title: Mathematical PKPD and safety model of bispecific TfR/BACE1 antibodies for the optimization of antibody uptake in brain.
abstract: Treatment of diseases of the central nervous system by monoclonal antibodies may be limited by the restricted uptake of antibodies across the blood-brain barrier (BBB). An antibody targeting transferrin receptor (TfR) has been shown to take advantage of the receptor-mediated transcytosis properties of TfR in order to cross the BBB in mice, with the uptake in the brain being dependent on the affinity to TfR. In the bispecific format with arms targeting both TfR and β-secretase 1 (BACE1), altering the affinity to TfR has been shown to impact systemic exposure and safety profiles. In this work, a mathematical model incorporating pharmacokinetic/pharmacodynamic (PKPD) and safety profiles is developed for bispecific TfR/BACE1 antibodies with a range of affinities to TfR in order to guide candidate selection. The model captures the dependence of both systemic and brain exposure on TfR affinity and the subsequent impact on brain Aβ40 lowering and circulating reticulocyte levels. Model simulations identify the optimal affinity for the TfR arm of the bispecific to maximize Aβ reduction while maintaining reticulocyte levels. The model serves as a useful tool to prioritize and optimize preclinical studies and has been used to support the selection of additional candidates for further development.
authors.affiliation: Preclinical and Translational Pharmacokinetics Department, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Kapil
authors.initials: K
authors.lastname: Gadkar
authors.affiliation: Preclinical and Translational Pharmacokinetics Department, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Daniela Bumbaca
authors.initials: DB
authors.lastname: Yadav
authors.affiliation: Department of Neuroscience, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Joy Yu
authors.initials: JY
authors.lastname: Zuchero
authors.affiliation: Safety Assessment Department, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Couch
authors.affiliation: Preclinical and Translational Pharmacokinetics Department, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Jitendra
authors.initials: J
authors.lastname: Kanodia
authors.affiliation: Preclinical and Translational Pharmacokinetics Department, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Margaret K
authors.initials: MK
authors.lastname: Kenrick
authors.affiliation: Department of Neuroscience, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Jasvinder K
authors.initials: JK
authors.lastname: Atwal
authors.affiliation: Antibody Engineering Department, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Dennis
authors.affiliation: Preclinical and Translational Pharmacokinetics Department, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Saileta
authors.initials: S
authors.lastname: Prabhu
authors.affiliation: Department of Neuroscience, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Watts
authors.affiliation: Preclinical and Translational Pharmacokinetics Department, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Sean B
authors.initials: SB
authors.lastname: Joseph
authors.affiliation: Preclinical and Translational Pharmacokinetics Department, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: ramanujan.saroja@gene.com.
authors.forename: Saroja
authors.initials: S
authors.lastname: Ramanujan
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D018033:Antibodies, Bispecific / Q000009:adverse effects* / Q000493:pharmacokinetics*; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D051379:Mice; D008962:Models, Theoretical; D011990:Receptors, Transferrin / Q000378:metabolism*; D012156:Reticulocytes / Q000187:drug effects / Q000378:metabolism; D057900:Transcytosis / Q000187:drug effects; D014168:Transferrin / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D011990:Receptors, Transferrin; D014168:Transferrin; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse
keywords: Amyloid β; Pharmacodynamics; Pharmacokinetics; Reticulocytes; Transferrin receptor; β-Secretase