Scientists develop artificial chemical receptor to assist viral transduction for T cell engineering

Phys.org | April 15, 2019

Engineered T cell immunotherapy, such as chimeric antigen receptor T cell (CAR-T) and T cell receptor T cell (TCR-T) therapy, has emerged as a potent therapeutic strategy for treating tumors. However, the genetic manipulation of primary T cells remains inefficient, especially during the clinical manufacturing process. There's an urgent need to develop a reliable method for the preparation of engineered T cells. A research team led by Prof. Cai Lintao at the Shenzhen Institutes of Advanced Technology (SIAT) of the Chinese Academy of Sciences and other collaborators developed a "safe, efficient and universal" technique based on bioorthogonal chemistry and glycol-metabolic labeling for viral-mediated engineered T cell manufacturing. Their findings were published in Advanced Functional Materials. In this strategy, the functional azide motifs were anchored on T cell surfaces via the intrinsic glycometabolism of exogenous azide-glucose, thus serving as an artificial ligand for viral binding. The complementary functional moiety dibenzocyclooctyne (DBCO)/-conjugated PEI1.8K (PEI-DBCO) was coated on the lentiviral surface, which strengthened the virus-T cell interaction through DBCO/azide bioorthogonal chemistry.

Spotlight

Optogenetic approaches in cell biology applications are becoming more and more ubiquitous as molecular toolkits expand. However, identifying which pattern illumination technologies to use with them may be challenging. This white paper provides an overview of the molecular probes available to the cell biologist and how they have been applied in different fields, going over specific examples from modulation of intracellular signaling pathways to organelle positioning dynamics.

Spotlight

Optogenetic approaches in cell biology applications are becoming more and more ubiquitous as molecular toolkits expand. However, identifying which pattern illumination technologies to use with them may be challenging. This white paper provides an overview of the molecular probes available to the cell biologist and how they have been applied in different fields, going over specific examples from modulation of intracellular signaling pathways to organelle positioning dynamics.

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AI

eureKARE and DNAlytics Form Partnership to Develop a Proprietary AI Platform

eureKARE | July 07, 2021

eureKARE, a pioneering new company focused on financing and building next-generation biotechnology companies in the disruptive fields of the microbiome and synthetic biology, today announced an agreement with DNAlytics, a Belgian company applying data sciences to healthcare, to develop eureKARE's proprietary Artificial Intelligence (AI) platform to support its Biotech start-upstart-up studios, eureKARE. Unlike conventional start-upstart-up incubation methods, which begin with new science and then attempt to find an issue to address with it, eureKARE's methodology reverses this. eureKARE is committed to first finding an unmet need and then enlisting the best scientists and experts to provide an innovative solution to launch exciting new ventures. This process will be aided by eureKARE's one-of-a-kind AI platform, which will assist the business in identifying top academic researchers, locating new ideas and approaches in development, and scaling existing portfolio companies. About eureKARE eureKARE is a ground-breaking new company focusing on financing and establishing next-generation biotechnology start-ups in the microbiome and synthetic biology cutting-edge areas. eureKARE employs a two-step investing strategy to create long-term value. Through its biotech start-upstart-up studios eureKABIOME (Microbiome) and eureKASYNBIO, the company promotes translational research by developing and financing new companies based on high-value European science (Synthetic biology). In addition, the company aims to engage in more mature biotech companies. It will systematically propose to provide some liquidity to early investors, thus fulfilling a crucial demand in the European biotech sector. EureKARE has a fast-expanding portfolio of companies with the potential to disrupt the life sciences sector, led by its prominent founder, Alexandre Mouradian, and a pan-European team. About DNAlytics DNAlytics is based in Louvain-la-Neuve, Belgium, specializing in data science for the healthcare sector, including data management, bioinformatics, biostatistics, Machine Learning, and other Artificial Intelligence methods. DNAlytics products are utilized in clinical research, the creation of biotech drugs and medical devices, public health studies, and the monitoring and optimization of bio-manufacturing processes. In addition, DNAlytics assists a wide range of clients and partners in extracting scientifically sound observations and practical conclusions from complex data sets.

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INDUSTRIAL IMPACT

McMaster, Sartorius Stedim Biotech team up to advance biomanufacturing processes with next-gen tech

