GPC1

A research team has developed a theranostics approach to both diagnose and treat certain pancreatic cancer cases. They radioactively labeled a monoclonal antibody targeting glypican-1, which is highly expressed in pancreatic cancer, then administered it to disease model mice. One label, 89Zr, showed high uptake in tumors, which would allow early detection of pancreatic cancer with PET scans. Another label, 211At, was used with alpha therapy to significantly slow tumor growth. Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers worldwide, with a 5-year survival rate of less than 10%. Many PDAC tumors in early stage go undetected because they are not found using conventional imaging methods, including fluorodeoxyglucose positron emission tomography (PET) scans. To more efficiently combat this pancreatic cancer, a team led by researchers at Osaka University is combining diagnostic and therapeutic procedures into a single integrated process: 'theranostics'. In an article recently published in Journal of Nuclear Medicine, the team has developed a 'radio-theranostics' strategy that uses a new radioactive antibody to target glypican-1 (GPC1), a protein highly expressed in PDAC tumors. Theranostics, particularly radio-theranostics, has been receiving increasing attention because, by radio-labeling the compounds used to target certain molecules in cancer cells, diagnosis and treatment can be carried out sequentially. "We decided to target GPC1 because it is overexpressed in PDAC but is only present in low levels in normal tissues," explains Tadashi Watabe, lead author of the study. The team used a monoclonal antibody (mAb), an antibody designed to target a certain molecule, to target GPC1. The mAb could be labeled with radioactive zirconium (89Zr) or radioactive astatine (211At). They worked with a xenograft mouse model, which involved human pancreatic cancer cells being injected into a mouse that developed into a full tumor that could be experimentally treated and monitored. These mice were intravenously administered 89Zr-labeled GPC1 mAb. They were also given 211At-labeled GPC1 mAb to examine the antitumor effects. "We monitored 89Zr-GPC1 mAb internalization over seven days with PET scanning," explains Kazuya Kabayama, the second author of the article. "There was strong uptake of the mAb into the tumors, suggesting that this method could support tumor visualization. We confirmed that this was mediated by its binding to GPC1, as the xenograft model that had GPC1 expression knocked out showed significantly less uptake." The researchers next tested this model with alpha therapy using 211At-GPC1 mAb, a method that could support radioactive label-based delivery of a therapeutic molecule to its target. Administration of 211At-GPC1 mAb resulted in DNA double-strand break induction in the cancer cells, as well as significantly reduced tumor growth. Control experiments showed that these antitumor effects did not occur when mAb internalization was blocked. Additionally, non-radiolabeled GPC1 mAb did not induce these effects. "Both radiolabeled versions of the GPC1 mAb we examined showed promising results in PDAC," says Watabe. "89Zr-GPC1 mAb showed high tumoral uptake, while 211At-GPC1 mAb could be used for targeted alpha therapy to support suppression of PDAC tumor growth." These highly impactful data demonstrate the potential for using a theranostics approach in PDAC, a disease in dire need of new diagnostic and therapeutic options. In the future, this could lead to early detection of PDAC with PET imaging and systemic treatment with alpha therapy.

