title: Anti-CD70 immunocytokines for exploitation of interferon-γ-induced RIP1-dependent necrosis in renal cell carcinoma.
abstract: Metastatic renal cell carcinoma (RCC) is an incurable disease in clear need of new therapeutic interventions. In early-phase clinical trials, the cytokine IFN-γ 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-γ, and its direct anti-tumor effects, including its ability to kill tumor cells, remains mostly unexploited. We have previously shown that IFN-γ induces RIP1 kinase-dependent necrosis in cells lacking NF-κB survival signaling. RCC cells display basally-elevated NF-κB activity, and inhibiting NF-κB in these cells, for example by using the small-molecule proteasome blocker bortezomib, sensitizes them to RIP1-dependent necrotic death following exposure to IFN-γ. While these observations suggest that IFN-γ-mediated direct tumoricidal activity will have therapeutic benefit in RCC, they cannot be effectively exploited unless IFN-γ 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-γ is fused to an antibody targeting the putative metastatic RCC biomarker CD70. These immunocytokines display high levels of species-specific IFN-γ activity and selective binding to CD70 on human RCC cells. Importantly, the IFN-γ immunocytokines function as well as native IFN-γ 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-γ-driven tumoricidal activity in RCC.
authors.affiliation: Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America.
authors.forename: Peirong
authors.initials: P
authors.lastname: Chen
authors.forename: Shoko
authors.initials: S
authors.lastname: Nogusa
authors.forename: Roshan J
authors.initials: RJ
authors.lastname: Thapa
authors.forename: Calvin
authors.initials: C
authors.lastname: Shaller
authors.forename: Heidi
authors.initials: H
authors.lastname: Simmons
authors.forename: Suraj
authors.initials: S
authors.lastname: Peri
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Adams
authors.forename: Siddharth
authors.initials: S
authors.lastname: Balachandran
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D053282:CD27 Ligand / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000201:enzymology / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D009336:Necrosis; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013045:Species Specificity
chemical_list: D000998:Antiviral Agents; D001897:Boronic Acids; D053282:CD27 Ligand; D011719:Pyrazines; D011993:Recombinant Fusion Proteins; D050794:STAT1 Transcription Factor; D000069286:Bortezomib; D007371:Interferon-gamma; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases