Phase I study of ACE-041, a novel inhibitor of vascular maturation, in patients with advanced solid tumors or relapsed/refractory multiple myeloma.

TPS179 Background: Activin receptor-like kinase 1 (ALK1) is a type I receptor belonging to the TGFβ superfamily of proteins that is transiently expressed on arterial endothelial cells during development and in response to injury or disease (Seki et al. Circ. Res. 2003). ALK1 signaling plays a pivotal role in the maturation phase of angiogenesis and is therefore critical to vasculature development. ACE-041 is a soluble receptor fusion protein consisting of the ligand-binding extracellular domain of human ALK1 linked to a human IgG1-Fc region. ACE-041 binds with high affinity to BMP9 and BMP10 but does not bind to either TGFβ1, 2 or 3; VEGF or bFGF. By inhibiting their interaction with ALK1, ACE-041 blocks ALK1-mediated signaling, prohibiting vascular endothelial cell maturation and further vascular development. Unlike other angiogenesis inhibitors that act on the initial proliferative phase, ACE-041 blocks a critical and convergent step in the maturation phase of angiogenesis. In vitro and in vivo studies ...