An anti-ACVR1 antibody exacerbates heterotopic ossification by fibro-adipogenic progenitors in fibrodysplasia ossificans progressiva mice.
An anti-ACVR1 antibody exacerbates heterotopic ossification by fibro-adipogenic progenitors in fibrodysplasia ossificans progressiva mice.
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DOI：
10.1172/jci153795
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发表时间：
2022-06-15
影响因子：
15.9
通讯作者：
Goldhamer, David J.
中科院分区：
文献类型：
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作者：
Lees-Shepard, John B.;Stoessel, Sean J.;Chandler, Julian T.;Bouchard, Keith;Bento, Patricia;Apuzzo, Lorraine N.;Devarakonda, Parvathi M.;Hunter, Jeffrey W.;Goldhamer, David J.
进行性骨化性纤维发育不良（FOP）是一种罕见的遗传性疾病，其特征是骨骼肌及相关软组织进行性且灾难性的异位骨化（HO）。FOP是由编码骨形态发生蛋白（BMP）I型受体ACVR1（ALK2）的基因发生显性突变引起的，其中最常见的是导致第206位的精氨酸被组氨酸替代（ACVR1[R206H]）。导致FOP的ACVR1受体突变的基本病理后果是使激活素A能够在成纤维脂肪祖细胞（FAPs）中启动经典的BMP信号传导，从而驱动HO。我们开发了一种针对ACVR1细胞外结构域的单克隆阻断抗体（JAB0505），并在两种独立的FOP小鼠模型中测试了其对HO的影响。尽管JAB0505抑制了野生型和ACVR1（R206H）过表达细胞系中依赖BMP的基因表达，但JAB0505治疗却极大地加剧了损伤诱导的HO。接受JAB0505治疗的小鼠表现出多个不同的异位病变病灶，这表明FAP募集到软骨内骨化的解剖区域异常广泛。与此同时，肌肉损伤后FAP群体生长失调，免疫反应异常持续。在没有激活素A的情况下，JAB0505也能驱动损伤诱导的HO，这表明JAB0505具有受体激动剂活性。这些数据对使用二价抗ACVR1抗体治疗FOP患者的安全性和有效性提出了严重的担忧。
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.