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Preprint WatchMildJune 24th, 2026

From DNA-Encoded Library (DEL) Screening to In Vivo Validation: LILRB4 (ILT3)-Targeted Small Molecules Reprograms Myeloid Immune Suppression

Abdel-Rahman, S.; Gabr, M.

A DEL-derived small molecule, APX1, binds LILRB4, disrupts LILRB4-ApoE signaling, and restores amyloid-beta clearance with cognitive benefit in the 5xFAD model.

Mild contradiction

1 prior failure

One documented clinical failure (Phase 1 or 2) overlaps with the claimed mechanism.

The indexed LILRB4 record holds one failure, the anti-LILRB4 antibody BND-35 discontinued in advanced solid tumors on a strategic decision (bnd-35-lilrb4-ilt3-myeloid-checkpoint-solid-tumors-phase1-strategic-termination). This preprint targets the same gene through a different route, a DNA-encoded-library-derived small molecule, APX1, that disrupts LILRB4-ApoE signaling and restores amyloid-beta clearance in Alzheimer's disease models. It does not replicate or contradict the indexed result, since that program was an oncology antibody and these data are neuroimmune. The signal worth tracking is that a target whose only clinical attempt ended on portfolio grounds is now drawing fresh chemistry in a separate indication, which is consistent with a low documented failure burden and an unsettled question of where LILRB4 inhibition pays off.

Abstract excerpt

LILRB4/ILT3 has emerged as an inhibitory microglial immune checkpoint implicated in ApoE-mediated suppression of amyloid-beta clearance in Alzheimer's disease. DNA-encoded library screening of about 3.6 billion compounds identified APX1 as a direct LILRB4 binder with submicromolar affinity that disrupts the LILRB4-ApoE interaction. In human iPSC-derived microglia APX1 suppressed SHP1/2 phosphorylation, attenuated NF-kB activation and IL-1beta secretion, and restored Abeta42 uptake; oral APX1 improved cognition and reduced amyloid burden in the 5xFAD mouse model.

Matching Claidex post-mortems

1 of 1 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.