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2023

Nat Commun. 2023 Aug 19;14(1):5053. doi: 10.1038/s41467-023-40681-4.

CD98hc is a target for brain delivery of biotherapeutics

Kylie S. Chew, Robert C. Wells, Arash Moshkforoush, Darren Chan, Kendra J. Lechtenberg, Hai L. Tran, Johann Chow, Do Jin Kim, Yaneth Robles-Colmenares, Devendra B. Srivastava, Raymond K. Tong, Mabel Tong, Kaitlin Xa, Alexander Yang, Yinhan Zhou, Padma Akkapeddi, Lakshman Annamalai, Kaja Bajc, Marie Blanchette, Gerald Maxwell Cherf, Timothy K. Earr, Audrey Gill, David Huynh, David Joy, Kristen N. Knight, Diana Lac, Amy Wing-Sze Leung, Katrina W. Lexa, Nicholas P. D. Liau, Isabel Becerra, Mario Malfavon, Joseph McInnes, Hoang N. Nguyen, Edwin I. Lozano, Michelle E. Pizzo, Elysia Roche, Patricia Sacayon, Meredith E. K. Calvert, Richard Daneman, Mark S. Dennis, Joseph Duque, Kapil Gadkar, Joseph W. Lewcock, Cathal S. Mahon, René Meisner, Hilda Solanoy, Robert G. Thorne, Ryan J. Watts, Y. Joy Yu Zuchero, Mihalis S. Kariolis.

Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA. Department of Pharmacology, University of California San Diego, 9500 Gilman Dr., La Jolla, 92093, CA, USA. Department of Neurosciences, University of California San Diego, 9500 Gilman Dr., La Jolla, 92093, CA, USA. Department of Pharmaceutics, University of Minnesota, Minneapolis, MN, USA.

Service type: Knock-in mice

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 (TVCD98hc). The pharmacokinetic and biodistribution properties of a CD98hc antibody transport vehicle (ATVCD98hc) 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 ATVCD98hc that impact FcγR engagement, changing the valency of CD98hc binding, and by altering the extent of target engagement with Fabs. Our study establishes TVCD98hc as a modular brain delivery platform with favorable kinetic, biodistribution, and safety properties distinct from previously reported BBB platforms.

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