Seng H. Cheng

Study of PolyA length's impact on #mRNA translation in in-vitro systems. Nice intro section covering the role of PABP.

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The more we understand how #CellTherapies help patients, the better we will be able to develop safer, durable, and efficacious treatments! #TheMoreWeKnow "The immune system overreaction known as cytokine release syndrome (CRS), and neurologic toxicities are two well-known side effects of CAR-T treatment. Last week, regulators removed a requirement for clinicians to report serious cases of the side effects as part of its Risk Evaluation and Mitigation Strategies for Gilead’s treatments Yescarta and Tecartus." https://lnkd.in/efmXtYZ5

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🔬 Discovering Biomarkers for Better Outcomes in Melanoma Treatment 🔬 Exciting news from ASCO 2024! Led by Jeffrey Weber, our team is proud to present pioneering findings on the role of predictive and pharmacodynamic biomarkers for response and toxicity in melanoma treatment. Our phase II trial combined tocilizumab (TOCI) with immune checkpoint inhibitors, reducing toxicity and revealing new biomarkers. Initiated in 2020-21, this work involved multiple high parametric flow cytometry panels to identify various myeloid, NK and functional CD4 and CD8 T cell populations linked to treatment outcomes. Our insights are paving the way for more personalized, effective melanoma management. 🔥 Hot Take: Inflammation Modulators are Here to Stay in Immuno-Oncology!🔥 📍 Check out our findings at ASCO Poster Abstract #9538; Poster Board #322. #ASCO2024 #MelanomaAwareness #TranslationalBiomarkers #TranslationalResearch

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Umoja Biopharma Announces Publication in Blood Highlighting Successful Generation of In Vivo CAR T-cells in Non-Human Primate Modeling First landmark, peer-reviewed publication of successful in vivo CAR T-cell data in an immune competent NHP model Data validate the VivoVec™ platform in a translationally relevant model and support its transition into human clinical testing, offering a potential paradigm shift in the field of CAR T-cell therapies Key Study Findings VivoVec particles (VVPs) incorporating CD80 and CD58 costimulation proteins exhibit enhanced capacity for in vivo CAR T-cell generation and produce CAR T-cells with increased antitumor functionality compared to those produced from VVPs displaying anti-CD3 scFvs alone. Combining the anti-CD3 scFv together with the ligand binding domains of CD80 and CD58 into a single multi-domain fusion (MDF) protein markedly augments the particles’ ability to bind, activate, and transduce T-cells. VVPs incorporating MDF compatible with NHP T-cell activation and costimulation potently generate anti-CD20 CAR T-cells in vivo, comprising up to 65% https://lnkd.in/eqsSTKjf

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The surge in approvals for #cellandgenetherapy (CGT) products offers hope for patients with chronic and #rarediseases that have long been without treatment options. The robust pipeline of innovative treatments presents compelling opportunities for investors, not only in early-stage ventures but also in midmarket and larger companies across the industry vertical. As the number of approved CGT products continues to rise, investors are increasingly interested in sectors such as raw materials, manufacturing equipment and services, and logistics. With the potential for substantial growth ahead, understanding the complexities and opportunities of the CGT market will be essential for investors seeking to capitalize on this development. 

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RNAi-based drug design: considerations and future directions More than 25 years after its discovery, the post-transcriptional gene regulation mechanism termed RNAi is now transforming pharmaceutical development, proved by the recent FDA approval of multiple small interfering RNA (siRNA) drugs that target the liver. Synthetic siRNAs that trigger RNAi have the potential to specifically silence virtually any therapeutic target with unprecedented potency and durability. Bringing this innovative class of medicines to patients, however, has been riddled with substantial challenges, with delivery issues at the forefront. Several classes of siRNA drug are under clinical evaluation, but their utility in treating extrahepatic diseases remains limited, demanding continued innovation. In this Review, we discuss principal considerations and future directions in the design of therapeutic siRNAs, with a particular emphasis on chemistry, the application of informatics, delivery strategies and the importance of careful target selection, which together influence therapeutic success. https://lnkd.in/ecB46Cfr

