Cancer cells are aggressive. They divide and multiply, create their own blood supply, invade healthy tissue, and resist death. Even when targeted therapies efficiently kill these cells, neighboring cells are often left behind. These bystander cells can be malicious. If left intact, they can lead to tumor regrowth, and many therapies that act like snipers against cancer cells leave bystander cells unscathed.
Now K.C. Nicolaou, a synthetic chemist at Rice University, and his colleagues have discovered that an antibiotic-linked antibody, known as an antibody-drug conjugate (ADC), kills bystander cells as efficiently as it kills targeted cancer cells.
“The bystander effect could be the key to opening new avenues for more effective anticancer ADCs that may improve targeted cancer therapies,” Nicolaou said in an email.
ADCs are gaining momentum against cancer. More than 80 ADCs are advancing 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 to the cancer.
Although payloads often come from natural sources such as bacteria and fungi, they can be very difficult to make 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 lichen from British Columbia.2 About a decade later, they streamlined the process.3
In new research reported in PNAS,4 Nicolaou and his team put the uncialamycin payload through its paces. They tested how well the antibiotic killed cultured cells when attached via six different linkers to antibodies targeting two proteins overexpressed in cancers, T1 and CD46. Some of the linkers worked better than others. But what stood out to Nicolaou was that uncialamycin was more potent than calicheamicin; it even removed bystander cells.
The finding was unexpected and unprecedented. “Uncialamycin is in the same drug class as calicheamicin, which is already FDA approved and does not mediate bystander killing. But this compound does,” said Zhiqiang An, a chemist and leading therapeutic antibody expert at the University of Texas in Houston.
No other enediynes have shown bystander killing. Nicolaou found the results encouraging and An could see their potential. “This uncialamycin could be a very unique compound class,” An said, although he’d like to see it tested further in other cancer models.
Uncialamycin ADCs also showed potency against small-cell lung cancer in mouse xenograft models, indicating that this type of payload may be useful for targeting solid tumors as well as liquid tumors. “[This] was not obvious based on the previous body of knowledge surrounding the calicheamicin enediyne ADCs,” Nicolaou said.
When you “expect the unexpected, far often serendipity is your ally,” he added.
- K.C. Nicolaou et al., “Asymmetric synthesis and biological properties of uncialamycin and 26-epi-uncialamycin,” Angew Chem Int, 47(1):185-89, 2008.
- J. Davies et al., “Uncialamycin, a new enediyne antibiotic,” Org Lett, 7(23):5233-36, 2005.
- K.C. Nicolaou et al., “Streamlined total synthesis of uncialamycin and its application to the synthesis of designed analogues for biological investigations,” J Am Chem Soc, 138(26):8235-46, 2016.
- K.C. Nicolaou et al., “Uncialamycin-based antibody–drug conjugates: Unique enediyne ADCs exhibiting bystander killing effect,” PNAS, 118(25), 2021.