Targeting Cancer from the Inside out

In times of stress, cancer cells move a protein normally found inside the cell to the cell surface, making it accessible to antibodies for immunotherapy.

cancer cells

The human immune system, including various immune cell types and regulatory proteins, can be activated or engineered to seek out and destroy cancer cells, serving as the foundation for cancer immunotherapy. Sometimes, for immune cells to attack cancer cells, a tumor-specific ‘tag’ needs to be expressed at the surface of malignant cells as a homing beacon. Such a tag can be recognized by an antibody—a protein that typically binds to molecules on the external surface of a cell.

In 1998, scientists led by Qi Zeng at A*STAR’s Institute of Molecular and Cell Biology (IMCB) first identified a protein tag named PRL3. Later, in 2001, Bert Vogelstein’s research group at Johns Hopkins University School of Medicine in the US demonstrated that PRL3 was associated with liver cancer metastasis. IMCB scientists also discovered that PRL3 was selectively overexpressed in many human cancer cells but not in healthy normal cells, and proceeded to generate a mouse antibody targeting PRL3. Then, in 2015, Zeng’s lab further developed a humanized antibody—PRL3-zumab—that again specifically binds to PRL3.

In this study, Zeng’s team wanted to test PRL3-zumab’s ability to treat liver cancer in mouse models. They found that PRL3-zumab inhibited the growth of PRL3-positive liver tumors and extended the median survival time of treated mice to 12 weeks, compared to just eight weeks in mice receiving the placebo. Because PRL3 is normally found inside cells, the researchers next investigated how the antibody managed to attach to its target in liver cancer cells.

The answer lay in the discovery that cancer cells expose PRL3 on their surfaces in response to stresses such as low oxygen levels or pH changes within the tumor microenvironment in vivo. One of the ways PRL3 gets externalized is via fat droplet-like structures called exosomes.

“Although found intracellularly, PRL3 is a valuable therapeutic option for immunotherapy given its upregulation in metastatic liver cancers. In addition, there are very few surface proteins that are unique to cancer cells that can serve for antibody targeting”, said Zeng.

Once bound to the PRL3 tumor antigen, PRL3-zumab attracts immune cells such as B-cells, natural killer cells and macrophages to the tumor microenvironment, resulting in tumor destruction via antibody-dependent cell-mediated cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP) pathways. Besides liver cancer cells, PRL3 is frequently overexpressed in many common cancer types, attesting to the clinical value of PRL3-zumab.

In 2015, together with A*ccelerate, A*STAR’s commercialization arm, Zeng founded an A*STAR spinoff company, called IntraImmuSG Pte Ltd (IISG), to develop PRL3-zumab for clinical trials. In 2016, the Health Sciences Authority (HSA) approved PRL3-zumab for Phase 1 clinical trials in Singapore, where it was found to be safe and well tolerated by cancer patients. In 2019, HSA approved the drug for Phase 2 clinical trials. IISG is keen to work with investors and partners to take PRL3-zumab through further clinical trials.

The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology (IMCB).