Delivering drugs to cancer cells without poisoning patient’s body

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Researchers at Texas A&M University’s College of Medicine and College of Engineering are collaborating to engineer antibody-drug conjugates (ADCs) that will be more effective against tumor cells while not being as toxic to healthy cells.

Their work, which has been funded by the Cancer Prevention and Research Institute of Texas and the National Institutes of Health, was published in the journal Nature Biotechnology.

ADCs represent a promising treatment for cancer. An ADC is, as its name suggests, an antibody linked to a potent drug that can kill cells.

The antibody is designed to bind to receptors on the outside of target cells and then carries the attached drug into the cell.

ADCs usually work well when the antibody attaches to receptors that are especially common on tumor cells. That way, the drug will primarily enter the cancerous cells, leaving the healthy cells alone.

However, despite improvements in ADC technology over the past 15 years or so, many ADCs have faced problems with toxicity towards normal tissue during their use in clinical trials.

“There is such a thing as a therapeutic window,” said E. Sally Ward, professor, Department of Molecular and Cellular Medicine, College of Medicine. Ward is a joint corresponding author of the paper with Raimund Ober, also a professor in the department.

“This is the difference between the amount of drug that is needed to kill the tumor cells and the amount that results in off-target toxicity towards normal cells,” Ward said. “For effective ADCs, we want this window to be as large as possible.”

To accomplish that, Ward and her team created an ADC that is sensitive to pH levels so that it separates from its target receptor after it enters the cell. This allows for the reloading of the receptor with additional ADC and more effective delivery of the drug to target cells.

Corresponding authors Yang Shen, assistant professor, and doctoral student Mostafa Karimi, both in the Department of Electrical and Computer Engineering, College of Engineering, are developing computational methods for modeling biological molecules, networks and data. In response to the challenges in modeling pH-dependent protein interactions, they expanded a multi-state protein design algorithm to model ADC-engineering effects.

“The computational study reported in the paper, reflecting the first stage of our collaboration, was mainly on reverse engineering pH-selective ADCs, in other words, generating mechanistic hypotheses and designing experiments to test the hypotheses,” Shen said. “What we have been working on since then is to translate the learned molecular mechanisms into rational design principles and forward engineer even more powerful ADCs.”

“This truly was an interdisciplinary project,” Ward said. “It has involved (bio)engineers and biologists using a combination of antibody engineering, microscopy, molecular modeling and studies in preclinical cancer models.”

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