ICOS Agonist Antibody for Paclitaxel-Induced Neuropathy
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Solution Overview
Problem
Current treatments for chemotherapy-induced peripheral neuropathy (CIPN) are inadequate in effectively alleviating pain, particularly for conditions caused by paclitaxel, as they fail to address the underlying neuro-immune modulation and cytokine imbalance.
Innovation Solution
Targeting the inducible co-stimulatory molecule (ICOS) signaling pathway with an ICOS agonist antibody to promote the conversion of T cells to an anti-inflammatory phenotype, increasing IL-10 expression, and reducing astrocyte and satellite cell gliosis in the spinal cord and dorsal root ganglia.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments for CIPN are used, then pain relief is provided to some extent, but they fail to effectively address neuro-immune modulation and cytokine imbalance
Solution Approach 1:
The patent uses ICOS agonist antibody as an intermediary molecule to bridge T cells and the neuro-immune system. The antibody binds to ICOS on T cells, triggering IL-10 secretion that mediates anti-inflammatory effects in the nervous system, thereby effectively addressing neuro-immune modulation in CIPN treatment
Solution Approach 2:
The patent changes the cytokine balance parameter by specifically increasing IL-10 levels through ICOS activation. This parameter change shifts the immune environment from pro-inflammatory to anti-inflammatory, effectively treating CIPN by addressing the underlying cytokine imbalance
2Reliability
If ICOS agonist antibody is administered to convert T cells to anti-inflammatory phenotype, then IL-10 expression increases and pain is reduced, but the mechanism involves complex immune system interactions
Solution Approach 1:
The patent employs the body's own immune system to treat itself. The ICOS agonist antibody activates endogenous T cells to secrete IL-10, which then self-regulates the inflammatory process and promotes pain resolution without requiring external complex intervention systems
Solution Approach 2:
The patent establishes a feedback loop where ICOS activation triggers IL-10 secretion, which in turn suppresses inflammation and modulates the immune response. This feedback mechanism automatically regulates the treatment effect based on the body's own immune status
Data Source
AI summary
Chemotherapy-induced peripheral neuropathy (CIPN) is a primary dose-limiting side effect caused by antineoplastic agents, such as paclitaxel. This causes damage to peripheral nerves and the dorsal root ganglia (DRG). Currently, there are no effective treatments for CIPN, which can lead to long-term morbidity in patients and survivors. Neuronal-immune interactions occur in CIPN and have been implicated both in the development and progression of the disease and disease resolution. The inventors investigated the potential role of Inducible co-stimulatory molecule (ICOS) in the resolution of CIPN. ICOS is an immune checkpoint molecule that is expressed on the surface of activated T cells and promotes proliferation and differentiation of T cells. They found that intrathecal administration of ICOS agonist antibody (ICOSaa) alleviates mechanical hypersensitivity caused by paclitaxel and facilitates the resolution of pain in female mice without a clear benefit in male mice. Administration of ICOSaa reduced astrocyte-gliosis in the spinal cord and satellite cell gliosis in the DRG of mice previously treated with paclitaxel. Mechanistically, ICOSaa treatment converted T cells in the DRG to an anti-inflammatory phenotype and also promoted pain resolution by increasing cytokine interleukin 10 (IL10) expression. In line with these observations, blocking IL10 activity occluded the effects of ICOSaa treatment on CIPN behavior in female mice. Suggesting a broader activity in neuropathic pain, ICOSaa also partially resolved mechanical hypersensitivity in the spared nerve injury (SNI) model. Our findings support a model wherein ICOSaa, upon engagement with T cells, induces an expansion of IL10 expression to facilitate neuropathic pain relief in female mice. ICOSaa treatment is in clinical development for solid tumors. Given our observation of resident T cells in the human DRG, ICOSaa therapy could be developed for testing in neuropathic pain clinical trials.