While regulatory agencies increasingly scrutinize and update requirements related to animal use in research, the need for robust in vivo data still remains critical to ensure the safety and efficacy of new therapeutics entering clinical trials. Non-human primates (NHPs) - the species formerly considered the most reliably translational - are falling out of regulatory favor, as well as bearing high costs to utilize, challenges in availability, and are simply a less feasible option for early-stage testing. Conversely, humanized transgenic mouse models are rapidly becoming the gold standard for preclinical pharmacokinetic (PK) studies.
JAX has developed a suite of humanized mouse models that exclusively express human FcRn, forming the foundation of the HuPK™ platform. These models have been successfully used to predict the clinical PK of antibody-based therapeutics, Fc-engineered variants, and albumin-conjugated drugs with accuracy comparable to NHPs.
In the absence of reliable preclinical data to predict the PK of antibody therapeutics in humans, Phase 1 clinical trials often rely on dose escalation studies - an approach that increases the risk of suboptimal efficacy, adverse side effects, and clinical failure.
JAX's FcRn humanized “Tg276” mice (strain #004919), which ubiquitously express human FCGRT at high levels in all tissues, and humanized “Tg32” mice (strain #014565), which express human FCGRT in a physiologically relevant pattern, offer robust in vivo platforms for identifying promising lead variants and predicting human antibody PK for allometric scaling. By incorporating FcRn transgenic mice into the preclinical development pipeline and allometric scaling workflows, you can easily identify lead drug candidates and aids in estimating therapeutic window of antibodies, reducing the need for risky and resource-intensive dose escalations in early-phase trials.
With its FcRn-binding capability for extended half-life, albumin is increasingly being used as a carrier for conjugated or genetically fused therapeutic moieties. Due to cross-species differences in FcRn-albumin binding, the utility of traditional mouse models to accurately predict the human PK of these therapeutics has been limited. To address this, JAX's HuPK™ portfolio includes human FcRn transgenic mouse models carrying additional, targeted mutations and transgenes to enable more accurate PK assessment of albumin-based drugs.
The Alb KO (strain #025201) expresses human FcRn and lacks both mouse albumin and FcRn, eliminating high-affinity competition that can confound PK assessments. The Tg32 hALB (strain #037524) builds on this model by also expressing human albumin, enabling evaluation of albumin-based drugs in a more physiologically relevant environment.
Blocking the binding between IgG and FcRn has emerged as a promising therapeutic strategy for treating autoimmune and alloimmune conditions. By blocking the IgG binding to FcRn, these therapies aim to accelerate clearance and reduce levels of disease-causing immunoglobulins. To support the development and optimization of such therapeutics, JAX's HuPK™ portfolio offers cutting-edge human FcRn transgenic mouse models. These models incorporate specific mutations and human transgenes designed to closely replicate human PK, providing a more predictive in vivo platform for evaluating FcRn antagonists and human IgG-based drugs.