A bispecific antibody targeting sclerostin and DKK-1 promotes bone mass accrual and fracture repair

Nature Communications

Volumn 7, Issue , 2016, Pages

  Florio, Monica ^a   Gunasekaran, Kannan ^a   Stolina, Marina ^a   Li, Xiaodong ^a   Liu, Ling ^a   Tipton, Barbara ^a   Salimi Moosavi, Hossein ^a   Asuncion, Franklin J ^a   Li, Chaoyang ^a   Sun, Banghua ^a   Tan, Hong Lin ^a   Zhang, Li ^a   Han, Chun Ya ^a   Case, Ryan ^a   Duguay, Amy N ^a   Grisanti, Mario ^a   Stevens, Jennitte ^a   Pretorius, James K ^a   Pacheco, Efrain ^a   Jones, Heidi ^a   Chen, Qing ^a   Soriano, Brian D ^a   Wen, Jie ^a   Heron, Brenda ^a   Jacobsen, Frederick W ^a   Brisan, Emil ^a   Richards, William G ^a   Ke, Hua Zhu ^a,b   Ominsky, Michael S ^a   more..

^a AMGEN INC   (United States)

^b UCB PHARMA   (Belgium)

Author keywords

[No Author keywords available]

Indexed keywords

BISPECIFIC ANTIBODY; DICKKOPF 1 ANTIBODY; DICKKOPF 1 PROTEIN; MESSENGER RNA; SCLEROSTIN; SCLEROSTIN ANTIBODY; UNCLASSIFIED DRUG; DKK1 PROTEIN, MOUSE; GLYCOPROTEIN; SIGNAL PEPTIDE; SOST PROTEIN, MOUSE;

ANTIBODY; BONE; FEEDBACK MECHANISM; INHIBITION; PRIMATE; PROTEIN; RODENT; THEORETICAL STUDY;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BONE MASS; BONE REMODELING; BONE STRENGTH; CONTROLLED STUDY; DRUG TARGETING; FEMALE; FEMUR DIAPHYSIS; FEMUR FRACTURE; FEMUR METAPHYSIS; FRACTURE HEALING; GENE EXPRESSION; MALE; MONOTHERAPY; MOUSE; NEGATIVE FEEDBACK; NONHUMAN; OSSIFICATION; RAT; SUBCUTANEOUS IMMUNOTHERAPY; UPREGULATION; ANIMAL; BONE DENSITY; BONE DEVELOPMENT; DISEASE MODEL; DRUG EFFECT; FRACTURE; GENETICS; HUMAN; KNOCKOUT MOUSE; MACACA FASCICULARIS; METABOLISM; PATHOPHYSIOLOGY; SPRAGUE DAWLEY RAT; WNT SIGNALING; WOUND HEALING;

ANIMALIA; PRIMATES; RODENTIA;

ANIMALS; ANTIBODIES, BISPECIFIC; BONE DENSITY; DISEASE MODELS, ANIMAL; FEMALE; FRACTURES, BONE; GLYCOPROTEINS; HUMANS; INTERCELLULAR SIGNALING PEPTIDES AND PROTEINS; MACACA FASCICULARIS; MALE; MICE; MICE, KNOCKOUT; OSTEOGENESIS; RATS; RATS, SPRAGUE-DAWLEY; WNT SIGNALING PATHWAY; WOUND HEALING;

EID: 84971221594     PISSN: None     EISSN: 20411723     Source Type: Journal    
DOI: 10.1038/ncomms11505     Document Type: Article

References (43)

