VIROLOGY:

SUMMARY: Multivalent single-domain antibodies may be the future of anti-viral agents.

Many viruses are well-equipped to evade the immune system and rapidly evolve resistance to synthetic anti-viral agents. Scientists still need broadly-effective anti-viral drugs, i.e. ones that target multiple viral subtypes and won't lose efficacy due to a relatively miniscule viral mutation.

Single-domain antibodies, fragments that are smaller than traditional antibodies, may be useful for these purposes. They can access portions of a viral surface unavailable to larger molecules, and can rapidly penetrate tissue.

Peter Vanlandschoot, Hans J. de Haard (Ablynx, Belgium), and coworkers have used single-domain antibodies towards developing highly effective anti-viral agents. They tested their antibodies against three viruses that cause severe infections in people.

Countering three dangerous RNA viruses.

The scientists immunized six llamas (two llamas for each virus) against respiratory syncytial virus, influenza H5N1 (bird flu), and rabies. They identified relevant single-domain antibodies, after infection, for large-scale production and use as multivalent entities (multiple antibody fragments on the same construct).

Multivalency doesn't negate the previously-mentioned small-size advantage. A flexible biochemical linker was placed between the antibody subunits, intended to enable binding at multiple locations in the same virus or between multiple viruses, and prevent viral conformational changes necessary for infection.

The most effective agents had IC₅₀ values (concentration at which 50% inhibition is observed, a common measure of drug efficacy) in the nanomolar to picomolar range. These values are up to 4000 times improved over that of corresponding monovalent constructs.

Since the surfaces of all three viruses are fundamentally different, the scientists' single-domain antibodies likely don't have a single common mode of action that can be countered by the viruses. The fact that viral subtypes were also neutralized further demonstrates the broad efficacy of these anti-viral agents.

Previous research suggests that these constructs remain in the body for approximately two days, and possibly more by rejiggering the specific formulation. Thus, this common limitation of single-domain antibodies is readily overcome.

Future developments.

Scientists at Ablynx have already successfully completed early-stage clinical trials of one single-domain antibody (testing in small groups of people for safety, not efficacy). Although more testing clearly needs to be conducted (and presumably will be), this development promises to be highly effective against the huge problem of drug resistance in viral infections.

NOTE: The scientists' research was funded by the Institute for the Promotion of Innovation by Science and Technology (Flemish governemnt) and Ablynx. Some of the scientists have commercial interest in this research.

Hultberg, A., Temperton, N. J., Rosseels, V., Koenders, M., Gonzalez-Pajuelo, M., Schepens, B., Itatí Ibañez, L., Vanlandschoot, P., Schillemans, J., Saunders, M., Weiss, R. A., Saelens, X., Melero, J. A., Verrips, C. T., Van Gucht, S., & de Haard, H. J. (2011). Llama-Derived Single Domain Antibodies to Build Multivalent, Superpotent and Broadened Neutralizing Anti-Viral Molecules PLoS ONE, 6 (4) DOI: 10.1371/journal.pone.0017665