Crystal-clear view of a key neuronal receptor opens door for new, targeted drugs

Phys.org | March 07, 2019

During brain development, billions of neuron nerve cells must find their accurate pathway in the brain in order to form trillions of neuronal circuits enabling cognitive, sensory and emotional wellbeing. To achieve this remarkable precision, migrating neurons use special protein receptors that sense the environment around them and guide the way so these neurons and their long extensions stay on the right path and avoid faulty turns. Rare defects in these neuronal guidance proteins can result in severe neurological conditions such as ataxia and epilepsy. In a new study published in Cell, Bar-Ilan University researchers and collaborators report on their discovery of the intricate molecular mechanism that allows the guidance receptor Robo to react to signals in its environment while avoiding premature activity that can lead to harmful outcomes. One of the most important protein signaling systems that control neuronal guidance consists of the cell surface receptor Robo and its cognate external guidance cue Slit. The deficit of either of these proteins results in defects in brain structure and function. For example, their absence compromises the brain's ability to form the correct connection across the corpus callosum, which is the region where neuronal extensions from the two brain hemispheres cross paths to innervate opposite sides of the body, a fundamental attribute of bilateral creatures.

Spotlight

Kedrion Biopharma and TLS cross paths in 2011 and find a common ground in sustaining research for orphan disease. Kedrion, the fifth player worldwide in plasma-derived therapeutic products, has localized a plant dedicated to research and development of orphan drugs in TLS, within a project between Kedrion, the Regione Toscana and Toscana Life Sciences Foundation.

Spotlight

Kedrion Biopharma and TLS cross paths in 2011 and find a common ground in sustaining research for orphan disease. Kedrion, the fifth player worldwide in plasma-derived therapeutic products, has localized a plant dedicated to research and development of orphan drugs in TLS, within a project between Kedrion, the Regione Toscana and Toscana Life Sciences Foundation.

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CELL AND GENE THERAPY

Innovent Announces First Patient Dosing of Universal Modular CAR-T Cell product IBI345

