Abstract
Background
The long apparent half life of IgG antibodies (~3 weeks) is due to the neonatal fragment crystallizable receptor (FcRn) recycling system. IgG binding to FcRn within the endosome protects IgG from degradation via the lysosome, and translocation of the FcRn:IgG complex back to cell surface then enables IgG to be released into the extracellular space, as illustrated in Fig 1. Autoimmune diseases (ex: myasthenia gravis) are characterized by elevated auto-IgGs, and FcRn antagonists are actively being developed as treatments to block the FcRn recycling system and deplete pathological auto-IgGs. To support the development of FcRn antagonists, we developed a human mechanistic PK/PD model to simulate drug PK and circulating endogenous IgG reduction upon FcRn inhibition. The model was developed using biological parameters from the scientific literature and was calibrated to published PK/PD data for two anti-FcRn monoclonal antibodies; nipocalimab (Nipo) and rozanolixizumab (Roza). The model uses the same parameters for both nipocalimab and rozanolixizumab, except for pH-specific binding affinities and elimination rate within the endosome compartments.
Conclusions
- Model simulations are in excellent agreement with the observed PK and PD data for both rozanolixizumab and nipocalimab
- Model simulations reveal that depletion of IgG is driven by endogenous elimination within the lysosome and corresponds to FcRn being nearly fully occupied by the drug
- Moreover, the model predicts that the onset and rate of IgG depletion are NOT dose-dependent, while duration of IgG depletion is dose-dependent
- This model can be used as a platform to optimize the pH-specific drug:FcRn binding affinities, dosage, and dosing schedules
- Model simulations suggest that an optimal molecule needs to have sufficiently tight binding to FcRn at pH 6 within the endosome, whereas IgG depletion is less sensitive to drug binding FcRn at pH 7.4
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