Internalization, intracellular trafficking, and biodistribution of monoclonal antibody 806: a novel anti-epidermal growth factor receptor antibody.
Overexpression of the epidermal growth factor receptor (EGFR) in epithelial tumors is associated with poor prognosis and is the target for a number of cancer therapeutics. Monoclonal antibody (mAb) 806 is a novel anti-EGFR antibody with significant therapeutic efficacy in tumor models when used as a single agent, and displays synergistic antitumor activity in combination with other EGFR therapeutics. Unlike other EGFR antibodies, mAb 806 is selective for tumor cells and does not bind to normal tissue, making it an ideal candidate for generation of radioisotope or toxin conjugates. Ideally, antibodies suited to these therapeutic applications must bind to and actively internalize their cognate receptor. We investigated the intracellular trafficking of fluorescently tagged mAb 806 in live cells and analyzed its biodistribution in a tumor xenografted nude mouse model. Following binding to EGFR, mAb 806 was internalized through dynamin-dependent, clathrin-mediated endocytosis. Internalized mAb 806 localized to early endosomes and subsequently trafficked to and accumulation in lysosomal compartments. Furthermore, biodistribution analysis in nude mice showed specific uptake and retention of radiolabeled mAb 806 to human tumor xenografts. These results highlight the potential use of mAb 806 for generation of conjugates suitable for diagnostic and therapeutic use in patients with EGFR-positive malignancies.
Perera
Rushika M
RM
Ludwig Institute for Cancer Research, Austin Hospital, Heidelberg, Victoria 3084, Australia.
Zoncu
Roberto
R
Johns
Terrance G
TG
Pypaert
Marc
M
Lee
Fook-Thean
FT
Mellman
Ira
I
Old
Lloyd J
LJ
Toomre
Derek K
DK
Scott
Andrew M
AM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics*; D000918:Antibody Specificity; D001692:Biological Transport; D045744:Cell Line, Tumor; D022163:Clathrin-Coated Vesicles / Q000378:metabolism; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D000939:Epitopes / Q000276:immunology; D066246:ErbB Receptors / Q000276:immunology*; D006801:Humans; D018796:Immunoconjugates / Q000493:pharmacokinetics; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000276:immunology*; D014018:Tissue Distribution; D014162:Transfection
D000911:Antibodies, Monoclonal; D000939:Epitopes; D018796:Immunoconjugates; D009363:Neoplasm Proteins; C518939:monoclonal antibody 806; C512478:EGFR protein, human; D066246:ErbB Receptors