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.
Toxicol Appl Pharmacol
; 379: 114657, 2019 09 15.
Article
en En
| MEDLINE
| ID: mdl-31326447
ABSTRACT
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⯵g/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⯵g/kg. Peak cytokine levels following the single and ascending doses were 60,095â¯pg/mL and 1221â¯pg/mL for IL-6; 353â¯pg/mL and 14â¯pg/mL for TNF-α; 123â¯pg/mL and 16â¯pg/mL for IFN-γ; and 2219â¯pg/mL and 42â¯pg/mL for IL-2. The tolerance acquired with daily ascending doses up to 1000⯵g/kg remained in effect for the following weekly doses of 1000⯵g/kg.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Linfocitos T
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Anticuerpos Biespecíficos
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Antineoplásicos Inmunológicos
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Síndrome de Liberación de Citoquinas
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Inmunoterapia
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Neoplasias
Límite:
Animals
Idioma:
En
Revista:
Toxicol Appl Pharmacol
Año:
2019
Tipo del documento:
Article
País de afiliación:
Japón