Nobel laureate takes pride in success of bioorthogonal chemistry for cancer treatment
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It’s not often that a 2 a.m. phone call marks the highlight of someone’s career.
“It woke me up, and I looked at the phone and saw the call was from Sweden,” Carolyn R. Bertozzi, PhD, told Healio. “It was a shocking, surreal experience to receive that phone call.’’
That call notified Bertozzi, professor of chemistry at Stanford University, that she had been awarded the 2022 Nobel Prize in Chemistry for her role in developing bioorthogonal reactions, which enable scientists to explore cells and track biological processes without interfering with the normal chemistry of the cell.
Bioorthogonal chemistry is being applied to cancer treatment by José M. Mejía Oneto, MD, PhD, CEO of Shasqi Inc., which has developed a way to safely deliver high doses of chemotherapy without impacting nearby tissues.
“I’m so happy that José has taken on this challenge of deploying bioorthogonal chemistry for cancer treatment, and that he has been so successful,” said Bertozzi,
who also serves as Baker family director of Stanford ChEM-H, Anne T. and Robert M. Bass professor in the School of Humanities and Sciences, and professor, by courtesy, of chemical and systems biology and of radiology at Stanford Medicine. “If you listen to interviews I’m giving about how bioorthogonal chemistry can benefit humanity, I go right to José and Shasqi as an example.”
When Bertozzi learned she won the Nobel with K. Barry Sharpless, PhD, professor at Scripps Research, and Morten Meldal, PhD, professor at University of Copenhagen, she was told that her life was about to change.
Three months later, it has, indeed, changed.
“It’s been a whirlwind with all the interviews and attention I’m not accustomed to,” she said. “They tell me that eventually, it does die down. I’m just trying to go with the flow.”
Click chemistry in living organisms
Sharpless, Hartmuth Kolb, PhD, and M.G. Finn, PhD, introduced click chemistry in 2001. It involves chemical reactions in which specific pairs of molecules react selectively with one another and ignore their environment, according to a Stanford University press release.
Bertozzi and her research team showed these reactions can occur in cells or animals. This phenomenon, known as bioorthogonal chemistry, refers to any chemical reaction that can occur within a living system without disrupting the biochemical processes of the organism.
“The point of bioorthogonal chemistry is to take two things that form a bond together, and they can do this even inside something as messy and complicated as a biological organism, like a human body,” Bertozzi said. “That’s challenging for chemistry because there are a lot of chemicals in the body — all the proteins and sugars and water. The bioorthogonal reaction involves two components that ignore all of that. Despite all that messiness, they find each other and form a bond.”
In the late 1990s, Bertozzi and her colleagues had a specific interest in doing molecular imaging of biological molecules in living bodies.
“We had this idea that we could do molecular imaging if we could do chemistry on biological molecules with imaging probes in the human body or laboratory animals,” she said. “However, there were no chemical reactions at that time that had the qualities we would need to do this chemistry in a living system.”
Bertozzi and her colleagues created some bioorthogonal reactions that worked at the time, and these reactions proved useful for many applications in biomedicine, both in Bertozzi’s lab and other labs.
“Other people started to invent their own bioorthogonal reactions, and the field took on a life of its own,” she said. “Then José came along.”
Safer delivery of chemotherapy
Mejía Oneto received training as a PhD chemist, physician and surgeon, with a specialty in orthopedics. He took an interest in bioorthogonal chemistry in graduate school and had an idea to use it as a way to deliver medicines very specifically to tissues of interest.
“Cancer is now the focus of his company, Shasqi Inc., but he started out broader than that,” Bertozzi said. “José was formulating a company around this idea and he reached out to me when I was moving my lab from Berkeley to Stanford. I got really excited because I had been thinking for a long time about the opportunities to use bioorthogonal chemistry in humans for drug delivery or to create new kinds of medicines.”
Bioorthogonal chemistry is the foundation of Shasqi’s Click Activated Protodrugs Against Cancer (CAPAC) platform, which facilitates the safe and precise delivery of a chemotherapy drug to the tumor site at unprecedented doses. Shasqi’s lead asset, SQ3370, uses bioorthogonal chemistry in humans with the chemotherapeutic agent doxorubicin as the payload.
Bertozzi had started various companies over the previous 10 years and spoken with investors about doing in vivo bioorthogonal chemistry, but had never gotten much traction on the idea.
“People thought it was crazy and risky,” she said, “but then José had managed to convince the people at Y Combinator that there might be a ‘there’ there. He was very fearless — I would say intrepid. He decided to try and make a go of this. I was very happy that he invited me to be a consultant and adviser along the way.”
