8G0M

Structure of complex between TV6.6 and CD98hc ECD

Summary for 8G0M

• Entry DOI: 10.2210/pdb8g0m/pdb
• Descriptor: 4F2 cell-surface antigen heavy chain, TV 6.6 Fc fragment, beta-D-galactopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-2)-alpha-D-mannopyranose-(1-6)-[alpha-D-mannopyranose-(1-3)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: transport vehicle, transport protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 74635.94

Authors

Kariolis, M.S.,Lexa, K.,Liau, N.P.D.,Srivastava, D.,Tran, H.,Wells, R.C. (deposition date: 2023-01-31, release date: 2023-10-18, Last modification date: 2024-11-06)

Primary citation

Chew, K.S.,Wells, R.C.,Moshkforoush, A.,Chan, D.,Lechtenberg, K.J.,Tran, H.L.,Chow, J.,Kim, D.J.,Robles-Colmenares, Y.,Srivastava, D.B.,Tong, R.K.,Tong, M.,Xa, K.,Yang, A.,Zhou, Y.,Akkapeddi, P.,Annamalai, L.,Bajc, K.,Blanchette, M.,Cherf, G.M.,Earr, T.K.,Gill, A.,Huynh, D.,Joy, D.,Knight, K.N.,Lac, D.,Leung, A.W.,Lexa, K.W.,Liau, N.P.D.,Becerra, I.,Malfavon, M.,McInnes, J.,Nguyen, H.N.,Lozano, E.I.,Pizzo, M.E.,Roche, E.,Sacayon, P.,Calvert, M.E.K.,Daneman, R.,Dennis, M.S.,Duque, J.,Gadkar, K.,Lewcock, J.W.,Mahon, C.S.,Meisner, R.,Solanoy, H.,Thorne, R.G.,Watts, R.J.,Zuchero, Y.J.Y.,Kariolis, M.S.
CD98hc is a target for brain delivery of biotherapeutics.
Nat Commun, 14:5053-5053, 2023

PubMed 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). The pharmacokinetic and biodistribution properties of a CD98hc antibody transport vehicle (ATV) are assessed in humanized CD98hc knock-in mice and cynomolgus monkeys. Compared to most existing BBB platforms targeting the transferrin receptor, peripherally administered ATV 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 that impact FcγR engagement, changing the valency of CD98hc binding, and by altering the extent of target engagement with Fabs. Our study establishes TV as a modular brain delivery platform with favorable kinetic, biodistribution, and safety properties distinct from previously reported BBB platforms.

PubMed: 37598178
DOI: 10.1038/s41467-023-40681-4

Experimental method

X-RAY DIFFRACTION (2.25 Å)