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1.
Acta Pharmacol Sin ; 43(11): 2841-2847, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35468993

RESUMO

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.


Assuntos
Antineoplásicos , Doenças do Sistema Nervoso Periférico , Ratos , Animais , Fator de Crescimento Neural , Anticorpos Monoclonais/uso terapêutico , Qualidade de Vida , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Dor , Antineoplásicos/efeitos adversos , Receptor trkA/metabolismo
2.
FEBS Open Bio ; 12(7): 1325-1335, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35417079

RESUMO

Current treatment options for diabetic neuralgia are limited and unsatisfactory. Tanezumab, a monoclonal antibody that blocks nerve growth factor (NGF) signaling, has been shown to be effective in relieving the clinical symptoms of osteoarthritis pain, chronic low back pain, cancer pain induced by bone metastasis, and diabetic neuralgia. However, the clinical development of tanezumab has been terminated due to the risk of induction of rapidly progressive osteoarthritis (RPOA), and no other NGF antibodies have been examined for their ability to treat diabetic neuralgia in either animal models or clinical trials. In this study, a humanized high-affinity NGF monoclonal antibody (mAb), huAb45 that could neutralize the interaction between NGF and its high-affinity receptor TrkA. In a mouse diabetic neuralgia model, it effectively relieved neuropathic pain. This study may serve as the necessary foundation for future studies of huAb45 to potentially treat diabetic neuralgia.


Assuntos
Diabetes Mellitus , Neuropatias Diabéticas , Osteoartrite , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Anticorpos Monoclonais/farmacologia , Diabetes Mellitus/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Modelos Animais de Doenças , Camundongos , Fator de Crescimento Neural/metabolismo
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