Nivolumab

Nivolumab, also named Opdivo, is a monoclonal antibody used to treat advanced non-small cell lung cancer (NSCLC) by inhibiting a cellular pathway called programmed death-1(PD-1).

Nivolumab binds to PD-1 which is on the surface of T cells, thereby blocking the immunosuppressive signaling pathway triggered by PD-1/PD-2 and restoring the antitumor function of T cells.

Nivolumab binds PD-1 with high specificity [1], and nivolumab can effectively inhibit PD-1 interact with its ligands (PD-L1 and PD-L2, with IC50 values of 2.52 and 2.59 nmol/L, respectively). In CHO cells, using FACS to evaluate ligand binding to PD-1, there was no obvious difference between nivolumab-mediated inhibition of PD-1 binding to PD-L1 (IC50 value of 1.04 nmol/L) and PD-L2 (IC50 value of 0.97 nmol/L). Moreover, when lack of antigen or T-cell receptor stimulus, nivolumab had no stimulatory effect and couldn’t cause nonspecific lymphocyte activation [2].  

In cynomolgus monkey model with 10 and 50 mg/kg Nivolumab (i.v.), serum nivolumab seems to be no obvious change and no substantial sex differences. Treated with 50 mg/kg nivolumab, T4 and TSH levels were unchanged but T3 had a reversible 28% decrease in females, and in males there were no changes in T3, T4 or TSH levels [2]. Nivolumab might lack toxicity in monkeys, but the toxicity had been observed in human clinical trials, nivolumab had had a favorable safety profile in a phase I trial [1]. A problem worth studying is that in PD-1-deficient mice observed pneumonitis which bred onto the MRL genetic background rather than other genetic backgrounds [2].

References:

[1] Sundar R, Cho B C, Brahmer J R, et al. Nivolumab in NSCLC: latest evidence and clinical potential [J]. Therapeutic Advances in Medical Oncology, 2015, 7(2):85-96.

[2] Wang C, Thudium K B, Han M, et al. In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates [J]. Cancer Immunol Res, 2014, 2(9):846-856.