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New Antibody Targets Proteins Inside Cancer Cells

Clinical trials for leukemia could start in a year (Mar. 13)

Researchers at Memorial Sloan-Kettering Cancer Center have discovered a monoclonal antibody that can effectively reach inside cancer cells — a key goal for these anticancer agents, since most proteins that cause or are associated with cancer are hidden inside cancer cells.

Unlike other human therapeutic monoclonal antibodies, which can target only proteins that remain on the outside of cancer cells, the new monoclonal antibody — called ESK1 — targets a protein that resides on the inside of the cell.

ESK1 is directed at a protein known as WT1, which is over-expressed in a range of leukemias and other cancers, including myeloma and breast, ovarian, and colorectal cancers. WT1 is a high-priority target for cancer drugs because it is an oncogenic protein, meaning that it supports the formation of cancer. In addition, WT1 is found in few healthy cells, so the drugs that target it are less likely to cause adverse side effects.

“This is a new approach for attacking WT1, an important cancer target, with an antibody therapy. This is something that was previously not possible,” said David A. Scheinberg, MD, PhD, co-inventor of the antibody. “There has not been a way to make small-molecule drugs that can inhibit WT1 function. Our research shows that you can use a monoclonal antibody to recognize a cancer-associated protein inside a cell, and it will destroy the cell.”

The first studies of the antibody are showing promise in preclinical research as a treatment for leukemia, as reported in the March 13 issue of Science Translational Medicine.

ESK1 was engineered to mimic the functions of T-cell receptors — key components of the immune system. T cells have a receptor system that is designed to recognize proteins that are inside cells. As intracellular proteins get broken down as part of regular cellular processes, human leukocyte antigen (HLA) molecules carry fragments of those proteins — known as peptides — to the cell surface. When T cells recognize certain peptides as abnormal, the T cell kills the diseased cell.

In the new study, the investigators showed that ESK1 alone was able to recognize WT1 peptides and kill cancer cells in the test tube and also in mouse models for two different types of human leukemia.

Additional studies must be done in the laboratory before ESK1 is ready to be tested in patients; but the monoclonal antibody was engineered to be fully human, which should speed the time it takes to move the drug into the clinic. Researchers expect that the first clinical trials for leukemia could begin in about a year.

Source: Memorial Sloan-Kettering Cancer Center; March 13, 2013.

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