Pfizer Global Research and Development, La Jolla, CA, USA.
Regul Toxicol Pharmacol. 2011 Mar;59(2):334-42. doi: 10.1016/j.yrtph.2010.11.005. Epub 2010 Dec 3.
Nerve growth factor (NGF) is an important mediator of pain and hyperalgesia and has become a target of novel analgesic therapeutics. Tanezumab is a humanized IgG(2) antibody that binds NGF with high affinity and specificity. In a study to assess the toxicity and pharmacokinetic properties of tanezumab in adult, male and female, cynomolgus monkeys following weekly intravenous administration of 1, 10, or 30 mg/kg for up to 26 weeks (followed by an 8-week recovery period), tanezumab was well tolerated with no macroscopic or microscopic effects on those brain, spinal cord, nerve, or ganglia sections evaluated. One fifth of tanezumab-treated monkeys developed an antibody response to tanezumab that prevented maintenance of tanezumab exposure between dosing. In the antibody-negative animals, accumulation of tanezumab was observed; steady state was achieved approximately 8 weeks after the first dose of study drug, and exposure to tanezumab was approximately dose proportional with no observed difference between male and female animals. One monkey died during the study; this monkey had findings suggestive of hypersensitivity reaction. The favorable toxicity and pharmacokinetic profile of tanezumab seen in this study supports its further evaluation for the treatment of pain in clinical practice.
神经生长因子（NGF）是疼痛和痛觉过敏的重要介质，已成为新型镇痛治疗的靶点。替扎尼定是一种人源化 IgG(2)抗体，与 NGF 具有高亲和力和特异性。在一项评估替扎尼定在成年雄性和雌性食蟹猴中的毒性和药代动力学特性的研究中，每周静脉给予 1、10 或 30mg/kg，连续 26 周（随后进行 8 周恢复期），替扎尼定耐受性良好，未观察到大脑、脊髓、神经或神经节切片有宏观或微观影响。五分之一接受替扎尼定治疗的猴子对替扎尼定产生了抗体反应，从而阻止了替扎尼定在给药间隔内的暴露。在抗体阴性动物中，观察到替扎尼定的蓄积；在首次给予研究药物后约 8 周达到稳态，替扎尼定的暴露与剂量呈比例，雄性和雌性动物之间无差异。一只猴子在研究期间死亡；这只猴子的发现提示存在过敏反应。本研究中替扎尼定表现出良好的毒性和药代动力学特征，支持其在临床实践中进一步评估用于治疗疼痛。