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"Proteolysis Targeting Chimeras (#PROTAC's) are heterobifunctional molecules that recruit an E3 #Ubiquitin ligase to ubiquitinate a specific protein of interest (POI) and tag it for degradation. Since their inception 20 years ago, PROTACs have transformed the landscape of #SmallMolecule #DrugDiscovery due to their ability to offer event-driven pharmacology and their potential to target previously undruggable POIs! While harnessing E3 ligases is clearly an effective strategy to degrade specific POIs, each of the ligands for the aforementioned E3s has potential limitations. Unlocking novel E3 ligases for use in heterobifunctional PROTAC #Degraders is of high importance to the pharmaceutical industry!" In this fantastic article published via the American Chemical Society, the Journal of #MedicinalChemistry, researchers from AstraZeneca describe the discovery of a ligand with optimized #Potency and #Specificity towards ligase recruitment and #CryoEM supported structure-based #DrugDesign: https://lnkd.in/etyjDJdQ "The design of heterobifunctional molecules aims to effect #ProteinDegradation of multiple POIs, including BRD4. Despite extensive efforts toward this goal, the team was not able to demonstrate PROTAC mediated degradation of any of these putative #DrugTargets, suggesting that DCAF15-mediated heterobifunctional degradation may not be broadly applicable. Moreover, apparent DCAF15-mediated degradation of BRD4 was later proven to not be DCAF15-mediated, but via DCAF16! This, as well as recent reports in the literature around BRD4 degradation mediated by monofunctional #SmallMolecules, are a reminder to exercise caution when using the popular pair of (+)-JQ1 ligand and BRD4 protein to demonstrate heterobifunctional degradation. Robust #MechanismOfAction (MoA) experiments to support PROTAC-mediated BRD4 degradation should be an important part of any research in this area!" #CryoEM #TargetedProteinDegradation #InducedProximity

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Encouraging and exciting results with SELLAS' CDK9 inhibitor SLS009 (also known as GFH009) in relapsed or refractory acute myelogenous leukemia (AML). Whilst being associated with a complex underlying MOA (see: https://lnkd.in/eSQMUFZi), SLS009 is a novel agent poised to become a 'best-in-class' therapeutic asset for certain AML patients (guided by emerging biomarker data) and seems to be combinable with other antileukemic drugs. https://lnkd.in/ezVWgE2Q

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Google releases Tx-LLM, A Large Language Model for Therapeutics drug discovery and development. Tx-LLM rised from Google's Med-PaLM 2, and built to analyze a variety of chemical or biologics candidate to facilitate multi-modality driven drug-discovery pipeline, and with trained capability of navigating around some of the known toxicity. Free full text link: https://lnkd.in/etacc_5d Abstract: Developing therapeutics is a lengthy and expensive process that requires the satisfaction of many different criteria, and AI models capable of expediting the process would be invaluable. However, the majority of current AI approaches address only a narrowly defined set of tasks, often circumscribed within a particular domain. To bridge this gap, we introduce Tx-LLM, a generalist large language model (LLM) fine-tuned from PaLM-2 which encodes knowledge about diverse therapeutic modalities. Tx-LLM is trained using a collection of 709 datasets that target 66 tasks spanning various stages of the drug discovery pipeline. Using a single set of weights, Tx-LLM simultaneously processes a wide variety of chemical or biological entities (small molecules, proteins, nucleic acids, cell lines, diseases) interleaved with free-text, allowing it to predict a broad range of associated properties, achieving competitive with state-of-the-art (SOTA) performance on 43 out of 66 tasks and exceeding SOTA on 22. Among these, Tx-LLM is particularly powerful and exceeds best-in-class performance on average for tasks combining molecular SMILES representations with text such as cell line names or disease names, likely due to context learned during pretraining. We observe evidence of positive transfer between tasks with diverse drug types (e.g., tasks involving small molecules and tasks involving proteins), and we study the impact of model size, domain finetuning, and prompting strategies on performance. We believe Tx-LLM represents an important step towards LLMs encoding biochemical knowledge and could have a future role as an end-to-end tool across the drug discovery development pipeline. Google DeepMind

