Fig. 5: Pharmacokinetics and distribution of ATV^CD98hc are distinct from ATV^TfR.

a, b PK of ATV^CD98hc.6.8:DNP (170 nM K_D) and ATV^TfR.35.23.4:DNP (620 nM K_D) in plasma (a) and brain (b) following a single 50 mg/kg IV dose. Plasma clearances for both ATVs were increased relative to anti-DNP (5.3 mL/d/kg), and plasma clearance for ATV^TfR.35.23.4:DNP (39.0 mL/d/kg) was increased compared to ATV^CD98hc.6.8:DNP (17.7 mL/d/kg). Both ATV^CD98hc.6.8:DNP and ATV^TfR.35.23.4:DNP had increased brain exposure compared to control and had different exposure profiles compared to each other. c, d PK of mono- and biATV^CD98hc6.39:BACE1 (94 nM K_D) in plasma (c) and brain (d) following a single 50 mg/kg IV dose. Both mono- and biATV^CD98hc6.39:BACE1 had higher plasma clearance compared to control, and biATV^CD98hc6.39:BACE1 (35.9 mL/d/kg) had higher plasma clearance compared to monovalent (19.9 mL/d/kg). Compare to the plasma clearance measured for mono- and biATV^CD98hc.6.8:DNP (19.6 and 43.9 mL/d/kg, respectively Fig. 3b). Both mono- and biATV^CD98hc6.39:BACE1 had increased brain exposure compared to control, and were not significantly different from each other. a–d Graphs display mean ± SEM, n = 5/group. Two-way ANOVA. Data points not shown were <LLOD. *p < 0.05, ****p < 0.0001. See Supplementary Table 6 for exact p values. e Immunohistochemical localization of huIgG for mono- and biATV^CD98hc.6.8:BACE1 (purple) in cortical brain sections, LAMP2 (green), and NeuN (yellow) 7 days after a single 50 mg/kg IV dose. Scale bars = 7 µm. Overlays are shown with colocalization of huIgG and Lamp2 within NeuN positive neurons is pseudocolored in white. Representative images are shown from n = 5 animals/treatment group, n = 2 IHC sections per animal. f, g Simulated brain uptake, clearance, and total net flux for mono- and biATV^CD98hc:DNP (f) and ATV^CD98hc: BACE1(g). Simulations are performed for a 50 mg/kg IV dose of ATV^CD98hc, CD98hc K_D = 170 nM. Source data are provided as a Source Data file.