Accelerate drug development with immune cell humanized mice

Model systems are critical to preclinical drug development processes, but the translation of mouse model research findings into potential human clinical outcomes has its limitations. This is especially challenging when studying human-specific viruses such as HIV, or the complex interactions between human immune systems and tumors. While some researchers look to non-human primate models instead, which can bring additional supply, cost, and time considerations^1,2, the Jackson Laboratory (JAX) has developed a cutting-edge solution – the humanized mouse.

We spoke to Dr. Sierra Kent, Associate Director of the Core Portfolio at JAX Mice, Clinical and Research Services (JMCRS) to learn how JAX’s platform increases the likelihood of selecting the right candidates to move forward in the drug development process.

Establishing a functional human immune system within the mouse

Prior to designing human studies, drug developers often need to test therapeutics for their interactions with the human immune system and human cancer cells. Many therapeutics specifically act upon human targets, or depend on reactions unique to human cells, meaning that often mouse or non-human primate models are simply not appropriate.

Humanized mice are a powerful tool to solve this problem. Created by engrafting genetically optimized mice with human cells, this establishes a functional human immune system within the mouse. As Kent explains, “unlike non-human primate pre-clinical models, humanized mice have the exact human cells, proteins, and other therapeutic targets that only exist in humans. These models are human immune system avatars representing the human population which can be used to test therapeutics that will subsequently be used in clinical trials.”

“The performance of a therapeutic in a humanized mouse is significantly more similar to the potential performance in a human than compared to a non-humanized mouse,” Kent adds. “In some cases, humanized mouse data is sufficient to avoid the use of non-human primates in preclinical drug development, decreasing both costs and timeline.”

Kent also emphasizes that, “these models support JAX’s goal of aligning with the 3Rs of animal research, including the refinement and subsequent reduction of animals used in research.” Humanized mice reduce the number of animals needed by providing a more accurate and human-relevant model, which can decrease the necessity for additional animal testing. By yielding more reliable results in preclinical studies, humanized mice help streamline research processes and minimize the overall use of animals in drug development, aligning with the FDA Modernization Act 2.0.

Adopting the gold standard

Selecting the right strain of mouse for your project is critical to optimizing results and enabling drug development decisions to be based on data that best translates into clinical outcomes.

“The two most basic and often replicated mouse strains used for creating humanized mice are the JAX NSG^® and NRG mice,” says Kent. “NSG was the first strain used to create human immune system mice and has been adopted globally as the gold standard, evidenced by the highest number of publications for any humanized mouse strain.” He asserts that, “JAX is a leader in producing variants of the NSG strain that enables the most complex testing scenarios because they produce the most human-like immune systems following cell engraftment.”

Both NSG and NRG mice are extremely immunodeficient and able to support human immune cell engraftment. “But NRG mice have the additional advantages of being more tolerant to irradiation and genotoxic agents that are often used as oncology combination therapies,” says Kent. “More similar to human tolerance than NSG or related strains.”

These strain variants can be engrafted with human peripheral blood mononuclear cells (PBMCs) or CD34+ human hematopoietic stem cells (HSC). Each model offers different advantages for testing different types of therapeutics.

“PBMCs are a mature cell population that can be collected from any non-fetal human and engrafted directly into a mouse to create a transiently humanized mouse with the exact blood composition of the donor,” explains Kent. Conversely, “HSCs harvested from umbilical cords that may otherwise be discarded are engrafted into mice to create humanized mice that develop a human immune system from human stem cells. This process is only possible with a complex genetically optimized mouse and enables long preclinical studies similar to those performed in human subjects,” he elaborates.

Reflective of the diverse human population

Another consideration during study design is cohort variation, which occurs when humanized mice have been created with cells from different donors. Kent explains, “JAX creates sufficiently large cohorts of humanized mice from single donors to avoid this variability.” Adding that, “by using multiple single donor cohorts researchers can also investigate the effects of their therapeutics across a diverse group of human samples, reflective of the diverse human population.”

Support from model selection to running studies

“JAX is the leader in the development and characterization of humanized mice,” asserts Kent. “Because JAX is continuously running preclinical studies with humanized mice, we’ve developed a deep understanding of how molecules and tumor cells will behave in each humanized mouse strain.”

This knowledge is shared with clients interested in conducting preclinical studies with JAX, Kent enthuses. “This improves the speed and quality of study design, significantly reducing the need for optimization and the likelihood of inconclusive or failed studies.”

For more information about JAX’s offerings, watch the webinar on preclinical in vivo services and discover how humanized mice are reshaping the biologic drug development pipeline. For support with model selection, download JAX’s whitepaper on using humanized mice for infectious disease research, and compare humanized mouse models for immuno-oncology.

References

1. Harding J.D., Nonhuman Primates and Translational Research: Progress, Opportunities, and Challenges. ILAR Journal, 2017;58(2):141–150. doi:10.1093/ilar/ilx033
2. Nakamura T., Fujiwara K., Saitou M., Tsukiyama T. Non-human primates as a model for human development. Stem Cell Reports. 2021;16(5):1093-1103. doi: 10.1016/j.stemcr.2021.03.021