Immunodeficient mouse models are important tools across a range of biomedical research fields, including oncology, immunology, infectious disease, stem cell biology, and more. Their availability has advanced mechanistic knowledge of diseases and enabled progress in drug discovery and development. The most recently available model, B-NDG (NOD.CB17-Prkdcscid IL2rgtm1/BcgenHsd) – developed by Biocytogen, and now licensed by Inotiv– has a uniquely high degree of immunodeficiency. Below, we discuss some benefits of the B-NDG model and describe the recent research made possible by its availability.
The features and benefits of the B-NDG model
B-NDG is an albino, single-gene knockout mouse that was generated by deleting the common gamma chain (IL2rg) gene from NOD-scid mice with severe immunodeficiency using CRISPR-Cas9 technology (see the figure below for an illustration of how the B-NDG mouse was generated). The model lacks mature T and B cells or functional natural killer cells and displays a deficiency in cytokine signaling. Therefore, the B-NDG mouse is one of the most immunodeficient models available, and is suitable for engraftment with human hematopoietic stem cells, peripheral blood mononuclear cells, and human tumor cells or tissues.
In addition, minimal rejection of human-derived cells makes the B-NDG mouse an ideal host for transplantation of PDXs (Patient-Derived Xenografts). The model retains the heterogeneous characteristics of tumor tissues, and therefore accurately recapitulates patient characteristics.
Inotiv’s Associate Director of Strategic Marketing, Travis Rothrock, tells us why he is excited about the new availability of this model for research: “The B-NDG can be used to study standard therapies, or to understand how a PDX would grow, for example. But, the real benefit of this model is the option to humanize it, engraft a cell line or a PDX, allow it to grow, and then inject a monoclonal antibody or checkpoint inhibitor to see if they can cause the tumor to shrink over time.”
Characterizing the B-NDG model
Inotiv is working with collaborators to fully characterize the B-NDG mouse and compare it with other immunodeficient models. In a recent study, tumor growth was found to be accelerated in B-NDG mice compared to a group of NSGTM mice, which are also highly immunodeficient (illustrated below). The model’s performance in these studies indicate several benefits, described below.
The B-NDG model in action
The features of the model described above increase the likelihood of successful translation from preclinical laboratory work to human efficacy studies. The model has already been used in research to generate CDX and PDX tumor models and human immune system reconstituted models. It has also been used in in vivo efficacy studies of agents that target immune checkpoints, drug-sensitivity testing, and for optimizing treatments with CAR-modified T cells. Just some of this work is described in more detail below:
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PDX colorectal model
- To evaluate the in vivo efficacy of silvestrol, alone or in combination with oxaliplatin, against colorectal tumors, Chen et al (2019) developed colorectal cancer PDX models by xenografting patient tumor samples into the flanks of B-NDG mice. The study concluded that silvestrol inhibited tumor growth and had a synergistic effect with oxaliplatin to induce apoptosis in PDXs.
- To evaluate the in vivo efficacy of silvestrol, alone or in combination with oxaliplatin, against colorectal tumors, Chen et al (2019) developed colorectal cancer PDX models by xenografting patient tumor samples into the flanks of B-NDG mice. The study concluded that silvestrol inhibited tumor growth and had a synergistic effect with oxaliplatin to induce apoptosis in PDXs.
- A novel strategy for developing memory CAR-T cells
- Treatment with CAR-modified T cells targeting CD19 has been successful in patients with relapsed/refractory B cell malignancies, but remission occurs frequently. To evaluate whether the activity of CAR-T cells could be maintained, Chen et al., (2020) used B-NDG mice to determine how the cells could be optimally restimulated. This led to improved survival and delayed tumor occurrence.
In summary, the B-NDG immunodeficient mouse offers many benefits compared to other models. The model has been used to successfully establish PDX and CDX models and is well suited for studies that require humanization. In addition, ongoing work to further characterize the model, including the very low levels of PDX rejection, is likely to establish B-NDG mice as a promising research tool capable of successfully recapitulating human diseases.
A more comprehensive list of studies utilizing the B-NDG model, along with a more detailed characterization of the animals, can be found here. If you are interested in using this model in your research, our specialists are available to discuss your needs. In addition, if you’d like to collaborate with us in characterizing the B-NDG model, we’d be keen to hear from you.
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