APR January/February 2022 - 20

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FORMULATION AND DEVELOPMENT
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Improving Preclinical
Drug Safety by
Evaluating Cytokine
Release Syndrome in
Humanized Mice
James Keck, PhD
Senior Director, Innovation and Product Development
The Jackson Laboratory
The human immune system is a powerful, intricate defense system that
is effective against a wide range of microorganisms and other invading
contaminants. However, one's own immune system can pose a serious
threat when it responds incorrectly or overreacts to stimuli such as an
infectious disease or therapeutic drug. Well-known adverse immune
responses include severe allergic reactions, rheumatoid arthritis, and
type 1 diabetes. Across the fields of drug development, infectious
disease research, and clinical practice, many experts are concerned
with a less-familiar phenomenon: cytokine release syndrome (CRS).
White blood cells can become overactivated, rapidly releasing
cytokine signaling proteins that then activate more white blood cells.
This escalating cycle can cause symptoms ranging from mild fever and
inflammation to lethal organ failure.
In 1999, 17-year-old clinical trial participant Jesse Gelsinger tragically
died of a cytokine storm after receiving a gene therapy injection;
this high-profile case stalled gene therapy research for many years.
In 2006, six healthy clinical trial participants developed CRS that led
to organ failure shortly after receiving a monoclonal antibody drug
called TGN1412. This example left the scientific community especially
rattled because preclinical trials in rats, monkeys, and in vitro human
cells had given no warning of CRS risk for that therapeutic. To prevent
incidents like these and satisfy regulators, pharmaceutical researchers
need preclinical tools that accurately model potential human immune
responses without unnecessarily endangering patients.
The solution: humanized mice. Engrafting human immune systems
into mice yields a versatile preclinical platform for generating
reproducible, translationally-relevant data about the safety and
efficacy of novel therapeutics. With this tool, scientists can evaluate
CRS risk, perform dose ranging studies, and observe downstream
organ effects of immune responses in a diversified population, giving
better predictions of clinical outcomes.
Comparing Humanized
Mice CRS Studies to Other
Preclinical Approaches
Up to 97 percent of immuno-oncology therapeutics fail in clinical trials,
with 50 percent of failures resulting from safety or efficacy problems.1
Current preclinical assays do not present fast, cost-effective methods
for de-risking drug development. To avoid losing precious time and
money, pharmaceutical developers should only move the most
promising candidates beyond lead selection. The more information
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| January/February 2022
APR January/February 2022

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