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  • sonquiqua sonquiqua May 21, 2012 5:57 PM Flag

    GPNMB and CDX-011 great article with background

    There are several reasons for this interest in GPNMB-targeted therapies for cancer. First, it is highly expressed at the surface of cancer cells , but is predominantly expressed intracellularly in normal cells,
    such as macrophages or melanocytes. This expression pattern makes GPNMB particularly attractive for antibody-based therapies because, as a target, it would be more readily accessible in cancer cells than in normal cells, thereby reducing potential complications owing to bystander effects. It is also highly expressed in several aggressive cancers, including melanoma (a cancer with high propensity to metastasize to bone) , glioma and breast cancer. Finally, ectopic expression of GPNMB, or its murine orthologue Osteoactivin, in glioma, hepatocellular carcinoma and breast cancer cells is sufficient to enhance invasive phenotypes in vitro and metastasis capabilities in vivo. We have identified Osteoactivin as a gene that is highly expressed in aggressive bone-metastatic sub-populations of 4T1 breast cancer cells, and demonstrated that, when Osteoactivin was overexpressed in weakly metastatic 66cl4 breast cancer cells, it promotes breast cancer metastasis to bone in vivo. GPNMB-mediated induction of pro-invasive matrix metalloproteases, such as MMP-3 and MMP-9, may represent one mechanism by which it promotes metastasis. CR011–vcMMAE (CR011), which is now referred to as glembatumumab vedotin or CDX-011, is a GPNMB-targeted therapeutic that belongs to a class of drugs known as antibody–drug conjugates (ADCs). These drugs consist of antibodies that bind to cell surface molecules, which are linked to highly potent cytotoxins. In the case of CDX-011, the cytotoxin is auristatin E – a tubulin destabilizer. ADCs bind to the extracellular domain of their target protein on the surface of cancer cells, which is then rapidly internalized. ADCs are pro-drugs that require the release of the cytotoxin for activation. Upon internalization, the drug is released and induces cell-cycle arrest and apoptosis of the cancer cell. At concentrations as low as 2.5 mg/kg, CDX-011 was capable of inducing complete regression in 100% of GPNMB expressing SK-Mel-2- and SK-Mel-5-xenografted melanoma tumors. Interestingly, treatment with imatinib and inhibitors of the Erk pathway enhance cell-surface expression of GPNMB in cancer cells, which, in turn, increases sensitivity to CDX-011. This suggests that CDX-011 efficacy could be further enhanced by combining it with additional targeted therapies. In clinical trials, CDX-011 is currently being investigated in two multicenter Phase II trials; one for patients with unresectable melanoma and the other for patients with locally advanced or metastatic breast cancer (NCT00704158). Preliminary results from these trials were presented at the 2009 annual meeting of the American Society for Clinical Oncology and were very promising. To date, with 34 melanoma and 18 breast cancer patients treated with CDX-011, tumor shrinkage was reported in 58% of melanoma patients and 50% of breast cancer patients CDX- 011 does appear to target GPNMB expressed in normal tissues – most notably in the skin – and can induce rash formation. Interestingly, patients who experienced rash within their first cycle of treatment also had significantly longer progression-free survival (PFS) than CDX-011- treated patients who did not develop rash, suggesting that rash may be indicative of a patients’ ability to tolerate and respond to the drug. Moreover, in a subset of 13 melanoma patients, there was a striking tendency for patients with the highest levels of tumoral GPNMB expression to experience the longest PFS times. These preliminary data suggest that tumoral GPNMB expression and incidence of rash will serve as important predictors for response to CDX-011 therapy in the future. These insights will be useful for sparing patients who are unlikely to benefit and selecting a group of patients who are most likely to respond for CDX-011 therapy

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