Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is one of the pervasive side effects of chemotherapy, leading to poor quality of life in cancer patients. Discovery of powerful analgesics for CIPN is an urgent and substantial clinical need. Nerve growth factor (NGF), a classic neurotrophic factor, has been identified as a potential therapeutic target for pain. In this study, we generated a humanized NGF monoclonal antibody (DS002) that most effectively blocked the interaction between NGF and tropomyosin receptor kinase A (TrkA). We showed that DS002 blocked NGF binding to TrkA in a dose-dependent manner with an IC50 value of 6.6 nM; DS002 dose-dependently inhibited the proliferation of TF-1 cells by blocking the TrkA-mediated downstream signaling pathway. Furthermore, DS002 did not display noticeable species differences in its binding and blocking abilities. In three chemotherapy-induced rat models of CIPN, subcutaneous injection of DS002 produced a significant prophylactic effect against paclitaxel-, cisplatin- and vincristine-induced peripheral neuropathy. In conclusion, we demonstrate for the first time that an NGF inhibitor effectively alleviates pain in animal models of CIPN. DS002 has the potential to treat CIPN pain in the clinic.
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Acknowledgements
This work was supported by the China National Major Scientific and Technological Special Project [2019ZX09732002-006]; the National Natural Science Foundation of China [81872785 and 81673347]; the Shanghai Municipal Commission of Science and Technology of China [17431904400, 19YF1457400 and 21S11904500]; the Institutes for Drug Discovery and Development, Chinese Academy of Sciences [CASIMM0120202007 and CASIMM0120202008]; and the Major Scientific and Technological Special Project of Zhongshan City [191022172638719 and 210205143867019].
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CHW, LT and YLC conceived the study and designed the experiments. ZJL, ZBX, JT, GJC, GJL, LY, KXW, HPD, HQ, QW, and GFW conducted the experiments. ZJL and CHW wrote the manuscript. All authors read and approved the final manuscript.
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Jie Tan and Yi-li Chen received stipends from Shanghai Mabstone Biotechnologies, Ltd, and Lei Tang, Gan-jun Chen, Guo-jian Liu, Lin Yuan, Kai-xin Wang, Hua-ping Ding, Zuo-bin Xie, and Chun-he Wang from Dartsbio Pharmaceuticals, Ltd. The remaining authors declare no conflicts of interest.
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Liang, Zj., Tan, J., Tang, L. et al. NGF monoclonal antibody DS002 alleviates chemotherapy-induced peripheral neuropathy in rats. Acta Pharmacol Sin 43, 2841–2847 (2022). https://doi.org/10.1038/s41401-022-00904-8
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DOI: https://doi.org/10.1038/s41401-022-00904-8
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