Targeting of ADAMTS5's ancillary domain with the recombinant mAb CRB0017 ameliorates disease progression in a spontaneous murine model of osteoarthritis

Abstract

All histological scores were significantly decreased in the CRB0017 12 μg/knee group compared to vehicle, while administration of CRB0017 1.2 μg was associated with a trend to a decrease in the same parameters. Therefore, CRB0017 administered twice in 3 months could modify the course of OA in the STR/ort mouse, by delaying cartilage breakdown as assessed histologically. The procedure of blind scoring of the histological samples clearly showed that knee intra-articular administration of CRB0017, an anti-ADAMTS5 antibody, dose-dependently improved disease progression in a relevant animal model of OA.

Therapeutic effects of an anti-ADAMTS-5 antibody on joint damage and mechanical allodynia in a murine model of osteoarthritis

“…The protection against cartilage degradation reported here is concordant with a recent study, which used a different ADAMTS-5 mAb in STR/Ort mice, a strain that develops spontaneous OA [20]. In that study, two intra-articular injections of ADAMTS-5 mAb administered at 5 months (at which time mice have mild-to-moderate OA [21]) and 6.5 months of age were shown to slow progression of cartilage degradation by 8 months of age [20].…”

“…In that study, two intra-articular injections of ADAMTS-5 mAb administered at 5 months (at which time mice have mild-to-moderate OA [21]) and 6.5 months of age were shown to slow progression of cartilage degradation by 8 months of age [20]. Effects on other joint tissues or on behavioral changes were not assessed as part of that study.…”

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

“…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].…”

The STR/ort mouse model of spontaneous osteoarthritis – an update

“…The importance of MMPs in AC degradation in STR/ort mice has been tested by administration of Ro 32-3555, an orally active collagenase selective inhibitor which protected against OA development (Table I) 41 . In addition, intra-articular injections of CRB0017 (anti-ADAMTS5 antibody) dose-dependently slowed OA progression in STR/ort mice ageing from 5 to 8 months (Table I) 42 . The likelihood that the STR/ort mouse model will help identify new preventative, protective and curative avenues targeting AC in OA joints is therefore well supported.…”