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Century Therapeutics Raises $60 Million, Acquires Clade Therapeutics, and Expands Pipeline of Allogeneic, iPSC-Derived Cellular Therapies - https://lnkd.in/ehDg3gC9 Century Therapeutics, Inc (NASDAQ: IPSC), an innovative biotechnology company developing induced pluripotent stem cell (iPSC)-derived cell therapies in immuno-oncology and autoimmune and inflammatory diseases, announced plans to expand clinical development for its lead program, CNTY-101, a CD19-targeting iNK cell therapy, into additional autoimmune disease indications. CNTY-101 is currently being evaluated in a clinical trial in B-cell malignancies (ELiPSE-1) as well as a planned clinical trial in systemic lupus erythematosus (SLE) (CALiPSO-1), which is on track to be initiated in the first half of 2024. Century plans to pursue additional autoimmune disease indication regulatory filings in 2024. Century’s increased research and development activities in autoimmune diseases are further supported by a $60 million private placement of its common stock to certain institutional investors. Concurrently, Century announced pipeline and platform enhancements through the acquisition of Clade Therapeutics, Inc. (“Clade”), a privately-held biotech company focused on discovering and delivering engineerable, off-the-shelf, scalable, and consistent stem cell-based medicines, with a focus on iPSC-derived αβ T cells. The acquisition brings additional iPSC-focused pipeline programs and technology to Century spanning across cancer and autoimmune diseases. “Today’s news signifies a transformative milestone for Century, as we accelerate and broaden our research and development initiatives in autoimmune diseases and iPSC-derived cell therapy on a larger scale. With support from a distinguished group of investors, coupled with the acquisition of Clade, we are poised for continued success,” said Brent Pfeiffenberger, Pharm.D., Chief Executive Officer of Century. “Under the leadership of a pioneering team of scientists and senior leaders with decades of experience in stem cell biology and iPSC differentiation enabled by significant capital investment from their investors, Clade has established a discovery engine with industry-changing potential,” said Hy Levitsky, M.D., President of R&D of Century. Read more at: https://lnkd.in/ehDg3gC9 #ipsc #cancer #autoimmunediseases

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iPSC Applications in Cell Therapy, Drug Discovery, and Beyond - https://lnkd.in/eHMZ4hk In recent years, iPSC-derived cells have increasingly been used within preclinical testing and early stage-stage trials. The first clinical trial using iPSCs started in 2008, and today, that number has surpassed 100 worldwide. Most of these clinical trials do not involve the transplant of iPSCs into humans, but rather, the creation and evaluation of iPSC lines for clinical purposes. Within these trials, iPSC lines are created from specific patient populations to determine if these cell lines could be a good model for a disease of interest. Companies involved with the commercialization of iPSC-derived cell therapeutics include: Allele Biotechnology & Pharmaceuticals Inc., Aspen Neuroscience, Inc., Avery Therapeutics, Inc., Bayer, BlueRock Therapeutics, Bone Therapeutics, Brooklyn Immuno Therapeutics, CellOrigin Biotech, Cellectis, Century Therapeutics, Inc, Citius Pharmaceuticals, Inc., Clade Therapeutics, Cynata Therapeutics, CytoMed Therapeutics Limited, Cytovia Therapeutics, EdiGene Inc., Editas Medicine, Eterna Therapeutics, Exacis Biotherapeutics, Fate Therapeutics Inc., FUJIFILM Cellular Dynamics, Inc, Greenstone Biosciences, Heartseed Inc., Healios K.K., HebeCell Corp, Hopstem Biotechnology Co., Ltd., Implant Therapeutics Inc., I Peace, Inc.| Cell and Gene Therapy Manufacturing, cGMP iPSCs | CDMO, iPSirius, IPS HEART, Jacobio Pharma, Keio University, Kyoto University Hospital, Laverock Therapeutics, Neuropath Therapeutics Ltd., Notch Therapeutics, Novo Nordisk, Osaka University, Pluristyx, Inc., REPROCELL, RIKEN, RheinCell Therapeutics GmbH, RxCell Inc, Ryne Biotechnology, Inc., Sana Biotechnology, Inc., SCG Cell Therapy, SCM Lifescience, Semma Therapeutics, and more. Read more at: https://lnkd.in/eHMZ4hk #ipsc #celltherapy #stemcell

