title: Antibodies to cell surface proteins redirect intracellular trafficking pathways.
abstract: Antibody-mediated intracellular delivery of therapeutic agents has been considered for treatment of a variety of diseases. These approaches involve targeting cell-surface receptor proteins expressed by tumors or viral proteins expressed on infected cells. We examined the intracellular trafficking of a viral cell-surface-expressed protein, rabies G, with or without binding a specific antibody, ARG1. We found that antibody binding shifts the native intracellular trafficking pathway of rabies G in an Fc-independent manner. Kinetic studies indicate that the ARG1/rabies G complex progressively co-localized with clathrin, early endosomes, late endosomes, and lysosomes after addition to cells. This pathway was different from that taken by rabies G without addition of antibody, which localized with recycling endosomes. Findings were recapitulated using a cellular receptor with a well-defined endogenous recycling pathway. We conclude that antibody binding to cell-surface proteins induces redirection of intracellular trafficking of unbound or ligand bound receptors to a specific degradation pathway. These findings have broad implications for future developments of antibody-based therapeutics.
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
authors.forename: Christine A
authors.initials: CA
authors.lastname: St Pierre
authors.forename: Deborah
authors.initials: D
authors.lastname: Leonard
authors.forename: Silvia
authors.initials: S
authors.lastname: Corvera
authors.forename: Evelyn A
authors.initials: EA
authors.lastname: Kurt-Jones
authors.forename: Robert W
authors.initials: RW
authors.lastname: Finberg
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology*; D000937:Antigen-Antibody Reactions; D000956:Antigens, Viral / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D006023:Glycoproteins / Q000276:immunology / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D010957:Plasmids; D011485:Protein Binding; D021381:Protein Transport / Q000276:immunology*; D011990:Receptors, Transferrin / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014168:Transferrin; D014759:Viral Envelope Proteins / Q000276:immunology / Q000378:metabolism
chemical_list: D000906:Antibodies; D000956:Antigens, Viral; D006023:Glycoproteins; D008565:Membrane Proteins; D011990:Receptors, Transferrin; D014168:Transferrin; D014759:Viral Envelope Proteins; C064951:glycoprotein G, Rabies virus