Updates in the Development of ImmunoRNases for the Selective Killing of Tumor Cells

Abstract

Targeted cancer therapy includes, amongst others, antibody-based delivery of toxic payloads to selectively eliminate tumor cells. This payload can be either a synthetic small molecule drug composing an antibody-drug conjugate (ADC) or a cytotoxic protein composing an immunotoxin (IT). Non-human cytotoxic proteins, while potent, have limited clinical efficacy due to their immunogenicity and potential off-target toxicity. Humanization of the cytotoxic payload is essential and requires harnessing of potent apoptosis-inducing human proteins with conditional activity, which rely on targeted delivery to contact their substrate. Ribonucleases are attractive candidates, due to their ability to induce apoptosis by abrogating protein biosynthesis via tRNA degradation. In fact, several RNases of the pancreatic RNase A superfamily have shown potential as anti-cancer agents. Coupling of a human RNase to a humanized antibody or antibody derivative putatively eliminates the immunogenicity of an IT (now known as a human cytolytic fusion protein, hCFP). However, RNases are tightly regulated in vivo by endogenous inhibitors, controlling the ribonucleolytic balance subject to the cell's metabolic requirements. Endogenous inhibition limits the efficacy with which RNase-based hCFPs induce apoptosis. However, abrogating the natural interaction with the natural inhibitors by mutation has been shown to significantly enhance RNase activity, paving the way toward achieving cytolytic potency comparable to that of bacterial immunotoxins. Here, we review the immunoRNases that have undergone preclinical studies as anti-cancer therapeutic agents.

Keywords: apoptosis inducers; cancer immunotherapy; human RNases; humanized cytolytic fusion proteins (hCFPs); ranpirnase.

Figure 1

Mechanism of action following targeted Angiogenin delivery to a cell. Angiogenin binds to a membrane receptor (blue wedge), localizes to the nucleus and engages in rRNA processing. Under stress conditions, Ang is found more prolifically in the cytosol, where it degrades tRNA and blocks biosynthesis. An Ang-based hCFP is designed to be selectively internalized via a disease-associated antigen and delivered to the cytosol, where it degrades tRNA similarly to free cytosolic Ang. Both free Ang and immuno-Ang are sensitive to cytosolic RNH1 inhibition.