title: Effect of antigen-dependent clearance on pharmacokinetics of anti-heparin-binding EGF-like growth factor (HB-EGF) monoclonal antibody.
abstract: Heparin-binding EGF-like growth factor (HB-EGF) is a member of the EGF family and is an important therapeutic target in some types of human cancers. KM3566 is a mouse anti-HB-EGF monoclonal antibody that neutralizes HB-EGF activity by inhibiting the binding of HB-EGF to its receptors. Based on the results of our pharmacokinetics study, a humanized derivative antibody, KHK2866, is rapidly cleared from serum and shows nonlinear pharmacokinetics in cynomolgus monkeys. In this study, we examined the antigen-dependent clearance of an anti-HB-EGF monoclonal antibody in vivo and in vitro in order to pharmacokinetically explain the rapid elimination of KHK2866. We revealed tumor size-dependent clearance of KM3566 in in vivo studies and obtained good fits between the observed and simulated concentrations of KM3566 based on the two-compartment with a saturable route of clearance model. Furthermore, in vivo imaging analyses demonstrated tumor-specific distribution of KM3566. We then confirmed rapid internalization and distribution to lysosome of KM3566 at a cellular level. Moreover, we revealed that the amounts of HB-EGF on cell surface membrane were maintained even while HB-EGF was internalized with KM3566. Recycled or newly synthesized HB-EGF, therefore, may contribute to a consecutive clearance of KM3566, which could explain a rapid clearance from serum. These data suggested that the rapid elimination in pharmacokinetics of KM3566 is due to antigen-dependent clearance. Given that its antigen is expressed in a wide range of normal tissue, it is estimated that the rapid elimination of KHK2866 from cynomolgus monkey serum is caused by antigen-dependent clearance.
authors.affiliation: a R&D Division, Kyowa Hakko Kirin Co. Ltd., Shimotogari, Nagaizumi-cho , Sunto-gun , Shizuoka , Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kasai
authors.forename: Yukitaka
authors.initials: Y
authors.lastname: Yoshikawa
authors.forename: Junichi
authors.initials: J
authors.lastname: Enokizono
mesh_terms: D000465:Algorithms; D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood / Q000493:pharmacokinetics*; D000941:Antigens / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D066257:Heparin-binding EGF-like Growth Factor / Q000276:immunology*; D006801:Humans; D008247:Lysosomes / Q000276:immunology / Q000378:metabolism; D008252:Macaca fascicularis; D008657:Metabolic Clearance Rate; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D018613:Microscopy, Confocal; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000941:Antigens; D066257:Heparin-binding EGF-like Growth Factor
keywords: ADCC, antibody-dependent cellular cytotoxicity; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; HB-EGF; HB-EGF, heparin-binding EGF-like growth factor; IVIS, In Vivo Imaging System; LLOQ, lower limit of quantification; SCID mouse, severe-combined immunodeficient mouse; SPR, surface plasmon resonance; antibody; clearance; internalization; pharmacokinetics