Shaping the Future of the Immunotherapeutic Development Pipeline

February 12, 2021

Determining the pharmacodynamic (PD) and pharmacokinetic (PK) properties of human antibodies using traditional methods has been historically difficult and time consuming. This is especially true when it comes to testing immunomodulatory antibody therapeutics in animal models given the increased potency of this kind of therapeutic when compared with small molecule therapeutics. However, when it comes to using in vivo animal models to identify the antibody variants with ideal profiles around PD/PK, safety, and efficacy, The Jackson Laboratory (JAX) has been leading the charge with creating and validating solutions.

Beginning in the early stages of the therapeutic development pipeline, JAX’s development of a transgenic strain lacking murine FcRn gives researchers the ability to do something that can’t be done with wild type mice – accurately predict a human antibody half-life. Through these studies, therapeutic developers are able to make informed dosing decisions prior to entering clinical trials.

When it comes to testing preclinical immunotherapeutic efficacy, there is arguably no better platform than the humanized NSG portfolio. These mice have humanized immune systems and can be co-engrafted with a human tumor allowing researchers to analyze the effectiveness of a human-specific immunotherapy. However, when the immune system is activated to combat tumors, adverse and sometimes fatal effects can occur, one example being cytokine release syndrome.

Predicting Cytokine Release Syndrome (CRS) is crucial when examining the toxicity of an immunotherapeutic, but it wasn’t until recently when JAX’s Dr. Jim Keck developed a platform of immunodeficient models engrafted human PBMCs that made the predictability of CRS possible. Using a variety of donors, these studies offer not just a clinical level of donor-to-donor variability, but also have shown greater sensitivity and specificity than alternative in vitro options. For the first time, researchers can examine the safety and efficacy of their immunotherapeutic in one quick – less than two weeks – study.