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.
Interleukin (IL)-18 has profound antitumor activity when administered at high doses as a single agent for prolonged periods in BALB/c mice bearing late, well-established MOPC-315 tumors. Management with a qD x 27 schedule resulted in regression of tumors in all animals receiving 5 mg/kg/d. A protracted daily management regimen appears to be necessary to induce regression in this advanced tumor model. Biologic markers were assessed and appear to be potentially useful in evaluating the immunologic and antitumor activity of IL-18. The biomarkers of IL-18's immunologic activity include, but are not limited to, IL-1alpha, IL-2, IL-8, IL-10, IL-12, IL-13, interferon-gamma, tumor necrosis factor-alpha, and granulocyte-macrophage colony-stimulating factor. The profile of these circulating cytokines and their expression levels at baseline, and after IL-18 delivery, can be measured in the serum, as well as from splenocytes of mice or human peripheral blood mononuclear cells derived from either normal subjects or patients with cancer. We compared IL-18 and IL-12 alone or in combination for their ability to induce cytokine production and natural killer cytolytic activity. Our data support the notion that IL-18 induces a predominantly Th1 response, and that the mechanism of IL-18 activity differs from that of IL-12. The biologic activity of IL-18 management revealed by increases in serum levels of cytokines and enhancement of natural killer cytolytic activity will be useful as clinical trials initiate in 2002. Expression of interferon-gamma and granulocyte-macrophage colony-stimulating factor serum levels correlates directly over a broad dose escalation with the level of IL-18. Therefore, this provides a convenient pharmacodynamic reference to the biologic response to IL-18 that may serve to guide the conduct of clinical trials.
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