Modified Opsonins - A Potential Tool In The War Against Cancer

A modified opsonin bound to antibody (FcMBL) could become a broad-spectrum potent tool in the treatment of several cancer types by binding to carbohydrate ligands on the surface of cancer cells, according to a recent study conducted at the Wyss Institute at Harvard University.

New Target In the War Against Cancer - The Reason Behind This Study

Several studies and research projects are still continuing to work at finding the elusive cure against cancer although giant strides have been made and several new immunotherapies have been developed to keep cancer in check and improve the quality of the patient’s life and prolong survival. When the tumor cells detach from a primary malignancy, they gain access to the blood stream (circulating tumor cells or CTCs) and spread to other parts of the body forming metastases; they then signify a stage in the cancer which has a graver prognosis and one that is more difficult to treat.

The current research team aims to target these CTCs and eliminate them, offering an attractive and exciting approach to cancer diagnosis and treatment.

Currently, there are not many effective agents that target these circulating cells which probably make up 1 out of ten thousands of cells in the blood making it all the more difficult to recognize and capture them.

Modified FcMBL Opsonin To Capture Circulating Tumor Cells

To overcome the existing gap, scientists at the Wyss Institute adapted the FcMBL, originally engineered to act as a broad-spectrum microbial capturing agent, to target these CTCs instead.

• Most of the cancer cells express aberrant sugar molecules on their surface similar to pathogens and are therefore vulnerable to capture by the MBL opsonin.
• The carbohydrate molecules expressed by healthy body cells are not bound by the MBL opsonin.
• The mannose binding lectin was fused with the Fc antibody fragment to stabilize it. This combination was termed FcMBL.
• When magnetic beads coated with FcMBL were added to a suspension of pathogens, the opsonin bound the pathogens like flies to flypaper.
• When a magnetic field was then applied, the beads dragged the bound cells towards the magnet.
• The team tested the activity of the FcMBL against cancer cells by implanting fluorescent-labeled breast cancer cells in mice and 4 weeks later, tested the blood of the mice for the presence of CTCs by adding the FcMBL opsonin coated magnetic beads and applying a magnetic field.
• It was seen that CTCs bound to the opsonin were moving rapidly compared to normal cells. The concentrations of CTCs in blood was shown to be reduced by more than 93%.

“The FcMBL-coated beads are unlikely to be bound to normal cells, and so when we measured the movement of cancer cells versus normal cells, the cancer cells moved much faster because they were being dragged to the magnet by the beads," explains first author Joo Kang, Ph.D., who was a Technology Development Fellow at the Wyss Institute while completing this study and is now an Assistant Professor at the Ulsan National Institute of Science and Technology.

• The scientists then tested the FcMBL coated beads against six additional cancer cell types, including lung carcinoma, human non-small cell lung cancer, and glioblastoma. The FcMBL-coated beads bound all six types of tumor cells with >90% efficiency, similar to epithelial cell adhesion molecule (EpCAM) targeting methods. Additionally they were also able to target two cancer types that are not successfully captured by anti-EpCAM antibodies (lung carcinoma and glioblastoma).

What are Opsonins?

A molecule that aids recognition and promotes engulfment of the target cell (microbe, tumor cell) by the immune cell is called an opsonin. Examples include mannose binding lectin (MBL), IgG antibody and C3b. MBL binds to a range of sugars such as N-acetyl-D-glucosamine, mannose, N-acetyl-mannosamine, glucose and fucose. This allows the protein to interact with a wide selection of viruses, bacteria, yeasts, fungi and protozoa decorated with such sugars on their surfaces.

How is FcMBL Superior to EpCAM in Capturing CTCs?

Current CTC binding methods mostly employ a cancer cell marker, the epithelial cell adhesion moleculeEpCAM, which is highly expressed on the surface of tumor cells. However, interestingly, EpCAM expression on cancer cells reduces when tumor cells become CTCs, making EpCAM-based tests irrelevant especially when it is most important to know if a patient's cancer has metastasized.

"Our results suggest that while the EpCAM marker can be useful for some tumors, it becomes less and less useful over time as EpCAM expression decreases and the cell becomes metastatic," says Michael Super, Ph.D., Lead Senior Staff Scientist at the Wyss Institute and co-author of the paper. "Our FcMBL system can either be used as an alternative to EpCAM-based diagnostics, or as a follow-up method once EpCAM ceases to be expressed."

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Future Research Plans

The team plans to expand the current research and determine exactly which sugar molecules on the CTCs are targeted by the FcMBL opsonin to improve efficiency of capture.

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To conclude in the words of senior author of the study and Wyss Founding Director Donald Ingber, who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School (HMS), as well as a Professor of Bioengineering at Harvard's School of Engineering and Applied Sciences, "The FcMBL opsonin technology has already been shown to be an extremely broad-spectrum capture agent for pathogens; this new finding that it has similar broad-spectrum binding activity for many different types of circulating cancer cells is equally exciting, and once again demonstrates the power of leveraging biological design principles when developing new medical innovations."

References:

1. Joo H. Kang, Harry Driscoll, Akiko Mammoto, Alexander L. Watters, Bissrat Melakeberhan, Alexander Diaz, Michael Super, Donald E. Ingber. An Engineered Human Fc-Mannose-Binding-Lectin Captures Circulating Tumor Cells. Advanced Biosystems, 2017; 1700094
2. The role of mannose-binding lectin in health and disease. - (https://www.ncbi.nlm.nih.gov/pubmed/14568388)

Source-Medindia