Zeng Lab
PRL-3 Phosphatase & Cancer Therapy
Our Research
Our lab focuses on developing immunotherapy against tumor-specific antigens. Compared to traditional chemotherapy, targeted therapy is more favored in the clinic as it is safer and more effective in cancer treatment.
We are a pioneer in using the novel approach of using antibodies to target intracellular tumor-specific antigens. This challenges conventional thinking that antibodies cannot target intracellular antigens due to their large size. It also implies that a treasure trove of intracellular targets could be further explored for cancer therapy.
Our lab has reproducibly demonstrated therapeutic efficacy of antibodies targeting intracellular antigens such as PRL3 in mouse tumor models. Subsequently, we discovered that the intracellular antigen PRL3 can be externalized onto the surface of cancer cells, which then allows for antibody binding. We found evidence that this activates the ADCC/ADCP, which result in the killing of cancer cells by NK cells, macrophages, and B cells.
Cancer immunotherapy is an emerging field and has shown promise in extending life expectancy and promoting tumor remission in cancer patients. We hope to contribute to this research field and improve the quality of life for our cancer patients.
PRL3
In 1998, we identified PRL3 gene (Zeng et al., BBRC 1998). In 2001, Professor Vogelstein and his team from Johns Hopkins University first demonstrated a role of PRL3 gene in cancer progression and metastasis (Saha et al., Science 2001). Studies from many research laboratories worldwide have since validated the oncogenic role of PRL3.
PRL3 is an intracellular protein that is specifically overexpressed in many tumors but undetectable in most normal tissues. Hence, we anticipate that PRL3 is an excellent tumor specific antigen for cancer therapy with fewer side effects. Traditionally, intracellular oncoproteins such as PRL3 are targeted by small molecule inhibitors, mainly because large antibody drugs are presumed to be inaccessible to cells. However, we have since shown that targeting PRL3 using mAb can reduce tumor growth in pre-clinical mouse models, demonstrating that targeting intracellular antigens is a viable strategy for cancer therapy. We have generated the humanized mAb against PRL3, known as PRL3-zumab, which has completed Phase I clinical trials (Chee CE, 2023). There are ongoing Phase II clinical trials in Singapore, US, China, and Malaysia.
Our team has dedicated decades of translational research in multiple acute cancer mouse models to develop a new concept of using PRL3 antibody (instead of small chemical inhibitors) to target intracellular PRL3 protein as a novel cancer immunotherapy. Professor Soldano Ferrone, a well-known immunologist from Harvard Medical School described our concept findings (Guo et al., Science Translational Medicine, 2011) as ‘Hidden Immunotherapy Targets Challenge Dogma’ (Perspective STM, 2011).
Recently, we demonstrated that the intracellular PRL3 could be flipped ‘inside-out’ or externalized in the tumor micro-environment and to be bound by PRL3-zumab , which then recruits the immune cells to tumor site, leading to tumor cell death. We revealed the scientific molecular mechanism of action (MOA) model as shown on the left (Thura et al., Nature Communications 2019).
PRL3 oncotarget is overexpressed in > 80 % of tumors across 11 common cancer types that we have examined namely, Acute Myeloid Leukemia (AML), Lung, Liver, Pancreas, Thyroid, Gastric, Kidney, Bladders, Breast, Colon and Prostate. Furthermore, PRL3 oncoprotein has also been reported to be overexpressed in other cancer types, such as Cervical, Ovary, Myeloma, Multiple myeloma, Lymphoma, and many more.
Since PRL3 is a highly tumor-specific target, we therefore generated PRL3-zumab , the First-in-Class humanized antibody as a ‘Research Product’ to move into First in Man in 2017. PRL3-zumab specifically targets PRL3 overexpressing tumors and will not damage surrounding healthy tissues because they do not express the PRL3 oncotarget and this is an alternative to chemotherapy.
We anticipate that our PRL3-zumab is a unique antibody drug to treat multiple cancers overexpressing intracellular PRL3.
Our technology represents an innovative approach of an unconventional cancer immunotherapy against a broad range of cancer types. PRL3-zumab antibody drug will significantly increase therapeutic efficacies and reduce side effects to cancer patients.