title: Comparative binding, endocytosis, and biodistribution of antibodies and antibody-coated carriers for targeted delivery of lysosomal enzymes to ICAM-1 versus transferrin receptor.
abstract: 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.
authors.affiliation: Fischell Department of Bioengineering, School of Engineering, University of Maryland College Park, College Park, MD 20742, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Papademetriou
authors.forename: Carmen
authors.initials: C
authors.lastname: Garnacho
authors.forename: Daniel
authors.initials: D
authors.lastname: Serrano
authors.forename: Tridib
authors.initials: T
authors.lastname: Bhowmick
authors.forename: Edward H
authors.initials: EH
authors.lastname: Schuchman
authors.forename: Silvia
authors.initials: S
authors.lastname: Muro
mesh_terms: D000818:Animals; D000906:Antibodies / Q000378:metabolism*; D016466:CHO Cells; D002478:Cells, Cultured; D020099:Coated Materials, Biocompatible / Q000493:pharmacokinetics; D006224:Cricetinae; D003412:Cricetulus; D004337:Drug Carriers / Q000378:metabolism / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems; D004705:Endocytosis / Q000502:physiology*; D056947:Enzyme Replacement Therapy / Q000379:methods; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology* / Q000378:metabolism; D016464:Lysosomal Storage Diseases / Q000628:therapy; D008247:Lysosomes / Q000201:enzymology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy / Q000379:methods; D011485:Protein Binding / Q000502:physiology; D011990:Receptors, Transferrin / Q000276:immunology* / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D000906:Antibodies; D020099:Coated Materials, Biocompatible; D004337:Drug Carriers; D011990:Receptors, Transferrin; D018799:Intercellular Adhesion Molecule-1