B-NDG hIL15 Mice: Where Enhanced Human Immune Reconstitution Fuels NK-Dependent Therapies
Highly immunodeficient mouse models enable human immune system reconstitution, allowing the engraftment of human tissues or cells for research on immune function, therapeutic efficacy, and disease modeling. While these models effectively reconstitute human T cells, the lack of human IL15—an essential cytokine for NK cell maturation—hinders human NK cell reconstitution, limiting research on NK cell biology and the evaluation of NK-dependent immunotherapies (Gergues et al., 2021; Huang et al., 2022; Liu et al., 2023).
To address this challenge, Biocytogen developed B-NDG hIL15 mice, an IL15-humanized model based on our highly immunodeficient B-NDG mice. This advanced model expresses human IL15 but not mouse IL15, providing the necessary cytokine support for NK cell development. It significantly improves human NK cell reconstitution, making B-NDG hIL15 mice a powerful tool for studying NK cells and evaluating NK-dependent therapies.
B-NDG hIL15 Mice Enhance Human NK Cell Reconstitution
Upon engrafting human CD34+ hematopoietic stem cells (HSCs), peripheral blood mononuclear cells (PBMCs), or NK cells, B-NDG hIL15 mice showed a significant?increase in both the frequency and absolute number of reconstituted human NK cells compared to B-NDG mice. Other immune cells like T cells, B cells, and myeloid cells also exhibited enhanced reconstitution.
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Human CD34+ HSC-reconstituted model
When human HSCs were engrafted into B-NDG hIL15 mice (huHSC-B-NDG hIL15 mice), the reconstitution of human NK cells was significantly improved in both adult and newborn mice compared with B-NDG mice.
Human CD34+ HSC engraftment in B-NDG hIL15 mice (adult) enhances human NK cell reconstitution
Human CD34+ HSC engraftment in B-NDG hIL15 mice (neonatal) enhances the reconstitution of human NK cells and other immune cells like T cells, B cells, and myeloid cells
NK cells isolated from the spleen of huHSC-B-NDG hIL15 mice possess tumor-killing activity against Jurkat cells
B-NDG hIL15 mice exhibit a high and stable reconstitution rate of human CD34+ HSCs.
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Human PBMC-reconstituted model
Human NK cell-reconstituted model
Applications in Preclinical Oncology Research
We have successfully established various cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models using HSC-, PBMC-, or NK cell-reconstituted B-NDG hIL15 mice, enabling in vivo evaluation of therapeutics in a humanized immune environment. These models have been leveraged to assess antibodies such as anti-human CLDN18.2 and anti-human CD3×HER2 bispecific antibodies, demonstrating their effectiveness in suppressing tumor growth.
In vivo efficacy of anti-human CLDN18.2 antibody in CDX model established with huHSC-B-NDG hIL15 mice
In vivo efficacy of anti-human CD3×HER2 BsAb in PDX model established with huHSC-B-NDG hIL15 mice
In vivo efficacy of anti-human CLDN18.2 antibody in CDX model established with huNK-B-NDG hIL15 mice
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References
Gergues, Marina, et al. “Development of CD19 CAR Engineered Human Placental CD34+-Derived Natural Killer Cells (CAR19-CYNK) As an Allogeneic Cancer Immunotherapy.” Blood 138 (2021): 2779.
Huang, Dehao, et al. “Lateral plate mesoderm cell-based organoid system for NK cell regeneration from human pluripotent stem cells.” Cell Discovery 8.1 (2022): 121.
Liu, Xiaowei, et al. “Immune checkpoint HLA-E: CD94-NKG2A mediates evasion of circulating tumor cells from NK cell surveillance.” Cancer Cell 41.2 (2023): 272-287.
Fehniger, Todd A., and Michael A. Caligiuri. “Interleukin 15: biology and relevance to human disease.”?Blood, The Journal of the American Society of Hematology?97.1 (2001): 14-32.