Undergrads expand the chemical toolbox for cancer drugs

A recent publication, including 10 undergraduates, shows proof of concept for next-generation antibody therapies. (Photo by Stephen Salpukas)

Thanks to modern therapies, a cancer diagnosis is no longer an automatic death sentence. But many patients still suffer from unwanted side effects and limited efficacy. In a recent Bioconjugate Chemistry publication, William & Mary researchers designed an antibody-drug conjugate (ADC) with the potential to improve the potency and decrease the cost of currently approved cancer drugs.

Like guided missiles carrying warheads, ADCs are designed to seek out cancer cells and hit them with a powerful toxin. Made up of an antibody (the missile's GPS, which homes in on the cancer) and a drug (the payload), they represent a major advancement over traditional non-targeted cancer therapies. Young's research group takes this next-generation approach one step further.

"If we think of currently approved ADCs as vehicles, having one seat for a payload, our ADC has two," said Young. "This expands the capacity of these therapies to carry more or different types of drugs."

When tested against breast cancer cells, their ADC - loaded with a toxin and a fluorescent probe - caused nearly complete cell death within eight hours.

"I think the most exciting thing is the development of a new reaction that is rapid and efficient and has application to preparing therapeutics that have enhanced properties," said Young. "This has a lot of potential to make cancer treatments safer and more powerful with fewer detrimental side effects."

Perhaps most significantly, this reaction is bioorthogonal - meaning it can occur inside a biological system without interfering with the natural chemistry of the human body.

"Of the many known chemical reactions, only a handful can occur under the conditions required by biology - 37 degrees Celsius, neutral pH, in water - without disrupting native cellular chemistry," said Young. "In fact, the development of bioorthogonal chemistry was just awarded the Nobel Prize in 2022. So, for undergraduate-led research to expand this rare class of chemistry is truly remarkable."

The study's authors include 10 students from Young's lab, along with former student collaborators from the University of California, Berkeley, and the University of California, San Francisco.

Designing Better Cancer Therapies

Fourteen ADCs have been approved by the Food and Drug Administration since 2000, including treatments for breast, lung and bladder cancer. But like any innovation, these therapies still face challenges. Namely, ADCs don't always deliver a stable dose and, because they typically only carry one toxin at a time, they have limited power to kill cancer, leaving the door open for disease recurrence.

"Getting an ADC to deliver a stable, predictable dose is a challenge that arises due to the fundamental building blocks of proteins," said Young. "Proteins can do a lot of cool things, but their functionality is completely made up of 20 naturally occurring amino acids."

Those amino acids use only five out of the 118 elements on the periodic table. This redundancy in their code limits the chemistry they can perform.

"When you're trying to attach a drug to a protein, this chemical similarity can make it very hard to control exactly where and how much of the drug you add," said Young. "This leads to problems with drug dosage, stability and how the body reacts to it."

In practice, this can cause variability in how much drug a patient receives from dose to dose, which "obviously isn't ideal," stated Young.

To overcome this challenge, Young's lab is leveraging non-canonical amino acids (ncAAs). The idea behind ncAAs, Young said, is to engineer proteins with novel reactivity that doesn't exist naturally in the human body.

For the current study, Young's lab used an ncAA to incorporate a triple bond into their antibody. Chemically distinct from anything else in the protein, this bond stood out like a flashing neon sign, attracting the toxin they wanted to attach.

"Inserting this bond gives us confidence that our antibody carries exactly one drug, since there's only one handle it can react with in the protein," said Young.

The triple bond and toxin were linked using a chemical reaction the lab had previously adapted to work under physiologic conditions - making it work without disrupting the delicate structure of the antibody. By using this reaction to introduce another triple bond (i.e., another chemically distinct handle), their antibody was primed to accept one more payload and become multivalent.

A novel reaction for multivalence

"Currently approved ADCs are what you call monovalent, meaning they only have one handle where you can attach a drug," said Young. "We wanted to increase flexibility and potency by engineering a multivalent complex, capable of carrying two drugs or one drug and one fluorescent probe."

In a novel reaction, his students used the triple bond chemistry to couple an aminooxy functionality, adding a fluorescent probe. The resulting antibody-toxin-probe conjugate showed proof of concept as a multivalent ADC when tested against breast cancer cells.

"Our results demonstrate the creation of a multivalent ADC that was specific, potent and trackable, a triple threat to cancer," said Young. "While we used a fluorescent probe as the second payload in this study, future work could replace it with another drug to attack the cancer through a different mechanism and combat the potential risk of treatment resistance."

Notably, their reaction was very quick to complete, used commercially available reagents and was performed in what chemists call a one-pot fashion, meaning all steps occur in a single vessel.

"To the average person, these might seem like trivial details, but in the drug development world, these reaction conditions are very exciting," said Young. "If our process were scaled up, which has to be done if a drug goes to market, these conditions would make it fairly efficient and cost-effective."

From students to published researchers

An estimated 85% of undergraduates participate in faculty-mentored research at W&M, a stat that Young's lab exemplifies. Averaging 20 students, his lab is always a beehive of activity, teaching students the skills they need to advance diverse careers in science and beyond. Robert Gourdie '24, first author on the current paper, is currently pursuing his doctorate in chemical biology at the University of California, Berkeley.

"Not many undergraduates can say they led a project with concrete applications for cancer treatments," said Gourdie. "The caliber of the journal we published in and the number of other undergraduate authors on the paper speak to W&M's distinction as a place where students transform into scientists."

Students say Young's mentorship balances instruction and freedom, supporting their learning while giving him the flexibility to manage a busy teaching schedule and lead W&M's pre-med advising program.

"Doug has been an amazing mentor," said Tyler Skeen '26, one of the authors on the Bioconjugate Chemistry paper. "He's created a real community in the lab where we start out by learning from more experienced students and then eventually begin to lead experiments and train incoming students ourselves. I've learned so many technical skills since joining the lab as a freshman, while also growing my communication skills through presentations and papers."

Catherine Tyson, Communications Specialist

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