However, preclinical in vivo research is often challenged by a lack of translational relevance to the clinic. This limitation is exacerbated by the sometimes limited value of traditional clinical endpoints to correlate to disease progression and drug response.
The integration of immune system biomarkers into preclinical studies is needed to bridge this gap, but the availability and relevance of mouse models and mouse immune biomarkers has lagged behind the development of those same human biomarkers in the clinic.
Given the challenges of testing novel immuno-oncology therapies in mice, researchers at The Jackson Laboratory (JAX) utilize the NOD scid gamma (NSG™) recipient mouse, developed by JAX Professor Lenny Shultz, PhD. These highly immunodeficient mice, NSG™ (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ,) and the NSG™ variant, NSG™-SGM3 (NOD.Cg-Prkdcscid Il2rgtm1Wjl Tg(CMV-IL3, CSF2, KITLG)1Eav/MloySzJ), are highly capable of engrafting human hematopoietic stem cells (hu-HSC) and support the development and function of multiple aspects of human immunity.
The current gold standard for reconstitution of the human immune system, NSG™ mice, provide excellent human T-cell responses and partially impaired human myeloid lineage development. The NSG™-SGM3 variant expresses human hematopoietic growth factors that improve normal human myeloid cell development after hu-HSC transplantation and promotes AML xenograft efficiency.
These mouse models support hematopoietic stem cell engraftment and differentiation and contain nearly all populations of the human immune system. They have been used extensively as an innovative immuno-oncology platform capable of recapitulating the donor-
specific diversity of response observed in clinical trials. Since its debut, the number of peer-reviewed publications highlighting the NSG™ mouse model has grown year over year, with over 150 publications in 2018 alone.
Mice humanized with CD34+ hematopoietic stem cells (HSC™) are in vivo models to study not only immuno-oncology, but can also be used to model infectious diseases, graft rejection, and for screening the efficacy and safety of genetically modified stem cells. The mice are created by first sub-lethally irradiating NSG™ or NSG™-SGM3 mice at 3–4 weeks of age, followed by subsequent tail vein injection of human CD34+ HSCs isolated from cord blood. Human CD34+ cells stably engraft the bone marrow and multi-lineage hematopoiesis occurs.
The CD34+ HSC humanized model has the longest research span, over 12 months, capable of T-cell dependent inflammatory responses with no donor cell immune reactivity toward the host. Cell development includes T cells (MHC-restricted CD4 and CD8), monocytes, mast cells, and dendritic cells.
Another humanized model, PBMC humanized mice, is created
with adult peripheral blood mononuclear cells (PBMCs). The hu-PBMC model enables studies such as immuno-oncology and graft-verses-host disease (GvHD). They feature quick engraftment and enable short-to mid-term studies involving the modulation of strong effector and memory T-cell function. The latest model from JAX is the humanized NSG™-IL-15 mouse (NOD.Cg-Prkdcscid Il2rgtm1Wjl Tg(IL15)1Sz/SzJ). This model enables researchers to study in vivo efficacy for compounds targeting NK cells.
With a comprehensive collection of cutting-edge in vivo models, JAX provides access to the most appropriate model to investigate a range of diseases, in addition to executing preclinical efficacy studies- including hundreds of studies in these humanized mouse models. JAX efficacy studies include a comparison to clinically-approved immunosuppressive drugs, midpoint and terminal blood samples, survival curves, and detailed study reports. Other study options include FACS analysis of collected blood samples, tissue collection, additional treatment arms, and alternative benchmarking agents.
When considering the in vivo models and readouts, it can be helpful to use a mechanistic view, such as T-cell activation/suppression, antigen-presenting cell (APC) activation and antigen presentation, cytokine signaling, and lymphocyte infiltration. Using a combination of clinical and mechanistic readouts, researchers can gain insight into therapeutic and prophylactic-targeted treatment options.
Understanding and studying the variation among donor-to-donor or patient-to-patient response to immunomodulation drugs remains a significant barrier, in addition to the widespread access and construction of valuable, humanized animal models. To assist scientists in gaining ready access to these humanized models, JAX has developed a humanized mice resource that has produced over 10,000 humanized NSG™ variants each year and can provide study-ready cohorts of inventoried hu-CD34-NSG™ and hu-CD34-NSG™-SGM3 mice, or hu-PBMC NSG™ and hu-PBMC NSG™-SGM3 mice upon request.