Proteomics

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CD98hc is a target for brain delivery of biotherapeutics


ABSTRACT: Brain exposure of systemically administered biotherapeutics is highly restricted by the blood-brain barrier (BBB). Here, we report the engineering and characterization of a BBB transport vehicle targeting the CD98 heavy chain (CD98hc or SLC3A2) of heterodimeric amino acid transporters (TV^CD98hc). The pharmacokinetic and biodistribution properties of a CD98hc antibody transport vehicle (ATV^CD98hc) are assessed in humanized CD98hc knock-in mice and cynomolgus monkeys. Compared to most existing BBB platforms targeting the transferrin receptor, peripherally administered ATVCD98hc demonstrates differentiated brain delivery with markedly slower and more prolonged kinetic properties. Specific biodistribution profiles within the brain parenchyma can be modulated by introducing Fc mutations on ATV^CD98hc that impact FcgR engagement, changing the valency of CD98hc binding, and by altering the extent of target engagement with Fabs. Our study establishes TV^CD98hc as a modular brain delivery platform with favorable kinetic, biodistribution, and safety properties distinct from previously reported BBB platforms.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Alzheimer's Disease 1

SUBMITTER: Mario Malfavon  

LAB HEAD: Joy Zuchero

PROVIDER: PXD044159 | Pride | 2023-07-31

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
ID019_Vessels_CB_MSF.msf Msf
ID019_Vessels_MF_CB_MSF.msf Msf
ID019_Vessels_MF_MSF.msf Msf
ID019_Whole_Brain_MSF.msf Msf
IV_CB_DG008462.raw Raw
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