ARCHIVED - Llama antibody research generates multi-licensing opportunities

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March 08, 2008— Ottawa, Ontario

Llamas produce not one but two types of antibodies.
Llamas produce not one but two types of antibodies.

More than a decade of NRC research on llama antibodies is bearing fruit in the form of multiple patent applications being licensed to biotechnology firms in Canada and Belgium. These licences are helping NRC's partners develop a variety of llama antibody-based products designed to detect microbial pathogens, and treat cancer or other diseases.

Llamas may look harmless, but their immune system harbours some unique weapons against disease. In the 1990s, biologists in Belgium reported that unlike other mammals, the camelid family – which includes llamas, camels and alpacas – produce not one but two types of antibodies: the conventional Y-shaped molecules consisting of four protein chains; and smaller, two-chain antibodies. Within these two-chain antibodies, the part that recognizes and clings to foreign molecules, called "antigens", during an immune attack has been dubbed a single-domain antibody (sdAb).

Despite their modest size, single-domain antibodies can grasp their antigenic targets as firmly as conventional antibodies. What's more, they are hardier than monoclonal antibodies, the current standard antibody format for therapeutic purposes. "Single-domain antibodies are more resistant to heating and digestive system enzymes, so they have more potential applications," says Dr. Roger MacKenzie, leader of the antibody engineering group at the NRC Institute for Biological Sciences (NRC-IBS) in Ottawa. "Single-domain antibodies are also easier to make. Monoclonal antibodies are produced in mammalian cell culture, whereas sdAbs can be made a lot faster and cheaper using yeast or bacteria hosts."

How do antibodies work?

An antibody is a natural protein produced by white blood cells when mounting an immune response to a foreign substance (antigen) introduced in the body. Common antigens include proteins at the surface of bacteria or viruses. The antibody latches onto the antigen and either destroys it directly or makes it easier for white blood cells to eliminate the unwanted foreign substance.

In the mid-1990s, a team of NRC researchers developed a library containing about 1 billion different sdAb templates. "Our team took blood from a "naïve", or non-immunized, llama such that the single-domain antibodies in the library are not heavily biased towards certain antigens," says Dr. Yves Geoffrion, business officer at NRC-IBS. Scientists can then use the library to search for sdAbs that will cling to antigen molecules found on potential drug targets such as bacteria, viruses and cancer cells.

"To find the antibody you want, you just go fishing," explains Dr. Geoffrion. "It's like Velcro – whatever sticks to the antigen that you 'dip' in our library will be the sdAb you're looking for."

While NRC was putting together its "naïve library" of llama antibodies, the Belgian biotech firm Ablynx – formed from the original team that discovered the unusual camelid antibodies – had developed another isolation method. "Ablynx's approach is to immunize a camel or llama. The animal's immune response is to produce single-domain antibodies against a specific antigen, which the company isolates," says Dr. Geoffrion. Since both Ablynx and NRC hold intellectual property on complementary sdAb production methods, the two organizations have reached technology licensing agreements that allow each party to use the other's methods, with a view to developing commercial products.

Besides their llama library, NRC-IBS researchers have patented other single-domain antibodies with commercial potential. One of these has been licensed to Helix Biopharma, a Toronto-area biotechnology company, which is developing a lung cancer therapeutic agent called L-DOS47 that combines the NRC-developed sdAb and a proprietary molecule from Helix. (Helix intends to seek approval this year to begin a Phase I clinical trial with L-DOS47.)

NRC's antibody engineering group, from left to right: Dr. Jianbing Zhang, Dr. Mehdi Arbabi, Dr. Jamshid Tanha, Dr. Roger MacKenzie, Dr. Yves Geoffrion. In the 1990s, Dr. Arbabi was a member of the Belgian team that discovered single domain antibodies.
NRC's antibody engineering group, from left to right: Dr. Jianbing Zhang, Dr. Mehdi Arbabi, Dr. Jamshid Tanha, Dr. Roger MacKenzie, Dr. Yves Geoffrion. In the 1990s, Dr. Arbabi was a member of the Belgian team that discovered single domain antibodies.

In 2001, the antibody engineering group and the cerebrovascular research group at NRC-IBS, led by Dr. Danica Stanimirovic, produced the world's first sdAb to cross the "blood-brain barrier" -- a protective layer of cells that prevents most foreign molecules from readily entering the brain. "The blood-brain barrier rejects many things, including drugs," says Dr. Jamshid Tanha, a member of Dr. MacKenzie's team. "We've developed single-domain antibodies that are 'transcytotic', which means they can get across the cells of the brain's protective layer. You can use them like a truck to drive through the barrier and deliver a payload of drugs to cancerous cells or other disease targets inside the brain." NRC has licensed its blood-brain barrier-crossing sdAb to Ablynx, and other companies have also expressed interest in this unique technology.

Led by Dr. Jianbing Zhang and Dr. MacKenzie, the antibody engineering group has also created five-sided antibodies called pentabodies -- starfish-shaped molecules with five identical sdAb "fingers" [see: Code Name: Pentabody]. "These super-strength single domain antibodies are up to 10,000 times better at grasping antigen targets," says Dr. MacKenzie. An Ottawa-based start-up company has licensed this technology to develop diagnostic tools for clients. Dow AgroSciences has also licensed the pentabody technology for animal health and food safety applications.

Clearly, the NRC research conducted during the last decade on camelid antibodies is beginning to show some promising results.

Enquiries: Media relations
National Research Council of Canada
613-991-1431
media@nrc-cnrc.gc.ca

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