title: Preclinical pharmacokinetics, pharmacodynamics, tissue distribution, and tumor penetration of anti-PD-L1 monoclonal antibody, an immune checkpoint inhibitor.
abstract: MPDL3280A is a human monoclonal antibody that targets programmed cell death-1 ligand 1 (PD-L1), and exerts anti-tumor activity mainly by blocking PD-L1 interaction with programmed cell death-1 (PD-1) and B7.1. It is being investigated as a potential therapy for locally advanced or metastatic malignancies. The purpose of the study reported here was to characterize the pharmacokinetics, pharmacodynamics, tissue distribution and tumor penetration of MPDL3280A and/or a chimeric anti-PD-L1 antibody PRO304397 to help further clinical development. The pharmacokinetics of MPDL3280A in monkeys at 0.5, 5 and 20 mg · kg(-1) and the pharmacokinetics / pharmacodynamics of PRO304397 in mice at 1, 3 10 mg · kg(-1) were determined after a single intravenous dose. Tissue distribution and tumor penetration for radiolabeled PRO304397 in tumor-bearing mouse models were determined. The pharmacokinetics of MPDL3280A and PRO304397 were nonlinear in monkeys and mice, respectively. Complete saturation of PD-L1 in blood in mice was achieved at serum concentrations of PRO304397 above ∼ 0.5 µg · mL(-1). Tissue distribution and tumor penetration studies of PRO304397 in tumor-bearing mice indicated that the minimum tumor interstitial to plasma radioactivity ratio was ∼ 0.3; saturation of target-mediated uptake in non-tumor tissues and desirable exposure in tumors were achieved at higher serum concentrations, and the distribution into tumors was dose-and time-dependent. The biodistribution data indicated that the efficacious dose is mostly likely higher than that estimated based on simple pharmacokinetics/pharmacodynamics in blood. These data also allowed for estimation of the target clinical dose for further development of MPDL3280A.
authors.affiliation: a Genentech Research and Early Development, Genentech, Inc. , South San Francisco , CA , USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Deng
authors.affiliation: a Genentech Research and Early Development, Genentech, Inc. , South San Francisco , CA , USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Bumbaca
authors.affiliation: a Genentech Research and Early Development, Genentech, Inc. , South San Francisco , CA , USA.
authors.forename: Cinthia V
authors.initials: CV
authors.lastname: Pastuskovas
authors.affiliation: a Genentech Research and Early Development, Genentech, Inc. , South San Francisco , CA , USA.
authors.forename: C Andrew
authors.initials: CA
authors.lastname: Boswell
authors.affiliation: a Genentech Research and Early Development, Genentech, Inc. , South San Francisco , CA , USA.
authors.forename: David
authors.initials: D
authors.lastname: West
authors.affiliation: a Genentech Research and Early Development, Genentech, Inc. , South San Francisco , CA , USA.
authors.forename: Kyra J
authors.initials: KJ
authors.lastname: Cowan
authors.affiliation: a Genentech Research and Early Development, Genentech, Inc. , South San Francisco , CA , USA.
authors.forename: Henry
authors.initials: H
authors.lastname: Chiu
authors.affiliation: a Genentech Research and Early Development, Genentech, Inc. , South San Francisco , CA , USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: McBride
authors.affiliation: a Genentech Research and Early Development, Genentech, Inc. , South San Francisco , CA , USA.
authors.forename: Clarissa
authors.initials: C
authors.lastname: Johnson
authors.affiliation: a Genentech Research and Early Development, Genentech, Inc. , South San Francisco , CA , USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xin
authors.affiliation: a Genentech Research and Early Development, Genentech, Inc. , South San Francisco , CA , USA.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Koeppen
authors.affiliation: a Genentech Research and Early Development, Genentech, Inc. , South San Francisco , CA , USA.
authors.forename: Maya
authors.initials: M
authors.lastname: Leabman
authors.affiliation: a Genentech Research and Early Development, Genentech, Inc. , South San Francisco , CA , USA.
authors.forename: Suhasini
authors.initials: S
authors.lastname: Iyer
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology; D000912:Antibodies, Neoplasm / Q000276:immunology / Q000494:pharmacology; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology; D016466:CHO Cells; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000276:immunology; D006224:Cricetinae; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D008252:Macaca fascicularis; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D009363:Neoplasm Proteins
keywords: Anti-PD-L1; PD-L1; pharmacodynamics; pharmacokinetics; tissue distribution; tumor penetration