Phalguni Deswal @Phalguni_GD Biosygen also has two other T-cell therapies in Phase I/II clinical development. Image Credit: Juan Gaertner / Shutterstock. Biosyngen received an all-clear from the US Food and Drug Administration (FDA) on the Investigational New Drug (IND) application for the BRL03 to start Phase I/II trials. BRL03 is a T-cell receptor (TCR) therapy that isolates a patient’s T-cells and then genetically modifies them to target specific cell antigens. These modified T-cells are then infused back into the patient. BRL03 would be investigated to treat lung, gastric, and other advanced solid tumours. Recommended Reports Reports LOA and PTSR Model - Gene Therapy to Target KK-LC-1 for Oncology GlobalData Reports LOA and PTSR Model - Monoclonal Antibody Conjugate to Target GPC1 for Oncology GlobalData View all BRL03 was developed using Biosyngen’s drug discovery platform, IDENTIFIER. The IDENTIFIER platform utilises TCR and tumour proteome databases to discover, screen and optimise therapies. Biosyngen also uses its MSE-T technology platform to decrease T-cell depletion, leading to sustained tumour-suppressing effects. Cell therapies are a growing area of interest in the immuno-oncology (IO) field. As per GlobalData, the IO sector was worth approximately $48bn in 2022 . GlobalData is the parent company of Pharmaceutical Technology . The Singapore-based company also has other T-cell therapies in its pipeline. BRG01 is an Epstein–Barr virus (EBV) targeted chimeric antigen receptor (CAR) T-cell therapy, which is currently in Phase I/II (NCT05864924) clinical development in the US and China. Phase I of the trial is expected to be completed by the end of 2023. BRG01 is also being investigated for the treatment of EBV-positive lymphoma. Biosyngen is also developing a tumour infiltrating lymphocyte (TIL) therapy, BST02. As part of the TIL therapy, the patient’s own tumour-infiltrating lymphocytes, a type of T-cell, are isolated, and then the best-targeted lymphocytes are selected. These lymphocytes are then expanded and infused back into the patient. Cell & Gene Therapy coverage on Pharmaceutical Technology is supported by Cytiva . Editorial content is independently produced and follows the highest standards of journalistic integrity. Topic sponsors are not involved in the creation of editorial content. Free Whitepaper Cell and gene therapies: Pipe dream to pipeline The cell and gene industry is gaining momentum, with a new wave of therapies promising to transform the way doctors treat, and even cure, disease. In this report, Cytiva and GlobalData have collaborated to explore the rise of the cell and gene therapy industries, the current state of the market, present and future opportunities for advancement, and the challenges that lie ahead. By Cytiva Thematic By downloading this case study, you acknowledge that GlobalData may share your information with Cytiva Thematic and that your personal data will be used as described in their Privacy Policy

Hu14.18 is in development for the treatment of newly diagnosed high-risk neuroblastoma. Credit: Kateryna Kon/Shutterstock.com. Renaissance Pharma has signed an agreement to in-license St Jude Children’s Research Hospital’s Hu14.18K322A (Hu14.18), an anti-GD2 humanised monoclonal antibody (mAb) in development for treating newly diagnosed high-risk neuroblastoma (HRNB). According to the agreement, Renaissance gained exclusive development, manufacturing and commercialisation rights to Turkey, Japan, Europe, China, Canada, and the US. Recommended Reports Reports LOA and PTSR Model - CD19 Antibody GlobalData Reports LOA and PTSR Model - Monoclonal Antibody Conjugate to Target GPC1 for Oncology GlobalData View all Companies Intelligence St. Jude Children’s Research Hospital Inc European Medicines Agency Renaissance Inc St Jude Renaissance Pharma, Inc. View all The company will now interact with the Food and Drug Administration (FDA), European Medicines Agency (EMA) and other regulatory agencies for seeking approval in their respective countries. Hu14.18 has demonstrated favourable patient outcomes with overall survival of 86% and event-free survival of 73.7% in a Phase II trial. In the trial, Hu14.18 was used as induction therapy and additionally, within post-consolidation therapy. Out of the total patients treated, 66.7% achieved a partial response or better after the first two chemo-immunotherapy induction cycles while 96.8% achieved the same at the end of induction. Renaissance Pharma CEO Simon Ball said: “Renaissance Pharma now has its full attention on bringing this humanised antibody to market as expeditiously as possible. “The collaboration with St Jude marks the intention of Renaissance and we must now play our part in making the product available.” An estimated 300 patients are diagnosed with HRNB in the US and 500 in Europe. This high-risk disease is said to be the most common cancer in children under one year of age. They are currently treated with surgery, radiotherapy, stem cell transplantation, and multiple cycles of chemotherapy. St Jude’s paediatric oncologist Sara Federico said: “It is exciting and deeply meaningful to see how our clinical efforts to develop Hu14.18 may now have the potential to positively impact patients with high-risk neuroblastoma around the world.”