischemia and ischemia/reperfusion-induced retinopathy.
Treatment of diabetes mellitus and its complications such as diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy.
Treatment of retinopathies, including diabetic and ischemic retinopathy.
Potential use for local or systemic therapy delivered to affected tissues or organs expressing CD40.
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