Akeso's AK135 Shows Promise for Chemotherapy-Induced Neuropathy in Preclinical Studies
Key Insights
Akeso (search) presented preclinical data for AK135, a novel IL-1RAP (search) targeting antibody, at SITC 2025, demonstrating effective blockade of three key inflammatory pathways.
The antibody significantly alleviated neuropathic pain (search) in a dose-dependent manner in chemotherapy-induced peripheral neuropathy (search) mouse models while maintaining good tolerability.
AK135 is currently in Phase I clinical trials for treating CIPN (search), a prevalent side effect affecting 50-90% of chemotherapy patients with limited treatment options.
Akeso (search), Inc. unveiled promising preclinical data for its novel IL-1RAP (search) targeting antibody AK135 at the 40th Annual Meeting of the Society for Immunotherapy of Cancer (SITC) in National Harbor, Maryland. The results demonstrated that AK135 effectively blocks three key pro-inflammatory signaling pathways—IL-1 (search), IL-33 (search), and IL-36 (search)—providing significant pain relief in chemotherapy-induced peripheral neuropathy (search) (CIPN (search)) models.
Targeting Multiple Inflammatory Pathways
The preclinical studies revealed that AK135 exhibits high affinity for IL-1RAP (search), with binding activity comparable to or superior to the control antibody CAN04, as demonstrated through ELISA, Fortebio molecular interaction technology, and flow cytometry analyses. Reporter gene assays confirmed that AK135 effectively inhibits the activation of IL-1 (search), IL-33 (search), and IL-36 (search) signaling pathways, showing excellent half-maximal inhibitory concentration (IC50) values across all three pathways.
In tumor cell models, AK135 significantly reduced the secretion of pro-inflammatory cytokines, including IL-6 and IL-8, induced by IL-1 (search), IL-33 (search), and IL-36 (search) stimulation.
Dose-Dependent Efficacy in Neuropathy Models
To evaluate in vivo efficacy, researchers established a CIPN (search) mouse model using intermittent low-dose paclitaxel administration. Following AK135 treatment, the paw withdrawal threshold (PWT) was significantly increased, indicating effective alleviation of mechanical allodynia with dose-dependent efficacy.
Throughout the treatment period, mice in all dose groups maintained stable body weight with no significant signs of toxicity, demonstrating good tolerance profiles.
Addressing an Unmet Medical Need
CIPN (search) represents a prevalent and dose-limiting side effect of chemotherapy, affecting 50-90% of treated patients, with 30-40% progressing to chronic neuropathic pain (search). 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 damaged neurons play a key role in CIPN (search) pathogenesis. IL-1 (search) receptor accessory protein (IL-1RAP (search)/IL-1RAcP) serves as a critical mediator of inflammatory signaling, amplifying responses through the interleukin-1 (IL-1), interleukin-33 (IL-33 (search)), and interleukin-36 (IL-36 (search)) pathways.
Clinical Development Progress
AK135 is a novel antagonistic antibody targeting IL-1RAP (search), internally developed by Akeso (search) for treating CIPN (search). By precisely blocking IL-1RAP, the product simultaneously inhibits the three core inflammatory signaling pathways, providing relief from neuroinflammatory responses at their source.
The drug candidate is currently in Phase I clinical trials for the treatment of CIPN (search), representing a potential breakthrough for patients experiencing this debilitating side effect of cancer treatment.