Targeted drug delivery
Mejía Oneto described the approaches Shasqi Inc. has developed for using bioorthogonal chemistry to deliver drugs.
“One way was to have a direct injection of a biopolymer that includes one of the click reagents, and that material is designed to stay in that location, so it artificially provides a lot of that click chemistry reagent in that tumor and tumor microenvironment,” he said. “That differentiates that tumor from anything else in the body.”
Bertozzi discussed how Mejía Oneto’s company has utilized bioorthogonal chemistry to deliver chemotherapy drugs while sparing nearby healthy tissue. Mejía Oneto has devised an approach to chemically modify a hydrogel polymer commonly used as a cosmetic filler. A bioorthogonal chemical is put on the filler, which is then injected into the tumor microenvironment.
“It just sits there, takes up some space and does nothing — it’s harmless,” Bertozzi said. “Then, the next day, they inject a chemotherapy drug into the same patient by IV infusion. The chemotherapy drug has the other bioorthogonal group on it that makes the drug inactive and harmless. When it encounters that filler material in the tumor microenvironment, the reaction happens and the drug is released. Now you get this very local burst of toxic poison in the tumor but nowhere else in the body.”
Additionally, Mejía Oneto has been focusing on chemotherapy agents that have immune-potentiating activity, Bertozzi said.
“They get an immune reaction against the dying cancer cells at the same time as they are being killed,” she said. “It’s very elegant.”
Mejía Oneto said he presented critical pieces of data on SQ3370 last year at two major oncology conferences, European Society for Medical Oncology and Society for Immunotherapy of Cancer. In one study, Mejía Oneto and colleagues demonstrated that they could give more than 12 times the usual dose of the chemotherapy drug they were evaluating.
“Usually, you receive six doses in your lifetime, and we’re giving more than twice that every 21 days,” he said. “That’s because we can concentrate the power of this drug just at the tumor. When you have this really high amount of drug at the tumor, you end up seeing changes in the immune response. So, we actually increase the immune-fighting cells at the tumor, and we have proof of this through our phase 1 data in humans.”
Mejía Oneto said this innovation has now moved into phase 2 trials, where it will be investigated for use in soft tissue sarcomas and head and neck cancers.
“That would meet areas of need where we don’t have great therapies yet,” he said.
‘Something to look forward to’
For Bertozzi, one of the best parts about winning the Nobel Prize was being able to share it with those who have been in her life from the beginning, she said.
Her father, a 91-year-old retired physics professor at MIT, had been depressed during the past year over the death of Bertozzi’s mother. Bertozzi said she is grateful he lived to see her achievement and share it with her.
“This gave him something to look forward to and get excited about,” she said. “He and my two sisters came with me to Stockholm. We were there for almost 2 weeks.”
Bertozzi described the trip to Sweden as a “crazy” nonstop agenda of morning-to-night events for 6 consecutive days.
“It was like a completely different planet than what I’m used to,” she said. “It was exhausting but exciting, and I was so glad my father got to be there to see it.”
Bertozzi said winning the coveted prize has led her to reflect on her life and the goals that ultimately drove her to work toward this achievement. She said although winning the Nobel has been life-changing, she always strives to keep her eye on the true prize — helping humanity.
“You do a lot of self-reflection when you have a big moment in your life, and I thought about the reason we worked so hard to make these chemistries — to benefit human health, either in the long term as research tools or the shorter term as new therapeutic modalities,” she said.
Mejía Oneto expressed his gratitude for Bertozzi’s help and support over the years, and said he is excited for the future of bioorthogonal chemistry.
“There was a lot of skepticism around this at first — people didn’t think it would be possible, the body is just too complicated,” he said. “The power of bioorthogonal chemistry is just incredible. We’re just scraping the top of what is truly possible.”
For more information:
Carolyn R. Bertozzi, PhD, can be reached at Bertozzi Group, Department of Chemistry, 380 Roth Way, MC: 5080, Stanford, CA 94305-4401; email: bertozzi@stanford.edu.
José M. Mejía Oneto, MD PhD, can be reached at 665 3rd St., Suite 501, San Francisco, CA 94107; email: jose@shasqi.com.
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Stanford’s Carolyn Bertozzi wins Nobel in chemistry (press release). Available at: news.stanford.edu/2022/10/05/carolyn-bertozzi-wins-nobel-chemistry/. Published Oct. 5, 2022. Accessed Dec. 23, 2022.
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