A HUMANIZED FCRN TRANSGENIC MOUSE FOR PRECLINICAL PHARMACOKINETICS STUDIES

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ABSTRACT 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 h FCRN 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 h FCRN transgenic mouse termed SYNB-h FCRN . Using CRISPR/Cas9-assisted gene targeting, we prepared a strain with a simultaneous knockout of m Fcrn and insertion of a h FCRN 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 h FCRN- mediated protection. These newly generated SYNB-h FCRN mice provide another valuable animal model for use in preclinical pharmacokinetics studies during early drug development. Materials availability Cryopreserved germline cells from the strains are available from the MMRRC. Dr. Jarnagin will provide sequencing and other evidence supporting strain identity and the plasmids used for constructions.

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