title: Phenotype of TPBG Gene Replacement in the Mouse and Impact on the Pharmacokinetics of an Antibody-Drug Conjugate.
abstract: The use of predictive preclinical models in drug discovery is critical for compound selection, optimization, preclinical to clinical translation, and strategic decision-making. Trophoblast glycoprotein (TPBG), also known as 5T4, is the therapeutic target of several anticancer agents currently in clinical development, largely due to its high expression in tumors and low expression in normal adult tissues. In this study, mice were engineered to express human TPBG under endogenous regulatory sequences by replacement of the murine Tpbg coding sequence. The gene replacement was considered functional since the hTPBG knockin (hTPBG-KI) mice did not exhibit clinical observations or histopathological phenotypes that are associated with Tpbg gene deletion, except in rare instances. The expression of hTPBG in certain epithelial cell types and in different microregions of the brain and spinal cord was consistent with previously reported phenotypes and expression patterns. In pharmacokinetic studies, the exposure of a clinical-stage anti-TPBG antibody-drug conjugate (ADC), A1mcMMAF, was lower in hTPBG-KI versus wild-type animals, which was evidence of target-related increased clearance in hTPBG-KI mice. Thus, the hTPBG-KI mice constitute an improved system for pharmacology studies with current and future TPBG-targeted therapies and can generate more precise pharmacokinetic and pharmacodynamic data. In general the strategy of employing gene replacement to improve pharmacokinetic assessments should be broadly applicable to the discovery and development of ADCs and other biotherapeutics.
authors.forename: George
authors.initials: G
authors.lastname: Hu
authors.affiliation: §Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Pearl River, New York 10965, United States.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Leal
authors.affiliation: ∥Global Biotherapeutic Technologies, Pfizer Inc., Cambridge, Massachusetts 02139, United States.
authors.forename: Qingcong
authors.initials: Q
authors.lastname: Lin
authors.forename: Timothy
authors.initials: T
authors.lastname: Affolter
authors.affiliation: #Oncology Research Unit, Pfizer Inc., Pearl River, New York 10965, United States.
authors.forename: Puja
authors.initials: P
authors.lastname: Sapra
authors.affiliation: ∥Global Biotherapeutic Technologies, Pfizer Inc., Cambridge, Massachusetts 02139, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: Bates
authors.affiliation: #Oncology Research Unit, Pfizer Inc., Pearl River, New York 10965, United States.
authors.forename: Marc
authors.initials: M
authors.lastname: Damelin
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics; D006801:Humans; D018796:Immunoconjugates / Q000493:pharmacokinetics*; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype
chemical_list: C581920:A1mcMMAF; D061067:Antibodies, Monoclonal, Humanized; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; C063709:trophoblastic glycoprotein 5T4, human
keywords: 5T4; A1mcMMAF; ADC; TPBG; antibody−drug conjugate; gene replacement; humanized mouse; pharmacokinetics