CD98hc is a target for brain delivery of biotherapeutics

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))....

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Detalles Bibliográficos
Autores principales: Chew, Kylie S., Wells, Robert C., Moshkforoush, Arash, Chan, Darren, Lechtenberg, Kendra J., Tran, Hai L., Chow, Johann, Kim, Do Jin, Robles-Colmenares, Yaneth, Srivastava, Devendra B., Tong, Raymond K., Tong, Mabel, Xa, Kaitlin, Yang, Alexander, Zhou, Yinhan, Akkapeddi, Padma, Annamalai, Lakshman, Bajc, Kaja, Blanchette, Marie, Cherf, Gerald Maxwell, Earr, Timothy K., Gill, Audrey, Huynh, David, Joy, David, Knight, Kristen N., Lac, Diana, Leung, Amy Wing-Sze, Lexa, Katrina W., Liau, Nicholas P. D., Becerra, Isabel, Malfavon, Mario, McInnes, Joseph, Nguyen, Hoang N., Lozano, Edwin I., Pizzo, Michelle E., Roche, Elysia, Sacayon, Patricia, Calvert, Meredith E. K., Daneman, Richard, Dennis, Mark S., Duque, Joseph, Gadkar, Kapil, Lewcock, Joseph W., Mahon, Cathal S., Meisner, René, Solanoy, Hilda, Thorne, Robert G., Watts, Ryan J., Zuchero, Y. Joy Yu, Kariolis, Mihalis S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10439950/
https://www.ncbi.nlm.nih.gov/pubmed/37598178
http://dx.doi.org/10.1038/s41467-023-40681-4
Descripción
Sumario: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 ATV(CD98hc) 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 FcγR 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.

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