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

• DOI: 10.1371/journal.pone.0061446
• Publication Date: 2013-04-17T20:49:15Z
• Authors: Peirong Chen; Shoko Nogusa; Roshan J. Thapa; Calvin Shaller; Heidi Simmons; Suraj Peri; Gregory P. Adams; Siddharth Balacha...
• Keywords: Science; Recombinant Fusion Proteins; Antiviral Agents; Bortezomib; Interferon-gamma; Mice; Necrosis; 03 medical and health sciences; Cell Line, Tumor; Animals; Humans; Phosphorylation; Carcinoma, Renal Cell; 0303 health sciences; Cell Death; Q; R; Boronic Acids; Kidney Neoplasms; 3. Good health; STAT1 Transcription Factor; Pyrazines; Receptor-Interacting Protein Serine-Threonine Kinases; Medicine; Research Article; CD27 Ligand; Protein Binding; Signal Transduction

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 however, focused on indirect immunomodulatory properties IFN-γ, and its direct anti-tumor effects, including ability to kill tumor cells, remains mostly unexploited. We have previously shown that induces RIP1 kinase-dependent necrosis cells lacking NF-κB survival signaling. RCC display basally-elevated activity, inhibiting these example by using small-molecule proteasome blocker bortezomib, sensitizes them RIP1-dependent necrotic death following exposure IFN-γ. While observations suggest IFN-γ-mediated tumoricidal activity will benefit they cannot be effectively exploited unless targeted vivo. Here, we describe generation characterization two novel 'immunocytokine' chimeric proteins, which either human or murine fused antibody targeting putative metastatic biomarker CD70. immunocytokines high levels species-specific selective binding CD70 cells. Importantly, function well native inducing when deployed presence bortezomib. results provide foundation vivo exploitation IFN-γ-driven RCC.