Targeting lysosomal
enzymes to receptors involved in transport into and across cells holds promise to enhance peripheral and brain delivery of
enzyme replacement therapies (ERTs) for lysosomal storage disorders. Receptors being explored include those associated with
clathrin-mediated pathways, yet other pathways seem also viable. Well characterized examples are that of
transferrin receptor (TfR) and
intercellular adhesion molecule 1 (ICAM-1), involved in
iron transport and leukocyte extravasation, respectively. TfR and
ICAM-1 support ERT delivery via
clathrin- vs.
cell adhesion molecule-mediated mechanisms, displaying different valency and size restrictions. To comparatively assess this, we used
antibodies vs. larger multivalent antibody-coated carriers and evaluated TfR vs.
ICAM-1 binding and endocytosis in endothelial cells, as well as in vivo biodistribution and delivery of a model lysosomal
enzyme required in peripheral organs and brain:
acid sphingomyelinase (ASM), deficient in types A-B
Niemann Pick disease. We found similar binding of
antibodies to both receptors under control conditions, with enhanced binding to activated endothelium for
ICAM-1, yet only anti-TfR induced endocytosis efficiently. Contrarily, antibody-coated carriers showed enhanced binding, engulfment, and endocytosis for
ICAM-1. In mice, anti-TfR enhanced brain targeting over anti-ICAM, with an opposite outcome in the lungs, while carriers enhanced
ICAM-1 targeting over TfR in both organs. Both targeted carriers enhanced ASM delivery to the brain and lungs vs. free ASM, with greater enhancement for anti-ICAM carriers. Therefore, targeting TfR or
ICAM-1 improves lysosomal
enzyme delivery. Yet, TfR targeting may be more efficient for smaller conjugates or fusion
proteins, while
ICAM-1 targeting seems superior for multivalent carrier formulations.