Modern cancer drugs, which combine tumor-fighting drugs with proteins that specifically target cancer cells, are a relatively new class of drugs that are often given to patients who have not responded to standard chemotherapy. Although the drug is precise, it can only attack one type of target within cancer cells at a time. This limits their effectiveness against tumors that contain multiple types of targets, and becomes more likely as the cancer progresses or if the tumor becomes resistant to conventional treatments.
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. Researchers have dramatically improved the effectiveness of drugs already approved by the U.S. Food and Drug Administration by modifying them so that they self-assemble in the body and attack multiple cancer targets.
This study was published on July 15th. nature.
We showed that when two cancer-targeting antibodies combine in the body, they more effectively accumulate in tumors and improve treatment response. ”
Dr. Patricia M. Ribeiro Pereira, Assistant Professor of Radiology, WashU Medicine Mallinckrodt Institute of Radiology, Research Member, Siteman Cancer Center, Barnes-Jewish Hospital, WashU Medicine
“We’re very excited here because we see that we don’t have to create a completely new drug platform for each therapeutic target,” Ribeiro Pereira added. “We can reuse antibodies that already exist to improve treatments.”
Two medicines in one
Antibody-drug conjugates have revolutionized cancer treatment in recent years, with 15 such drugs approved since 2011 to treat leukemia, lung cancer, cervical cancer, breast cancer, and more.
These drugs combine three ingredients, each with a specialized role. One is a cytotoxic drug that kills cancer cells when administered to the appropriate cells. The other is an antibody protein that binds to receptors specific to cancer cells, so the drug acts specifically within the tumor and does not attack healthy tissue. The third is a linking molecule that connects the other two components.
Because each drug can bind to only one antibody partner, these conjugates are highly specific and attack only cells that contain the appropriate receptor. Therefore, although it is highly effective against relatively homogeneous tumors, its long-term efficacy against more complex tumors containing diverse cell types is limited.
Ribeiro Pereira and her team have developed an approach to overcome these limitations using what is known as click chemistry. This is a technology that allows adaptable connector molecules to click onto a variety of other compounds to form modular, interchangeable molecular structures. They created a self-assembling drug device that could be attached with a secondary antibody on demand, thereby doubling the types of receptors that could bind within the tumor.
Both antibodies used in this study are FDA-approved for cancer treatment and target receptors that control tumor growth. One antibody binds to the EGFR receptor. The second is the HER2 receptor. Another treatment allows two different types of HER2 antibodies to bind to different parts of the same receptor, allowing them to work together more effectively.
Ribeiro Pereira and colleagues first treated mice that modeled pancreatic, gastric, or breast cancer tumors, which contained cells that expressed the EGFR receptor and other cells that expressed the HER2 receptor, with antibodies that targeted EGFR or that bound to specific parts of the HER2 receptor. All antibodies were designed using one half of a special “click” molecule.
About a day later, the researchers administered a second type of HER2 antibody that binds to a different part of the receptor and also has a complementary click partner along with the drug conjugate. Once inside the body, the two antibodies bind selectively. Depending on the approach, the HER2 receptor can be attacked twice as effectively, or both HER2 and EGRF can be targeted simultaneously. Both approaches gave tumors a one-two punch of antibody-drug conjugates, allowing for much more effective treatments than the FDA-approved version.
A radioactive tag developed by Ribeiro Pereira’s colleagues at WashU Medicine allows the team to visualize how much drug is bound to tumor cells. Ribeiro Pereira and colleagues found that tumor cells take up much higher amounts of modified antibody-drug conjugates than the typical amount of antibody-drug conjugates from which they are derived. This is probably because click chemistry promotes clustering of antibodies on the cancer cell surface and promotes internalization by the cells.
Tumors treated with the new form of the drug had significantly improved survival. In the pancreatic model, 90% of animals survived 120 days after treatment, whereas animals treated with standard antibody-drug conjugates survived for less than 80 days on average. The research team was also able to optimize a technique to reduce off-target accumulation of drugs in the liver.
Although the study tested the drug in models of pancreatic, stomach and breast cancer, Professor Ribeiro-Pereira said the modified antibody-drug conjugate could potentially treat many different tumor types and possibly many other diseases, including diseases that are currently very difficult to treat with conventional medicine. The tethered molecules used in this study take only 1 to 3 days to manufacture. A versatile click chemistry approach provides greater flexibility in creating precision medicines for individual patients.
“We are trying to optimize this tool so that antibodies can reach tumors that are usually very difficult to treat, such as brain tumors,” Ribeiro Pereira said. “This is exciting because we don’t have to start the drug development process from scratch. We can use drugs that are already FDA-approved, potentially bringing improved treatments to the clinic more quickly. At the same time, this approach is flexible enough to be adapted to new cancer targets as we learn more about the causes of treatment resistance.”
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Reference magazines:
Simo, C. others. (2026) Modular in vivo antibody ADC clicks to reverse drug resistance in tumors. Nature. DOI: 10.1038/s41586-026-10789-w. https://www.nature.com/articles/s41586-026-10789-w
