Der RANK-Ligand-Antikörper Denosumab als Beispiel der biotechnologischen Medikamentenentwicklung

H. Resch; A. Trubrich; R. Kocijan; Ch. Muschitz

doi:10.1055/s-0037-1619994

Osteologie, Table of Contents

Osteologie 2011; 20(03): 203-210
DOI: 10.1055/s-0037-1619994

Knochenzellbiologie und Osteoporosetherapie

Schattauer GmbH

Der RANK-Ligand-Antikörper Denosumab als Beispiel der biotechnologischen Medikamentenentwicklung

Denosumab – the RANKL-antibody as an example of the biotechnological development

H. Resch

¹Krankenhaus der Barmherzigen Schwestern Wien, II. Medizinische Abteilung, Akademisches Lehrkrankenhaus der Medizinischen Universität Wien, Österreich

,

A. Trubrich

¹Krankenhaus der Barmherzigen Schwestern Wien, II. Medizinische Abteilung, Akademisches Lehrkrankenhaus der Medizinischen Universität Wien, Österreich

,

R. Kocijan

¹Krankenhaus der Barmherzigen Schwestern Wien, II. Medizinische Abteilung, Akademisches Lehrkrankenhaus der Medizinischen Universität Wien, Österreich

,

Ch. Muschitz

¹Krankenhaus der Barmherzigen Schwestern Wien, II. Medizinische Abteilung, Akademisches Lehrkrankenhaus der Medizinischen Universität Wien, Österreich

› Author Affiliations

Abstract

Zusammenfassung

RANK-Ligand ist der wichtigste Faktor für die Bildung, Funktion und das Überleben von Osteoklasten, die für den kontinuierlichen Knochenumbau verantwortlich sind. Indem RANKL an RANK auf unreifen und reifen Osteoklasten bindet, fördert er die Osteoklastogenese und die Aktivität der reifen Zellen. In vivo wird RANKL durch Osteoprotegerin (OPG) negativ reguliert. OPG bindet an RANK-Ligand, neutralisiert ihn und hemmt so die Knochenresorption. Diese Faktoren liegen im gesunden Knochen in einem Gleichgewicht vor und ein Ungleichgewicht ist meist die Ursache für Knochenerkrankungen wie Osteoporose. Untersuchungen an Knockout- und transgenen Mäusen belegen die zentrale Rolle des RANKL/OPG-Systems beim Knochenstoffwechsel. Ovariektomierte Ratten dienen als Modell für die postmenopausale Osteoporose, die sich bei diesen Tieren durch Gabe von OPG wirksam behandeln lässt. Diese präklinischen Versuche mündeten in der klinischen Entwicklung von Denosumab. Denosumab ist ein zugelassener, vollhumaner, monoklonaler Antikörper, der mit hoher Affinität an den humanen RANK-Liganden bindet und dessen Aktivität reversibel hemmt. Klinische Studien der Phase III belegen die Wirksamkeit dieses neuartigen Wirkstoffs bei Patientinnen mit postmenopausaler Osteoporose.

Summary

RANK ligand has been identified as the primary mediator of osteoclast formation, function, and survival. Osteoclasts are responsible for continuous bone turnover. Osteoclastogenesis is initiated when RANK ligand binds to RANK on precursor osteoclasts and RANK increases activity of mature osteoclasts. In vivo RANKL is negatively controlled by osteoprotegerin (OPG). OPG binds to and neutralizes the effects of RANK ligand, thereby, inhibiting bone resorption. In healthy bone, these factors are balanced and an imbalance is a major cause of bone diseases such as osteoporosis. Research in knockout and transgenic mice revealed the pivotal role of the RANKL/OPG pathway in bone turnover. Ovariectomized rats are a model of postmenopausal osteoporosis, which could be treated effectively by OPG in these animals.These preclinical studies led to the development of Denosumab. Denosumab is an approved, fully human monoclonal antibody that binds with high affinity and inhibits the activity of human RANK ligand. Clinical phase 3 studies demonstrated efficacy of this novel agent in patients with postmenopausal osteoporosis.

