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 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 Calvert, Richard Daneman, Mark S. Dennis, Joseph Duque, Kapil Gadkar, Joseph W. Lewcock, Cathal Mahon, René Meisner, Hilda Solanoy, Robert G. Thorne, Ryan J. Watts, Y. Joy Yu Zuchero, Mihalis S. Kariolis
Abstract
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 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.