A precisely humanized FCRN transgenic mouse for preclinical pharmacokinetics studies.

Monoclonal antibodies (mAbs) are one of the fastest-growing classes of drugs and have been approved to treat several diseases, including cancers and autoimmune disorders. Preclinical pharmacokinetics studies are performed to determine the therapeutically meaningful dosages and efficacy of candidate drugs. These studies are typically performed in non-human primates; however, using primates is costly and raises ethical considerations. As a result, rodent models that better mimic human-like pharmacokinetics have been generated and remain an area of active investigation. Pharmacokinetic characteristics of a candidate drug, such as half-life, are partly controlled by antibody binding to the human neonatal receptor hFCRN. Due to the abnormally high binding of human antibodies to mouse FCRN, traditional laboratory rodents do not accurately model the pharmacokinetics of human mAbs. In response, humanized rodents expressing hFCRN have been generated. However, these models generally use large inserts randomly integrated into the mouse genome. Here, we report the production and characterization of a CRISPR/Cas9-mediated hFCRN transgenic mouse termed SYNB-hFCRN. Using CRISPR/Cas9-assisted gene targeting, we prepared a strain with a simultaneous knockout of mFcrn and insertion of a hFCRN mini-gene under the control of the endogenous mouse promoter. These mice are healthy and express hFCRN in the appropriate tissues and immune cell subtypes. Pharmacokinetic evaluation of human IgG and adalimumab (Humira®) demonstrate hFCRN-mediated protection. These newly generated SYNB-hFCRN mice provide another valuable animal model for use in preclinical pharmacokinetics studies during early drug development.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kurt Jarnagin reports financial support was provided by Bristol Myers Squibb Co. David R. Webb reports a relationship with Synbal, Inc. that includes: employment and equity or stocks. Kurt Jarnagin reports a relationship with Synbal, Inc. that includes: employment and equity or stocks. Shannon Xu reports a relationship with Synbal, Inc. that includes: employment and equity or stocks. Don van Fossan reports a relationship with Synbal Inc. that includes: employment and equity or stocks. Kristen Read reports a relationship with Synbal Inc. that includes: employment and equity or stocks. Dale O. Cowley reports a relationship with Transviragen, Inc. that includes: employment and equity or stocks. Oscar Alvarez reports a relationship with Synbal, Inc. that includes: employment and equity or stocks. Christopher M. Conner reports a relationship with Synbal, Inc. that includes: employment and equity or stocks.
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