Cancer cells are aggressive. They divide and multiply, creating their own blood supply, invading healthy tissue and resisting death. Even when targeted therapies kill these cells efficiently, adjacent cells are often left behind. These bystander cells can be malignant. If left intact, they can lead to tumor regrowth, and many therapies that act like snipers against cancer cells leave the cells of bystanders unharmed.
Now, KC Nicolaou, a synthetic chemist at Rice University, and his colleagues have found that an antibiotic-linked antibody known as an antibody-drug conjugate (ADC) kills bystander cells as efficiently as it kills targeted cancer cells.
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“The bystander effect could hold the key to opening new avenues for more effective anticancer ADCs that could improve targeted cancer therapies,” Nicolaou said in an email.
ADCs are gaining strength against cancer. More than 80 ADCs are progressing through clinical trials, and nearly a dozen have been approved as therapies. One of the first was a drug called Mylotarg, which was developed in the early 2000s to treat acute myeloid leukemia (AML). Like all ADCs, Mylotarg uses a linker to attach a payload — a chemotherapy drug called calicheamicin — to an antibody that delivers the treatment of the cancer.
An antibody-drug conjugate shows unprecedented bystander killing
Jenna Kripal, Rice University
While payloads often come from natural sources such as bacteria and fungi, they can be very difficult to create in the lab. Calicheamicin belongs to a class of compounds called enediynes that damage DNA. They are difficult to develop synthetically and only work well with specific linkers. In the mid-2000s, Nicolaou’s team developed a way to synthesize a compound with a structure similar to calicheamicin, called uncialamycin.1 originally obtained from an undescribed bacterium found in a British Columbia lichen.2 About a decade later, they streamlined the process.3
Reported in new research in PNAS,4 Nicolaou and his team put the uncalamycin charge to the test. They tested how well the antibiotic killed cultured cells when attached via six different linkers to antibodies that target two proteins overexpressed in cancers, T1 and CD46. Some lefts worked better than others. But what Nicolaou noticed was that uncialamycin was more potent than calicheamicin; it even removed bystander cells.
The finding was unexpected and unprecedented. “Uncialamycin is in the same class of drugs as calicheamicin, which is already FDA-approved and does not mediate killing bystanders. But this compound does,” said Zhiqiang An, a chemist and leading expert on therapeutic antibodies at the University of Texas at Houston.
No other enediynes have shown killing bystanders. Nicolaou found the results encouraging and An saw their potential. “This uncialamycin could be a very unique class of compounds,” An said, although he would like to see it tested further in other cancer models.
Uncialamycin ADCs also showed potential against small cell lung cancer in mouse xenograft models, indicating that this type of payload may be useful for targeting both solid tumors and liquid tumors. “[This] was not clear based on the previous knowledge surrounding the calicheamicin enediyne ADCs,” Nicolaou said.
When you “expect the unexpected, serendipity is often your ally,” he added.
- KC Nicolaou et al., “Asymmetric Synthesis and Biological Properties of Uncialamycin and 26-epi-uncialamycin,” Ange Chem Int, 47(1):185-89, 2008.
- J. Davies et al., “Uncialamycin, a New Enediyne Antibiotic,” Org Lett, 7(23):5233-36, 2005.
- KC Nicolaou et al., “Streamlined Total Synthesis of Uncialamycin and Its Application to the Synthesis of Designed Analogues for Biological Research,” J Am Chem Soc, 138(26):8235-46, 2016.
- KC Nicolaou et al., “Uncialamycin-based Antibody-Drug Conjugates: Unique Enediyne ADCs That Exhibit Bystander Killing Effect,” PNAS, 118(25), 2021.
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