Supplementary Materials

The PDF file includes:

  • Materials and Methods
  • Fig. S1. Initial TV library sorting and characterization of first-generation ATV:BACE1 clones.
  • Fig. S2. Affinity maturation of initial TV clones by soft mutagenesis.
  • Fig. S3. Affinity maturation of TV using a peripheral NNK walk.
  • Fig. S4. Design of a circularly permutated TfR apical domain.
  • Fig. S5. Affinity maturation of TV using a focused, peripheral library.
  • Fig. S6. Structural analysis of TV35 and TfRapical.
  • Fig. S7. TfRapical point mutations displayed on phage reveal the residues affecting affinity differences between hTfR and cTfR.
  • Fig. S8. Biophysical characterization of knob-in-hole ATV:BACE1 variants.
  • Fig. S9. TfR expression and subcellular localization are not affected by ATV:BACE1 incubation in HEK293T cells.
  • Fig. S10. Characterization of TfR expression in TfRmu/hu KI mice.
  • Fig. S11. Immunohistochemical localization of anti-BACE1 and ATV:BACE1 in TfRmu/hu KI mice brain regions after a dose (50 mg/kg).
  • Fig. S12. Quantification of huIgG1 in TfRmu/hu KI mouse cortex from SRCM.
  • Fig. S13. Characterization of brain TfR expression after dose.
  • Fig. S14. PK of ATV:BACE1 variants in WT mice and safety of ATV:BACE1 in cynomolgus monkeys.
  • Table S1. Representative TV sequences isolated from soft mutagenesis affinity maturation library.
  • Table S2. Crystallographic parameters for the TV35:TfRapical structure.
  • Legend for data file S1
  • References (6466)

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Other Supplementary Material for this manuscript includes the following: