Modern anticancer medications that combine tumor-fighting drugs with proteins that specifically target cancer cells are a relatively new class of drug, often given to patients for whom standard chemotherapy has not worked. The drugs are precise, but can attack only one kind of target in the cancer cell at a time. This limits their effectiveness against tumors containing multiple types of targets, which becomes more likely as a cancer progresses or as tumors become resistant to conventional therapies.
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, which are known as antibody-drug conjugates. By modifying such drugs already approved by the U.S Food and Drug Administration so that they self-assemble in the body and attack more than one cancer target, the researchers dramatically improved the effectiveness of these medications.
The study was published July 15 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, PhD , 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."
Two drugs in one
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 cancer, 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 that 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.
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 apparatus 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, 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 an antibody targeting either 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 the HER2 antibody, that binds to a different portion of that receptor, with a drug conjugate and that also carried the complementary click partner. Once in the body, the two antibodies then selectively snapped together. Depending on the approach, the HER2 receptor could be attacked twice as effectively, or both HER2 and EGRF could be targeted at the same time. Both approaches gave the tumor a one-two punch of antibody-drug conjugate — and it made the treatment far more effective than the FDA-approved versions.
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 that they were derived from, possibly because the click chemistry promotes clustering of antibodies on the cancer cell surface, which enhances internalization by the cell.
Tumors treated with the new form of the drugs resulted in significantly improved survival: as much as 90% of the animals survived 120 days after treatment in the pancreatic model, where 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.
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 only take 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."
Simó C, Vanover AC, Albanus RD, Panikar SS, Shmuel S, Benton A, Giraldo-Guzman J, Luna JM, Xu Y, Berry N-K, Keltee N, Liu J, Dehdashti F, Pereira PMR. Modular in vivo antibody-ADC click to reverse drug resistance in tumors. Nature. July 15. DOI: 10.1038/s41586-026-10789-w
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health (R37CA276498 and R21CA291680), internal funds provided by the Mallinckrodt Institute of Radiology, and the American Cancer Society (IRG-21–133–64–03) and the Breast Cancer Alliance. Further support came from the Alvin J. Siteman Cancer Center through The Foundation for Barnes-Jewish Hospital and the National Cancer Institute (P30 CA091842). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Other support came from the W. M. Keck Foundation and the American Cancer Society Award (PF-25-1515996-01-PFCDET), National Institutes of Health (K99AG086583), a Gates Sr. Alzheimer's Disease Research Fellowship from the Alzheimer's Disease Data Initiative, the National Cancer Institute of the National Institute of Health under Award Number K22CA282357. The Preclinical Imaging Facility was supported by NIH/NCI Siteman Cancer Center (SCC) Support Grant P30CA091842, NIH instrumentation grants S10OD018515 and S10OD030403, and internal funds provided by the Mallinckrodt Institute of Radiology. TEM and confocal experiments were supported by the Washington University School of Medicine, The Children's Discovery Institute of Washington University, and St. Louis Children's Hospital (CDI-CORE-2015-505 and CDI-CORE-2019-813) and the Foundation for Barnes-Jewish Hospital (3770 and 4642). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
About WashU Medicine
WashU Medicine is a global leader in academic medicine, including biomedical research, patient care and educational programs with 3,100 faculty. Its National Institutes of Health (NIH) research funding portfolio is the second largest among U.S. medical schools and has grown 78% since 2016. Together with institutional investment, WashU Medicine commits over $1.6 billion annually to basic and clinical research innovation and training. Its faculty practice is consistently among the top five in the country, with more than 2,550 faculty physicians practicing at 200 locations. WashU Medicine physicians exclusively staff Barnes-Jewish and St. Louis Children's hospitals — the academic hospitals of BJC HealthCare — and Siteman Cancer Center , a partnership between BJC HealthCare and WashU Medicine and the only National Cancer Institute-designated comprehensive cancer center in Missouri and southern Illinois. WashU Medicine physicians also treat patients at BJC's community hospitals in our region. With a storied history in MD/PhD training, WashU Medicine recently dedicated $100 million to scholarships and curriculum renewal for its medical students, and is home to top-notch training programs in every medical subspecialty as well as physical therapy, occupational therapy, and audiology and communications sciences.
