Anti-CD70 Immunocytokines for Exploitation of Interferon-[gamma]-Induced RIP1-Dependent Necrosis in Renal Cell Carcinoma

• Published in: PloS one Vol. 8; no. 4; p. e61446
• Main Authors: Chen, Peirong, Nogusa, Shoko, Thapa, Roshan J, Shaller, Calvin, Simmons, Heidi, Peri, Suraj, Adams, Gregory P, Balachandran, Siddharth
• Format: Journal Article
• Language: English
• Published: Public Library of Science 17-04-2013
• Subjects: Cancer metastasis; Health aspects; Immunologic factors; Interferon; Necrosis; Renal cell carcinoma
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0061446

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-[kappa]B survival signaling. RCC cells display basally-elevated NF-[kappa]B activity, and inhibiting NF-[kappa]B 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.