Focusing on Glycans as Novel Drugs and Therapeutic Targets
Biotherapeutic protein producers have taken pains to ensure consistency in glycosylation of recombinant therapeutic proteins, mostly due to the potential immunogenic properties of non-self glycans, the impact of glycosylation pharmacokinetics, and glycan in vivo functionality. But according to an article published in the January 3 edition of Science, researchers are increasingly turning to modifications in these sugars that normally decorate proteins to develop clinically effective therapeutics.
In the January 3 Science article, titled "Emerging Principles for the Therapeutic Exploitation of Glycosylation," Martin Dalziel, Ph.D., and colleagues at Oxford University discuss what researchers have, to date, learned about glycans in the context of pathogen invasion, cancer and autoimmunity, and congenital diseases. The authors reveal recent advances in recombinant cellular biosynthetic technologies that can produce defined “glycoforms,” and they describe several clinically effective therapeutics that have already been developed with such glycoforms.
The authors point out that glycans are not only essential to glycoprotein folding, cellular homeostasis, and immune regulation but are involved in multiple disease conditions. An increased molecular and structural understanding of the mechanistic role that glycans play in these pathological processes has driven the development of therapeutics and illuminated novel targets for drug design.
This knowledge has enabled the treatment of metabolic disorders and the development of antivirals, shaped cancer and viral vaccine strategies, and led to the development of specific drug glycoforms—for example, monoclonal antibodies—with enhanced potency.
In one such application, Dr. Dalziel and his colleagues note that HIV vaccine development is based on targeting the viral carbohydrate coat. This carbohydrate coat, the investigators have shown, remains remarkably constant despite huge variation in the underlying viral protein. The researchers have also been investigating using microbial mimics of this shield to elicit antibodies that can protect against the virus, showing that broadly neutralizing antibodies can recognize this shield despite structural variation in these “self” carbohydrate structures.
The investigators say they have also structurally characterized how different glycans impact antibody Fc structure and how they can be manipulated to fine-tune antibody effector functions. In addition, they say, they are developing a new approach for enhancing therapeutic antibodies against cancer that involves deactivating competing endogenous antibodies that can limit the potency of anticancer antibodies.
Methods, they and other authors have pointed out, are now becoming available that allow the production of recombinant monoclonal antibodies, rMAbs, bearing preselected oligosaccharides (glycoforms) to provide maximum efficacy for a given disease indication.