Schlüsselwörter

RANK-Ligand - Osteoprotegerin - Osteoporose - Denosumab

Keywords

RANK ligand - osteoprotegerin - osteoporosis - denosumab

Full Text

References

Literatur
1 Karsenty G, Wagner EF. Reaching a genetic and molecular understanding of skeletal development. Dev Cell 2002; 02: 389-406.
2 Rauner M, Sipos W, Pietschmann P. Osteoimmunology. Int Arch Allergy, Immunol 2007; 143: 31-48.
3 Pietschmann P, Stöckl J, Draxler J. et al. Functional and phenotypic characteristics of dendritic cells generated in human plasma supplemented medium. Scand J Immunol 2000; 51: 377-383.
4 Yoshida H, Hayashi S, Kunisada T. et al. The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 1990; 345: 442-444.
5 Lacey DL, Timms E, Tan HL. et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998; 93: 165-176.
6 Kostenuik PJ, Shalhoub V. Osteoprotegerin: a physiological and pharmacological inhibitor of bone resorption. Curr Pharm Des 2001; 07: 613-635.
7 Kong YY, Yoshida H, Sarosi I. et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 1999; 397: 315-323.
8 Chen G, Sircar K, Aprikian A. et al. Expression of RANKL/RANK/OPG in primary and metastatic human prostate cancer as markers of disease stage and functional regulation. Cancer 2006; 107: 289-298.
9 Simonet WS, Lacey DL, Dunstan CR. et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997; 89: 309-319.
10 Bucay N, Sarosi I, Dunstan CR. et al. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 1998; 12: 1260-1268.
11 Collin-Osdoby P. Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin. Circ Res 2004; 95: 1046-1057.
12 Hofbauer LC, Schoppet M. Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases. JAMA 2004; 292: 490-495.
13 Wutzl A, Brozek W, Lernbass I. et al. Bone morphogenetic proteins 5 and 6 stimulate osteoclast generation. J Biomed Mater Res A 2006; 77: 75-83.
14 Winzer M, Rauner M, Pietschmann P. Glycitein decreases the generation of murine osteoclasts and increases apoptosis. Wien Med Wochenschr 2010; 160: 446-451.
15 Eghbali-Fatourechi G, Khosla S, Sanyal A. et al. Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. J Clin Invest 2003; 111: 1221-1230.
16 Patsch JM, Kohler T, Berzlanovich A. et al. Trabecular bone microstructure and local gene expression in iliac crest biopsies of men with idiopathic osteoporosis. J Bone Miner Res 2011; 26: 1584-1592.
17 Fata JE, Kong YY, Li J. et al. The osteoclast differentiation factor osteoprotergerin ligandis essential for mammary gland development. Cell 2000; 103: 41-50.
18 Asselin-Labat ML, Vaillant F, Sheridan JM. et al. Control of mammary stem cell function by steroid hormone signalling. Nature 2010; 465: 796-802.
19 Li J, Sarosi I, Yan XQ. et al. RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci USA 2000; 97: 1566-1571.
20 Ominsky MS, Stolina M, Li X. et al. One year of transgenic overexpression of osteoprotegerin in rats suppressed bone resorption and increased vertebral bone volume, density, and strength. J Bone Miner Res 2009; 24: 1234-1246.
21 Ross AB, Bateman TA, Kostenuik PJ. et al. The effects of osteoprotegerin on the mechanical properties of rat bone. J Mater Sci Mater Med 2001; 12: 583-588.
22 Rauner M, Stupphann D, Haas M. et al. The HLA-B27 transgenic rat, a model of spondyloarthritis, has decreased bone mineral density and increased RANKL to osteoprotegerin mRNA ratio. J Rheumatol 2009; 36: 120-126.
23 Ominsky MS, Li X, Asuncion FJ. et al. RANKL inhibition with osteoprotegerin increases bone strength by improving cortical and trabecular bone architecture in ovariectomized rats. J Bone Miner Res 2008; 23: 672-682.
24 Hughes AE, Ralston SH, Marken J. et al. Mutations in TNFRSF11A, affecting the signal peptide of RANK cause familial expansile osteolysis. Nat Genet 2000; 24: 45-48.
25 Whyte MP, Obrecht SE, Finnegan PM. et al. Osteoprotegerin deficiency and juvenile Paget´s disease. N Engl J Med 2002; 347: 175-184.
26 Body JJ, Greipp P, Coleman RE. et al. A phase I study of AMGN-0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases. Cancer 2003; 97: 887-892.
27 McClung MR, Lewiecki EM, Cohen SB. et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 2006; 354: 821-831.
28 Green LL. Antibody engineering via genetic engineering of the mouse: XenoMouse strains are a vehicle for the facile generation of therapeutic human monoclonal antibodies. J Immunol Methods 1999; 231: 11-23.
29 Lobo ED, Hansen RJ, Balthasar JP. Antibody pharmacokinetics and pharmacodynamics. J Pharm Sci 2004; 93: 2645-2668.
30 Rodriguez RD, Sutjandra L, Peterson MC. et al. Population pharmacokinetic meta-analysis of Denosumab in healthy and cancer subjects and postmenopausal women with osteopenia or osteoporosis. 2009 AAPS National Biotechnology Conference. Abstract T2083.
31 Elliott R, Kostenuik P, Chen C. Denosumab is a selective inhibitor of human receptor activator of NF-?B ligand that blocks osteoclast formation in vitro and in vivo. European Organisation for Research and Treatment of Cancer (EORTC) 2006. Abstract #197.
32 Body JJ, Facon T, Coleman RE. et al. A study of the biological receptor activator of nuclear factor-?B ligand inhibitor, Denosumab, in patients with multiple myeloma or bone metastases from breast cancer. Clin Cancer Res 2006; 12: 1221-1228.
33 Peterson MC, Stouch BJ, Martin SW. et al. The pharmacokinetics of Denosumab (AMG 162) following various multiple subcutaneous dosing regimen in postmenopausal women with low bone mass. J Bone Miner Res 2005; 20 (Suppl. 01) S293.
34 Block G, Bone HG, Fang L. et al. A single dose study of denosumab in patients with various degrees of renal impairment. American Journal of Kidney Diseases 2010; 55: B46.
35 Burkiewicz JS, Scarpace SL, Bruce SP. Denosumab in osteoporosis and oncology. Ann Pharmacother 2009; 43: 1445-1455.
36 Lewiecki EM, Miller PD, McClung MR. et al. Twoyear treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low BMD. J Bone Miner Res 2007; 22: 1832-1841.
37 Miller PD, Bolognese MA, Lewiecki EM. et al. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone 2008; 43: 222-229.
38 Miller PD, Wagman RB, Peacock M. et al. Effect of Denosumab on Bone Mineral Density and Biochemical Markers of Bone Turnover: Six-Year Results of a Phase 2 Clinical Trial. J Clin Endocrinol Metab 2011; 96: 394-402.
39 Cummings SR, Martin JS, McClung MR. et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009; 361: 756-765.
40 Papapoulos S, Chapurlat R, Brand ML. et al. Fiveyear denosumab treatment of postmenopausal women with osteoporosis: results from the first two years of the FREEDOM trial extension. Osteoporosis Int. 2011 22. (Suppl 1): Abstract #OC25; verfügbar unter: http://www.ecceo11-iof.org/abstracts/ index.html Zugriff am 27.7.2011.
41 Bone HG, Bolognese M, Yuen C. et al. Effects of Denosumab on Bone Mineral Density and Bone Turnover in Postmenopausal Women. J Clin Endocrin Metab 2008; 93: 2149-2157.
42 Brown JP, Prince RL, Deal C. et al. Comparison of the Effect of Denosumab and Alendronate on BMD and Biochemical Markers of Bone Turnover in Postmenopausal Women With Low Bone Mass: A Randomized, Blinded, Phase 3 Trial. J Bone Miner Res 2009; 24: 153-161.
43 Kendler DL, Roux C, Benhamou CL. et al. Effects of Denosumab on Bone Mineral Density and Bone Turnover in Postmenopausal Women Transitioning from Alendronate Therapy. J Bone Miner Res 2010; 25: 72-81.
44 Smith MR, Egerdie B, Hernández NToriz. et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med 2009; 361: 745-755.
45 Toulis KA, Anastasilakis AD. Increased risk of serious infections in women with osteopenia or osteoporosis treated with denosumab. Osteoporos Int 2010; 21: 1963-1964.
46 Ellis GK, Bone HG, Chlebowski R. et al. Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J Clin Oncol 2008; 26: 4875-4882.
47 Hsu H, Lacey DL, Dunstan CR. et al. Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci USA 1999; 96: 3540-3545.
48 Mizuno A, Kanno T, Hoshi M. et al. Transgenic mice overexpressing soluble osteoclast differentiation factor (sODF) exhibit severe osteoporosis. J Bone Miner Metab 2002; 20: 337-344.
49 Lacey DL, Tan HL, Lu J. et al. Osteoprotegerin ligand modulates murine osteoclast survival in vitro and in vivo. Am J Pathol 2000; 157: 435-448.
50 Morony S, Capparelli C, Lee R. et al. A chimeric form of osteoprotegerin inhibits hypercalcemia and bone resorption induced by IL-1beta, TNF-alpha, PTH, PTHrP, and 1,25(OH)₂D₃ . J Bone Miner Res 1999; 14: 1478-1485.