Companies in Race to Develop a Simpler Approach
Clive Cookson
Press Date: Monday, April 10, 2006
Financial Times
Monoclonal antibodies have been the great success story of biotechnology over the past decade. Since 1997 their worldwide sales have grown from zero to an estimated Dollars 14bn last year.
Eighteen drugs based on monoclonal antibodies have reached the market, including such well-known brands as Herceptin, Rituxan and Avastin for cancer and Humira and Remicade for arthritis, and hundreds more are at various stages of research and development.
Yet, for all their promise, MAbs (to use the common abbreviation) are still troublesome drugs.
Setting aside the severe adverse reaction suffered last month by the first six volunteers to receive a new antibody made by TeGenero of Germany - which may have been a one-off problem - MAbs are large and complicated molecules.
This makes them very expensive to develop and manufacture, so patients (or healthcare organisations) have to pay many thousands of dollars for each course of treatment. And their size means that direct injection is the only practical delivery mechanism.
A considerable research effort is therefore under way to develop stripped-down MAbs that would be simpler and cheaper, perhaps safer and potentially small enough to take by mouth.
Although several biotech companies are involved, two in particular stand out: Ablynx, based in Belgium, and Domantis, with a scientific centre in the UK and business headquarters in the US. The pair make a good case study, because they have much in common - their corporate age, development, funding and product portfolio are similar - though there are interesting differences too.
Both companies are developing antibodies that are just one-tenth the size of a full-scale MAb but still have the key capability to recognise and bind to a specific target or antigen. Ablynx calls its products Nanobodies (NAbs), while Domantis produces Domain Antibodies (DAbs).
The companies are about five years old, though their underlying technologies originated with discoveries made independently in Belgium and the UK 15 years ago.
The scientific starting point for Ablynx was the finding by Raymond Hamers and colleagues at the Free University of Brussels that camelids - a group of animals including camels and llamas - naturally produce compact antibodies with just two molecular chains. By contrast, humans and other mammals make antibodies with four linked chains.
The Belgian researchers pared these camelid antibodies back further to the smallest possible unit, the Nanobody.
Domantis traces its history back to the discovery by Greg Winter and colleagues at the Laboratory of Molecular Biology in Cambridge of a way to isolate Domain Antibodies directly from human antibodies.
Of course each company claims that its approach is superior. Ablynx emphasises the advantage of beginning with naturally small antibodies that require less complex molecular engineering than Domain Antibodies. Domantis, in turn, proclaims the human rather than animal origin of its technology.
To the outsider, however, the resemblance between DAbs and NAbs is striking. Both have outstanding chemical stability. They withstand heat, acidity and many enzymes that destroy most other proteins. This not only helps their manufacturing and processing but also opens up medical applications that are not open to full-scale MAbs.
"For example, Nanobodies are not broken down in the stomach and intestine, so they will enable us to go after targets in the gastro-intestinal tract," says Mark Vaeck, a co-founder of Ablynx. One of the company's most advanced preclinical programmes is an oral treatment for inflammatory bowel disease.
While DAbs are also capable of reaching targets through oral delivery, Domantis is giving a higher priority to delivery via an inhaler into the lungs to treat asthma and chronic obstructive pulmonary disease (COPD), says Ian Tomlinson, chief scientist.
DAbs and NAbs are extraordinarily versatile. In principle they can be made to target an almost infinite range of targets - or combined to bind to more than one antigen at the same time, as with Domantis's dual-targeting DAbs.
The latter may help in the treatment of multifactorial diseases. For example one experimental product is designed to neutralise both IL-4 and IL-13 in asthma patients.
Both Ablynx and Domantis are working in the anti-inflammatory and oncology fields. They have several collaborative deals already in place - Domantis's partners include Bristol-Myers Squibb, Abbott, Peptech, ImClone, Argenta and Tanox; Ablynx's partners include Novartis, Centocor, Kirin Brewery and P&G Pharma - and they expect to announce more this year.
Clinical trials of NAbs and DAbs are expected to start within the next year or so. The TeGenero disaster at Parexel's Northwick Park drug testing unit near London may have cast a cloud over antibody research, but Ablynx and Domantis executives believe the severe immune reaction suffered by the six volunteers will turn out to be unique to the MAb they were given.
"We don't really know yet what happened at Northwick Park," says Dr Moses who took over as Ablynx chief executive last month from Dr Vaeck, having been the company's non-executive chairman since November 2004. "As we are in the antibody area we will look carefully at what happened but we should remember that tens of thousands of clinical trial volunteers have received antibody products without a problem."
Ablynx has so far raised Euros 33m from a range of biotech investment funds in continental Europe, the UK and US. Dr Moses says the company plans a further private funding round this summer - raising perhaps Euros 25m from its existing investors - followed by an IPO next year if market conditions are favourable.
Domantis raised Dollars 30m in its last funding round in December, bringing the total so far to Dollars 83m. Bob Connelly, chief executive, says the likely timing of Domantis's IPO is for the second half of next year or first half of 2008.
The two companies differ more in their geographical spread. Domantis is moving its business, finance, legal and regulatory operations to the US, Mr Connelly says: "The principal driver is access to the US capital markets; we have targeted Nasdaq from the beginning for our IPO."
But he says there is no plan to move Domantis's scientific operations across the Atlantic from Cambridge, where they started.
Domantis also has a strong Australian link through Peptech, a Sydney-based biotech company, which has a 34 per cent shareholding and several research collaborations with it. "Ablynx is very much a European company and we shall keep our centre of gravity in Europe," says Dr Moses.
The two companies did clash over intellectual property, when Domantis challenged the breadth of Ablynx's European patent claims. The dispute ended last year with a compromise ruling that narrowed their scope but left most in place.
Relations between the companies now seem distant but not hostile. "There is loads of space for both of us," says Dr Moses.
