NeuroMab™ Anti-BACE1 BBB Shuttle Antibody(NRZP-1022-ZP3678)

Figure 1 depicts the results of experiments on recombinant amyloid precursor protein (APP) processing in 293-HEK cells using various anti-BACE1 antibodies (LC6, LC9, YW412.8, YW412.8.30, YW412.8.31, and YW412.8.51)An IgG antibody (Xolair®) that does not bind BACE1 was used as a control.

Figure 2 provides a graph comparing the results of an ELISA comparing the competitive binding of the YW412.8 anti-BACE1 antibody to itself, another anti-BACE1 antibody (LC6), the active site BACE1 binding peptide (OM99-2), and the exosite BACE1 binding Show. Peptide (BMS1).

Figure 3 shows the results of experiments examining the contribution of BACE1 to Aβ1-40 levels in wild-type mice.

Figure shows the results of a genetic study examining the contribution of BACE1 to Aβ1-40 production in mice. Panel B shows the effect of administration of control IgG or anti-BACE1 YW412.8.31 (50 mg/kg) 24 or 48 hours after dosing on Aβ1-40 production in plasma and CNS (cortex).

Figure 4 provides the results of the YW412.8.31 anti-BACE1 antibody in vivo

Figure is a plot of individual pharmacokinetic versus pharmacodynamic readouts showing the PK/PD relationship of the YW412.8.31 anti-BACE1 antibody in this mouse model.

Figure 5 Comparison of experiments showing the administration of YW412.8.31 anti-BACE1 antibody to hAPP transgenic mice

Figure 6 shows the PK analysis of a single dose of YW412.8.31 anti-BACE1 (1 or 10 mg/kg) delivered to BALB/C mice by IV injection.

Figure 7 shows the PK analysis of rhesus monkeys dosed with control IgG or YW412.8.31 anti-BACE1 antibody (30 mg/kg) by IV delivery.

Figure 8 is the experimental results of administration of control IgG or anti-BACE1 antibody YW412.8.31 to macaques by IV delivery.

Plasma and CSF samples were taken at 7 days, 2 days and immediately before dosing to set the mean of the baseline Aβ1-40 levels in each monkey. Plasma Aβ1-40 was measured at different times.

Figure 9 depicts Aβ production following systemic administration of YW412.8.31 in wild-type mice.

Graph is a graph showing Aβ1-40 production following administration of a single dose of control IgG or YW412.8.31 (100 mg/kg) to C57Bl/6J mice by IP injection.

Figure 10 depicts Aβ production following systemic administration of YW412.8.31 in wild-type mice.

Figure is a graph showing Aβ1-40 production after administration of control IgG or YW412.8.31 (30 or 100 mg/kg) by 3 IP injections, each 4 days apart.

Figure 11 is the experimental results of administering control IgG or anti-BACE1 antibody YW412.8.31 to rhesus monkeys by IV delivery.

Plasma and CSF samples were taken at 7 days, 2 days and immediately before dosing to set the mean of the baseline Aβ1-40 levels in each monkey. CSF Aβ1-40 was measured at different times.

Figure 12 shows the PK analysis of rhesus monkeys dosed with control IgG or YW412.8.31 anti-BACE1 antibody (30 mg/kg) by IV delivery.

Total anti-BACE1 or control antibody concentrations in CSF samples were measured using a monkey-adsorbed goat anti-human IgG polyclonal antibody.

Figure 13 shows the PK analysis of a single dose of YW412.8.31 anti-BACE1 (1 or 10 mg/kg) delivered to BALB/C mice by IV injection.

Serum PK was analyzed up to 21 days after dosing. Two separate PK assays were used: one that detects all anti-BACE1 in serum (total mAb), and one that detects only unbound anti-BACE1 in serum (free mAb). Single-dose PK analysis in BACE1+/+, BACE1+/− and BACE1−/− mice confirmed the non-linearity observed in the initial study and suggested that the enhanced clearance was indeed target-mediated

Figure 14 Provides the results of in vivo YW412.8.31 anti-BACE1 antibody

Graph shows a graph of Aβ1-40 levels observed in plasma and hippocampus of mice treated with two different concentrations of YW412.8.31 anti-BACE1 antibody compared to vehicle control treatment.