New Engineering Approach May Enhance Drug Development

The recent design of a better variant for erythropoietin (EPO) revealed that rational design can improve in vivo efficacy and the safety of protein therapeutics, as well as reducing potential side effects and accelerating new drug development.

Protein therapeutics can lead to negative side effects, and the natural hormone EPO that’s secreted by the kidneys to increase red blood cell production is no exception.

For the study, published in the Proceedings of the National Academy of Sciences, researchers looked to create a strategy for engineering protein fusion without any side effects.

“Our concept is completely general,” said corresponding study author Pamela Silver, PhD. “We can reduce the toxicity of approved protein drugs, and may also be able to rehabilitate protein fusion drugs that have so far failed in clinical trials due to unacceptable side effects.”

Although EPO activates red blood cell production, it also causes dangerous complications like blood clotting and boosted blood vessel growth.

Often times, these patients will suffer from higher rates of heart attack, accelerated tumor growth, and stroke. In response to the negative effects, the FDA has issued a black box label for EPO, warning patients of serious hazards associated with the drug.

Researchers decided to address this issue by rationally designing a more effective, multi-part drug molecule.

“Compared to currently available EPO drugs, our molecule is engineered to prevent EPO from binding to and activating cells that promote side effects such as blood clotting or tumor growth,” said senior study author Jeffrey Way, PhD. “This cell-targeted EPO approach demonstrates a new theoretical basis for the rational design of engineered protein fusion drugs.”

For the study, researchers genetically mutated the EPO protein, reducing its ability to bind to cell receptors. Next, a chain of amino acids were used as a flexible linker to attach the mutated EPO to a specific antibody fragment.

When the fusion protein molecules were delivered to the mice, the antibody fragments moved toward the membranes of red blood cell precursors, binding to them, while also bringing along the EPO molecules on the opposite end of the linkers.

Being in such close quarters to the surface of the cells, the tethered EPO moved around until they formed into place on the cells receptors. This process allowed for side effects to be avoided and only the red blood cell production was increased.

“Our rational design strategy is unique compared to current industry approaches,” said first study author Devin Burrill, PhD. “Our goal is to use our method to advance predictive drug design and minimize the time between drug concept and commercialization.”

Drug development typically focuses on the strength of the drug interactions with the target, but the study authors shied away from this.

“The principles of synthetic biology influenced our efforts,” said study co-author James Collins, PhD. “In drug development, the focus is typically on increasing the strength of interaction with a drug target, but here we found that weakening an interaction was useful. This illustrates how we need to adopt alternative, non-traditional approaches if we want to build complex, multi-part therapeutics.”

This cell targeted approach could also be used in other areas, according to researchers. A novel design of a cancer drug that causes unwanted side effects called targeted interferon alfa was also unveiled.

“This is another great example of how using a synthetic 'bottom-up' engineering approach and leveraging the power of biological design - this time at the scale of individual molecules interacting on cell membranes - can lead to breakthrough technologies for medicine that overcome limitations that hold back more conventional approaches,” said Donald Ingber, MD, PhD, founding director of Wyss Institute.