Super-antibodies break the cell barrier

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Super-antibodies break the cell barrier

http://www.newscientist.com/news/news.jsp?id=ns99994881

Andy Coghlan

 

15:23 19 April 04

 

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Super-antibodies 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 super-antibody technology.

 

Super-antibodies 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.

 

 

Theraputic antibodies

 

The beauty of a cell-penetrating super-antibody 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.

 

 

Molecular ferries

 

 

Antibody-based treatments are already being used to treat diseases in

several ways (see graphic). 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 in

April. 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 super-antibody 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.

 

 

Cell suicide

 

 

As a proof of principle, the company developed a super-antibody that binds

to and blocks caspase-3, an enzyme inside cells that triggers cell suicide.

The super-antibody 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 super-antibody of this kind can be developed to block cell

death in people who have just had heart attacks or strokes.

 

 

 

 

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Weblinks

 

 

InNexus Biotechnology

 

Super-antibodies, InNexus Biotechnology

 

BioVentures, London 2004

 

 

 

 

 

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.

Super-antibodies, 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, UK, 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 super-antibodies 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.