With some manipulation a deadly protein has become an efficient carrier for antibody drugs
A team of Massachusetts Institute of Technology (MIT) researchers has turned the delivery system used by the bacteria responsible for causing anthrax (bacillus anthacis) into a drug delivery system for administering cancer drugs.
The anthrax toxin has three major components. One is a protective antigen (PA), which binds to receptors called TEM8 and CMG2 that are found on most mammalian cells. Once PA attaches to the cell, it forms a docking site for two anthrax proteins called lethal factor (LF) and edema factor (EF). These proteins are pumped into the cell through a narrow pore and disrupt cellular processes, often resulting in the cell’s death.
But this system can be made harmless by removing the sections of the LF and EF proteins that are responsible for their toxic activities, leaving behind the sections that allow the proteins to penetrate cells.
The MIT team altered the anthrax toxin by replacing the toxic regions with antibody mimics, which can kill cancer cells. In their study, they targeted several proteins, including Bcr-Abl, which causes chronic myeloid leukaemia. They also successfully blocked hRaf-1, a protein that is overactive in many cancers.
This is the first demonstration of effective delivery of antibody mimics into cells
The study is published in the journal ChemBioChem.
Bradley Pentelute, the Pfizer-Laubauch Career Development Assistant Professor of Chemistry at MIT, led the research.
This is the first demonstration of effective delivery of antibody mimics into cells, which could allow researchers to develop new drugs for cancer and many other diseases, says Pentelute.
Several antibody drugs have been developed to target other receptors found on cancer-cell surfaces. However, the potential usefulness of this approach has been limited by the fact that it is very difficult to get proteins inside cells. This means that many potential targets have been ‘undruggable’, Pentelute says.
‘Crossing the cell membrane is really challenging,’ he says. ‘One of the major bottlenecks in biotechnology is that there really doesn’t exist a universal technology to deliver antibodies into cells.’
The MIT team is now testing this approach to treat tumours in mice and is also working on ways to deliver the antibodies to specific types of cells.