Cetrelimab

Cetrelimab (JNJ 63723283; JNJ 3283) is a humanized IgG4κ mAb targeting PD-1. Cetrelimab binds PD-1 (Kd=1.72 nM, HEK293) to block the interaction of PD-1 with PD-L1 and PD-L2 (IC50s=111.7 ng/mL and 138.6 ng/mL, respectively). Cetrelimab stimulates peripheral T cells, increases IFN-γ, IL-2, TNF-α level and inhibits tumor growth in vivo[1].

Research Areas >> Cancer

Signaling Pathways >> Immunology/Inflammation >> Interleukin Related

Signaling Pathways >> Immunology/Inflammation >> PD-1/PD-L1

PD-1/PD-L1, PD-1/PD-L2, IFN-γ, IL-2, and TNF-α[1]

Cetrelimab (0.01-30 nM; 5 d) binds to endogenous PD-1 on activated CD4+ and CD8+ T cells with EC50s of 0.16-0.22 µg/mL and 0.17-0.22 µg/mL, respectively[1]. Cetrelimab (0.01-30 μg/mL; 24 h) reverse PD-1-mediated suppression of TCR signaling in Jurkat-PD-1 NFAT reporter cells with CHO-K1 expressing PD-L1[1]. Cetrelimab (0.001-100 nM; 6 d) increases IFN-γ, IL-2, and TNF-α with EC50s of 0.08 ng/mL, 0.07 ng/mL, and 0.02 ng/mL, respectively[1]. Cetrelimab binds to PD-1 in cynomolgus with a Kd value of 0.9 nM[1].

Cetrelimab (10 mg/kg; i.p.; single dose) has antitumor efficacy, and decreases tumor volume in PD-1 knock-in (hPD-1KI) mice with MC38 tumor[1]. Cetrelimab (10 mg/kg; i.p.; once every 5 days for 30 d) results significant increases in peripheral blood CD8+ T cells in patient-derived xenograft (PDX) lung model in mice[1]. Cetrelimab (10-100 mg/kg; i.v.; once weekly for 5 weeks) has well tolerance in cynomolgus model[1]. Cetrelimab (0.1-10 mg/kg; i.v.; single dose, monitored for 57 d) shows an nonlinear pharmacokinetics (PK) in cynomolgus, possibly attributable to target-mediated drug deposition (TMDD)[1]. Animal Model: hPD-1KI model with mouse PD-1 ECD replaced by the human PD-1 ECD[1] Dosage: 10 mg/kg Administration: Intraperitoneal injection; single dose at day 7 after tumor implantation Result: hPD-1KI mice develop normally and have no immune abnormalities. Significantly lowered tumor volume at Day 21. Animal Model: Patient-derived xenograft (PDX) LG1306 lung model in mice[1] Dosage: 10 mg/kg Administration: Intraperitoneal injection; every 5 days for 6 cycles Result: Significantly reduced patient-derived tumor volume by 32%. Animal Model: Good Laboratory Practice (GLP) toxicity study in cynomolgus[1] Dosage: 0, 10, 30, or 100 mg/kg Administration: Intravenous injection; once weekly for 5 weeks Result: Showed well tolerance in cynomolgus.

[1]. DeAngelis N, et al. Discovery and pharmacological characterization of cetrelimab (JNJ-63723283), an anti-programmed cell death protein-1 (PD-1) antibody, in human cancer models. Cancer Chemother Pharmacol. 2022 Apr;89(4):515-527.