Extended Data Fig. 3: ATV:4D9 and ATV:TREM2 demonstrate similar mechanisms of action with high affinity stalk binding epitopes and cellular function. | Nature Neuroscience

Extended Data Fig. 3: ATV:4D9 and ATV:TREM2 demonstrate similar mechanisms of action with high affinity stalk binding epitopes and cellular function.

From: A TREM2-activating antibody with a blood–brain barrier transport vehicle enhances microglial metabolism in Alzheimer’s disease models

Extended Data Fig. 3

(a) Antibody schematic comparing human specific ATV:TREM2 and mouse specific ATV:4D9 with high affinity TREM2 binding. (b) Epitope map of overlapping stalk binding regions for ATV:TREM2 and ATV:4D9 Fabs (space filled model of TREM2 ECD1). The binding epitope of ATV:4D9 antibody is located 12-amino acids N-terminal of the ADAM cleavage site at His157. (c) FACS analysis of cell binding of ATV:TREM2 to hTREM2-DAP12 HEK293 or parental cells. Endogenous TfR expression on HEK293 cells drives weak binding observed for ATV:ISO and ATV:TREM2 (n = 3 independent experiment, mean ± SEM). (d) FACS detection of ATV:TREM2 (100 nM) binding to WT and TREM2 KO iMG with isotype control (ATV:ISO). (e) Soluble TREM2 measured in the supernatant of hTREM2-DAP12 HEK293 cells dosed with ATV:TREM2 for 24 h shows dose-dependent reduction of sTREM2 to levels similar to 1 uM GM6001 (n = 3 independent experiment, mean ± SEM). (f) ATV:TREM2 and lipid ligands induce pSyk signaling in iMG 24 h post antibody exposure (n = 3 independent experiments, Tukey’s multiple comparisons test, mean ± SEM). (g) Human monocytes cultured in limited M-CSF with plate coated ATV:TREM2 or ATV:ISO shows dose-dependent activity of ATV:TREM2 (EC50 0.95 +/− 0.45 nM). Representative data from one out of four human donors are shown.

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