A novel class of simple chain antibodies that overcome many of the physical limitations of monoclonal antibodies have been isolated from the adaptive immune system of sharks.
Shark variable new antigen receptors (VNAR) are the smallest molecule of this type identified in any animal. At around one-twelfth of the size of a human antibody, VNARs can penetrate both the blood-brain barrier and deep inside tumours much more easily than the larger globular monoclonal antibodies, yet still retain a high specificity and affinity for the target.
Researchers at the University of Aberdeen’s Scottish Biologics Drug Discovery Facility have already patented this technology in several countries, most recently in the US, and it has been used successfully to generate lead compounds in inflammatory disease and cancer. VNARs have been modified to carry chemotherapeutic drugs, but their simple single chain structure makes them amenable to combinational therapy enabling more than one target or biological pathway to be modified simultaneously. The US patent also protects the researchers’ candidate molecule hE06, which can extend the useful potency of partner drugs in the body from hours to weeks.
Dr Caroline Barelle, who will be the chief executive of new patent-owning biotech company Elasmogen when it spins out of the university, said: “This joining by conjugation chemistry of toxic ‘war-heads’ to relatively delicate proteins can sometimes be a tricky process. One might predict that proteins that come from sharks would be tough – and in this case they really are. This means that we can use ‘harsh conjugation chemistry’ to get efficient loading of drugs onto our VNAR domain to generate a molecule that can both enhance the efficacy of other drugs by increasing their time in the body, whilst also being a potent cancer killer in its own right.”
The Elasmogen team has already demonstrated that its tumour-specific VNARs can bind to external receptors on cancer cells and then be internalised or ‘swallowed’. Once inside, the VNARs can release their drug partner, killing the cell almost instantly. This VNAR-drug conjugate (VDC) approach reduces side effects because the treatment successfully targets cancer cells and not surrounding healthy tissue. The team predicts that the first VNARs could be in patient trials within three years.
Dr Barelle said: “Sharks are often considered the most sophisticated and ruthless of predators. We hope that by harnessing the power of their immune system we can turn VNARs into the same ruthless killers of cancer cells.”