Fig 1: Activity of IIB-Fc:ALK4-Fc heterodimer in wild-type mice. Eight-week-old wild-type C57BL/6 mice (n = 9 per group) were injected s.c. with IIB-Fc:IIB-Fc (10 mg/kg), IIB-Fc:ALK4-Fc (either 3 mg/kg or 10 mg/kg), or vehicle control (PBS) twice weekly for 28 days. (A) Percentage change in mouse total body weight from day -1 to day 28. (B) Weight of the gastrocnemius muscle isolated by dissection on day 28. (C) Percentage change in total fat mass normalized to body weight from day -1 to day 27 as assessed by NMR. (D) Percentage change in bone mineral density from day -1 to day 27 as assessed by DXA. Data are means ± SEM. See Supplemental Table S2 for associated statistics. Veh vehicle; mg/kg milligrams per kilogram; NS not significant. *P < 0.05, ***P < 0.001 vs. vehicle.
Fig 2: Profiles of ligand dissociation kinetics for heterodimeric ligand traps vary with type I receptor component. (A) Domain schematics depicting variants based on naturally occurring pairings of TGF-β superfamily type I receptor ECDs with ActRIIB ECD. The Fc domains of heterodimeric fusion proteins are modified (Mod) to promote desired pairing of monomers during cellular production. H6, histidine hexamer. (B–D) Ligand sequestration profiles for ActRIIB-Fc-based heterodimeric traps vary markedly with the identity of the partnered type I receptor ECD. Semi-schematic graphs depict the change in off-rate (kd) of key ligands, as determined by surface plasmon resonance (see Table 1 for exact values), when one ECD in the IIB-Fc:IIB-Fc homodimer is replaced with ALK4 (B), ALK7 (C), or ALK3 (D).
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