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In the quest to advance therapeutic development, the creation of transgenic mouse models expressing human proteins has become increasingly prevalent. These models have a unique ability to address gaps in the scientific toolkit and reduce dependence on non-human primates. Recently, mouse models expressing the human neonatal Fc receptor (FcRn) have come to the forefront as critical models for assessing the pharmacokinetics (PK) of antibody-based therapeutics and determination of first-in-human dosing.

FcRn plays a pivotal role in modulating the pharmacokinetics of IgG antibodies, which have a high degree of target specificity. However, mouse and rat FcRn do not bind human IgG with the same affinity as human FcRn and thus should not be used to make clinical predictions. Two models in particular, in which the endogenous mouse gene encoding FcRn (Fcgrt) is deleted, and carrying the “Tg32” or “Tg276” alleles encoding the human FcRn, have now been used to measure and predict the half-life of hundreds of antibodies.

Similarly, albumin, with its capacity for binding diverse ligands, plays a pivotal role in drug binding and distribution and influences drug distribution and metabolism. All current humanized FcRn mouse models either express mouse albumin, which has an exceptionally high affinity for human FcRn causing extreme levels of competition for FcRn protection, or are deficient in mouse albumin and removed this unnaturally high level of competition.

A new FcRn platform mouse model, soon to be released by The Jackson Laboratory, the “Tg32 hAlb”, combines the known translational validity of the Tg32 FcRn model with an allele expressing human albumin at levels that are in the physiologically normal range. The human albumin levels in Tg32 hAlb mice will provide biologically appropriate competition for human FcRn protection for albumin formatted therapeutics being characterized. This new model presents another leap forward in modeling therapeutic PK as the first truly appropriate mouse model for translating PK data for albumin formatted therapeutics. The translational relevance of research findings heavily relies on the similarity between experimental models and human biology.

Conventional mouse models often fall short due to disparities in protein structure and function. However, the introduction of human albumin into mice bridges this gap, enabling researchers to simulate human-specific processes accurately.
This enhanced translational relevance is pivotal in various research domains, including drug development, toxicology studies, and understanding disease pathogenesis. By incorporating human albumin expression in mouse models, researchers gain a more accurate representation of drug metabolism and pharmacokinetics, facilitating the development of safer and more effective therapies. This precision enhances preclinical drug testing, expediting the transition from bench to bedside.

Tg32 hAlb mice are currently being characterized by The Jackson Laboratory’s Preclinical Services team using administered human albumin, human albumin engineered to enhance its protection by FcRn, and albumin-conjugates of these same format combinations to evaluate how they are protected in the presence of endogenous human albumin. In addition to characterizing the PK of albumin formatted therapeutics, Tg32 hAlb mice can also be used to characterize therapeutics engineered to bind to and be carried by human albumin.  As well, therapeutics engineered to target human FcRn function to recycle IgG will be best characterized in this new mouse model as off-target blocking of albumin recycling can be closely monitored.

These models offer a transformative platform for studying human physiology, disease mechanisms, and therapeutic interventions with unparalleled precision. From refining drug development processes to unraveling intricate disease pathways, these models will continue to shape the landscape of modern medicine and pave the way for innovative therapeutic strategies.


Jackson Laboratory GEN Sponsored Article March2024 QR code


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