Scientists developed a monoclonal antibody (mAb) that selectively targets pancreatic cancer cells. This is an early step toward new treatments for a deadly malignancy that is the third leading cause of cancer deaths.
The scientists from the National Cancer Institute (NCI), Center for Cancer Research (CCR), Chemical Biology Laboratory (CBL), and collaborators from the Frederick National Laboratory’s (FNL) Center for Advanced Preclinical Research (CAPR) reported their findings in the International Journal of Molecular Sciences.
A monoclonal antibody is a laboratory-made protein that acts like human antibodies to fight disease. The monoclonal antibody called F5 homes in on cancerous pancreatic cells with a high degree of affinity while sparing noncancerous cells. Although typically nontoxic by themselves, monoclonal antibodies can be modified to kill cancer cells or may lead to other therapies, such as antibody-drug conjugates, targeted immunotherapies, or chimeric antigen receptor T cells (CAR-Ts) guided by F5 to malignant tissues.
“We are exploring several of these modalities to hopefully produce new drug agents with improved efficacy over current therapies,” said lead NCI scientist Joseph Barchi Jr. of CBL.
Pancreatic cancer is one of the deadliest malignancies because the organ is in a difficult-to-reach location, tumors recruit surrounding tissue to ward off the immune system, and the disease can worsen without symptoms until late stages when surgery is futile. The overall five-year survival rate is just 13 percent, and this mortality rate has remained high for many years despite rigorous efforts by cancer researchers and drug developers to curb this.
“There is thus an obvious need for enhanced methods of early detection and more effective therapeutic options,” said Serguei Kozlov, the lead scientist at CAPR.
The F5 monoclonal antibody was raised to the extracellular tandem repeat (TR) sequence of a mucus protein, mucin 4 (MUC4), which is expressed only on the surface of pancreatic tumor cells and not normal pancreatic cells. Mucins are heavily modified in the TR domain with a common post-translational modification called Mucin-type O-linked glycosylation. This specific type of protein modification in tumors may promote progression and metastasis, making it an attractive target for therapeutic intervention.
The researchers examined F5’s binding ability in three established tumor cell lines, two that expressed MUC4 and one that did not. All three were implanted in mice and allowed to form suitable-size tumor lesions before being analyzed. The monoclonal antibody accumulated in the tumors expressing high levels of MUC4, but little was found in tumors that lacked MUC4.
These observations inspired further studies in patient-derived xenograft (PDX) models of pancreatic tumors in which freshly dissected patient tumor biopsy tissue is transplanted into mice. They used several PDX samples high in MUC4 as well as others that lacked MUC4.
Upon examination, they found high concentrations of F5 in the MUC4-positive cancerous lesions. A direct comparison with a MUC4-negative PDX group was not possible since the MUC4-negative PDX models did not establish viable tumors in the mice.
Dr. Barchi believes that the search for more tumor-selective mAbs that can potentially be developed into clinically relevant therapies is highly dependent on the structure of the immunogen used in the selection process.
“Aberrant tumor glycosylation is an essential feature of any cell-surface antigen target of antibody-based therapies,” he said. “We are working to determine the exact glycan structures on tumor-associated MUC4 to guide the synthesis of the most potent immunogens for improved antitumor activity.”
Dr. Kozlov said, “The findings of this collaborative study pave the way for innovative approaches in effective treatment of recalcitrant malignancies, such as pancreatic cancer, by targeting distinct biochemical signatures uniquely earmarking diseased, but not healthy, tissue.”
Both Barchi and Kozlov agree that the success of the current research underscores the value of multi-disciplinary endeavors in cancer science that combine expertise of chemical biologists and preclinical drug developers toward a common goal.
Barchi and his post-doctoral fellow, Achyut Dahal led the research, while collaborators Jerome Schlomer and Laura Bassel of Kozlov’s group at CAPR/FNL were essential contributors to the work.
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