EVade™ Ribonucleases

Pancreatic ribonucleases (RNases) are naturally internalized by cells through endocytosis. Once internalized, wild type ribonucleases are bound by a protein called ribonuclease inhibitor, which blocks the ribonuclease from degrading RNA. The amino acid changes in the EVadeTM RNases diminish their binding to the inhibitor protein found in the cytosol of cells. This evasion allows the EVadeTM RNase to degrade RNA inside cells, resulting in cell death. The selectivity of QBI-139 for cancer cells is a result of binding to anionic glycans, which are overexpressed on cancer cells.

Pathway of EVade™ Ribonucleases

Pancreatic RNases are naturally internalized by cells through endocytosis. Once internalized, wild type RNases are bound by a protein called RNase inhibitor (RI), which blocks the RNase from degrading RNA. QBI-139 is a variant of the wild type human pancreatic RNase 1 with 95% sequence identity to the wild type protein. The amino acid changes in QBI-139 allow the RNase to evade the inhibitor protein and degrade RNA inside cells, resulting in cell death. RNA has been validated as a target by the use of 5-fluorourcail and related drugs that disrupt RNA synthesis. In vitro treatment of pancreatic cancer cells with QBI-139 results in decreased cell viability and an increase in caspase activity, a marker of apoptosis. In addition, staining the DNA of pancreatic cancer cells treated with QBI-139 resulted in the fragmented DNA characteristic of apoptotic cells.

The selectivity of the EVadeTM RNases for cancer cells is not due to a genetic mutation/rearrangement or rate of cell division but results from binding to anionic glycans, which are overexpressed on cancer cells. The Raines laboratory has demonstrated that the cytotoxicity of an RI evasive RNase is decreased by reducing anionic carbohydrates on the cell surface. This feature is key to the safety profile of QBI-139, which avoids many adverse events associated with targeting rapidly dividing cells, such as myelosuppression.

Quintessence Biosciences is looking for partners with an interest in novel cancer therapies and their potential for combination with targeted therapy.

Related Publications: Ribonuclease A variants with potent cytotoxic activity. Leland PA, Schultz LW, Kim BM, Raines RT. Proc Natl Acad Sci USA. 1998, 95, 10407-12. Pubmed

Endowing human pancreatic ribonuclease with toxicity for cancer cells. Leland PA, Staniszewski KE, Kim BM, Raines RT. J Biol Chem. 2001, 276, 43095-102. Pubmed

Cellular uptake of ribonuclease A relies on anionic glycans. Chao TY, Lavis LD, Raines RT. Biochemistry. 2010, 49, 10666-73 Pubmed