Daily ascending dosing in cynomolgus monkeys to mitigate cytokine release syndrome induced by ERY22, surrogate for T-cell redirecting bispecific antibody ERY974 for cancer immunotherapy

• Published in: Toxicology and applied pharmacology 2019-09, Vol.379, p.114657, Article 114657
• Main Authors: Iwata, Yoshika, Sasaki, Masanori, Harada, Asako, Taketo, Junko, Hara, Toshiko, Akai, Sho, Ishiguro, Takahiro, Narita, Atsushi, Kaneko, Akihisa, Mishima, Masayuki
• Format: Article
• Language: English
• Subjects: Bispecific Antibody; CD3; Cynomolgus Monkey; Cytokine Release Syndrome (CRS); GPC3
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2019.114657

CD3 bispecific constructs show promising therapeutic potential as anti-tumor antibodies, but it has concurrently been difficult to manage cytokine release syndrome (CRS) in clinical use. Currently, the most effective measure for reducing CRS is considered a combination of intra-patient/animal dose escalation and corticosteroid premedication. To examine how effectively an intra-animal ascending dose regimen without premedication would mitigate CRS, we compared plasma cytokine levels in two groups of cynomolgus monkeys; one group was given a single dose, and the other a three-fold daily ascending dose of a CD3 bispecific construct that targets and cross-reacts with both glypican 3 and CD3 (ERY22). Ascending doses up to 1000 μg/kg of ERY22 dramatically reduced the peak cytokine levels of IL-6, TNF-α, and IFN-γ, IL-2 as well the clinical severity of CRS compared with a single dose of 1000 μg/kg. Peak cytokine levels following the single and ascending doses were 60,095 pg/mL and 1221 pg/mL for IL-6; 353 pg/mL and 14 pg/mL for TNF-α; 123 pg/mL and 16 pg/mL for IFN-γ; and 2219 pg/mL and 42 pg/mL for IL-2. The tolerance acquired with daily ascending doses up to 1000 μg/kg remained in effect for the following weekly doses of 1000 μg/kg. •ERY22 is a surrogate anti-GPC3/CD3 bispecific antibody for cancer immunotherapy.•Single injection with 1000 μg/kg of ERY22 caused severe CRS in cynomolgus monkey.•Daily ascending dose of ERY22 up to 1000 μg/kg dramatically reduced CRS.•The tolerance remained in effect for the following weekly doses of 1000 μg/kg.