La Trobe University scientists are pioneering the use of modified shark antibodies in the quest for new and better therapies against diseases such as malaria, cancers and rheumatoid arthritis.
The process takes genes from sharks and modifies them in a laboratory by adding proteins that cause random mutations – mimicking the way the human immune system works – to develop antibodies capable of defensive responses against a range of diseases.
Developed by La Trobe molecular biologist Associate Professor Mick Foley, an international leader in malarial research, and his CSIRO colleague Dr Stewart Nuttall, the scientists have built the world’s first test tube ‘library’ of disease-targeting antibodies based on modified shark antibodies.
According to the scientists, because shark antibodies are much smaller, chemically more robust and biologically more stable than conventional antibodies, they are well suited for targeted therapy – raising the prospect of new therapies that can be taken orally instead of injected.
The scientists recently showcased their emerging technology at the BIO-2008 convention in San Diego, California.
Announcing this potentially innovative role for sharks, Victorian Premier Mr John Brumby said there was a multibillion- dollar global market for antibody treatments and the shark gene extraction technique had attracted significant interest at BIO-2008.
‘While Victorian scientists are not the first to recognise the potential of shark antibodies as a new line of defence against disease, existing technologies require shark handlers immunising the shark and letting the shark develop the antibodies,’ Mr Brumby said. ‘This technology has been patented and bears all the hallmarks of being the next generation of antibody-based diagnostic and therapeutic treatments.’
Scientists at AdAlta, the Melbourne-based company now developing the technology at La Trobe University, say that shark antibodies are highly effective in killing malarial parasites in vitro, through a unique protein-binding process that blocks molecular function.
Dr Foley, AdAlta’s chief scientific officer, and Dr Stewart Nuttall, the company’s consultant scientist, made this discovery in 2004, revealing that a shark antibody has a long, finger-like loop that projects from the surface and binds into a cavity on the target protein.
The antibody disrupts the normal signalling chain of command and inhibits malaria protein from invading human red blood cells.
Irreverently tagged as ‘giving malaria the finger’, this sub-cellular sabotage conjured images of the development of the anti-influenza pharmaceutical Relenza.
‘When we saw the pictures of the shark antibody binding to a hole in the protein, we immediately thought of a situation like the flu,’ Dr Foley says. ‘It’s like covering up part of a keyhole. You don’t have to cover the whole keyhole; if you cover up part of it, you can’t get the key in.’
The scientists have since completed many studies showing that if a shark antibody selected from the library binds to a malaria protein and is then put into a malaria parasite in culture, it kills the parasite. Other biotechnology companies are also working in this area, including Haptogen, a Scottish company recently acquired by Wyeth pharmaceuticals.
Unlike AdAlta, Dr Foley says, Haptogen obtains shark antibodies by immunising sharks and harvesting their blood.
‘We take the genes from normal sharks and put them into a genetic vector, then add in random bits of protein, similar to what the human immune system does. This "library" is in a single test tube in the freezer. We can select antibodies in the laboratory and by maturing and optimising these you will get something that binds very tightly,’ he says.
‘The aim is to use these shark antibodies as a way of finding high-affinity binding agents to bind to anything we want – such as a molecule on cancer cells, or inflammatory proteins that you could then use in therapy.’
Unlike their UK-based competitors who recently advertised for ‘experienced biologists with sharkhandling abilities’, Dr Foley says AdAlta’s work is strictly lab and land- based. ‘Because their intellectual property depends on immunising the shark and letting it develop the antibodies, they need shark handlers. We don’t. It’s all done in the laboratory. It is quicker, more efficient – and a bit safer,’ he says.
(Source: La Trobe University: July 2008)