Fig. 3: Human IgG1 antibodies with Fc engineered for improved FcRn affinity at neutral pH demonstrate increased serum clearance, enhanced brain uptake and partitioning, and improved target engagement in hFcRn mice.

A–C A single IV injection (50 mg/kg) of engineered human IgG1 Fc region variants was administered to hFcRn transgenic mice. Serum antibody exposure (AUC) over 7 days (A), brain antibody concentration at day 3 (B) and % brain:serum ratio at day 3 (C) are plotted as correlations to hFcRn affinity at pH 7.4 for each variant. n = 4 biologically independent animals per group per time point. YTE results from Fig. 1D–F are included to represent an antibody with improved hFcRn affinity at pH 6.0 but not 7.4. (Note: YY data points are derived from data in Fig. 3D, E). D–F A single IV injection (50 mg/kg) of anti-BACE1 hIgG1 WT or FcRn 7.4 variants YY or YQAY was administered to hFcRn transgenic mice. The Fc variant antibodies demonstrated faster serum clearance (D), higher brain antibody concentrations (E), and reduced brain Aβ concentrations (F) over 7 days post-dose. n = 5 biologically independent animals per group per time point. (Statistical significance between Fc variant treated groups and respective WT treated group was evaluated over time by 2-way ANOVA or mixed effect analysis with Tukey or Dunnett’s multiple comparisons test using Graphpad Prism 9.5.1; *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001).