Advances in the development of novel aggrecanase inhibitors

Gilbert, Adam M.; Bikker, Jack; O’Neil, Steven V.

doi:10.1517/13543776.2011.539204

Cited by 31 publications

(22 citation statements)

References 17 publications

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“…Although numerous reports of aggrecanase inhibitors exist [25, 34, 35], we believe this is the first example of a direct comparison of fully selective inhibitors with sub-nanomolar potency. The proposed novel ‘allosteric lock’ mechanism of action suggested for some of the mAbs described here (Fig 2) supports the observed selective neutralization of protease activity and appears distinct from other metalloprotease neutralizing mAbs which largely target the catalytic active site directly and frequently lack full selectivity [36, 37].…”

Section: Discussionmentioning

confidence: 99%

Translational development of an ADAMTS-5 antibody for osteoarthritis disease modification

Larkin

Löhr

Elefante

et al. 2015

Osteoarthritis and Cartilage

103

104

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Objective/Method Aggrecanase activity, most notably ADAMTS-5, is implicated in pathogenic cartilage degradation. Selective monoclonal antibodies (mAbs) to both ADAMTS-5 and ADAMTS-4 were generated and in vitro, ex vivo and in vivo systems were utilized to assess target engagement, aggrecanase inhibition and modulation of disease-related endpoints with the intent of selecting a candidate for clinical development in osteoarthritis (OA). Results Structural mapping predicts the most potent mAbs employ a unique mode of inhibition by cross-linking the catalytic and disintegrin domains. In a surgical mouse model of OA, both ADAMTS-5 and ADAMTS-4-specific mAbs penetrate cartilage following systemic administration, demonstrating access to the anticipated site of action. Structural disease modification and associated alleviation of pain-related behavior were observed with ADAMTS-5 mAb treatment. Treatment of human OA cartilage demonstrated a preferential role for ADAMTS-5 inhibition over ADAMTS-4, as measured by ARGS neoepitope release in explant cultures. ADAMTS-5 mAb activity was most evident in a subset of patient-derived tissues and suppression of ARGS neoepitope release was sustained for weeks after a single treatment in human explants and in cynomolgus monkeys, consistent with high affinity target engagement and slow ADAMTS-5 turnover. Conclusion This data supports a hypothesis set forth from knockout mouse studies that ADAMTS-5 is the major aggrecanase involved in cartilage degradation and provides a link between a biological pathway and pharmacology which translates to human tissues, non-human primate models and points to a target OA patient population. Therefore, a humanized ADAMTS-5-selective monoclonal antibody (GSK2394002) was progressed as a potential OA disease modifying therapeutic.

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Section: Discussionmentioning

confidence: 99%

Translational development of an ADAMTS-5 antibody for osteoarthritis disease modification

Larkin

Löhr

Elefante

et al. 2015

Osteoarthritis and Cartilage

103

104

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“…Some of these compounds are claimed to be specific, whereas others have effect against both enzymes, against other ADAMTS members, or even against MMPs (Wittwer et al, 2007;Tortorella et al, 2009). The Wyeth/Pfizer compound was recently used in a phase I clinical trial in osteoarthritis (Hellio le Graverand-Gastineau, 2010;Gilbert et al, 2011). The main endogenous inhibitor of ADAMTS4 and ADAMTS5 is tissue inhibitor of metalloproteinases (TIMP)-3, with K i values in the subnanomolar range (Kashiwagi et al, 2001).…”

Section: Wwwintechopencom the Role Of Synovial Macrophages And Macrmentioning

confidence: 99%

The Role of Synovial Macrophages and Macrophage-Produced Mediators in Driving Inflammatory and Destructive Responses in Osteoarthritis

Bondeson¹,

Wainwright²,

Hughes³

et al. 2012

Principles of Osteoarthritis- Its Definition, Character, Derivation and Modality-Related Recognition

100

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“…This results in loss of the bulk of the aggrecan molecule from the articular cartilage, and therefore, this cleavage step is critical for the development of osteoarthritis (6,7). Accordingly, many pharmaceutical programs over the last two decades have focused on developing disease-modifying osteoarthritis drugs targeting ADAMTS-4 and ADAMTS-5 (8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

An aggrecan fragment drives osteoarthritis pain through Toll-like receptor 2

Miller

Miller²,

Ishihara

et al. 2017

Preprint

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Pain is the predominant symptom of osteoarthritis, but the connection between joint damage and the genesis of pain is not well understood. Loss of articular cartilage is a hallmark of osteoarthritis, and it occurs through enzymatic degradation of aggrecan by ADAMTS-4/5-mediated cleavage in the interglobular domain (E 373 -374 A). Further cleavage by MMPs (N 341 -342 F) releases a 32-amino-acid aggrecan fragment (32-mer). We investigated the role of this 32-mer in driving joint pain. We demonstrated that the 32-mer excites dorsal root ganglion (DRG) nociceptive neurons, both in culture and in intact explants.Treatment of cultured sensory neurons with the 32-mer induced them to express the proalgesic chemokine, MCP-1/CCL2. These effects were mediated through Toll-like receptor (TLR)2, which we demonstrated was expressed by nociceptive neurons. In addition, intraarticular injection of the 32-mer provoked knee hyperalgesia in wild-type but not Tlr2 null mice. Blocking the production or action of the 32-mer in transgenic mice prevented the development of knee hyperalgesia in a murine model of osteoarthritis. These findings suggest that the aggrecan 32-mer fragment directly activates TLR2 on joint nociceptors and is an important mediator of the development of osteoarthritis-associated joint pain.

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Advances in the development of novel aggrecanase inhibitors

Cited by 31 publications

References 17 publications

Translational development of an ADAMTS-5 antibody for osteoarthritis disease modification

Translational development of an ADAMTS-5 antibody for osteoarthritis disease modification

The Role of Synovial Macrophages and Macrophage-Produced Mediators in Driving Inflammatory and Destructive Responses in Osteoarthritis

An aggrecan fragment drives osteoarthritis pain through Toll-like receptor 2

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