(596ai) Mechanism-Based Pharmacokinetic Model to Predict Endogenous Autoantibody Clearance Levels

Immunoglobulin G (IgG) is the major antibody in the serum which is involved in secondary immune response against foreign microorganisms. The neonatal Fc receptor, FcRn, is responsible for controlling the half-life of antibodies [1] by protecting them from degradation via recycling. A range of autoimmune diseases are characterized by the involvement of self-reactive antibodies in pathogenesis. As a result, engineered antibodies have been developed to inhibit the FcRn function to modulate IgG half-lives [2, 3]. In particular, engineered antibodies with increased affinities for FcRn (Abdegs) can enhance the clearance rates of endogenous IgGs by inhibiting the FcRn function. As such, Abdegs have potential for the treatment of autoimmunity [4].

In this study, we developed a mechanism-based pharmacokinetic model that describes the FcRn-mediated IgG recycling pathway and reveals the effect of Abdegs on radiolabeled mIgG1pharmacokinetics. The developed FcRn trafficking pathway is based on experimental observations and  includes the following novel aspects: (i) a weak interaction of FcRn and IgG at neutral pH, (ii) 1:2 stoichiometric interaction of IgG with FcRn both at neutral and acidic pH, (iii) synthesis of endogenous FcRn, (iv) degradation of free and bound FcRn complexes only in the lysosomes. The parameters governing the model were obtained from experimentally determined pharmacokinetics of radiolabeled mIgG1 in mice.

Our model accurately captures the serum radiolabeled mIgG1 data (concentration/time) in the absence and presence of Abdegs. The simulations can predict the effect of Abdegs on the clearance of endogenous IgG in a mouse. We show that endogenous IgG levels drop to 70%, 58% and 46% levels with the injection of 0.5, 1 and 2 mg/mouse concentrations of Abdegs, respectively. These simulation results are in agreement with the experimentally observed endogenous clearance levels. Finally, we show that our model can reliably predict pharmacokinetics of mutated IgGs that have varied affinities towards FcRn and therefore aid in the engineering of novel antibodies towards customized control of endogenous IgG half-lives.

References

1. Ghetie V, Ward ES: Multiple roles for the major histocompatibility complex class I-related receptor FcRn. In., vol. 18; 2000: 739-766.

2. Low SC, Mezo AR: Inhibitors of the FcRn:IgG protein-protein interaction. AAPS Journal 2009, 11(3):432-434.

3. Ward ES, Ober RJ: Chapter 4: Multitasking by Exploitation of Intracellular Transport Functions the Many Faces of FcRn. Adv Immunol 2009, 103:77-115.

4. Patel DA, Puig-Canto A, Challa DK, Montoyo HP, Ober RJ, Ward ES: Neonatal Fc receptor blockade by Fc engineering ameliorates arthritis in a murine model. Journal of Immunology 2011, 187(2):1015-1022.