An anti-ACVR1 antibody exacerbates heterotopic ossification by fibro-adipogenic progenitors in fibrodysplasia ossificans progressiva mice
John B. Lees-Shepard, … , Jeffrey W. Hunter, David J. Goldhamer
John B. Lees-Shepard, … , Jeffrey W. Hunter, David J. Goldhamer
Published May 3, 2022
Citation Information: J Clin Invest. 2022;132(12):e153795. https://doi.org/10.1172/JCI153795.
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Research Article Bone biology

An anti-ACVR1 antibody exacerbates heterotopic ossification by fibro-adipogenic progenitors in fibrodysplasia ossificans progressiva mice

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease characterized by progressive and catastrophic heterotopic ossification (HO) of skeletal muscle and associated soft tissues. FOP is caused by dominantly acting mutations in the gene encoding the bone morphogenetic protein (BMP) type I receptor, ACVR1 (ALK2), the most prevalent of which results in an arginine to histidine substitution at position 206 (ACVR1[R206H]). The fundamental pathological consequence of FOP-causing ACVR1 receptor mutations is to enable activin A to initiate canonical BMP signaling in fibro-adipogenic progenitors (FAPs), which drives HO. We developed a monoclonal blocking antibody (JAB0505) against the extracellular domain of ACVR1 and tested its effect on HO in 2 independent FOP mouse models. Although JAB0505 inhibited BMP-dependent gene expression in wild-type and ACVR1(R206H)-overexpressing cell lines, JAB0505 treatment profoundly exacerbated injury-induced HO. JAB0505-treated mice exhibited multiple, distinct foci of heterotopic lesions, suggesting an atypically broad anatomical domain of FAP recruitment to endochondral ossification. This was accompanied by dysregulated FAP population growth and an abnormally sustained immunological reaction following muscle injury. JAB0505 drove injury-induced HO in the absence of activin A, indicating that JAB0505 has receptor agonist activity. These data raise serious safety and efficacy concerns for the use of bivalent anti-ACVR1 antibodies to treat patients with FOP.

Authors

John B. Lees-Shepard, Sean J. Stoessel, Julian T. Chandler, Keith Bouchard, Patricia Bento, Lorraine N. Apuzzo, Parvathi M. Devarakonda, Jeffrey W. Hunter, David J. Goldhamer

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Figure 2

JAB0505 profoundly exacerbates HO and extends the period of lesional growth in FOP mice.

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JAB0505 profoundly exacerbates HO and extends the period of lesional gro...
(A) Representative μCT images of HO in Acvr1FLEx(R206H)/+; CAG-CreERT2 mice 20 days after cardiotoxin-induced injury of the gastrocnemius muscle (Untreated, n = 3; JAB0505, n = 4). (B) Representative μCT images of HO (pseudocolored green) in Acvr1tnR206H/+; Tie2-Cre mice 21 days after pinch injury of the gastrocnemius muscle (Untreated, n = 11; JAB0505, n = 10). (C) Quantification of HO volumes as a function of time after muscle pinch injury of Acvr1tnR206H/+; Tie2-Cre mice. Untreated, n = 11; JAB0505 (10 mg/kg), n = 6. Error bars represent ±SEM. ****P ≤ 0.0001 by 2-way ANOVA with Sidak’s multiple-comparison test. (D) Paired single transverse slice and 3D reconstructed μCT images of the distal hind limb of Acvr1tnR206H/+; Tie2-Cre mice at the indicated times after hind limb muscle pinch injury with and without administration of JAB0505. Mineralized bone in the slice images is pseudocolored green. Radio-opaque lesional tissue below the threshold set for quantification of mineralized bone (white arrows in day 14 slices) is extensive at day 14 in JAB0505-treated mice. Mineralized bone in day 14 slices is barely visible at this magnification. HO volumes are given for images prior to day 35. The tibia and fibula are labeled with asterisks in the day 14 slices. Pelvic bones present in day 21, 28, and 35 slices of JAB0505-treated mice are denoted with arrowheads. To avoid confusion with HO, the baculum present in some images was removed by segmentation.