Sartorius Stedim Biotech S.A | August 23, 2021

Sartorius Stedim Biotech, a leading international partner of the biopharmaceutical industry, has entered into a partnership with McMaster University to improve manufacturing processes of antibody and virus-based treatments for diseases such as COVID-19, cancers, and genetic disorders. Using a state-of-the-art multi-column chromatography system provided by Sartorius Stedim Biotech, the McMaster team will "perfect" a process for the purification of therapeutic viruses that is more effective and cheaper than those currently available. This will pave the way for new and more affordable treatments to reach patients with a variety of needs. "Teaming up with Sartorius Stedim Biotech is an exciting opportunity for McMaster Engineering. This research will push the envelope in leading advanced, cutting-edge research in bio-manufacturing," says John Preston, associate dean, research, innovation and external relations in the Faculty of Engineering. "Establishing industry-friendly, collaborative environments is critical in solving real-world problems." This work aims to support the Sustainable Development Goals (SDG) set out by the United Nations, designed to give our people and planet a better future. More effective bio-manufacturing can make advanced biotherapeutics cost-effective and available to more people globally. "This partnership with McMaster University will lead to impactful research that will make important treatments available at a greater scale. We see this as a way to expand our research development and bring SDG-aligned pharmaceuticals to Canadian and global markets," says Brandon Corbett, research scientist at Sartorius Stedim Biotech. David Latulippe, associate professor of Chemical Engineering, and Prashant Mhaskar, professor of Chemical Engineering and Canada Research Chair in Nonlinear and Fault-Tolerant Control, are leading this project with Sartorius Stedim Biotech. The collaboration will initially run for four years. What is chromatography? Chromatography is an essential purification technology in biomanufacturing. To produce biotherapeutics, scientists use a bioreactor with specialized cell lines and customized growth media. Next, the biotherapeutic must go through a series of purification steps, often with duplicate steps to satisfy the requirements of regulatory bodies. Sartorius Stedim Biotechs' multi-column chromatography system uses parallel processing strategies to make the process more resource and cost-efficient. "Our ultimate goal is to perfect the downstream chromatography process by combining detailed experimental work with advanced process modelling concepts," says Latulippe. "This way, we can control the outcome and fix the processes on site, as production is happening, so everything is always 'on spec'." Currently, monoclonal antibodies are the leading biotherapeutic being used to fight against COVID-19. Training the next generation As part of the partnership, Sartorius Stedim Biotech will provide student training opportunities at their research and development facilities in North America and Europe. Ian Gough, a graduate of McMaster's Chemical and Bioengineering program, has already started working on this project. Gough is a former member of the Summer Studentship Internship program from BioCanRx, a Networks of Centres of Excellence program. Claire Velikonja, a recent chemical engineering graduate from the University of Toronto, will join the team in September. Both Gough and Velikonja received a Canada Graduate Scholarship from Natural Sciences and Engineering Research Council of Canada (NSERC) to provide additional support for their first year of graduate studies. A profile of Sartorius Stedim Biotech Sartorius Stedim Biotech is a leading international partner of the biopharmaceutical industry. As a total solutions provider, the company helps its customers to manufacture biotech medications safely, rapidly and economically. Headquartered in Aubagne, France, Sartorius Stedim Biotech is quoted on the Eurolist of Euronext Paris. With its own manufacturing and R&D sites in Europe, North America and Asia and an international network of sales companies, Sartorius Stedim Biotech has a global reach. The Group has been annually growing by double digits on average and has been regularly expanding its portfolio by acquisitions of complementary technologies. In 2020, the company employed more than 7,500 people, and earned sales revenue of 1,910 million euros. About McMaster University Ranked among the world's top engineering schools, the Faculty of Engineering plays a significant role in helping McMaster University earn its reputation as one of Canada's most innovative universities. Our focus is on experiential, problem-based learning, and our interdisciplinary approach to collaboration results in smarter insights, groundbreaking ideas, and greater optimism. This approach is helping us create a Brighter World.

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CELL AND GENE THERAPY

Imara Announces Primary Endpoint Change in the Ardent Phase 2b Clinical Trial of Tovinontrine (IMR-687) in Sickle Cell Disease

