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
| Autor: | Yoshika Iwata, Junko Taketo, Masayuki Mishima, Akihisa Kaneko, Toshiko Hara, Asako Harada, Takahiro Ishiguro, Masanori Sasaki, Atsushi Narita, Sho Akai |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine CD3 Complex medicine.drug_class T-Lymphocytes medicine.medical_treatment T cell Pharmacology Toxicology Drug Administration Schedule Interferon-gamma 03 medical and health sciences Antineoplastic Agents Immunological 0302 clinical medicine Neoplasms Antibodies Bispecific Animals Medicine Dosing biology Interleukin-6 Tumor Necrosis Factor-alpha business.industry medicine.disease Macaca fascicularis Regimen Cytokine release syndrome 030104 developmental biology Cytokine medicine.anatomical_structure 030220 oncology & carcinogenesis biology.protein Interleukin-2 Corticosteroid Premedication Immunotherapy Antibody Cytokine Release Syndrome business |
| Zdroj: | Toxicology and Applied Pharmacology. 379:114657 |
| ISSN: | 0041-008X |
| DOI: | 10.1016/j.taap.2019.114657 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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