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« FORMULATION AND DEVELOPMENT
Testing Multiple Modalities in
Humanized Mice
Many substances are capable of triggering CRS, but drugs with a direct
influence on the immune system receive the greatest scrutiny when it
comes to immunotoxicity. It can be particularly difficult to predict how
newer immunomodulatory modalities such as bispecific antibodies and
cell therapies will affect patients after being administered. An in vivo
CRS evaluation study enables scientists and drug developers to map out
potential downstream biological reactions and fine-tune dose planning.
Bispecific Antibodies
Bispecific monoclonal antibodies, also known as bispecifics,
simultaneously bind two unique antigens or two separate epitopes
of the same antigen. While this multifaceted approach expands these
drugs' arsenal of strategies for recruiting the immune system to fight
cancer, it also expands the array of potential off-target effects. As a
result, it can be more difficult to predict how these therapeutics will
affect cytokine levels and other systems.
Testing bispecifics preclinically in humanized mice with multiple PBMC
donors enables scientists to study biodistribution, organ infiltration,
and other things that cannot be observed in vitro, especially not at the
same time. In validation studies, researchers have observed significant
donor-specific variation in cytokine release levels following injection
of bispecific antibody drugs.
Furthermore, these mice can be used for preclinical drug interaction
studies that offer robust predictions of whether each drug
combination will affect cytokine release levels. These studies not only
yield greater amounts of systemic data but also provide more accurate
and translatable results than standard experiments because they are
more likely to capture any effects resulting from features unique to
human immune cells.
CAR-T Cell Therapies
CAR-T cell therapies involve injecting a patient with T cells that have
been modified to express a chimeric antigen receptor (CAR) protein
that primes them to hunt down and attack cancer cells. While these
immunotherapies demonstrate great potential for treating a wide
range of difficult cancers, they also pose a high risk of CRS. The
modified T cells-efficient killing machines-are difficult to control
once they've been introduced into a patient. Studies show that 37-93
percent of lymphoma patients and 77-93 percent of leukemia patients
experience CRS after receiving CAR-T cell therapy, and approximately
50 percent of patients involved in early CAR-T cell therapy clinical
trials have required intensive care management.5
Yet other patients
barely develop a mild fever. Preclinical studies in a diverse humanized
mouse population can help scientists pinpoint factors that make some
patients' negative responses stronger than others. In vivo evaluation
studies allow scientists to observe cascading cytokine release effects
and systemic interactions between modified CAR-T cells and other
tissues, rather than just the cancerous cells' targets. Gaining a better
understanding of CRS and a holistic data set resulting from CAR-T cell
treatment will not only de-risk clinical trials but could also help medical
professionals pinpoint more effective interventions for patients who
do experience this toxicity.
Conclusion
In vivo CRS assays in humanized mice may potentially keep clinical trial
participants safer while helping bring more effective therapies more
quickly to patients in need. Pharmaceutical developers can develop
potentially safer efficacious drugs and save resources that can be
poured into optimizing and delivering the most promising candidates.
This humanized mouse platform also has broader applications for
helping scientists understand human immunity on a deeper level. For
example, future studies could reveal underlying biological factors that
make some people more likely to develop CRS in response to specific
infectious diseases. Researchers may also uncover broader trends
in factors that affect variations in patients' responses to different
treatment categories-such as monoclonal antibodies compared to
cell therapies-when it comes to both safety and efficacy profiles.
Leveraging humanized mouse studies effectively will help the
pharmaceutical and healthcare industries be more informed and
effective going forward.
References
1.
2.
3.
4.
5.
Fogel DB. Factors associated with clinical trials that fail and opportunities for improving the
likelihood of success: A review. Contemp Clin Trials Commun. 2018;11:156-164.
Grimaldi C, Finco D, Fort MM et al. Cytokine release: A workshop proceedings on the stateof-the-science,
current challenges and Future Directions. Cytokine. 2016;85:101-108.
Ye C, Yang H, Cheng M, et al. A rapid, sensitive, and reproducible in vivo PBMC humanized
murine model for determining therapeutic‐related cytokine release syndrome. The FASEB
Journal. 2020;34(9):12963-12975.
Eastwood D, Findlay L, Poole S, et al. Monoclonal antibody TGN1412 trial failure explained
by species differences in CD28 expression on CD4+ effector memory T cells. Br J Pharmacol.
2010;161(3):512-526.
Santomasso B, Bachier C, Westin J, Rezvani K, Shpall EJ. The other side of CAR T-cell
therapy: Cytokine release syndrome, neurologic toxicity, and financial burden. American
Society of Clinical Oncology Educational Book. 2019;(39):433-444.
Author Biography
Dr. Keck is the Senior Director for Innovation and Product
Development at The Jackson Laboratory and a recent
recipient of JAX's Presidential Innovation Fellow Award.
In this role, he is responsible for developing and driving
cutting-edge immuno-oncology and autoimmune platforms and
services to empower preclinical drug developers across the globe, as well
overseeing internal and external collaborations that may lead to new JAX
product offerings.
www.americanpharmaceuticalreview.com |
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APR January/February 2022

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