Imara | November 22, 2021

Imara Inc. a clinical-stage biopharmaceutical company dedicated to developing and commercializing novel therapeutics to treat patients suffering from rare inherited genetic disorders of hemoglobin and other serious diseases, today announced a change to the primary endpoint for the Ardent clinical trial, a Phase 2b study of tovinontrine (IMR-687) in patients with sickle cell disease (SCD), based on the recommendation of the U.S. Food and Drug Administration (FDA). Imara requested feedback from the FDA on the draft statistical analysis plan (SAP) for the Ardent trial in which fetal hemoglobin (HbF) response was the primary endpoint and annualized rate of vaso-occlusive crises (VOCs) was the key secondary endpoint. In reviewing the Ardent draft SAP and prior to any database lock for analysis, the FDA recommended that Imara change the primary endpoint to be annualized rate of VOCs. HbF response will continue to be evaluated as a key secondary endpoint. The endpoint revisions do not affect the conduct of the trial or operational aspects of the study. As part of its recommendation, the FDA suggested further interactions regarding the revised SAP and engagement on the potential of the current program for regulatory decision-making. “We welcome the FDA’s recommendations and are in the process of changing the primary endpoint of the Ardent trial to be annualized rate of VOCs and moving HbF response to be a key secondary endpoint. A reduction in VOC rate is an established approval endpoint, and we are engaging the FDA further on this and related topics, including possible streamlined paths to registration.” Rahul Ballal, Ph.D., President and Chief Executive Officer of Imara Dr. Ballal continued, “In light of this endpoint revision, the previously planned fourth quarter interim analysis will no longer occur. That interim analysis had been designed to have a focus on safety and pharmacodynamic biomarkers, including HbF, but did not include a review of VOCs. The first review of data from the Ardent trial, including annualized VOC rate, will be conducted when all subjects have completed assessment at Week 24 or terminated early, and is planned for the first quarter of 2022, subject to our upcoming discussions with the FDA. Final data analysis from the Ardent trial remains on track for the second half of 2022. In June 2021, we reported promising data from our Phase 2a and open label extension clinical trials in SCD that demonstrated reduced annualized rates of VOCs in patients treated with tovinontrine versus placebo. We expect to present updated 12-month VOC data from our ongoing Phase 2a open label extension clinical trial at the American Society of Hematology Annual Meeting in December 2021.” About the Ardent Phase 2b Clinical Trial The Ardent Phase 2b clinical trial is a fully-enrolled, global, randomized, double-blind, placebo-controlled, multicenter study with approximately 115 adult patients with sickle cell disease (SCD) enrolled. The planned primary efficacy objective will be to evaluate the annualized rate of vaso-occlusive crises (VOCs) in patients dosed with tovinontrine (IMR-687) as compared to placebo. A key secondary endpoint will be to evaluate the proportion of all patients with fetal hemoglobin (HbF) response, defined as an absolute increase from baseline of at least 3% in HbF, as compared to placebo. Additional endpoints include the evaluation of the effect of tovinontrine versus placebo on other VOC-related outcome measures, HbF-associated biomarkers, markers of red blood cell hemolysis, white blood cell adhesion markers and quality of life measures over the course of a one-year treatment period. The FDA has granted Orphan Drug, Fast Track and Rare Pediatric Disease designations and the European Commission has granted Orphan Drug designation for tovinontrine for the treatment of SCD. About Tovinontrine (IMR-687) Tovinontrine is a highly selective and potent small molecule inhibitor of phosphodiesterase-9 (PDE9). PDE9 selectively degrades cyclic guanosine monophosphate (cGMP), an active signaling molecule that plays a role in vascular biology and hemoglobin production in red blood cells. Lower levels of cGMP are found in people with sickle cell disease (SCD) and beta-thalassemia and are associated with reduced blood flow, increased inflammation, greater cell adhesion and reduced nitric oxide mediated vasodilation. Blocking PDE9 acts to increase cGMP levels, which is associated with several benefits including the potential reactivation of fetal hemoglobin (HbF), a natural hemoglobin produced during fetal development. Increased levels of HbF in RBCs have been demonstrated to improve symptomology and substantially lower disease burden in both patients with SCD and patients with beta-thalassemia. About Sickle Cell Disease Sickle cell disease (SCD), a hemoglobinopathy, is a rare inherited red blood cell disorder. The disease causes structural abnormalities in hemoglobin that cause red blood cells to become inflexible and elongated, ultimately blocking blood flow to organs, which can lead to vaso-occlusive crises (VOCs). SCD is characterized by debilitating pain, progressive multi-organ damage and early death. The global prevalence of SCD is estimated to be approximately 4.4 million patients, including an estimated 100,000 patients in the United States and 134,000 patients in the European Union. About Imara Imara Inc. is a clinical-stage biotechnology company dedicated to developing and commercializing novel therapeutics to treat patients suffering from rare inherited genetic disorders of hemoglobin and other serious diseases. Imara is advancing tovinontrine (IMR-687), a highly selective, potent small molecule inhibitor of PDE9 that is an oral, potentially disease-modifying treatment currently in clinical development for sickle cell disease and beta-thalassemia and preclinical development for heart failure with preserved ejection fraction, or HFpEF. Imara is also advancing IMR-261, an oral activator of nuclear factor erythroid 2–related factor 2, or Nrf2. Cautionary Note Regarding Forward-Looking Statements Statements in this press release about future expectations, plans and prospects, as well as any other statements regarding matters that are not historical facts, may constitute “forward-looking statements” within the meaning of The Private Securities Litigation Reform Act of 1995. These statements include, but are not limited to, statements relating to (i) the Company’s plans to change the primary and secondary endpoints for the Ardent Phase 2b clinical trial of tovinontrine (IMR-687), (ii) the timing for reporting of additional data from the Ardent Phase 2b and open label extension clinical trials of tovinontrine in patients with sickle cell disease and (iii) the Company’s planned discussions with the FDA regarding the regulatory pathway for tovinontrine. The words “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,” “potential,” “predict,” “project,” “should,” “target,” “will,” “would” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including: the impact of extraordinary external events, such as the risks and uncertainties resulting from the impact of the COVID-19 pandemic on the Company’s business, operations, strategy, goals and anticipated milestones, including its ongoing and planned research activities and ability to readout data from the Ardent Phase 2b and open label extension clinical trials of tovinontrine in sickle cell disease; the Company’s ability to advance the development of tovinontrine under the timelines it projects in current and future clinical trials, demonstrate in any current and future clinical trials the requisite safety and efficacy of tovinontrine; and other factors discussed in the “Risk Factors” section of the Company’s most recent Quarterly Report on Form 10-Q, which is on file with the Securities and Exchange Commission and in other filings that the Company makes with the Securities and Exchange Commission in the future. Any forward-looking statements contained in this press release speak only as of the date hereof, and the Company expressly disclaims any obligation to update any forward-looking statement, whether as a result of new information, future events or otherwise.

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