The anti-ADAMTS-5 nanobody®, M6495, protects against cartilage breakdown in cartilage and synovial joint tissue explant models

Siebuhr, Anne Sofie; Bay-Jensen, A.-C.; Thudium, C.S.; Karsdal, Morten; Serruys, Benedikte; Werkmann, Daniela; Michaelis, M.; Ladel, C.; Lindemann, Sven

doi:10.1016/j.joca.2018.02.402

Cited by 10 publications

(5 citation statements)

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“…Furthermore, the anti-ADAMTS-5 inhibiting nanobody®-M6495 was able to suppress the release of degradation biomarkers and aggrecan fragments leading to reduced activation of TLR2. Thus, M6495 show potential cartilage protective and anti-inflammatory effects 49 .…”

Section: Discussionmentioning

confidence: 99%

Inflammation and joint destruction may be linked to the generation of cartilage metabolites of ADAMTS-5 through activation of toll-like receptors

Sharma

Drobinski

Kayed

et al. 2020

Osteoarthritis and Cartilage

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Objective: Links between pain and joint degradation are poorly understood. We investigated the role of activation of Toll-like receptors (TLR) by cartilage metabolites in initiating and maintaining the inflammatory loop in OA causing joint destruction. Methods: Synovial membrane explants (SMEs) were prepared from OA patients' synovial biopsies. SMEs were cultured for 10 days under following conditions: culture medium alone, OSM þ TNFa, TLR2 agonist -Pam2CSK4, Pam3CSK4 or synthetic aggrecan 32-mer, TLR4 agonist -Lipid A. Release of pro-inflammatory and degradation biomarkers (acMMP3 and C3M) were measured by ELISA in conditioned media along with IL-6. Additionally, human cartilage was digested with ADAMTS-5, with or without the ADAMTS-5 inhibiting nanobody -M6495. Digested cartilage solution (DCS) and synthetic 32-mer were tested for TLR activation in SEAP based TLR reporter assay. Results: Western blotting confirmed TLR2 and TLR4 in untreated OA synovial biopsies. TLR agonists showed an increase in release of biomarkers -acMMP3 and C3M in SME. Synthetic 32-mer showed no activation in the TLR reporter assay. ADAMTS-5 degraded cartilage fragments activated TLR2 in vitro. Adding M6495 e an anti-ADAMTS-5 inhibiting nanobody®, blocked ADAMTS-5-mediated DCS TLR2 activation. Conclusion: TLR2 is expressed in synovium of OA patients and their activation by synthetic ligands causes increased tissue turnover. ADAMTS-5-mediated cartilage degradation leads to release of aggrecan fragments which activates the TLR2 receptor in vitro. M6495 suppressed cartilage degradation by ADAMTS-5, limiting the activation of TLR2. In conclusion, pain and joint destruction may be linked to generation of ADAMTS-5 cartilage metabolites.

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Section: Discussionmentioning

confidence: 99%

Inflammation and joint destruction may be linked to the generation of cartilage metabolites of ADAMTS-5 through activation of toll-like receptors

Sharma

Drobinski

Kayed

et al. 2020

Osteoarthritis and Cartilage

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Section: Current and Recent Targets In Chondroprotectionmentioning

confidence: 99%

“…However, a triple-blinded randomized controlled trial did not show any reduction in symptoms but did show an increase in adverse effects [24]. ADAMTS-inhibitorsAnti-ADAMTS-5 nanobodyCurrently awaiting results from phase I clinical trial (NCT03224702) after in vitro studies showed protection against cartilage breakdown [25]. Phase I clinical trial of multiple ascending doses of anti-ADAMTS-5 nanobody in knee OA, due for completion in May 2019 (NCT03583346).Anti-proteaseAlpha-2-macroglobulinPhase I trial to look at the reduction of pro-inflammatory synovial fluid biomarkers in OA due for completion in 2019 (NCT03656575).Cathepsin K inhibitorMIV-711MIV-711 was well tolerated in a phase I study in healthy subjects [26].…”

Section: Current and Recent Targets In Chondroprotectionmentioning

confidence: 99%

Chondroprotective Factors in Osteoarthritis: a Joint Affair

Mimpen

Snelling

2019

Curr Rheumatol Rep

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Purpose of the Review Osteoarthritis is widely regarded as a spectrum of conditions that affect all joint tissues, typified by a common entity: cartilage loss. Here, we review recent progress and challenges in chondroprotection and discuss new strategies to prevent cartilage loss in osteoarthritis. Recent Findings Advances in clinical, molecular, and cellular characterization are enabling improved stratification of osteoarthritis subtypes. Integration of next-generation sequencing and "omics" approaches with clinically relevant readouts shows promise in delineating both subtypes of disease and meaningful trial end points. Novel delivery strategies are enabling jointspecific delivery. Summary Chondroprotection requires a whole joint approach, stratification of patient groups, and use of patient-relevant end points. Drug development should continue to explore new targets, while using modern technologies and recent knowledge to revisit unsuccessful therapeutics from the past. The overarching goal for chondroprotection is to provide the right treatment(s) for the right patient at the right time.

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“…Inhibitors of the aggrecanase ADAMTS5 were recently evaluated in a phase 2 clinical trial but failed in all endpoints [32,33]. Anti-ADAMTS5 antibodies are also under study [34]. In addition, molecules capable of promoting cartilage repair have also been investigated.…”

Section: Introductionmentioning

confidence: 99%

Polymer particles for the intra-articular delivery of drugs to treat osteoarthritis

et al. 2021

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Osteoarthritis (OA) is a leading cause of chronic disability. It is a progressive disease, involving pathological changes to the entire joint, resulting in joint pain, stiffness, swelling, and loss of mobility. There is currently no disease-modifying pharmaceutical treatment for OA, and the treatments that do exist suffer from significant side effects. An increasing understanding of the molecular pathways involved in OA is leading to many potential drug targets. However, both current and new therapies can benefit from a targeted approach that delivers drugs selectively to joints at therapeutic concentrations, while limiting systemic exposure to the drugs. Delivery systems including hydrogels, liposomes, and various types of particles have been explored for intra-articular drug delivery. This review will describe progress over the past several years in the development of polymer-based particles for OA treatment, as well as their in vitro, in vivo, and clinical evaluation. Systems based on biopolymers such as polysaccharides and polypeptides, as well as synthetic polyesters, poly(ester amide)s, thermoresponsive polymers, poly(vinyl alcohol), amphiphilic polymers, and dendrimers will be described. We will discuss the role of particle size, biodegradability, and mechanical properties in the behavior of the particles in the joint, and the challenges to be addressed in future research.

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The anti-ADAMTS-5 nanobody®, M6495, protects against cartilage breakdown in cartilage and synovial joint tissue explant models

Cited by 10 publications

References 0 publications

Inflammation and joint destruction may be linked to the generation of cartilage metabolites of ADAMTS-5 through activation of toll-like receptors

Inflammation and joint destruction may be linked to the generation of cartilage metabolites of ADAMTS-5 through activation of toll-like receptors

Chondroprotective Factors in Osteoarthritis: a Joint Affair

Polymer particles for the intra-articular delivery of drugs to treat osteoarthritis

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