title: Dose dependent pharmacokinetics, tissue distribution, and anti-tumor efficacy of a humanized monoclonal antibody against DLL4 in mice.
abstract: Delta-like-4 ligand (DLL4) plays an important role in vascular development and is widely expressed on the vasculature of normal and tumor tissues. Anti-DLL4 is a humanized IgG1 monoclonal antibody against DLL4. The purpose of these studies was to characterize the pharmacokinetics (PK), tissue distribution, and anti-tumor efficacy of anti-DLL4 in mice over a range of doses. PK and tissue distribution of anti-DLL4 were determined in athymic nude mice after administration of single intravenous (IV) doses. In the tissue distribution study, radiolabeled anti-DLL4 (mixture of (125)Iodide and (111)Indium) was administered in the presence of increasing amounts of unlabeled anti-DLL4. Dose ranging anti-DLL4 anti-tumor efficacy was evaluated in athymic nude mice bearing MV522 human lung tumor xenografts. Anti-DLL4 had nonlinear PK in mice with rapid serum clearance at low doses and slower clearance at higher doses suggesting the involvement of target mediated clearance. Consistent with the PK data, anti-DLL4 was shown to specifically distribute to several normal tissues known to express DLL4 including the lung and liver. Maximal efficacy in the xenograft model was seen at doses ≥ 10 mg/kg when tissue sinks were presumably saturated, consistent with the PK and tissue distribution profiles. These findings highlight the importance of mechanistic understanding of antibody disposition to enable dosing strategies for maximizing efficacy.
authors.affiliation: a Department of Preclinical and Translational Pharmacokinetics and Pharmacodynamics; Genentech, Inc ; South San Francisco , CA USA.
authors.forename: Amrita V
authors.initials: AV
authors.lastname: Kamath
authors.forename: Victor
authors.initials: V
authors.lastname: Yip
authors.forename: Priyanka
authors.initials: P
authors.lastname: Gupta
authors.forename: C Andrew
authors.initials: CA
authors.lastname: Boswell
authors.forename: Daniela
authors.initials: D
authors.lastname: Bumbaca
authors.forename: Peter
authors.initials: P
authors.lastname: Haughney
authors.forename: Joni
authors.initials: J
authors.lastname: Castro
authors.forename: Siao Ping
authors.initials: SP
authors.lastname: Tsai
authors.forename: Glenn
authors.initials: G
authors.lastname: Pacheco
authors.forename: Sarajane
authors.initials: S
authors.lastname: Ross
authors.forename: Minhong
authors.initials: M
authors.lastname: Yan
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Damico-Beyer
authors.forename: Leslie
authors.initials: L
authors.lastname: Khawli
authors.forename: Ben-Quan
authors.initials: BQ
authors.lastname: Shen
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000097:blood / Q000276:immunology / Q000493:pharmacokinetics*; D019540:Area Under Curve; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology / Q000494:pharmacology; D007205:Indium Radioisotopes / Q000493:pharmacokinetics; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D008657:Metabolic Clearance Rate; D008819:Mice, Nude; D014018:Tissue Distribution; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D007074:Immunoglobulin G; D007205:Indium Radioisotopes; D047908:Intracellular Signaling Peptides and Proteins; D007457:Iodine Radioisotopes; D008565:Membrane Proteins; C064045:delta protein
keywords: DLL4; antibody; cancer; pharmacokinetics; tissue distribution