CD98hc is a target for brain delivery of biotherapeutics.

Autor: Chew KS; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Wells RC; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Moshkforoush A; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Chan D; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Lechtenberg KJ; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Tran HL; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Chow J; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Kim DJ; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Robles-Colmenares Y; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Srivastava DB; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Tong RK; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Tong M; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Xa K; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Yang A; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Zhou Y; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Akkapeddi P; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Annamalai L; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Bajc K; 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., Blanchette M; 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., Cherf GM; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Earr TK; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Gill A; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Huynh D; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Joy D; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Knight KN; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Lac D; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Leung AW; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Lexa KW; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Liau NPD; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Becerra I; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Malfavon M; 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., McInnes J; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Nguyen HN; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Lozano EI; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Pizzo ME; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Roche E; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Sacayon P; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Calvert MEK; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Daneman R; 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., Dennis MS; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Duque J; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Gadkar K; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Lewcock JW; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Mahon CS; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Meisner R; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Solanoy H; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Thorne RG; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA.; Department of Pharmaceutics, University of Minnesota, Minneapolis, MN, USA., Watts RJ; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA., Zuchero YJY; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA. zuchero@dnli.com., Kariolis MS; Denali Therapeutics, Inc., 161 Oyster Point Blvd., South San Francisco, CA, 94080, USA. kariolis@dnli.com.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Aug 19; Vol. 14 (1), pp. 5053. Date of Electronic Publication: 2023 Aug 19.
DOI: 10.1038/s41467-023-40681-4
Abstrakt: 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.
(© 2023. Springer Nature Limited.)
Databáze: MEDLINE
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