Fig. 4: Anti-BACE1 hIgG1 variants with improved affinity to primate FcRn at neutral pH demonstrate faster serum clearance and improved brain uptake and enhanced CNS pharmacodynamic response in cynomolgus monkeys.

A single dose (50 mg/kg) of anti-BACE1 hIgG1 or hIgG1 Fc variants with enhanced binding to human and cynomolgus monkey FcRn at neutral pH (YY, YEY, YQAY, YPY) was delivered by IV injection to cynomolgus monkeys (n = 4 per group). Fc variants show reduced serum antibody concentrations compared to WT hIgG1 over the first 7 days post-dose (A), indicative of faster clearance. Serum antibody concentrations continue to drop over 28 days post-dose (B). Brain tissue was collected from animals dosed with anti-BACE1-WT, anti-BACE1-YY or anti-BACE1-YQAY at 2 or 7 days post-dose, and average brain antibody concentrations were determined (2 animals per time point) (C). BACE1 antibodies with modified Fcs were present at higher concentrations in brain than the anti-BACE1 WT Fc antibody. The ratio of the concentration of antibody in the brain relative to the concentration of antibody in the serum (D) shows that the modified Fcs (YY, YQAY) resulted in an increase in the proportion of anti-BACE1 antibody in the brain. Mean CSF antibody concentrations at 1, 2 or 7 days post-dose were also measured, and are reported as either absolute concentration (E) or as a ratio of the concentration in CSF relative to the concentration in the serum (F). Anti-BACE1 antibodies with modified Fcs showed a trend for greater CSF concentrations and partitioning as compared to anti-BACE1 with a WT Fc. Anti-BACE1 hIgG1 Fc variants showed a reduction in sAPPβ/ɑ ratio in the CSF (G) and brain (H). The extent of reduction was comparable in brain (open symbols) and CSF (closed symbols) (I). sAPPβ/α ratio decreased with higher brain concentrations of the Fc variant antibodies (J). Anti-BACE1 hIgG1 Fc variants showed a decrease in circulating endogenous levels of IgG (K). The number of biologically independent animals per group is: n = 4 for serum measurements, except Day 7 YY n = 2; n = 4 for CSF measurements, except Day 2 YY, YQAY and Day 7 YY n = 2; n = 2 for all brain measurements.. (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).