title: Impact of Cell-surface Antigen Expression on Target Engagement and Function of an Epidermal Growth Factor Receptor × c-MET Bispecific Antibody.
abstract: The efficacy of engaging multiple drug targets using bispecific antibodies (BsAbs) is affected by the relative cell-surface protein levels of the respective targets. In this work, the receptor density values were correlated to the in vitro activity of a BsAb (JNJ-61186372) targeting epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (c-MET). Simultaneous binding of the BsAb to both receptors was confirmed in vitro. By using controlled Fab-arm exchange, a set of BsAbs targeting EGFR and c-MET was generated to establish an accurate receptor quantitation of a panel of lung and gastric cancer cell lines expressing heterogeneous levels of EGFR and c-MET. EGFR and c-MET receptor density levels were correlated to the respective gene expression levels as well as to the respective receptor phosphorylation inhibition values. We observed a bias in BsAb binding toward the more highly expressed of the two receptors, EGFR or c-MET, which resulted in the enhanced in vitro potency of JNJ-61186372 against the less highly expressed target. On the basis of these observations, we propose an avidity model of how JNJ-61186372 engages EGFR and c-MET with potentially broad implications for bispecific drug efficacy and design.
authors.affiliation: From Janssen Research and Development, LLC, Spring House, Pennsylvania 19477 and.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Jarantow
authors.affiliation: From Janssen Research and Development, LLC, Spring House, Pennsylvania 19477 and.
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Bushey
authors.affiliation: From Janssen Research and Development, LLC, Spring House, Pennsylvania 19477 and.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Pardinas
authors.affiliation: From Janssen Research and Development, LLC, Spring House, Pennsylvania 19477 and.
authors.forename: Ken
authors.initials: K
authors.lastname: Boakye
authors.affiliation: From Janssen Research and Development, LLC, Spring House, Pennsylvania 19477 and.
authors.forename: Eilyn R
authors.initials: ER
authors.lastname: Lacy
authors.affiliation: Janssen Diagnostics, Janssen Research and Development, Huntingdon Valley, Pennsylvania 19104.
authors.forename: Renouard
authors.initials: R
authors.lastname: Sanders
authors.affiliation: From Janssen Research and Development, LLC, Spring House, Pennsylvania 19477 and.
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Sepulveda
authors.affiliation: From Janssen Research and Development, LLC, Spring House, Pennsylvania 19477 and.
authors.forename: Sheri L
authors.initials: SL
authors.lastname: Moores
authors.affiliation: From Janssen Research and Development, LLC, Spring House, Pennsylvania 19477 and MChiu@its.jnj.com.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Chiu
mesh_terms: D018033:Antibodies, Bispecific / Q000276:immunology*; D000954:Antigens, Surface / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D009154:Mutation; D010766:Phosphorylation; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D019859:Proto-Oncogene Proteins c-met / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D018033:Antibodies, Bispecific; D000954:Antigens, Surface; D007140:Immunoglobulin Fab Fragments; D012333:RNA, Messenger; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
keywords: bispecific antibody; c-MET; cancer therapy; cell-surface receptor; epidermal growth factor (EGF); epidermal growth factor receptor (EGFR); hepatocyte growth factor/scatter factor (HGF/SF); quantitative flow cytometry