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Chen P , Nogusa S , Thapa RJ , Shaller C , Simmons H , Peri S , Adams GP , Balachandran S
Anti-CD70 Immunocytokines for Exploitation of Interferon-gamma-Induced RIP1-Dependent Necrosis in Renal Cell Carcinoma
PLoS One. 2013 ;8(4) :e61446
PMID: 23613854    PMCID: PMC3629199   
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Metastatic renal cell carcinoma (RCC) is an incurable disease in clear need of new therapeutic interventions. In early-phase clinical trials, the cytokine IFN-gamma showed promise as a biotherapeutic for advanced RCC, but subsequent trials were less promising. These trials, however, focused on the indirect immunomodulatory properties of IFN-gamma, and its direct anti-tumor effects, including its ability to kill tumor cells, remains mostly unexploited. We have previously shown that IFN-gamma induces RIP1 kinase-dependent necrosis in cells lacking NF-kappaB survival signaling. RCC cells display basally-elevated NF-kappaB activity, and inhibiting NF-kappaB in these cells, for example by using the small-molecule proteasome blocker bortezomib, sensitizes them to RIP1-dependent necrotic death following exposure to IFN-gamma. While these observations suggest that IFN-gamma-mediated direct tumoricidal activity will have therapeutic benefit in RCC, they cannot be effectively exploited unless IFN-gamma is targeted to tumor cells in vivo. Here, we describe the generation and characterization of two novel 'immunocytokine' chimeric proteins, in which either human or murine IFN-gamma is fused to an antibody targeting the putative metastatic RCC biomarker CD70. These immunocytokines display high levels of species-specific IFN-gamma activity and selective binding to CD70 on human RCC cells. Importantly, the IFN-gamma immunocytokines function as well as native IFN-gamma in inducing RIP1-dependent necrosis in RCC cells, when deployed in the presence of bortezomib. These results provide a foundation for the in vivo exploitation of IFN-gamma-driven tumoricidal activity in RCC.
Chen, Peirong Nogusa, Shoko Thapa, Roshan J Shaller, Calvin Simmons, Heidi Peri, Suraj Adams, Gregory P Balachandran, Siddharth United States PloS one PLoS One. 2013 Apr 17;8(4):e61446. doi: 10.1371/journal.pone.0061446. Print 2013.