{
  "abstract": "Background Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent and dose-limiting side effect of chemotherapy, affecting 50-90% of treated patients, of which 30-40% progressing to chronic neuropathic pain. Despite its clinical significance, effective treatment options remain limited, and the underlying mechanisms are not fully understood. Emerging evidence suggests that pro-inflammatory cytokines released by the damaged neurons play a key role in CIPN pathogenesis. IL-1 receptor accessory protein (IL-1RAP) is a critical mediator of inflammatory signaling, amplifying responses through the interleukin-1 (IL-1), interleukin-33 (IL-33), and interleukin-36 (IL-36) pathways. We developed AK135, a novel antagonistic monoclonal antibody targeting IL-1RAP, to alleviate the peripheral neuralgia by inhibiting these pro-inflammatory signaling pathways.Methods Binding activities of AK135 to IL1RAP were measured by ELISA, Fortebio and FACS assay. The neutralizing bioactivity of AK135 in IL-1/IL-33/IL-36 signaling pathways were assessed by reporter gene assays. And the inhibition effect of AK135 in proinflammatory cytokines secretion induced by IL-1/33/36 were evaluated in tumor cells. A CIPN model in B6-hIL1RAP transgenic mice were established via intermittent low-dose paclitaxel induction. Then the pharmacological efficacy of AK135 in this model was evaluated.Results AK135 shows high affinity to IL-1RAP and exhibits potent neutralizing bioactivity in IL-1/IL-33/IL-36 signaling pathways, while Nadunolimab (CAN04) has a weaker blocking effect on the IL-33 and IL-36 signaling pathways, as shown in table 1. Furthermore, AK135 effectively suppresses IL-1/IL-33/IL-36-mediated biological responses and inhibits the secretion of proinflammatory cytokines (IL-6 and IL-8) by tumor cells. In a CIPN mouse model, AK135 administration significantly increased the paw withdrawal threshold (PWT) in a dose-dependent manner, indicating alleviation of neuropathic pain in CIPN. No significant body weight loss was observed across treatment groups, confirming good tolerability. Additionally, AK135 treatment led to a dose-dependent decrease in pain-related cytokines in spinal cord tissue homogenates, supporting its anti-inflammatory mechanism in pain relief.Conclusions As a potential chemotherapy companion drug, AK135 potently targets IL-1RAP to block IL-1/IL-33/IL-36-driven inflammatory signaling, mitigates proinflammatory cytokine release, and alleviates chemotherapy-induced peripheral neuropathy (CIPN) in preclinical models. Its dose-dependent efficacy in pain relief, coupled with good tolerability, underscores AK135’s potential to improve the quality of life for chemotherapy patients through its anti-inflammatory mechanism.Abstract 1189 Table 1Neutralizing bioactivity in IL-1/IL-33/IL-36 signaling pathways",
  "authors": [
    {
      "affiliations": [
        "Akeso Biopharma Inc., Zhongshan, China"
      ],
      "name": "Zhaoliang Huang"
    },
    {
      "affiliations": [
        "Akeso Biopharma Inc., Zhongshan, China"
      ],
      "name": "Chunshan Jin"
    },
    {
      "affiliations": [
        "Akeso Biopharma Inc., Zhongshan, China"
      ],
      "name": "Tingting Zhong"
    },
    {
      "affiliations": [
        "Akeso Biopharma Inc., Zhongshan, China"
      ],
      "name": "Xinghua Pang"
    },
    {
      "affiliations": [
        "Akeso Biopharma Inc., Zhongshan, China"
      ],
      "name": "Wenrong Liu"
    },
    {
      "affiliations": [
        "Akeso Biopharma Inc., Zhongshan, China"
      ],
      "name": "Lingzhi Zhang"
    },
    {
      "affiliations": [
        "Akesobio, Zhongshan, China"
      ],
      "name": "Jing Min"
    },
    {
      "affiliations": [
        "Akeso Biopharma Inc., Zhongshan, China"
      ],
      "name": "Baiyong Li"
    }
  ],
  "title": "1189 AK135, a novel antagonistic antibody targeting IL-1RAP for CIPN therapy",
  "uid": "15041805-fe17-5424-a775-e9accbb48579"
}