Innovent Biologics | February 21, 2022

Innovent Biologics, Inc. a world-class biopharmaceutical company that develops, manufactures and commercializes high-quality medicines for the treatment of oncology, metabolic, autoimmune and other major diseases, today announced the first patient dosing for its first-in-class IgG-based universal "modular" Claudin 18.2-targeting chimeric antigen receptor T (CAR-T) cell product (development code: IBI345) for the treatment of advanced Claudin18.2-positive solid tumors in an investigator-initiated-trial (IIT). Since Innovent announced its strategic cooperation with Roche on June 9, 2020, this is the first disclosure of the development milestone for the cell therapy products based on Roche's proprietary innovative technology platform. CAR-T cell therapy has established a meaningful role in the treatment of hematological tumors with 5 products approved by the FDA, and 2 by the NMPA in China, respectively; however, antitumor efficacy for solid tumors remains a challenge calling for technological breakthroughs. As the world's first universal "modular" CAR-T cell product, IBI345 has potentially differentiated advantages over conventional CAR-T cell therapy products, including: 1) leveraging antibody function to target tumor antigens and consequently amplifying the tumor antigen signal to guide CAR-T cells to enter the tumor, thus aiding in the initiation of tumor recognition and killing; 2) controlling the functional activity of the CAR-T cells via concomitantly administered antibodies which act as a bridge between the target cell and CAR-T cell, potentially providing a better safety profile; 3) allows for the sequential or simultaneous administration of more than one antibody targeting different antigen targets without changing CAR-T cells, to treat tumors with highly heterogeneous antigen expression or relapsed tumors due to antigen-loss, thereby improving the accessibility and increasing the flexibility of CAR-T cell therapy for patients. The principal investigator of the study, Professor Weichang Chen, the Secretary of the Party Committee and Chief Physician of the Department of Gastroenterology of the First Hospital Affiliated to Soochow University, pointed out: "As gastric and pancreatic cancer are highly aggressive tumors with high incidence rates in the world, patients are in urgent need of novel treatment options to improve clinical outcomes. IBI345, with its unique design to control CAR-T functional activity through the antibody bridging, will likely provide improved safety and efficacy. We look forward to the positive results of the safety, tolerability and efficacy data of IBI345 in patients with solid tumors, which will potentially provide a new option for the treatment of patients with advanced gastric or pancreatic cancer." "IBI345 is a highly differentiated CAR-T cell product with a new mechanism of action developed by Innovent based on Roche's proprietary technology. As a universal "modular" CAR-T cell therapy product, equipped with a precisely targeted antibody switch, it regulates the expansion of CAR-T cells to control side effects, potentially providing an opportunity to switch to another antibody that targets different antigens to prevent recurrence and treat different tumors. Our preclinical studies have validated this "modular" CAR-T technology, which provides us with the sufficient scientific data to initiate clinical studies. In the following clinical studies, we will explore the safety, tolerability, pharmacokinetics and preliminary efficacy of IBI345, and optimize the clinical dosage and regimen to support the subsequent IND application. We firmly believe that Innovent will be able to introduce more innovative cell therapies through platform technology innovation, product transformation and in-depth collaboration with the clinical academic community that will ultimately benefit more patients and families." Dr. Xu Wei, VP of Innovent, R&D Head of Cell Therapy About Claudin 18.2 Claudin protein is a critical component of tight junction complex molecules which play an important role in the life activities of the human body. On the one hand, tight junctions can function as a "barrier" to select the size and charge of substances, thereby regulating the transport of substances in the para-cellular pathway. For example, brain vascular endothelial cells can pass through this barrier, preventing blood from mixing with the extracellular fluid in the brain. On the other hand, tight junctions can also function as "fences", maintaining cell polarity by regulating the free diffusion of lipids and proteins between the apical and the basolateral membrane. About Gastric and Pancreatic adenocarcinoma Gastric and pancreatic cancer are both malignant tumors of the digestive system that seriously endanger human life and health. The latest global cancer statistics show that there will be about 1.089 million new cases of gastric cancer worldwide in 2020, accounting for 5.6% of the global cancer incidence, and about 768,000 deaths, accounting for 7.7% of the global cancer deaths. There are about 495,000 new cases of pancreatic cancer, accounting for 2.6% of the global cancer incidence, and about 466,000 deaths, accounting for 4.7% of the global cancer deaths. According to the national cancer statistics released by the National Cancer Center of China in 2019, the incidence of gastric cancer in China in 2015 was about 403,000, accounting for 10.26% of the total cancer incidence, second only to lung cancer at 20.03%, with an incidence rate of 29.31/100,000 people, and about 291,000 deaths, accounting for 12.45% of the total cancer deaths, behind lung and liver cancer, with a mortality rate of 21.16/100,000 people. In 2015, the number of cases and deaths of pancreatic cancer nationwide were 95,000 and 85,000 respectively, ranking the 10th and 6th in the incidence and mortality of malignant tumors. The mortality ratio of pancreatic cancer was 0.89, making it a true "King of Cancer". Despite the treatment progress in recent years, drug resistance, recurrence and metastasis are still inevitable. The 5-year survival rate of patients with advanced gastric cancer is about 5-20%, and the median survival rate is about 10 months. Pancreatic cancer has a worse prognosis, with a 5-year survival rate of only 6 to 8%. About IBI345 IBI345 is the first universal "modular" CAR-T cell product developed by Innovent based on Roche's proprietary technology. It is an internationally pioneered highly differentiated CAR-T cell product with a new mechanism of action. Different from conventional CAR-T cells that directly recognize and kill tumor cells, IBI345 comprises of two components, anti-Claudin18.2 antibodies and "modular" CAR-T cells where anti-Claudin18.2 antibody recognizes tumor antigen, thus calibrating and amplifying the antigen signal, and guides "modular" CAR-T cells to enter the tumor to initiate the cytotoxic and antitumor activity of CAR-T cells. Compared with conventional CAR-T cells, IBI345 has a variety of potential advantages, including dual effects of antibodies and CAR-T cells to increase antitumor efficacy, and flexible control of side effects by regulating CAR-T cell activity through antibodies; in addition, as having a universal CAR molecule, "modular" CAR-T cells can be easily switched to different antibodies without changing CAR-T cells, by sequentially or simultaneously administering more than one antibody targeting different antigen targets, to treat tumors with highly heterogeneous antigen expression or antigen-loss relapsed tumors, which holds a great potential to reduce the cost of CAR-T cell therapy and improve the accessibility of CAR-T cell therapy for patients. Innovent announced that first patient dosing has been completed in February 2022 in the investigator-initiated clinical trial of IBI345 for the treatment of advanced Claudin18.2-positive solid tumors, and enrollment is currently ongoing. The safety, tolerability, pharmacokinetics and preliminary efficacy of IBI345 will be explored, and the clinical dosage and regimen will be explored to provide clinical data support for the subsequent IND application. About Innovent Inspired by the spirit of "Start with Integrity, Succeed through Action," Innovent's mission is to develop, manufacture and commercialize high-quality biopharmaceutical products that are affordable to ordinary people. Established in 2011, Innovent is committed to developing, manufacturing and commercializing high-quality innovative medicines for the treatment of cancer, autoimmune, metabolic and other major diseases. On October 31, 2018, Innovent was listed on the Main Board of the Stock Exchange of Hong Kong Limited with the stock code: 01801.HK.

