Functionally diverse heteromeric traps for ligands of the transforming growth factor-β superfamily.

Autor: Kumar R; Acceleron Pharma, Cambridge, MA, USA., Grinberg AV; Acceleron Pharma, Cambridge, MA, USA.; Dragonfly Therapeutics, Waltham, MA, USA., Li H; Acceleron Pharma, Cambridge, MA, USA., Kuo TH; Acceleron Pharma, Cambridge, MA, USA., Sako D; Acceleron Pharma, Cambridge, MA, USA., Krishnan L; Acceleron Pharma, Cambridge, MA, USA., Liharska K; Acceleron Pharma, Cambridge, MA, USA.; Dragonfly Therapeutics, Waltham, MA, USA., Li J; Acceleron Pharma, Cambridge, MA, USA., Grenha R; Acceleron Pharma, Cambridge, MA, USA., Maguire MC; Acceleron Pharma, Cambridge, MA, USA., Briscoe SD; Acceleron Pharma, Cambridge, MA, USA., Pearsall RS; Acceleron Pharma, Cambridge, MA, USA.; Cellarity, Cambridge, MA, USA., Herrin BR; Acceleron Pharma, Cambridge, MA, USA., Suragani RNVS; Acceleron Pharma, Cambridge, MA, USA. rsuragani@acceleronpharma.com., Castonguay R; Acceleron Pharma, Cambridge, MA, USA. rcastonguay@acceleronpharma.com.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2021 Sep 15; Vol. 11 (1), pp. 18341. Date of Electronic Publication: 2021 Sep 15.
DOI: 10.1038/s41598-021-97203-9
Abstrakt: Ligands of the transforming growth factor-β (TGF-β) superfamily are important targets for therapeutic intervention but present challenges because they signal combinatorially and exhibit overlapping activities in vivo. To obtain agents capable of sequestering multiple TGF-β superfamily ligands with novel selectivity, we generated soluble, heterodimeric ligand traps by pairing the extracellular domain (ECD) of the native activin receptor type IIB (ActRIIB) alternately with the ECDs of native type I receptors activin receptor-like kinase 4 (ALK4), ALK7, or ALK3. Systematic analysis of these heterodimeric constructs by surface plasmon resonance, and comparison with their homodimeric counterparts, revealed that each type I receptor partner confers a distinct ligand-binding profile to the heterodimeric construct. Additional characterization in cell-based reporter gene assays confirmed that the heterodimeric constructs possessed different profiles of signaling inhibition in vitro, which translated into altered patterns of pharmacological activity when constructs were administered systemically to wild-type mice. Our results detail a versatile platform for the modular recombination of naturally occurring receptor domains, giving rise to inhibitory ligand traps that could aid in defining the physiological roles of TGF-β ligand sets or be directed therapeutically to human diseases arising from dysregulated TGF-β superfamily signaling.
(© 2021. The Author(s).)
Databáze: MEDLINE
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