Nivolumab (BMS-936558)

Nivolumab, an anti-cancer monoclonal antibody, is a programmed death receptor-1 blocking human IgG4 antibody to treat advanced (metastatic) non-small cell lung cancer.^[1]

In vitro efficacy test it shown that Nivolumab bound to CHO cells expressing PD-1 with an EC50 of 1.66 nmol/L and bound to PD-1 on activated T cells with an EC50 of 0.64 nmol/L. In the meanwhile, Nivolumab can inhibit the interaction between PD-1 and its ligands, PD-L1 and PD-L2, with IC50 values of 2.52 and 2.59 nmol/L, respectively. In vitro, at 1.5 ng/mL concentrations of nivolumab enhances T-cell reactivity in the presence of a T-cell receptor stimulus.^[1]

In vivo study it indicated that mice were treated with 50 mg/kg nivolumab, there were no changes in T3, T4, or TSH levels. After administration of 10 mg/kg and 50 mg/kg nivolumab in cynomolgus monkeys, the results shown that there were dramatically more CD8+ effector memory T cells in the 50 mg/kg group than in the 10 mg/kg and untreated groups and Na?ve T-cell populations were decreased in the 50 mg/kg group.^[1] In vivo, Nivolumab treatment (30 mg/kg, i.p.) inhibits growth of the TNBC MDA-MB-231 cell line in hu-CB-BRGS mice.^[3] BLT-NOG-EXL mice treated with either saline, 2.5, 5, or 10 mg/kg of nivolumab i.p. for 28 days, the results demonstrated a dose-dependent relationship in mortality.^[4] In vivo test it suggested that anti-PD-1 treatment with Nivolumab (10 mg/kg, i.v.) diminishes morphine antinociception in wild-type mice.^[5]

References:
[1].Wang C, et al. In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates. Cancer Immunol Res. 2014 Sep;2(9):846-56.
[2].Ramos-Levi AM, et al. Nivolumab-induced thyroid dysfunction in patients with lung cancer. Endocrinol Diabetes Nutr (Engl Ed). 2019 Jan;66(1):26-34. English, Spanish.
[3].Capasso A, et al. Characterization of immune responses to anti-PD-1 mono and combination immunotherapy in hematopoietic humanized mice implanted with tumor xenografts. J Immunother Cancer. 2019 Feb 8;7(1):37.
[4].Weaver JL, et al. BLT-Immune Humanized Mice as a Model for Nivolumab-Induced Immune-Mediated Adverse Events: Comparison of the NOG and NOG-EXL Strains. Toxicol Sci. 2019 May 1;169(1):194-208.
[5].Wang Z, et al. Anti-PD-1 treatment impairs opioid antinociception in rodents and nonhuman primates. Sci Transl Med. 2020 Feb 19;12(531):eaaw6471.

Nivolumab 是一种抗癌单克隆抗体,是一种程序性死亡受体-1 阻断人 IgG4 抗体,用于治疗晚期（转移性）非小细胞肺癌。^[1]

体外药效试验表明,Nivolumab 与表达 PD-1 的 CHO 细胞结合,EC50 为 1.66 nmol/L,与活化 T 细胞上的 PD-1 结合,EC50 为 0.64 nmol/L。同时,Nivolumab可以抑制PD-1与其配体PD-L1和PD-L2的相互作用,IC50值分别为2.52和2.59 nmol/L。在体外,浓度为 1.5 ng/mL 的 nivolumab 可在存在 T 细胞受体刺激物的情况下增强 T 细胞反应性。^[1]

体内研究表明,小鼠接受 50 mg/kg nivolumab 治疗后,T3、T4 或 TSH 水平没有变化。在食蟹猴中给予 10 mg/kg 和 50 mg/kg nivolumab 后,结果显示 50 mg/kg 组中的 CD8+ 效应记忆 T 细胞明显多于 10 mg/kg 组和未治疗组以及 NaÏve T - 50 mg/kg 组的细胞群减少。^[1] 在体内,Nivolumab 治疗（30 mg/kg,i.p.）抑制 hu 中 TNBC MDA-MB-231 细胞系的生长-CB-BRGS 小鼠。^[3] BLT-NOG-EXL 小鼠用盐水、2.5、5 或 10 mg/kg 的 nivolumab i.p. 处理。持续 28 天,结果表明死亡率存在剂量依赖性关系。^[4] 体内试验表明,使用 Nivolumab（10 mg/kg,静脉注射）进行抗 PD-1 治疗会降低吗啡镇痛作用在野生型小鼠中。^[5]