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MEDICAL

Entopsis Exploring Strategic Alternatives for its OpsisDx™ Platform

Berkery, Noyes & Co. | October 08, 2021

Entopsis, Inc., the developer of an unbiased approach to diagnostics using bio-molecular signatures with a focus on oncology, announced that it has engaged Berkery Noyes & Co. as its financial advisor to assist the company in pursuing strategic alternatives for their OpsisDxTM platform. OpsisDxTM is a urine-based technology platform that shifts the focus away from conventional RNA and DNA approaches, offering a highly sensitive and specific diagnostic test for the detection of early-stage cancers. Its IP-protected platform detects urine chemical signatures via a proprietary array, achieving clinically significant results through its proprietary machine learning algorithms. Validation studies on OpsisDxTM have initially focused on detecting early-stage cancers, and the platform has now expanded to detecting multiple other diseases in a highly scalable fashion. Now is the time to launch OpsisDxTM. There's greater acceptance of multi-disease testing platforms from a scientific, regulatory and business perspective; the industry as a whole has crossed the tipping point, We are seeking an established partner who shares our vision of empowering people with actionable, low costs and accurate healthcare information with an eye towards the long-term interests of Entopsis. - Obdulio Piloto, CEO of Entopsis Inc. AboutEntopsis, Inc., Entopsis utilizes a proprietary material science screening platform to develop cost-effective and impactful products.

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ProteoNic Announces Licensing of Technology for Boosting Therapeutic Protein Production to Immunomedics

ProteoNic | October 20, 2020

ProteoNic BV, a leading provider of technology and services in the field of production of biologics, today announced it has licensed its premium 2G UNic™ technology for boosting therapeutic protein production to Immunomedics, Inc. (NASDAQ: IMMU), a biopharmaceutical company developing immuno-therapeutics for the treatment of cancer and other diseases. Under the agreement, Immunomedics gains commercial rights for application of ProteoNic's technology platform to the development of specified proprietary products from mammalian cells. Financial details of the agreement were not disclosed. ProteoNic's protein expression technology improves production levels across a range of host cells, selection systems and protein targets. It increases transcription and translation rates via a combination of novel genetic elements, which together exert a powerful positive effect on recombinant protein production levels without impacting product quality or cell line stability attributes. 2G UNic™ can be readily combined with other protein expression-enhancing technologies to improve their performance.

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