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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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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:
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
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author 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.
author_facet 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.
author_sort Chew, Kylie S.
collection PubMed
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 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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spelling pubmed-104399502023-08-21 CD98hc is a target for brain delivery of biotherapeutics 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. Nat Commun Article 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. Nature Publishing Group UK 2023-08-19 /pmc/articles/PMC10439950/ /pubmed/37598178 http://dx.doi.org/10.1038/s41467-023-40681-4 Text en © The Author(s) 2023, corrected publication 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
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.
CD98hc is a target for brain delivery of biotherapeutics
title CD98hc is a target for brain delivery of biotherapeutics
title_full CD98hc is a target for brain delivery of biotherapeutics
title_fullStr CD98hc is a target for brain delivery of biotherapeutics
title_full_unstemmed CD98hc is a target for brain delivery of biotherapeutics
title_short CD98hc is a target for brain delivery of biotherapeutics
title_sort cd98hc is a target for brain delivery of biotherapeutics
topic Article
url 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
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