PXD044159-2

PXD044159 is an original dataset announced via ProteomeXchange.

Title	CD98hc is a target for brain delivery of biotherapeutics
Description	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.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_05:59:21.124.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Mario Malfavon
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2023-07-27 16:29:59	ID requested
1	2023-07-31 10:55:47	announced
⏵ 2	2024-10-22 05:59:21	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

submitter keyword: CNS drug delivery,CD98hc, biodistribution, protein engineering, blood-brain barrier

Joy Zuchero
contact affiliation	Denali Therapeutics
contact email	zuchero@dnli.com
lab head
Mario Malfavon
contact affiliation	Naval Information Warfare Center (NIWC) Pacific
contact email	Mario.malfavon.civ@us.navy.mil
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/07/PXD044159

PRIDE project URI

• PRIDE
  1. PXD044159
     1. Label: PRIDE project
     2. Name: CD98hc is a target for brain delivery of biotherapeutics