Antibody-Drug Conjugate Targeting uPAR Shows Promise for Pancreatic Cancer Treatment

Pancreatic cancer is the deadliest of all cancers. Only 12% of men diagnosed with pancreatic cancer are alive five years after diagnosis; 14% of women. In pancreatic cancer, symptoms are usually not obvious and usually appear later in its progression. Once this cancer spreads, it is difficult to treat because it cannot be completely removed by surgery.

In a new study, researchers from the Danish National Teaching and Research Hospital and the University of Copenhagen have made significant progress in developing pancreatic cancer treatments based on antibody-drug conjugate (ADC) technology. The relevant research results were recently published in the journal Science Advances, with the title of the paper "Targeting uPAR with an antibody-drug conjugate suppresses tumor growth and reshapes the immune landscape in pancreatic cancer models".

"We previously successfully developed a so-called ADC for the treatment of sarcomas and received approval from the U.S. Food and Drug Administration (FDA) for a clinical trial that will begin soon," says co-corresponding author Lars Henning Engelholm of the Center for Biotech Research and Innovation at the University of Copenhagen. "In our new study, we used the same technology to try to develop a new approach to treating pancreatic cancer."

"There has been little progress in the treatment of pancreatic cancer over the past 20 years. But our study shows that a new type of drug can fight this cancer on multiple fronts with promising results," says Engelholm. "The treatment directly kills both cancer cells and the supporting cells that the cancer uses to grow and protect itself."

By targeting the supporting cells, the treatment also releases toxins that kill neighboring cancer cells. In addition, destroying the supporting cells weakens the tumor structure, making it easier for the body's immune system to attack and eliminate the tumor. The ADC used in this study consists of three main components: an antibody that targets uPAR, a chemical linker that connects the antibody to the drug, and a potent chemotherapy drug. Once the ADC locates and enters the cancer cell, the chemical linker breaks down, activating the chemotherapy drug and killing the cancer cell from the inside.

Figure 1. Cellular uptake of anti-uPAR mAbs in uPAR-positive U937 cells. (Metrangolo V, et al., 2025)

Because ADC therapy is so precise and causes minimal damage to healthy cells, it is a likely candidate for treating cancers that are harder to treat. Engelholm explains, "What sets our ADC apart from existing treatments is that it is targeted and extremely accurate. By delivering chemotherapy inside cancer cells with this technology, we may see a significant reduction in side effects compared to traditional forms of treatment."

Engelholm and his team want to develop a treatment that could benefit future patients. Therefore, they made sure that the treatment could be tested on humans in clinical trials.

"As part of this process, we humanized the antibody in the ADC, meaning we changed its structure to make it similar to antibodies that naturally occur in the human body," says Engelholm. This tweak ensures that the body's immune system does not recognize the antibody as foreign and attack it. Humanization is a critical step in making the treatment safe and effective for patients and a key milestone on the road to clinical trials."

Engelholm's team is now working to further develop the drug and prepare it for clinical trials in pancreatic cancer patients. Engelholm said, "Pancreatic cancer is difficult to treat and one of the deadliest cancers. Currently, there are no ADCs approved to treat this cancer type. Our mission is to further develop this treatment to the point where it can attract funding from pharmaceutical or biotech companies or form the basis of a spin-off company that can take the next critical step toward human clinical trials in the next three to five years."

In the long term, this extremely accurate and effective treatment may also benefit patients with other types of cancer. Researchers are already exploring the potential of ADCs to treat other cancers that are in urgent need of better treatment options, such as triple-negative breast cancer and colon cancer. With continued support and collaboration, the hope is that ADCs will pave the way for new, effective treatments that will make a difference for patients suffering from some of the deadliest cancers.