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The neonatal Fc receptor (FcRn) was first identified in newborn rats, playing a vital role in transferring maternal IgG from breast milk into the neonate’s bloodstream—providing essential passive immunity. Studies later revealed that human placenta also expresses FcRn, enabling prenatal transport of maternal IgG to the fetus.
FcRn’s function is driven by pH-dependent binding: it tightly binds IgG in acidic endosomes (pH 6.0–6.5) and releases it in the neutral pH of blood (pH 7.4), thereby rescuing antibodies from degradation and significantly prolonging their half-life. Beyond recycling antibodies, FcRn helps shuttle IgG–antigen complexes inside immune cells, promoting their presentation to the immune system and amplifying immune responses (Roopenian and Shreeram 2007).
FcRn inhibition has proven therapeutic potential: rozanolixizumab and efgartigimod, FDA-approved FcRn inhibitors for myasthenia gravis, clear pathogenic IgG (Pyzik et al. 2023).
FcRn-mediated IgG protection and recycling (Source: Roopenian and Shreeram 2007)
Antibody pharmacokinetics (PK) is critical for optimizing dosing, exposure, and half-life—key factors that determine therapeutic safety and efficacy. It is influenced by attributes such as target-binding affinity, pH-dependent FcRn binding, and target-mediated drug disposition (TMDD).
However, FcRn-mediated recycling of IgG is species-specific. Human IgG typically binds more strongly to mouse FcRn than to human FcRn, often resulting in longer antibody half-lives in mice (Ober et al. 2001). This mismatch can lead to inaccurate PK predictions in standard mouse models.
Binding Affinity Differences Between Human and Mouse FcRn (Ober et al. 2001)
To overcome species differences in FcRn–IgG binding, Biocytogen developed FcRn humanized mice (B-hFcRn) by replacing the mouse FcRn gene with its human counterpart, driven by the native promoter. These models support robust in vivo efficacy, mechanistic, and PK studies, delivering the translational insights needed to confidently advance FcRn-targeted and IgG-based therapies.
Internally validated antibody half-lives (days) across humans, monkeys, B-hFcRn, and wild-type mice. B-hFcRn mice show a stronger correlation with human for antibody half-life than wild-type mice, highlighting their value in translational PK research.
In the development of humanized antibody therapeutics, scientists often apply targeted engineering strategies to improve efficacy, half-life, and safety. Among these, optimizing the Fc–FcRn interaction has proven effective for modulating the PK of IgG antibodies. For example, the YTE mutation—a triple substitution in the Fc region (M252Y/S254T/T256E)—enhances FcRn binding at acidic pH and significantly prolongs IgG serum half-life, making it a widely adopted strategy for extending the durability of therapeutic antibodies (Robbie et al. 2013.).
When evaluating the effect of the YTE mutation on antibody half-life, we observed that:
In B-hFcRn mice: The YTE mutation prolongs human antibody half-life and lowers clearance, as expected.
In wild-type C57BL/6 mice: The YTE mutation does not affect human antibody half-life, as it has little to no impact on binding to mouse FcRn.
Target-Mediated Drug Disposition (TMDD) plays a critical role in antibody drug development. It arises when a drug binds with high affinity to its pharmacological target, leading to internalization and degradation of the drug–target complex (Mager and Jusko 2001).
Biocytogen’s multi-target humanized mice, featuring humanized FcRn and drug targets, enable more accurate prediction of human antibody PK by capturing both FcRn-mediated recycling and target-mediated clearance.
B-hCD40/hFcRn mice exhibit TMDD and more accurately reflect in vivo anti-human CD40 antibody concentration changes compared to WT and B-hFcRn mice.
Accurately predicting antibody PK in humans is critical for successful drug development. To support this, we developed a population PK (PopPK) model for pembrolizumab, a PD-1 checkpoint inhibitor. Using high-quality in vivo PK data from Biocytogen’s FcRn humanized mice and methods adapted from Betts et al. (2018), we built the PopPK model and applied allometric scaling to project human clearance (CL):
CL_human = CL_mouse × (weight_human / weight_mouse)^0.9
The predicted human clearance of 0.121 mL/h/kg closely matched the observed clinical value of 0.119 mL/h/kg (Ahamadi et al. 2017) with only 1.68% error—highlighting the translational power of modeling using B‑hFcRn mice.
Model Diagnostics: Confidence in Predictive Power
Blue circles: Observed data
Red lines: Model-predicted trajectories
Population PK diagnostics showed strong agreement between observed and predicted values (DV vs. IPRED) and no time-dependent bias (CWRES vs. TIME), confirming model robustness.
Individual-Level Fits: Case Examples
Model predictions for three representative B-hFcRn subjects (IDs: 258690, 258700, 258710) demonstrated excellent agreement with observed plasma concentrations.
By combining B‑hFcRn mice with allometric scaling, we accurately predicted human PK for pembrolizumab—with just 1.68% clearance error. This platform enables reliable first-in-human dose projections and enhances the translational link between preclinical and clinical stages in antibody development.
Pyzik, Michal, et al. "The therapeutic age of the neonatal Fc receptor." Nature Reviews Immunology 23.7 (2023): 415-432.
Roopenian, Derry C., and Shreeram Akilesh. "FcRn: the neonatal Fc receptor comes of age." Nature reviews immunology 7.9 (2007): 715-725.
Ober, Raimund J., et al. "Differences in promiscuity for antibody–FcRn interactions across species: implications for therapeutic antibodies." International immunology 13.12 (2001): 1551-1559.
Robbie, Gabriel J., et al. "A novel investigational Fc-modified humanized monoclonal antibody, motavizumab-YTE, has an extended half-life in healthy adults." Antimicrobial agents and chemotherapy 57.12 (2013): 6147-6153.
Mager, Donald E., and William J. Jusko. "General pharmacokinetic model for drugs exhibiting target-mediated drug disposition." Journal of pharmacokinetics and pharmacodynamics 28.6 (2001): 507-532.
Ahamadi, M., et al. "Model‐based characterization of the pharmacokinetics of pembrolizumab: a humanized anti–PD‐1 monoclonal antibody in advanced solid tumors." CPT: pharmacometrics & systems pharmacology 6.1 (2017): 49-57.
