Mathematical PKPD and safety model of bispecific TfR/BACE1 antibodies for the optimization of antibody uptake in brain

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• 作者：Kapil Gadkar^a ; ¹ ; Daniela Bumbaca Yadav^a ; ¹ ; Joy Yu Zuchero^b ; Jessica A. Couch^c ; Jitendra Kanodia^a ; Margaret K. Kenrick^a ; Jasvinder K. Atwal^b ; Mark S. Dennis^d ; Saileta Prabhu^a ; Ryan J. Watts^b ; Sean B. Joseph^a ; Saroja Ramanujan^a ; ^{ramanujan.saroja@gene.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：TfR ; transferrin receptor ; BACE1 ; β-secretase 1 ; PK ; pharmacokinetics ; PD ; pharmacodynamics ; Aβ40 ; amyloid β ; MM ; Michaelis&ndash ; Menten
• 刊名：European Journal of Pharmaceutics and Biopharmaceutics
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：101
• 期：Complete
• 页码：53-61
• 全文大小：2197 K

文摘

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.