1. Baron, R. & Kneissel, M. WNT signalling in bone homeostasis and disease: from human mutations to treatments. Nat. Med. 19, 179-192 (2013).
2. Li, X. et al. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J. Biol. Chem. 280, 19883-19887 (2005).
3. van Bezooijen, R. L. et al. Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist. J. Exp. Med. 199, 805-814 (2004).
4. Brunkow, M. E. et al. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am. J. Hum. Genet. 68, 577-589 (2001).
5. Balemans, W. et al. Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J. Med. Genet. 39, 91-97 (2002).
6. Li, X. et al. Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J. Bone Miner. Res. 23, 860-869 (2008).
7. Bourhis, E. et al. Wnt antagonists bind through a short peptide to the first beta-propeller domain of LRP5/6. Structure 19, 1433-1442 (2011).
8. Ahn, V. E. et al. Structural basis of Wnt signaling inhibition by Dickkopf binding to LRP5/6. Dev. Cell 21, 862-873 (2011).
9. Cheng, Z. et al. Crystal structures of the extracellular domain of LRP6 and its complex with DKK1. Nat. Struct. Mol. Biol. 18, 1204-1210 (2011).
10. Bourhis, E. et al. Reconstitution of a frizzled8.Wnt3a.LRP6 signaling complex reveals multiple Wnt and Dkk1 binding sites on LRP6. J. Biol. Chem. 285, 9172-9179 (2010).
11. Mukhopadhyay, M. et al. Dickkopf1 is required for embryonic head induction and limb morphogenesis in the mouse. Dev. Cell 1, 423-434 (2001).
12. Ai, M., Holmen, S. L., Van Hul, W., Williams, B. O. & Warman, M. L. Reduced affinity to and inhibition by DKK1 form a common mechanism by which high bone mass-associated missense mutations in LRP5 affect canonical Wnt signaling. Mol. Cell Biol. 25, 4946-4955 (2005).
13. Semenov, M. V. & He, X. LRP5 mutations linked to high bone mass diseases cause reduced LRP5 binding and inhibition by SOST. J. Biol. Chem. 281, 38276-38284 (2006).
14. Balemans, W. et al. The binding between sclerostin and LRP5 is altered by DKK1 and by high-bone mass LRP5 mutations. Calcif. Tissue Int. 82, 445-453 (2008).
15. Estrada, K. et al. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat. Genet. 44, 491-501 (2012).
16. McClung, M. R. et al. Romosozumab in postmenopausal women with low bone mineral density. N. Engl. J. Med. 370, 412-420 (2014).
17. Padhi, D., Jang, G., Stouch, B., Fang, L. & Posvar, E. Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J. Bone. Miner. Res. 26, 19-26 (2011).
18. Munshi, N. C. et al. Early evidence of anabolic bone activity of BHQ880, a fully human anti-DKK1 neutralizing antibody: results of a phase 2 study in previously untreated patients with smoldering multiple myeloma at risk for progression. Blood (ASH Annual Meeting Abstracts) 120, 331 (2012).
19. Edenfield, W. J. et al. A phase 1 study evaluating the safety and efficacy of DKN-01, an investigational monoclonal antibody (Mab) in patients (pts) with advanced non-small cell lung cancer. J Clin Oncol (ASCO Annual Meeting Abstracts) 32 (suppl. abstr. 8068) (2014).
20. Iyer, S. P. et al. A Phase IB multicentre dose-determination study of BHQ880 in combination with anti-myeloma therapy and zoledronic acid in patients with relapsed or refractory multiple myeloma and prior skeletal-related events. Br. J. Haematol. 167, 366-375 (2014).
21. Recker, R. R. et al. A randomized, double-blind phase 2 clinical trial of blosozumab, a sclerostin antibody, in postmenopausal women with low bone mineral density. J. Bone Miner. Res. 30, 216-224 (2015).
22. Ominsky, M. S. et al. Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength. J Bone Miner Res. 25, 948-959 (2010).
23. Li, X. et al. Dickkopf-1 regulates bone formation in young growing rodents and upon traumatic injury. J. Bone Miner. Res. 26, 2610-2621 (2011).
24. Ominsky, M. S. et al. Inhibition of sclerostin by monoclonal antibody enhances bone healing and improves bone density and strength of nonfractured bones. J. Bone Miner. Res. 26, 1012-1021 (2011).
25. Bajada, S., Marshall, M. J., Wright, K. T., Richardson, J. B. & Johnson, W. E. Decreased osteogenesis, increased cell senescence and elevated Dickkopf-1 secretion in human fracture non union stromal cells. Bone 45, 726-735 (2009).
26. Stolina, M. et al. Temporal changes in systemic and local expression of bone turnover markers during six months of sclerostin antibody administration to ovariectomized rats. Bone 67, 305-313 (2014).
27. Chamorro, M. N. et al. FGF-20 and DKK1 are transcriptional targets of beta-catenin and FGF-20 is implicated in cancer and development. EMBO J. 24, 73-84 (2005).
28. Holmes, D. Buy buy bispecific antibodies. Nat. Rev. Drug Discov. 10, 798-800 (2011).
29. van Lierop, A. H., Moester, M. J., Hamdy, N. A. & Papapoulos, S. E. Serum Dickkopf 1 levels in sclerostin deficiency. J. Clin. Endocrinol. Metab. 99, E252-E256 (2014).
30. Anastasilakis, A. D. et al. The effect of teriparatide on serum Dickkopf-1 levels in postmenopausal women with established osteoporosis. Clin. Endocrinol. (Oxf.) 72, 752-757 (2010).
31. Robling, A. G. et al. Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J. Biol. Chem. 283, 5866-5875 (2008).
32. Bellido, T. et al. Chronic elevation of parathyroid hormone in mice reduces expression of sclerostin by osteocytes: a novel mechanism for hormonal control of osteoblastogenesis. Endocrinology 146, 4577-4583 (2005).
33. Ozaki, A., Tsunoda, M., Kinoshita, S. & Saura, R. Role of fracture hematoma and periosteum during fracture healing in rats: interaction of fracture hematoma and the periosteum in the initial step of the healing process. J. Orthop. Sci. 5, 64-70 (2000).
34. Wei, W. et al. Biphasic and dosage-dependent regulation of osteoclastogenesis by b-catenin. Mol. Cell. Biol. 31, 4706-4719 (2011).
35. Ominsky, M. S., Niu, Q. T., Li, C., Li, X. & Ke, H. Z. Tissue-level mechanisms responsible for the increase in bone formation and bone volume by sclerostin antibody. J. Bone Miner. Res. 29, 1424-1430 (2014).
36. Fulciniti, M. et al. Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma. Blood 114, 371-379 (2009).
37. Li, J. et al. Dkk1-mediated inhibition of Wnt signaling in bone results in osteopenia. Bone 39, 754-766 (2006).
38. Chen, Y. et al. Beta-catenin signaling plays a disparate role in different phases of fracture repair: implications for therapy to improve bone healing. PLoS Med. 4, e249 (2007).
39. Li, X. et al. Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J. Bone Miner. Res. 24, 578-588 (2009).
40. Lee, B. & Richards, F. M. The interpretation of protein structures: estimation of static accessibility. J. Mol. Biol. 55, 379-400 (1971).
41. Gunasekaran, K. et al. Enhancing antibody Fc heterodimer formation through electrostatic steering effects: applications to bispecific molecules and monovalent IgG. J. Biol. Chem. 285, 19637-19646 (2010).
42. Liu, Z. et al. A novel antibody engineering strategy for making monovalent bispecific heterodimeric IgG antibodies by electrostatic steering mechanism. J. Biol. Chem. 290, 7535-7562 (2015).
43. Estes, B. et al. Uncovering methods for the prevention of protein aggregation and improvement of product quality in a transient expression system. Biotechnol. Prog. 31, 258-267 (2015).