Development of novel NCG-hIL15 and hIL-2 mouse models for preclinical assessment of human NK cell function

Natural Killer (NK) cells are critical mediators of antitumor immunity, exerting direct cytotoxicity and secreting immunoregulatory cytokines. They play a particularly important role in antibody-dependent cellular cytotoxicity (ADCC), a key mechanism harnessed by many therapeutic antibodies. To study these mechanisms, humanized mouse models have been employed, however; conventional human immune cell transplanted immunodeficient mouse models poorly support NK cell engraftment, limiting their translational utility. To address this gap, we developed two human cytokine-expressing mouse models on the NCG triple-immunodeficient mouse model that lacks functional T cells, B cells, and NK cells. TheNCG-hIL2 and NCG-hIL15, were engineered to constitutively express human IL-2 and human IL-15, respectively. These models were assessed for their ability to sustain human NK cell development and function after reconstitution with human hematopoietic stem cells (HSCs). The NCG-hIL2 model showed enhanced human NK cell reconstitution, underscoring the essential role of IL-2 in NK cell maturation and survival. In contrast, the NCG-hIL15 model supported robust co-engraftment of human T and NK cells, making it particularly suitable for evaluating combination T and NK cell-directed immunotherapies. Both models were evaluated in preclinical immunotherapy studies. The NCG-hIL2 model proved highly effective for assessing ADCC-mediated antibodies such as Trastuzumab, Margetuximab, Rituximab, and Blinatumomab. Together, the NCG-hIL2 and NCG-hIL15 models provide powerful and complementary platforms for studying human NK cell biology, cytokine-driven immunity, and anticancer immunotherapy.