Target Engagement Models
Along with our range of immunology disease-specific models, we offer validated PD models to confirm target engagement and mechanism of action in support of a client’s drug discovery research. In addition to providing this valuable information on target engagement and mode of action, our immunologists can also run predictive immunotoxicology models to help mitigate risk of adverse immune responses, so that the best version of the drug is progressed to the clinic.
Charles River’s Pharmacodynamic Models include:
- Adoptive T cell transfer model (autoimmune setting)
- Adoptive T cell transfer model (immuno-oncology setting)
- Carragenaan Paw Edema Model
- CFA Paw Hyperalgesia
- Concanavalin A Induced Liver Injury
- Delayed-type hypersensitivity (DTH) models (type IV hypersensitivity)
- Graft vs Host Disease (GvHD) model
- IL-17-induced CXCL1 release model
- In vivo immune function studies
- Inflammatory cell recruitment models
- LPS-induced cytokine release models
- NLRP3 inflammasome activation model
- Passive cutaneous anaphylaxis (PCA) model (type I hypersensitivity)
- Poly:IC Intestinal Inflammation
- Thioglycollate Induced Peritonitis
Figure 1: AN IL-17 Mouse Model of CXCL1 Production: Graph showing IL17 antibody blocks serum CXCL1 production in IL17 challenged mice.
Frequently Asked Questions (FAQs) for Pharmacodynamic Models:
Why should I use pharmacodynamic models?
Pharmacodynamic – target engagement – models allow the role of the therapeutic to be examined outside of the disease setting. This can add value to a drug discovery program by providing information as early as possible, across multiple assay types, on whether target engagement is occurring, and whether a therapeutic is affecting its targeted or desired cell type in the expected manner.
Can I use a pharmacodynamic model for screening?
If wider screening and profiling of gene expression is required, nano-string analysis can be performed to establish how a therapeutic is influencing gene expression and how subsequent pathways are affected.
What is the difference between autoimmune PD models and immuno-oncology PD models?
Pharmacodynamic models can be utilized in two different ways. In an immuno-oncology setting where a therapeutic might be targeting a tumor, the immune system’s response is often suboptimal (e.g., T cells are often exhausted, so in this model T cells would be sub-optimally activated). Charles River uses immuno-oncology PD models such as the Adoptive T cell transfer model to evaluate whether a client’s therapeutic is enhancing the immune response and to see whether the effector function of T cells is as expected. This allows us to predict efficacy in syngeneic models by analyzing the efficacy of the test compounds on markers of T cell activation and effector function.
Alternatively, PD models can be used in an autoimmune setting with a very strong immune response, as T cells in this setting would be improperly activated. These PD models allow evaluation of therapeutics to down-regulate this immune response.