title: Addressing safety liabilities of TfR bispecific antibodies that cross the blood-brain barrier.
abstract: Bispecific antibodies using the transferrin receptor (TfR) have shown promise for boosting antibody uptake in brain. Nevertheless, there are limited data on the therapeutic properties including safety liabilities that will enable successful development of TfR-based therapeutics. We evaluate TfR/BACE1 bispecific antibody variants in mouse and show that reducing TfR binding affinity improves not only brain uptake but also peripheral exposure and the safety profile of these antibodies. We identify and seek to address liabilities of targeting TfR with antibodies, namely, acute clinical signs and decreased circulating reticulocytes observed after dosing. By eliminating Fc effector function, we ameliorated the acute clinical signs and partially rescued a reduction in reticulocytes. Furthermore, we show that complement mediates a residual decrease in reticulocytes observed after Fc effector function is eliminated. These data raise important safety concerns and potential mitigation strategies for the development of TfR-based therapies that are designed to cross the blood-brain barrier.
authors: Development Sciences, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Jessica A
authors: JA
authors: Couch
authors: Y Joy
authors: YJ
authors: Yu
authors: Yin
authors: Y
authors: Zhang
authors: Jacqueline M
authors: JM
authors: Tarrant
authors: Reina N
authors: RN
authors: Fuji
authors: William J
authors: WJ
authors: Meilandt
authors: Hilda
authors: H
authors: Solanoy
authors: Raymond K
authors: RK
authors: Tong
authors: Kwame
authors: K
authors: Hoyte
authors: Wilman
authors: W
authors: Luk
authors: Yanmei
authors: Y
authors: Lu
authors: Kapil
authors: K
authors: Gadkar
authors: Saileta
authors: S
authors: Prabhu
authors: Benjamin A
authors: BA
authors: Ordonia
authors: Quyen
authors: Q
authors: Nguyen
authors: Yuwen
authors: Y
authors: Lin
authors: Zhonghua
authors: Z
authors: Lin
authors: Mercedesz
authors: M
authors: Balazs
authors: Kimberly
authors: K
authors: Scearce-Levie
authors: James A
authors: JA
authors: Ernst
authors: Mark S
authors: MS
authors: Dennis
authors: Ryan J
authors: RJ
authors: Watts
mesh_terms: D000208:Acute Disease; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D018033:Antibodies, Bispecific / Q000009:adverse effects* / Q000276:immunology / Q000493:pharmacokinetics; D000915:Antibody Affinity / Q000276:immunology; D000918:Antibody Specificity / Q000276:immunology*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000276:immunology* / Q000473:pathology; D003165:Complement System Proteins / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D000882:Haplorhini / Q000097:blood; D006801:Humans; D051379:Mice; D011990:Receptors, Transferrin / Q000097:blood / Q000276:immunology*; D017701:Reticulocyte Count
chemical_list: D016229:Amyloid beta-Peptides; D018033:Antibodies, Bispecific; D011990:Receptors, Transferrin; D003165:Complement System Proteins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse