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

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

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