Abstract
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder whose most debilitating pathology is progressive and cumulative heterotopic ossification (HO) of skeletal muscles, ligaments, tendons, and fascia. FOP is caused by mutations in the type I BMP receptor gene ACVR1, which enable ACVR1 to utilize its natural antagonist, Activin A, as an agonistic ligand. The physiological relevance of this property is underscored by the fact that HO in FOP is exquisitely dependent on activation of FOP-mutant ACVR1 by Activin A, an effect countered by inhibition of Activin A via monoclonal antibody treatment. Hence, we surmised that ACVR1 antibodies that block activation of ACVR1 by ligand should also inhibit HO in FOP and provide an additional therapeutic option for this condition. Therefore, we generated ACVR1 monoclonal antibodies that block ACVR1’s activation by its ligands. Surprisingly, in vivo, these ACVR1 antibodies stimulate HO and activate signaling of FOP-mutant ACVR1. This property is restricted to FOP-mutant ACVR1 and results from ACVR1 antibody-mediated dimerization of ACVR1. Conversely, wild type ACVR1 is inhibited by ACVR1 antibodies. These results uncover an additional novel property of FOP-mutant ACVR1 and indicate that ACVR1 antibodies should not be considered as therapeutics for FOP.
Competing Interest Statement
SA, LH, LW, ND, SR, YR, QZ, NR, KCN, VK, SB, LJ, SF, JLS, AJM, ANE, VI, and SJH are employees of Regeneron Pharmaceuticals and either own or have owned stock in Regeneron Pharmaceuticals. LT and PBY have declared that no conflict of interest exists. KS is an employee of Adimab, LLC, and holds shares in Adimab, LLC.
Footnotes
Conflict of interest: SA, LH, LW, ND, SR, YR, QZ, NR, KCN, VK, SB, LJ, SF, JLS, AJM, ANE, VI, and SJH are employees of Regeneron Pharmaceuticals and either own or have owned stock in Regeneron Pharmaceuticals. LT and PBY have declared that no conflict of interest exists. KS is an employee of Adimab, LLC, and holds shares in Adimab, LLC.
We have revised the text to better explain as well as interpret (in the Discussion Section) some of our results. We have also moved Supplemental Figure 6 to the main text as Figure 3, because of the relevance of the corresponding findings for the main message of our manuscript, and we have rearranged the text accordingly, and renumbered the figures. Lastly, we have added one more supplemental figure to graphically summarize some of our key findings.