Antibodies break the cell barrier
Superantibodies that can bind to targets within cells, rather than on their surface, could lead to a new range of treatments for diseases, a biotech company claims. "Most good targets for diseases are inside cells," says Charles Morgan, president of InNexus Biotechnology of Vancouver, Canada, which has developed the superantibody technology. Superantibodies could be used to target bacteria and viruses (including HIV) inside cells, for instance, or abnormal proteins that turn cells cancerous. In theory, they could do everything that the small molecules of most conventional drugs do, and more. The beauty of a cell-penetrating superantibody is that it would be highly discriminating. Because antibodies can be far more specific than small-molecule drugs, and because they are not inherently toxic, they should have fewer side effects. The big disadvantage is that antibodies have to be injected as they do not survive in the stomach.
Antibody-based treatments are already being used to treat diseases in several ways. Over a dozen are now approved for use in people. However, like natural antibodies, all bind to molecules on the surface of cells or viruses. Antibodies under development can ferry other substances into cells, such as the toxin ricin, and they are sometimes engulfed by a cell after binding to its surface proteins, but none can enter cells freely and target molecules inside them. However, InNexus says a simple chemical modification enables any antibody to flit in and out of cells until it finds its target. The "key" that allows them to enter is a short protein segment called a membrane-translocating sequence (MTS), normally found in signalling proteins such as growth factors that can enter cells.
Several groups worldwide have shown that attaching MTS segments to other proteins allows them to enter cells. "We thought, can you do this with an antibody?" says Morgan, who presented the technology at a BioVentures biotech conference in London earlier this month. InNexus found a way to attach an MTS segment to a structure common to all antibodies. "And lo and behold, it worked," he says. Experiments with a fluorescently labelled superantibody show it enters all cells but accumulates only inside cells containing its target, Morgan says. He thinks the antibodies could last in the body for up to a month, entering and leaving cells until they find their target. As a proof of principle, the company developed a superantibody that binds to and blocks caspase-3, an enzyme inside cells that triggers cell suicide. The superantibody stopped human white blood cells from killing themselves when they were exposed to actinomycin D, a drug that normally triggers cell suicide (Apoptosis, vol 8, p 631). InNexus hopes a superantibody of this kind can be developed to block cell death in people who have just had heart attacks or strokes. Some researchers have their doubts. "A lot of work has been done trying to make antibodies that are stable in cells," says Andrew Bradbury of the Los Alamos National Laboratory in New Mexico. "But it's proved far more difficult than expected."
But Morgan says an antibody's stability depends on how it enters the cell. Those that are engulfed after binding to surface proteins end up in structures called endosomes, where they are likely to be destroyed. Superantibodies, however, enter the normal, safe environment of the cell. "There would definitely be loads of new targets if it worked," says Daniel Elger of biotech company Antisoma, based in London, which has developed an anti-cancer antibody that carries an enzyme into cells after binding to a surface receptor. But for purposes like blocking viral replication, the success of cell-penetrating superantibodies will depend on the concentrations they reach inside cells. "It would be down to the practicality of whether you could get enough in," he says.
