PRL-3

The quest for effective cancer treatments has long been hampered by a crucial limitation: conventional approaches like chemotherapy can’t differentiate between healthy and cancerous cells. This lack of specificity can damage healthy tissues along the way and trigger debilitating adverse effects. According to Qi Zeng, a Research Director at A*STAR’s Institute of Molecular and Cell Biology (IMCB), asserted that the crux of advancing cancer treatment lies in identifying molecular targets that are exclusively associated with tumours. This precision is especially critical for young children with cancer, who can be more vulnerable than adult patients. In 1998, Zeng and colleagues first discovered PRL3: a cancer-specific protein that controls various cellular processes. As they traced PRL3‘s footsteps over the years, they found that it contributed to the spread of malignant cells in many different cancer types. “Our lab has studied hundreds of adult tumour samples. We’ve found that approximately 80.6 percent of tumours in adults express PRL3, while adjacent normal tissue does not,” said Zeng. The team also pioneered the discovery of PRL3-zumab, the first humanised antibody therapy against PRL3, which showed a promising safety profile in adults during a clinical trial in 2017. In their latest study, Zeng and IMCB colleague Min Thura teamed up with Amos Hong Pheng Loh, Shui Yen Soh and other experts from the KK Women’s and Children’s Hospital, Singapore and Duke-NUS Medical School, Singapore, to investigate the use of PRL3-zumab in treating paediatric cancers. By analysing 65 tumour-derived and healthy tissues from paediatric patients, the researchers found that PRL3 was frequently expressed in soft tissue tumours in the muscles and kidneys, and in all neuroblastomas studied. Significantly, the presence of PRL3-positive tumours correlated with heightened angiogenesis—the creation of blood vessels that support tumour growth and metastasis. Spurred by these findings, the team was optimistic that PRL3-zumab might be as effective for children as it is in adults. “We did a first-in-child compassionate use trial of PRL3-zumab,” said Zeng, adding that the treatment was administered to a seven-year-old in critical condition with recurrent rhabdomyosarcoma, a soft tissue cancer. The team reported that PRL3-zumab, in combination with radiation therapy, temporarily stabilised the child’s condition, prolonged his life by three months and enhanced his quality of life even in an advanced stage of cancer. “The boy was off morphine and supplemental oxygen; he left the ICU to return home, and was even able to go to school for three days,” Zeng recalled. These outcomes support further exploration of PRL3 expression as a prognostic cancer biomarker, as well as PRL3-zumab use in paediatric patients with aggressive cancers who have exhausted all standard options, Zeng said. In December 2015, Zeng founded the spinoff biotech company Intra-ImmuSG, which is currently conducting phase 2 clinical trials with PRL3-zumab for adults with cancer in Singapore, China, the US and Malaysia. The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology (IMCB).

AsianScientist (Jul. 19, 2023) –An antibody drug known as PRL3-zumab, developed by Singaporean scientists, has demonstrated a strong safety profile in Phase I trials and drug efficacy in multi-national Phase II clinical trials of late-stage cancer patients. Results from the first-in-human Phase I study were recently published in Targeted Oncology. The clinical trial was conducted at the National University Cancer Institute, Singapore (NCIS), led by Chee Cheng Ean, Senior Consultant at NCIS, in collaboration with Intra-ImmunSG (IISG), the A*STAR spin-off biotechnology company that developed PRL3-zumab. PRL3-zumab is a first-in-class cancer immunotherapy that binds PRL3, a protein found inside tumour cells that helps cancer to spread. Though antibodies are traditionally thought to be too large to enter a cell, pioneering research led by Zeng Qi, research director at the Institute of Molecular and Cell Biology (IMCB), A*STAR, found that PRL3 could be flipped “inside-out” onto the surface of cancer cells due to stresses from the tumour microenvironment. This phenomenon provides an opportunity for PRL3-zumab to bind PRL3 and stimulate the host immune system to kill the cancer cells, thereby inactivating the cancer-favoring functions of PRL3 and shrinking the tumor. “It is incredibly unique that PRL3 is only specifically expressed in multiple types of cancer cells but not in normal cells. Hence, PRL3-zumab does not attack normal cells, which reduces side effects,” said Zeng, who is also the founder of IISG. “It is incredibly unique that PRL3 is only specifically expressed in multiple types of cancer cells but not in normal cells. Hence, PRL3-zumab does not attack normal cells, which reduces side effects,” said Zeng, who is also the founder of IISG. Indeed, in the Phase I trial, the team of clinicians and researchers found that PRL3-zumab was safe in late-stage cancer patients who had no other available treatments. The study’s dose-escalation (Phase Ia) cohort recruited 11 patients. These patients were treated with increasing doses of PRL3-zumab to determine if there were any side effects serious enough to prevent an increase in dosage of the treatment. The study found no such side effects and proceeded to its dose-expansion (Phase Ib) study. In this phase, the study recruited 16 patients with various tumor types, including breast, colorectal, gastric, liver, pancreatic cancer, and acute myeloid leukemia (AML), where it again found no severe drug-related side effects. The study also evaluated 24 patients for treatment efficacy and found that PRL3-zumab stabilized cancer progression in one-eighth of patients. Following the encouraging results of the Phase I trial, PRL3-zumab is undergoing Phase II clinical trials in Singapore, USA, China, and Malaysia to further evaluate its efficacy in patients. Excitingly, a case of exceptional treatment response has emerged from the Phase II trial in the US – PRL3-zumab has extended the life expectancy of a stage 4 gastric cancer patient, a 71-year-old male, by threefold. Furthermore, Zeng also provided additional insights on the ongoing Phase II trials. “Most of our patients have late-stage cancer with rapidly deteriorating health. Although PRL3-zumab was given at the last line of treatments, the drug still showed excellent safety and efficacy in a fair number of patients.” With these positive findings from the clinical trials, PRL3-zumab holds promise as a potential therapy for patients with hard-to-treat cancers. “I am excited to share that PRL3-zumab has demonstrated drug efficacy, particularly in rare aggressive diseases in ongoing trials. Since such patients have not received many treatments, their immune systems were not heavily exhausted by conventional treatments. As a first step, we are aiming for accelerated approval of PRL3-zumab to meet urgent unmet medical needs,” said Zeng. “I am excited to share that PRL3-zumab has demonstrated drug efficacy, particularly in rare aggressive diseases in ongoing trials. Since such patients have not received many treatments, their immune systems were not heavily exhausted by conventional treatments. As a first step, we are aiming for accelerated approval of PRL3-zumab to meet urgent unmet medical needs,” said Zeng. — Source: National University Cancer Institute, Singapore ; Image: Shelly Liew/ Asian Scientist Magazine The articles can be found at: Chee et al, A Phase I, First-in-Human Study of PRL3-zumab in Advanced, Refractory Solid Tumors and Hematological Malignancies Disclaimer: This article does not necessarily reflect the views of AsianScientist or its staff. #Antibodies #Cancer #National University Cancer Institute Singapore Pei Ling received her PhD in Biomedical Sciences from the Icahn School of Medicine at Mount Sinai, USA and her BSc in Biochemistry & Molecular Biology from Brown University, USA. She is currently a research fellow at the Institute of Molecular and Cell Biology and a freelance science writer. Pei Ling received her PhD in Biomedical Sciences from the Icahn School of Medicine at Mount Sinai, USA and her BSc in Biochemistry & Molecular Biology from Brown University, USA. She is currently a research fellow at the Institute of Molecular and Cell Biology and a freelance science writer.