title: Preclinical to Clinical Translation of Antibody-Drug Conjugates Using PK/PD Modeling: a Retrospective Analysis of Inotuzumab Ozogamicin.
abstract: A mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model was used for preclinical to clinical translation of inotuzumab ozogamicin, a CD22-targeting antibody-drug conjugate (ADC) for B cell malignancies including non-Hodgkin's lymphoma (NHL) and acute lymphocytic leukemia (ALL). Preclinical data was integrated in a PK/PD model which included (1) a plasma PK model characterizing disposition and clearance of inotuzumab ozogamicin and its released payload N-Ac-γ-calicheamicin DMH, (2) a tumor disposition model describing ADC diffusion into the tumor extracellular environment, (3) a cellular model describing inotuzumab ozogamicin binding to CD22, internalization, intracellular N-Ac-γ-calicheamicin DMH release, binding to DNA, or efflux from the tumor cell, and (4) tumor growth and inhibition in mouse xenograft models. The preclinical model was translated to the clinic by incorporating human PK for inotuzumab ozogamicin and clinically relevant tumor volumes, tumor growth rates, and values for CD22 expression in the relevant patient populations. The resulting stochastic models predicted progression-free survival (PFS) rates for inotuzumab ozogamicin in patients comparable to the observed clinical results. The model suggested that a fractionated dosing regimen is superior to a conventional dosing regimen for ALL but not for NHL. Simulations indicated that tumor growth is a highly sensitive parameter and predictive of successful outcome. Inotuzumab ozogamicin PK and N-Ac-γ-calicheamicin DMH efflux are also sensitive parameters and would be considered more useful predictors of outcome than CD22 receptor expression. In summary, a multiscale, mechanism-based model has been developed for inotuzumab ozogamicin, which can integrate preclinical biomeasures and PK/PD data to predict clinical response.
authors.affiliation: Department of Pharmacokinetics Dynamics and Metabolism, Pfizer Global Research and Development, Groton, Connecticut, 06340, USA. alison.betts@pfizer.com.|Department of Pharmacokinetics Dynamics and Metabolism - NBE, Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut, 06340, USA. alison.betts@pfizer.com.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Betts
authors.affiliation: Clinical Pharmacology and Pharmacometrics, Quantitative Sciences, Janssen Pharmaceuticals, Spring House, Pennsylvania, 19002, USA.
authors.forename: Nahor
authors.initials: N
authors.lastname: Haddish-Berhane
authors.affiliation: RES Group, Inc., 75 Second Avenue, Needham, Massachusetts, 02494, USA.
authors.forename: John
authors.initials: J
authors.lastname: Tolsma
authors.affiliation: RES Group, Inc., 75 Second Avenue, Needham, Massachusetts, 02494, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Jasper
authors.affiliation: Department of Pharmacokinetics Dynamics and Metabolism, Pfizer Global Research and Development, Groton, Connecticut, 06340, USA.
authors.forename: Lindsay E
authors.initials: LE
authors.lastname: King
authors.affiliation: Clinical Translational Technologies & Operations, Bristol-Myers Squibb Co., Pennington, New Jersey, 08534, USA.
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of World Wide Medicinal Chemistry, Pfizer Global Research and Development, Groton, Connecticut, 06340, USA.
authors.forename: Subramanyam
authors.initials: S
authors.lastname: Chakrapani
authors.affiliation: Immune Pharmaceuticals Inc., 430 East 29th Street, Suite 940, New York, New York, 10016, USA.
authors.forename: Boris
authors.initials: B
authors.lastname: Shor
authors.affiliation: Department of Clinical Pharmacology, Pfizer Global Research and Development, Collegeville, Pennsylvania, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Boni
authors.affiliation: Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, La Jolla, California, USA.
authors.forename: Theodore R
authors.initials: TR
authors.lastname: Johnson
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002986:Clinical Trials as Topic / Q000379:methods; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D000080045:Inotuzumab Ozogamicin; D051379:Mice; D008819:Mice, Nude; D012189:Retrospective Studies; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000493:pharmacokinetics* / Q000627:therapeutic use; D057170:Translational Research, Biomedical / Q000379:methods*; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C497867:CD22 protein, human; D007074:Immunoglobulin G; D051918:Sialic Acid Binding Ig-like Lectin 2; D000080045:Inotuzumab Ozogamicin
keywords: antibody-drug conjugate; clinical translation; inotuzumab ozogamicin; mechanistic modeling; pharmacokinetics-pharmacodynamics