Background/Purpose : There is huge interest in the family of “A Disintegrin And Metalloproteinase with ThromboSpondin motifs” (ADAMTS) proteinases, especially aggrecanase-2 (ADAMTS-5), as therapeutic targets in osteoarthritis (OA). CRB0017 is a chimeric murine/human IgG4 monoclonal antibody that specifically recognizes the spacer domain of human ADAMTS-5 and binds it with nanomolar affinity. CRB0017 is under preclinical development as a potential disease modifying osteoarthritis drug (DMOAD).

We previously published a brief report (Chiusaroli, Osteoarthritis Cartilage, 2013) showing the efficacy of intra-articular (i.a.) CRB0017 in a model of spontaneous OA, the STR/ort mouse. In this study we replicated the experiment in the STR/ort mouse and evaluated the activity of CRB0017 in two surgical models of OA in rodents: the Destabilization of Medial Meniscus (DMM) in mice; and the Medial Meniscal Tear (MMT) in rats. Moreover, all data collected were combined in a meta-analysis to estimate the overall effect size of CRB0017 in rodent models of OA.

Methods : Because it is hard to standardize different batches during early phases of a monoclonal antibody development, all experiments were done at the maximum feasible dose (MFD), as determined by the concentration achieved in each batch and by the maximum feasible volume for i.a. injection in rats and mice.

Male STR/ort mice were recruited at 5 months of age, randomized, and treated i.a. in each knee with CRB0017 or vehicle (4µl/knee). Four different experiments were conducted in the STR/ort mouse (MFDs: Exp1 12 µg/knee, n=34 evaluable joints; Exp2 11.2 µg/knee, n=28-29; Exp3 72 µg/knee n=33-38; Exp4 20 µg/knee, n=21-18). Treatment was repeated after 6 weeks (in Exp 4, 3 monthly administrations), and mice were killed 3 months after recruitment.

DMM was performed in C57BL/6J mice (10 weeks old at surgery; CRB0017 i.a. injection [MFD 72 µg in 4 µL] 1 week after surgery; injection repeated after 1 and 2 months; sacrifice at 3 months, n=19-20).

MMT was performed in Lewis rats (9 weeks old at surgery; CRB0017 i.a. injection [MFD 71 µg/knee in 15 µL] 1 week after surgery; sacrifice 3 weeks after treatment, n=15).

At sacrifice, the femorotibial joints were explanted and processed for histology. Scoring procedure was carried out in a blind fashion according to both Mankin’s (not shown) and OARSI methods. For quantitative outcome data, Cohen’s d effect size was used in the meta-analysis of OA models.

Results : CRB0017 markedly reduced the histological damage in spontaneous and surgical models of OA in mice and rats, which is consistent with a disease modifying activity. Pooled data (OARSI score) showed a highly significant overall effect size of 0.726 (Cohen’s d; see figure).

Conclusion : Aggregate data from clinically relevant models of spontaneous or surgical OA in rodents clearly show the potential of CRB0017 as a DMOAD. The product is slated to enter Phase I in early 2016.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/effect-size-of-the-anti-aggrecanase-2-monoclonal-antibody-crb0017-in-rodent-models-of-osteoarthritis/