A recyclable antibody shield preserves LDL receptor homeostasis and enables durable lipid control without immune...

Soluble ligand-neutralizing antibodies are constrained by antigen excess and immune complex-associated toxicity. Here, we describe αLR-Ab, a humanized antibody that protects the low-density lipoprotein receptor (LDLR) from proprotein convertase subtilisin/kexin type 9 (PCSK9) by targeting its EGF-A domain. Rather than transiently intercepting extracellular ligands, αLR-Ab sterically shields LDLR and redirects receptor trafficking through its native recycling pathway, thereby preventing PCSK9-mediated lysosomal degradation. This recycling-enabled receptor shielding supports durable LDL-C lowering, substantial dose sparing, and an eightfold increase in tolerance to PCSK9 excess in vitro. In humanized hypercholesterolemic mice, a single dose of αLR-Ab sustained LDL-C suppression for up to 24 days without inducing circulating immune complexes, perturbing free PCSK9 homeostasis, or promoting immune complex deposition in the renal cortex. Receptor shielding coupled with endogenous recycling, distinct from ligand neutralization or receptor degradation, defines a previously unexplored therapeutic modality for preserving homeostasis in chronic disease.