Cosibelimab

PD-L1 may be expressed on tumor cells and tumor-infiltrating immune cells and can contribute to the inhibition of the anti-tumor immune response in the tumor microenvironment. Binding of PD-L1 to the PD-1 and B7.1 receptors found on T cells and antigen presenting cells suppresses cytotoxic T-cell activity, T-cell proliferation, and cytokine production. Cosibelimab binds PD-L1 and blocks the interaction between PD-L1 and its receptors PD-1 and B7.1. This interaction releases the inhibitory effects of PD-L1 on the anti-tumor immune response. Cosibelimab has also been shown to induce antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro.

Cosibelimab exposure-response relationships and the time course of pharmacodynamic responses have not been fully characterized.

Cosibelimab pharmacokinetic parameters are presented as geometric mean (coefficient of variation) unless otherwise stated. At the recommended dosage, the cosibelimab steady-state maximum plasma concentration (C_max) is 492 µg/mL (24.3%) and area under curve (AUC) is 112000 µg*h/mL (39.6%). Cosibelimab C_max and AUC increased proportionally over the dose range of 800 mg to 1,200 mg following single dosing. Steady-state concentrations of cosibelimab are reached by 12 weeks.

At 1,200 mg every 3 weeks, the mean cosibelimab concentrations (coefficient of variation, CV%) at steady-state ranged between a minimum concentration of 120 µg/L (46.3%) and a maximum concentration of 453 µg/L (22.2%). Steady-state exposure was achieved after 84 days of treatment.

In patients with CSCC, cosibelimab steady-state exposure at 1,200 mg every 3 weeks (the recommended dosage) was comparable to the exposure at 800 mg every 2 weeks.

Distribution

Cosibelimab steady state volume of distribution is approximately 5.67 L (19.7%).

Elimination

Cosibelimab steady state elimination half-life is 17.8 days (43.8%), and the clearance is 0.256 L/day (41%).

Specific Populations

No clinically significant differences in the pharmacokinetics of cosibelimab were observed based on age (24.8 to 95.0 years), sex, race (79.6% White, 10.7% Asian, 0.5% African American, and 1.5% other), ethnicity (76.9% Not Hispanic/Latino and 4.9% Hispanic/Latino), ADA and nAb status, albumin (22 to 51 g/L), tumor type, tumor diameter, and renal impairment (CLcr 15 mL/min and higher). The effect of severe hepatic impairment (bilirubin >3 × ULN and any AST) on cosibelimab pharmacokinetics is unknown.

In animal models, inhibition of PD-L1/PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. Mycobacterium tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-L1 and PD-1 knockout mice and mice receiving PD-L1–blocking antibody have also shown decreased survival following infection with lymphocytic choriomeningitis virus.