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US 11,959,925 B2Granted
Method of determining toxicity of an immunomodulatory drug for use in humans
AssigneeThe Jackson Laboratory
InventorsJames Keck, Chunting Ye
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Abstract
Humanized mouse models and methods are provided for determining whether administration of an immunomodulatory drug likely elicits a severe cytokine release syndrome in a human. Humanized mouse models and methods are also provided for determining the immunotoxicity in a human of a drug candidate or of drug combinations.
Claims15
A method for assessing immune toxicity of an immunomodulatory agent on a human immune system, the method comprising:
- (a) subjecting an immunodeficient mouse to myeloablation;
- (b) administering 1.5×107-3.0×107 human peripheral blood mononuclear cells (PBMCs) to the immunodeficient mouse;
- (c) administering an immunomodulatory agent to the immunodeficient mouse fewer than 8 days after the administering of the human PBMCs;
- (d) measuring blood concentration of a human cytokine selected from interferon-gamma (IFN-γ), interleukin (IL)-10, IL-6, IL-2, IL-4, and tumor necrosis factor alpha (TNFα) in a sample from the immunodeficient mouse, within 24 hours of the administering of the immunomodulatory agent,
- (e) determining severity of cytokine release induced by the immunomodulatory agent based on a comparison of the blood concentration of the human cytokine to a threshold value;
- and
- (f) assessing immune toxicity of the immunomodulatory agent on the human immune system based on the severity of cytokine release.
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