Anti-ACVR1 antibodies exacerbate heterotopic ossification in fibrodysplasia ossificans progressiva (FOP) by activating FOP-mutant ACVR1
Senem Aykul, … , Vincent Idone, Sarah J. Hatsell
Senem Aykul, … , Vincent Idone, Sarah J. Hatsell
Published May 5, 2022
Citation Information: J Clin Invest. 2022;132(12):e153792. https://doi.org/10.1172/JCI153792.
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Research Article Bone biology

Anti-ACVR1 antibodies exacerbate heterotopic ossification in fibrodysplasia ossificans progressiva (FOP) by activating FOP-mutant ACVR1

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 anti–activin A via monoclonal antibody treatment. Hence, we surmised that anti-ACVR1 antibodies that block activation of ACVR1 by ligands should also inhibit HO in FOP and provide an additional therapeutic option for this condition. Therefore, we generated anti-ACVR1 monoclonal antibodies that block ACVR1’s activation by its ligands. Surprisingly, in vivo, these anti-ACVR1 antibodies stimulated HO and activated signaling of FOP-mutant ACVR1. This property was restricted to FOP-mutant ACVR1 and resulted from anti-ACVR1 antibody–mediated dimerization of ACVR1. Conversely, wild-type ACVR1 was inhibited by anti-ACVR1 antibodies. These results uncover an additional property of FOP-mutant ACVR1 and indicate that anti-ACVR1 antibodies should not be considered as therapeutics for FOP.

Authors

Senem Aykul, Lily Huang, Lili Wang, Nanditha M. Das, Sandra Reisman, Yonaton Ray, Qian Zhang, Nyanza Rothman, Kalyan C. Nannuru, Vishal Kamat, Susannah Brydges, Luca Troncone, Laura Johnsen, Paul B. Yu, Sergio Fazio, John Lees-Shepard, Kevin Schutz, Andrew J. Murphy, Aris N. Economides, Vincent Idone, Sarah J. Hatsell

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Figure 6

ACVR1[R206H;S330P] is activated by anti-ACVR1 antibodies but to a lesser degree than ACVR1[R206H].

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ACVR1[R206H;S330P] is activated by anti-ACVR1 antibodies but to a lesser...
(A and B) Acvr1[R206H]FlEx/+; GT(ROSA26)SorCreERT2/+ mice or Acvr1huecto;[R206H]FlEx;[S330P]/+; GT(ROSA26)SorCreERT2/+ (FOP[S330P]) mice were injected with tamoxifen to initiate the model and concurrently injected with anti-ACVR1 mAb 1 or isotype control antibody at 10 mg/kg weekly (n = 8/group). Total heterotopic bone volume was measured 3 weeks after initiation of the model. ACVR1 mAb 1 increased HO compared with isotype control in both mouse models, though to a lesser degree in FOP[S330P] mice. Data show the mean ± SD. *P < 0.05, ***P < 0.001 by 1-way ANOVA with Bonferroni’s multiple-comparison test. (C) Acvr1huecto;[R206H;S330P]/+; GT(ROSA26)SorCreERT2/+ ([R206H;S330P]/+) mES cells were treated with 10 nM activin A, anti-ACVR1 mAb 1, or anti-hACVR1 antibody and assessed for phosphorylated Smad1/5/8. Anti-hACVR1 mAb (that only binds ACVR1[huecto;R206H;S330P] and not WT mouse ACVR1) induced Smad1/5/8 phosphorylation, whereas mAb 1 (which recognizes both human and mouse ACVR1) did not drive an appreciable level of Smad1/5/8 phosphorylation.