The Anti-ADAMTS-5 Nanobody® M6495 Protects Cartilage Degradation Ex Vivo

Siebuhr, Anne Sofie; Werkmann, Daniela; Bay‐Jensen, Anne‐Christine; Thudium, Christian S.; Karsdal, Morten A.; Serruys, Benedikte; Ladel, Christoph; Michaelis, M.; Lindemann, Sven

doi:10.3390/ijms21175992

Cited by 36 publications

(26 citation statements)

References 43 publications

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“…AGG-523, an orally small molecule inhibitor of ADAMTS-4 and ADAMTS-5, was the first to enter the human phase I study (NCT00454298 and NCT00427687), but these trials were discontinued for unknown reasons. M6495, a novel anti-ADAMTS-5 inhibiting Nanobody, showed dose-dependent protection against cartilage deterioration in ex vivo cartilage cultures (Siebuhr et al, 2020). A phase Ib (NCT03583346) clinical trial to assess safety, tolerability, immunogenicity, pharmacokinetics, and pharmacodynamics of SC injections of M6495 in knee OA patients was completed in 2019, but the results have not yet been published.…”

Section: Mmp/adamts Inhibitorsmentioning

confidence: 99%

New Trends in Pharmacological Treatments for Osteoarthritis

et al. 2021

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Osteoarthritis (OA) is the leading cause of function loss and disability among the elderly, with significant burden on the individual and society. It is a severe disease for its high disability rates, morbidity, costs, and increased mortality. Multifactorial etiologies contribute to the occurrence and development of OA. The heterogeneous condition poses a challenge for the development of effective treatment for OA; however, emerging treatments are promising to bring benefits for OA management in the future. This narrative review will discuss recent developments of agents for the treatment of OA, including potential disease-modifying osteoarthritis drugs (DMOADs) and novel therapeutics for pain relief. This review will focus more on drugs that have been in clinical trials, as well as attractive drugs with potential applications in preclinical research. In the past few years, it has been realized that a complex interaction of multifactorial mechanisms is involved in the pathophysiology of OA. The authors believe there is no miracle therapeutic strategy fitting for all patients. OA phenotyping would be helpful for therapy selection. A variety of potential therapeutics targeting inflammation mechanisms, cellular senescence, cartilage metabolism, subchondral bone remodeling, and the peripheral nociceptive pathways are expected to reshape the landscape of OA treatment over the next few years. Precise randomized controlled trials (RCTs) are expected to identify the safety and efficacy of novel therapies targeting specific mechanisms in OA patients with specific phenotypes.

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Section: Mmp/adamts Inhibitorsmentioning

confidence: 99%

New Trends in Pharmacological Treatments for Osteoarthritis

et al. 2021

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“…Several antibodies that are in commercial drug development pipelines were tested in phase I clinical studies. Safety and dose escalation studies were recently completed for an ADAMTS5 nanobody (M6495, Merck KGaA) ( NCT03583346 , NCT03224702 ) demonstrating safety, tolerability and a reduction in aggrecan proteolysis ( Siebuhr et al, 2020 ). Further phase II clinical trials will be performed by Novartis ( Merck, 2021 ).…”

Section: Inhibitors Of Adamts Proteasesmentioning

confidence: 99%

Regulation of ADAMTS Proteases

Rose

Taye

Karoulias

et al. 2021

Front. Mol. Biosci.

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A disintegrin and metalloprotease with thrombospondin type I motifs (ADAMTS) proteases are secreted metalloproteinases that play key roles in the formation, homeostasis and remodeling of the extracellular matrix (ECM). The substrate spectrum of ADAMTS proteases can range from individual ECM proteins to entire families of ECM proteins, such as the hyalectans. ADAMTS-mediated substrate cleavage is required for the formation, remodeling and physiological adaptation of the ECM to the needs of individual tissues and organ systems. However, ADAMTS proteases can also be involved in the destruction of tissues, resulting in pathologies such as arthritis. Specifically, ADAMTS4 and ADAMTS5 contribute to irreparable cartilage erosion by degrading aggrecan, which is a major constituent of cartilage. Arthritic joint damage is a major contributor to musculoskeletal morbidity and the most frequent clinical indication for total joint arthroplasty. Due to the high sequence homology of ADAMTS proteases in their catalytically active site, it remains a formidable challenge to design ADAMTS isotype-specific inhibitors that selectively inhibit ADAMTS proteases responsible for tissue destruction without affecting the beneficial functions of other ADAMTS proteases. In vivo, proteolytic activity of ADAMTS proteases is regulated on the transcriptional and posttranslational level. Here, we review the current knowledge of mechanisms that regulate ADAMTS protease activity in tissues including factors that induce ADAMTS gene expression, consequences of posttranslational modifications such as furin processing, the role of endogenous inhibitors and pharmacological approaches to limit ADAMTS protease activity in tissues, which almost exclusively focus on inhibiting the aggrecanase activity of ADAMTS4 and ADAMTS5.

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“…This finding opens the possibility to specifically block ADAMTS-5 activity by small molecules or preferably, by antibodies [ 60 ]. In fact, employment of antibodies against ADAMTS-5, some of which have entered a phase I clinical trial, emerges as a promising therapeutic option against arthritic diseases [ 61 , 62 , 63 ].…”

Section: Hyalectans Cleavage By Adamtssmentioning

confidence: 99%

Hyalectanase Activities by the ADAMTS Metalloproteases

Fontanil

Mohamedi

Casado

et al. 2021

IJMS

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The hyalectan family is composed of the proteoglycans aggrecan, versican, brevican and neurocan. Hyalectans, also known as lecticans, are components of the extracellular matrix of different tissues and play essential roles in key biological processes including skeletal development, and they are related to the correct maintenance of the vascular and central nervous system. For instance, hyalectans participate in the organization of structures such as perineural nets and in the regulation of neurite outgrowth or brain recovery following a traumatic injury. The ADAMTS (A Disintegrin and Metalloprotease domains, with thrombospondin motifs) family consists of 19 secreted metalloproteases. These enzymes also perform important roles in the structural organization and function of the extracellular matrix through interactions with other matrix components or as a consequence of their catalytic activity. In this regard, some of their preferred substrates are the hyalectans. In fact, ADAMTSs cleave hyalectans not only as a mechanism for clearance or turnover of proteoglycans but also to generate bioactive fragments which display specific functions. In this article we review some of the physiological and pathological effects derived from cleavages of hyalectans mediated by ADAMTSs.

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The Anti-ADAMTS-5 Nanobody® M6495 Protects Cartilage Degradation Ex Vivo

Cited by 36 publications

References 43 publications

New Trends in Pharmacological Treatments for Osteoarthritis

New Trends in Pharmacological Treatments for Osteoarthritis

Regulation of ADAMTS Proteases

Hyalectanase Activities by the ADAMTS Metalloproteases

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