A bispecific antibody targeting sclerostin and DKK-1 promotes bone mass accrual and fracture repair.
A bispecific antibody targeting sclerostin and DKK-1 promotes bone mass accrual and fracture repair.
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DOI：
10.1038/ncomms11505
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发表时间：
2016-05-27
影响因子：
16.6
通讯作者：
Ominsky MS
中科院分区：
文献类型：
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作者：
Florio M;Gunasekaran K;Stolina M;Li X;Liu L;Tipton B;Salimi-Moosavi H;Asuncion FJ;Li C;Sun B;Tan HL;Zhang L;Han CY;Case R;Duguay AN;Grisanti M;Stevens J;Pretorius JK;Pacheco E;Jones H;Chen Q;Soriano BD;Wen J;Heron B;Jacobsen FW;Brisan E;Richards WG;Ke HZ;Ominsky MS
Wnt拮抗剂sclerostin的抑制增加骨质疏松症患者和临床前动物模型中的骨量。在这里，我们显示了在用硬化蛋白抗体处理的动物中Wnt拮抗剂Dickkopf-1（DKK-1）的水平增加，表明限制Wnt驱动的骨形成的负反馈机制。为了检验我们的假设，即两种因子的共抑制进一步增加骨量，我们设计了一类中第一个在Fab区具有单残基对突变的双特异性抗体，以促进有效和稳定的同源轻链-重链配对。我们证明了sclerostin和DKK-1的双重抑制导致啮齿动物和非人灵长类动物中协同骨形成。此外，通过靶向骨折愈合的不同方面，双特异性抗体与单一疗法相比显示出上级骨修复活性。这项工作支持这种药物治疗和预防骨折的潜力，并提供了一种有前途的治疗方法，以减少低骨量疾病的负担。 阻断Wnt抑制剂sclerostin和DKK- 1的抗体增强骨形成和骨折修复。在这里，作者表明这些单特异性抗体诱导限制疗效的补偿机制，并设计了一种sclerostin/DKK-1双特异性抗体，其促进啮齿动物中上级骨折修复和灵长类动物中的骨形成。
Inhibition of the Wnt antagonist sclerostin increases bone mass in patients with osteoporosis and in preclinical animal models. Here we show increased levels of the Wnt antagonist Dickkopf-1 (DKK-1) in animals treated with sclerostin antibody, suggesting a negative feedback mechanism that limits Wnt-driven bone formation. To test our hypothesis that co-inhibition of both factors further increases bone mass, we engineer a first-in-class bispecific antibody with single residue pair mutations in the Fab region to promote efficient and stable cognate light–heavy chain pairing. We demonstrate that dual inhibition of sclerostin and DKK-1 leads to synergistic bone formation in rodents and non-human primates. Furthermore, by targeting distinct facets of fracture healing, the bispecific antibody shows superior bone repair activity compared with monotherapies. This work supports the potential of this agent both for treatment and prevention of fractures and offers a promising therapeutic approach to reduce the burden of low bone mass disorders. Antibodies that block the Wnt inhibitors sclerostin and DKK- 1 enhance bone formation and fracture repair. Here the authors show these monospecific antibodies induce compensatory mechanisms that limit efficacy, and have designed a sclerostin/DKK-1 bispecific antibody that promotes superior fracture repair in rodents and bone formation in primates.