C26-16 Differential Tgfβ Antagonism in a Mouse Model of Peripheral Arteriovenous Malformation

Abstract Rationale ACTRIIA-Fc (sotatercept), the first-in-class Activin Signaling Inhibitor (ASI) therapy, has provided a new therapeutic option for pulmonary arterial hypertension (PAH) based on modulation of bone morphogenetic protein (BMP) and transforming growth factor β (TGFβ) signaling. Heritable PAH is associated with Loss-of-Function (LOF) mutations in several receptors and ligands of this pathway, including GDF2, BMP10, BMPR2, ACVRL1, ENG, and SMAD4, several of which are also associated with hereditary hemorrhagic telangiectasia (HHT) syndrome. Several drug candidates in this class have demonstrated the potential to induce arteriovenous malformations (AVMs), manifesting as epistaxis, telangiectasia, gastrointestinal AVMs, and pulmonary AVMs. We have devised a sensitive pre-clinical model to screen BMP/TGFβ modulating compounds for the potential to induce AVM in a genetically susceptible mouse strain. Methods We tested several recombinant ligand traps or antibodies that have been explored as candidate drugs in experimental PH or clinical PAH: anti-BMP9, anti-BMP10, ALK1-Fc (a BMP9/BMP10 ligand trap), ACTRIIA-Fc a.k.a. sotatercept, ACTRIIB-Fc (a combined activin/GDF/BMP9/BMP10 ligand trap), and isotype control. These antagonists were characterized for their binding affinities to an array of BMP/TGFβ ligands (BMP9, BMP10, BMP2, BMP6, GDF7, GDF8, activin A, activin B, and TGFβ1) using Bio-Layer Interferometry. Juvenile 129X1/SvJ mice were treated with recombinant BMP/activin ligand-traps or neutralizing antibodies (5-10 mg/kg i.p. twice weekly) for fifteen weeks, with serial monitoring of telangiectasias or bleeding via digital capillaroscopy, and complete blood counts at the completion of the study. Results ACTRIIA-Fc/sotatercept potently inhibited activin A/B, GDF8/11, and BMP10, but also had moderate affinity for BMP9. Treatment with ACTRIIB-Fc or ALK1-Fc led to high frequency (50%) digital AVM formation and bleeding in hind limb digits within 6 weeks, with greater penetrance occurring when treatment was started at a younger age. Treatment with ACTRIIA-Fc, anti-BMP10, or anti-BMP9 led to less frequent and milder AVMs, and at a delayed interval as compared to ACTRIIB-Fc or ALK1-Fc, whereas treatment with a combination of anti-BMP9 and anti-BMP10 elicited effects which were comparable to ACTRIIB-Fc or ALK1-Fc. Conclusions HHT mimicry in a susceptible mouse strain is age dependent. Potent antagonism of BMP9/BMP10 via ACTRIIB-Fc, ALK1-Fc, or a combination of anti-BMP9 and anti-BMP10 elicited potent AVM formation and bleeding in an HHT-prone mouse strain, whereas multi-ligand trap ACTRIIA-Fc elicited milder effects. This assay may be useful for screening the potential risk of AVMs in candidate BMP/TGFβ targeted therapies for PAH. This abstract is funded by: NIH