Improving Efficacy of RNase Cancer Therapy by Pharmacokinetics

DESCRIPTION (provided by applicant): The ultimate goal of this project is to develop a new safe AND effective tool for physicians to treat patients with cancer. The EVade Ribonucleases are recombinant variants of mammalian enzymes that are effective in mouse xenograft models of multiple cancer types without exhibiting significant toxicity. While they are effective, Quintessence is interested in increasing the potency of the EVade Ribonucleases to improve clinical outcome. Many of the FDA approved cancer therapies work by very similar mechanisms, including genotoxicity, anti- metabolite and microtubule binding. Newer, targeted therapies are being developed, with a few of these drugs already on the market. We believe an agent with a novel mechanism of action and mild side effect profile, such as an EVade Ribonuclease, is a strong candidate for cancer therapy. In Phase I, the pharmacokinetic profile of the EVade Ribonucleases was changed by conjugation with polyethylene glycol (PEG). These changes resulted in a significant increase (gt20%) in efficacy in vivo at five-fold lower doses than the unmodified Evade Ribonucleases. While benefits of PEG7EVade RNase conjugates has been demonstrated, additional research is necessary to ensure the lead candidate, a conjugate called QBI-206, can be successfully commercialized. The primary goal of the Phase II SBIR grant is to provide data to support the tangible benefits of the conjugate relative to the unconjugated Evade RNase QBI-139. The specific activities for the Phase II grant include: determination of the optimal schedule, a dose response and comparison of antibody formation to an unmodified EVade Ribonuclease. In addition, the side effects of QBI-206 will be compared to an unmodified EVade Ribonuclease (QBI-139) will be determined in a model that provides a direct link to doses to be used in human clinical trials. These activities are all directed to taking QBI-206 into a Phase I human clinical trial. PUBLIC HEALTH RELEVANCE: There is a clear and unfilled need for highly efficacious cancer therapeutics, and our goal is to provide an effective new tool for physicians to treat their patients who have cancer. Cancer is the second most common cause of death in the developed world. On a worldwide basis, cancer is responsible for 12.5% of deaths. New cases of cancer are expected to rise to 16M/year in 2020, up from 11M /yr in 2002. Cancer-related deaths are anticipated to rise from 6.7M to 10M over the same period.