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The JAX CRS assay has a highly flexible design applicable to a wide variety of human specific immune modulatory therapies. The assay can test both immunostimulatory and immunosuppressive therapies.
You can design your assay to compare several lead candidates side-by-side using a single well characterized human PBMC donor looking at modulation of cytokine release as the primary readout in PBMC humanized mice. In addition, human cells targeted by the candidates can be included to obtain both target cell efficacy and cytokine release mediated safety and toxicity evaluation simultaneously in a single assay. The assay can also be scaled up to examine these responses across multiple human PBMC donors to help determine the diversity of human response to the therapy.
Here are some frequently asked questions about this novel assay.
How does the JAX CRS Evaluation study differ from an in vitro cytokine release assay?
The JAX CRS Evaluation Study uses holistic physiological conditions, specifically human immune cells and mouse circulation/vasculature, which offers in vivo relevance. In vitro assays only measure immune cell responses in isolation. Epithelial cells play a large role in the systemic immune response through production of both cytokines and chemokines of their own. Prolonged and highly elevated cytokine production can lead to liver and other organ damage that cannot be assessed in vitro.
In addition, bispecific antibodies require engagement of both immune and therapeutic targets to stimulate a cytokine release response. Current in vitro assays are not designed to include the target cell population.
What cytokines have been measured so far?
JAX scientists have measured numerous cytokines and chemokines in this process, including IL2, IL4, IL6, IL10, IFN-γ, TNF-a, GM-CSF, MIP-1, MCP-1 and Granzyme B.
How do you know the effect being observed is not GvHD?
The JAX CRS Evaluation Study is designed to occur prior to the onset of GvHD. When a longer study is required, the NSG™ Class I/II MHC Double-knockout is recommended as this model is observed to have a delayed onset of acute GvHD.
What specific compounds and types of compounds have been tested so far?
JAX has tested several different therapeutic approaches including bispecific antibodies and checkpoint inhibitors. Specific compounds include: CD19XCD3 bispecific, TGN1412 analogue, antithymocyte globilun (ATG) polyclonal Ab, anti-CD3 mAb (OKT3) and anti-CD28 mAb, Keytruda (anti-PD-1) mAb, and rituximab (anti-CD20) mAb.
Can I get the same PBMC donor for subsequent assays?
Yes, JAX can set aside samples from particular donor lots for your experimental needs.
How do you decide on the model to use, among the NSG, SGM3, or the Class I/II MHC double knock out?
In choosing the most optimal model for any study, there are many aspects to consider including the type of therapy being studied, the mechanism of action of that therapy, and whether timing is an issue to be considered.
What controls are used in the assay?
The balance of efficacy and toxicity when modulating the immune system is an important consideration. JAX has pre-characterized different PBMC donors for cytokine release in response to OKT3 and anti-CD28 mAb. These antibodies are included in each experiment as positive control.
The JAX CRS Evaluation Study is a novel assay designed to provide necessary characterization data on a potential therapy. This assay utilizes human immune cells and mouse vasculature, which results in increased translational relevance. In comparison to in vitro assays that measure immune cell responses in isolation, this assay can test a wide range of therapeutics using human PBMCs in a biologically relevant In Vivo environment. To learn more about this novel assay, visit the CRS Assay page.