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Modern anticancer medications that combine tumor-fighting drugs with proteins that specifically target cancer cells are a relatively new class of drugs, often given to patients for whom standard chemotherapy has not worked. The drugs are precise but can attack only one type of target in a cancer cell at a time. This limits their effectiveness against tumors containing multiple types of targets, which becomes more likely as cancer progresses or tumors become resistant to conventional therapies.
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Researchers at Washington University School of Medicine in St. Louis have shown in mice that it is possible to increase the potential effectiveness of these drugs, known as antibody-drug conjugates. By modifying drugs already approved by the U.S. Food and Drug Administration so they self-assemble in the body and attack more than one cancer target, the researchers dramatically improved the medications' effectiveness.
The study was published in Nature.
"We've shown that when two cancer-targeting antibodies bind together inside the body, they accumulate at the tumor more effectively and improve treatment response," said Patrícia M. Ribeiro Pereira, Ph.D., an assistant professor of radiology at WashU Medicine Mallinckrodt Institute of Radiology and a research member of Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine.
"There is a lot of excitement here because we have shown that it isn't necessary to create a whole new drug platform for each therapeutic target," added Ribeiro Pereira. "We can repurpose antibodies that already exist to improve treatments."
Where current drugs fall short
In recent years, antibody-drug conjugates have been transforming cancer care, with 15 such drugs approved since 2011 for leukemia and lung, cervical and breast cancers, among others.
The medications combine three components, each with a specialized role. One is the cytotoxic drug that kills a cancer cell when directed to the correct cell. Another is the antibody protein that binds to receptors unique to cancer cells, so the drug acts specifically within tumors and does not attack healthy tissue. The third is a linking molecule that connects the other two components.
Because each drug can be attached to only one antibody partner, these conjugates are highly specific and attack only cells containing the appropriate receptors. This makes them very effective in relatively homogeneous tumors, but their long-term effectiveness against more complex tumors with a diversity of cell types is limited.
Click chemistry adds flexibility
Ribeiro Pereira and her team developed an approach to overcome these limitations using what's known as click chemistry, a technique that enables adaptable connector molecules to click into a variety of other compounds to form interchangeable molecular structures in a modular way. They created a self-assembling drug system that could tack on a second antibody if needed, thereby doubling the receptor types it could bind to in a tumor.
Both antibodies used in this study are FDA-approved for cancer therapies and target receptors that control tumor growth. One antibody binds to the EGFR receptor; the second binds to the HER2 receptor. Another form of the treatment allows two different types of HER2 antibody to bind to different parts of the same receptor, which helps them work together more effectively.
In mice modeling pancreatic, gastric or breast cancer tumors containing cells that expressed EGFR receptors and other cells that expressed HER2 receptors, Ribeiro Pereira's team first administered either an antibody targeting EGFR or an antibody that binds to a particular portion of the HER2 receptor. The antibodies had all been engineered with one-half of a specialized "click" molecule.
About a day later, the team administered a second type of HER2 antibody, which binds to a different portion of that receptor, conjugated with a drug and carrying the complementary click partner.
Once in the body, the two antibodies selectively "snapped" together. Depending on the approach, the HER2 receptor could be attacked twice as effectively, or both HER2 and EGFR could be targeted at the same time. Both approaches gave the tumor a one-two punch of antibody-drug conjugate—and made the treatment far more effective than the FDA-approved versions.
Stronger uptake, longer survival
Radioactive tags developed by Ribeiro Pereira's colleagues at WashU Medicine enabled the team to visualize how much drug bound to tumor cells.
Ribeiro Pereira and her team found that tumor cells took up much higher amounts of the modified antibody-drug conjugates than is typical for the antibody-drug conjugates from which they were derived, possibly because the click chemistry promotes clustering of antibodies on the cancer cell surface, which enhances internalization by the cell.
Treatment with the new form of the drugs resulted in significantly improved survival: Up to 90% of the animals survived 120 days after treatment in the pancreatic model, while animals treated with standard antibody-drug conjugates survived less than 80 days on average. The team also was able to optimize the technique to reduce off-target accumulation of the drug in the liver.
A faster path to adaptation
While this study tested the drug in pancreatic, gastric and breast cancer models, Ribeiro Pereira said the modified antibody-drug conjugates have the potential to treat many different tumor types and possibly many other diseases, including some that are currently very difficult to treat with conventional medicine.
The linking molecules used in this study take only one to three days to manufacture and allow for greater flexibility when creating precision medicines for individual patients because of the versatile click chemistry approach.
"We're trying to optimize this tool to help antibodies reach tumors that are normally very difficult to treat, such as brain tumors," Ribeiro Pereira said.
"It's exciting, because the drug development process doesn't need to start from the beginning—we can use drugs that are already FDA-approved, which could help bring improved treatments to the clinic more quickly. At the same time, the approach is flexible enough to be adapted to new cancer targets as we learn more about what drives treatment resistance."
More information: Patrícia Pereira, Modular in vivo antibody–ADC click to reverse drug resistance in tumours, Nature (2026). DOI: 10.1038/s41586-026-10789-w. www.nature.com/articles/s41586-026-10789-w
Provided by Washington University in St. Louis
This story was originally published on Medical Xpress.
