Cytotoxic Ribonucleases in Antibody-Drug Conjugates

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DESCRIPTION (provided by applicant): The goal of this project is to develop a safe yet potent antibody-drug conjugate (ADC) by utilizing an EVade(tm) Ribonuclease as the drug. The EVade(tm) Ribonucleases are variants of mammalian enzymes that are effective in mouse xenograft models of multiple cancer types without exhibiting significant toxicity. While they are effective, we are interested in increasing the potency of the EVade(tm) Ribonucleases to improve clinical outcome. Many of the newer, targeted cancer therapies, such as monoclonal antibodies, are approved only in combination with other agents, typically small molecule cytotoxics. Small molecule cytotoxics are potent, but tend to cause serious adverse effects. The combination of the small molecules with the targeted therapies leads to improved efficacy but cancels out any safety benefits of the targeted drugs. We would like to pursue a strategy that would increase the chances of successful treatment without adding toxic side effects. We will conjugate a well characterized antibody reactive against CEA-expresssing cancer cells to a unique cysteine engineered in a potent EVade(tm) Ribonuclease using a variety of linkers. The linkers will be varied in their reactivity towards the antibody (activated ester or hyrdzide) and the ribonuclease (maleimide, thiol, haloacetyl, and 2- pyridyldithio). Some of the linkers can be cleaved in the cell while others will remain stable. The antibody-ribonuclease conjugates will be tested for antigen binding and enzymatic activity. Active conjugates will be tested in vitro (cell proliferation) against CEA-expressing and cell lines not known to express CEA. Promising candidates will then be further screened in a mouse xenograft model with a CEA overexpressing cell line. The ultimate goal of this project is to develop a new safe AND effective tool for physicians to treat patients with cancer. 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. In the year 2003, the National Cancer Institute estimated that 1.3 million Americans will be newly diagnosed with cancer and that more than 1,500 Americans died from cancer each day.