title: Integrated pharmacokinetic, pharmacodynamic and immunogenicity profiling of an anti-CCL21 monoclonal antibody in cynomolgus monkeys.
abstract: QBP359 is an IgG1 human monoclonal antibody that binds with high affinity to human CCL21, a chemokine hypothesized to play a role in inflammatory disease conditions through activation of resident CCR7-expressing fibroblasts/myofibroblasts. The pharmacokinetics (PK) and pharmacodynamics (PD) of QBP359 in non-human primates were characterized through an integrated approach, combining PK, PD, immunogenicity, immunohistochemistry (IHC) and tissue profiling data from single- and multiple-dose experiments in cynomolgus monkeys. When compared with regular immunoglobulin typical kinetics, faster drug clearance was observed in serum following intravenous administration of 10 mg/kg and 50 mg/kg of QBP359. We have shown by means of PK/PD modeling that clearance of mAb-ligand complex is the most likely explanation for the rapid clearance of QBP359 in cynomolgus monkey. IHC and liquid chromatography mass spectrometry data suggested a high turnover and synthesis rate of CCL21 in tissues. Although lymphoid tissue was expected to accumulate drug due to the high levels of CCL21 present, bioavailability following subcutaneous administration in monkeys was 52%. In human disease states, where CCL21 expression is believed to be expressed at 10-fold higher concentrations compared with cynomolgus monkeys, the PK/PD model of QBP359 and its binding to CCL21 suggested that very large doses requiring frequent administration of mAb would be required to maintain suppression of CCL21 in the clinical setting. This highlights the difficulty in targeting soluble proteins with high synthesis rates.
authors.affiliation: a F. Hoffmann-La Roche Ltd. ; Basel , Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Dudal
authors.forename: K
authors.initials: K
authors.lastname: Subramanian
authors.forename: T
authors.initials: T
authors.lastname: Flandre
authors.forename: W S
authors.initials: WS
authors.lastname: Law
authors.forename: P J
authors.initials: PJ
authors.lastname: Lowe
authors.forename: A
authors.initials: A
authors.lastname: Skerjanec
authors.forename: J-C
authors.initials: JC
authors.lastname: Genin
authors.forename: M
authors.initials: M
authors.lastname: Duval
authors.forename: A
authors.initials: A
authors.lastname: Piequet
authors.forename: A
authors.initials: A
authors.lastname: Cordier
authors.forename: G
authors.initials: G
authors.lastname: Jarai
authors.forename: G
authors.initials: G
authors.lastname: Van Heeke
authors.forename: S
authors.initials: S
authors.lastname: Taplin
authors.forename: C
authors.initials: C
authors.lastname: Krantz
authors.forename: S
authors.initials: S
authors.lastname: Jones
authors.forename: A P
authors.initials: AP
authors.lastname: Warren
authors.forename: F R
authors.initials: FR
authors.lastname: Brennan
authors.forename: J
authors.initials: J
authors.lastname: Sims
authors.forename: P
authors.initials: P
authors.lastname: Lloyd
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000493:pharmacokinetics*; D000915:Antibody Affinity; D054421:Chemokine CCL21 / Q000037:antagonists & inhibitors*; D002853:Chromatography, Liquid; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology* / Q000494:pharmacology*; D007150:Immunohistochemistry; D008252:Macaca fascicularis; D013058:Mass Spectrometry
chemical_list: D000911:Antibodies, Monoclonal; C515478:CCL21 protein, human; D054421:Chemokine CCL21; D007074:Immunoglobulin G
keywords: FIH predictions; PK/PD model; biotherapeutics; chemokine; mAb; pharmacokinetics; preclinical