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We’re gonna need a bigger bond: studying sharks to make better mAbs

By Gareth MacDonald+

10-Jun-2014
Last updated on 29-Mar-2016 at 16:34 GMT2016-03-29T16:34:03Z

We’re gonna need a bigger bond: studying sharks to make better mAbs

Shark antibodies survive in urea concentrations that would denature other proteins thanks to a newly discovered structure that scientists say could be used to make therapeutic mAbs more robust.

With the possible exception of the unconvincing rubber one used in the movie Jaws, sharks do not usually dehydrate. 

The reason for this is that shark blood contains high concentrations of urea that stops them osmosing to death in the salty seas.

This is an impressive feat, but what is even more remarkable is that shark antibodies are not denatured by the urea.

Human antibodies would quickly unravel in such basic conditions, but shark immunoglobulins are able to function normally in the presence of urea and until recently nobody knew why.

Now, however, scientists at the Technische Universitaet Muenchen (TUM) and the Helmholtz Zentrum Muenchen claim to have identifed a structure called a "salt bridge" that allows shark antibodies to survive where human protesins would not. 

A Salt bridge is a bond between amino acids that gives proteins their tertiary structure. Salt bridges are present in both human and shark antibodies, the difference is that shark antibodies have more.

The additional bonds in the shark antibodies link structurally important amino acids and the large non-polar nucleus of the immunoglobulin fold, stabilising the molecule.

Researcher Johannes Buchner told BioPharma-Reporter.com that: “The extra salt bridge stabilizes important structural elements of the immunoglobulin fold in some shark antibody domains.

"The hydrophobic nucleus is found in all antibody domains, but it is slightly extended in some shark antibody domains also contributing to their stability.”

Industrial applications

Finding stuff out about sharks is cool.

However, said coolness notwithstanding, research grants are only usually granted if the information generated is of wider utility. 

Fortunately for Professor Bruchner and his team their finding has a practical application: making therapeutic antibodies more stable.

Stability is a critical factor for all antibody based therapies. Work in the lab can only be translated into product revenue if the antibody in question is robust enough to withstand the rigours of production, distribution and storage. 

Bruchner said the idea would be to replicate the shark salt bridges in therapeutic molecules, explaining that: “The sequence of the therapeutic antibodies would be slightly modified and then the antibodies would be produced in mammalian cells as they are today anyway.”

More trials?

One potential hurdle is that regulators do not usually respond well when drugmakers make changes to products.

Bruchner acknowledged this explaining that modifying existing biologics may necessitate additional trials; the changes being discussed “are minor, so likely no negative effects are expected.”

He added that: “We are in contact with manufacturers and hope that in a couple of years our idea might find an application in their products.”

Publication:
The structural analysis of shark IgNAR antibodies reveals evolutionary principles of immunoglobulins
Matthias J. Feige, Melissa A. Graewert, Moritz Marcinowski, Janosch Hennig, Julia Behnke, David Ausländerb, Eva M. Herold, Jirka Peschek, Caitlin D. Castro, Martin Flajnik, Linda M. Hendershot, Michael Sattler, Michael Groll, and Johannes Buchner
PNAS, Early Edition, Datum, http://www.pnas.org/cgi/doi/10.1073/pnas.1321502111

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