How was the Evade™ Ribonuclease Technology Discovered?

In 1988, a frog ribonuclease (Ranpirnase, later developed under the tradename Onconase®) was discovered to be toxic to cancer cells. (1)  This serendipitous discovery was a surprise to many people including Dr. Ronald T. Raines, a long time researcher of the bovine ribonuclease, Ribonuclease A or RNase A.

Dr. Raines discovered that unlike mammalian ribonucleases, the frog ribonuclease has very low binding affinity to the human ribonuclease inhibitor. Ribonuclease inhibitor is a ubiquitous protein in the cytosol of cells. The binding of the mammalian ribonucleases to ribonuclease inhibitor is depicted in the graphic below on the left.

Working with the bovine ribonuclease A, Dr. Raines discovered that he could make changes to a handful of amino acids in the structure of RNase A which would disrupt the interaction between these two proteins thereby turning a mammalian protein into a cancer drug. The graphic below shows the results of an in vitro study done against K-562 Chronic Myelogenous Leukemia cells

The graphic shows that even at high concentrations, the native RNase A does not kill K-562 cells.  But by making changes to the amino acid sequence of RNase A, the RNase A variant (referred to as QBI-108) is more toxic to the leukemia cells than the frog ribonuclease Ranpirnase (labeled with a prefix of "r" because it was produced using recombinant DNA technology).

The EVade™ Ribonuclease technology is based on endowing mammalian ribonucleases with the ability to evade the human ribonuclease inhibitor. The ribonuclease inhibitor protein binds to pancreatic ribonucleases, preventing the ribonuclease from degrading RNA. Disrupting the interaction between these two proteins (Ribonuclease and Ribonuclease Inhibitor) results in degradation of RNA in cancer cells. This interrupts the flow of information from DNA to proteins and leads to cell death.

As follow-on to these discoveries, Quintessence Biosciences has developed variants of human pancreatic ribonuclease 1 that have diminished binding to the ribonuclease inhibitor and therefore, has potent anti-cancer activity. The ribonucleases created with this technology are the basis of the EVade™ Ribonuclease therapeutic program. The initial lead candidate from this program is QBI-139.

 (1) Tamir Biotechnology (formerly Alfacell Corporation) has taken this frog ribonuclease into several human clinical trials, including a Phase IIIb confirmatory trial for the treatment of malignant mesothelioma.