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This review proposes a set of modifications to existing regulatory requirements for #mRNA products, based on a platform perspective for quality, manufacturing, preclinical, and clinical data. The authors address development and potential regulatory requirements when the mRNA sequences and LNP composition vary in different products as well. In addition, they propose considerations for self-amplifying mRNA, individualized oncology mRNA products, and mRNA therapeutics.  

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In 2022 when Illumina and GRAIL leadership where touting how many lives would be saved if only the antitrust authorities got out of the way, here's what was really happening. Please read carefully, shows how this "life saving" test doesn't work: "[With the] San Francisco firefighters, the test did not identify the statistically expected number of cancers, provided false positives for half the cancers it did identify, and missed at least three cases of confirmed cancer. In other words, the exercise showed Galleri to be a disaster." "In this example prominently featured on GRAIL’s website and in marketing materials as an example of how “multi-cancer early detection screening can be critical for those at elevated cancer risk”—GRAIL provided 1,786 screenings to a group of San Francisco firefighters and their family members, a “high risk” group for certain kinds of cancer. During that testing round, which was conducted on December 6, 2022—Galleri generated six false positives and identified only five instances of cancer." "...such a result is alarming in light of the fact that, based on statistical experience, cancer should have been detected in about 29 (not five) of the 1,786 tests. Moreover, of the five instances of where cancer signals were identified, two individuals already knew they had cancer to begin with. Further, all of the instances of detected cancer were at a “late stage,” and where the cancer was too advanced to make a difference for the patients. One firefighter was diagnosed with stage 3 pancreatic cancer and is now in hospice, while another firefighter was diagnosed with lung cancer, which has now metastasized to the brain." "Galleri also missed at least six instances in which the San Francisco firefighters actually had cancer—failing to identify instances of melanoma, prostate cancer, and lymphoma that were identified by private doctors just months after the Galleri test indicated “no cancer signal.” "Further, in one instance in the San Francisco firefighters screening where Galleri generated a false positive, the patient underwent a painful bone marrow biopsy procedure to determine whether the patient did have cancer. In that case, the patient’s bone marrow biopsy procedure, clinically shown to involve “unbearable pain” to the “worst possible pain” a patient can experience, revealed that there was, in fact, no cancer." "The screenings provided to the San Francisco firefighters were an expensive “disappointment.” According to Tony Stefani, the organization’s founder, the screenings demonstrated that the probability of catching an early-stage cancer through the Galleri test was “negligible,” and the screenings only caught “some serious cancers at a later stage,” which likely would have been detected within one or two months without the test. Given the test’s high costs and useless real-world performance, Stefani stated that Galleri was a total “disappointment” and that the foundation had been sold a “bill of goods.” 🤯🤯🤯

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In one of the most highly anticipated clinical trial readouts this year, an #RNA silencing treatment developed by Alnylam Pharmaceuticals reduced the risk of death, heart-related hospital visits and hospitalizations by 28% compared to placebo in patients with a heart muscle disease. The results, announced Monday, pave the way for Alnylam’s therapy vutrisiran to become the first RNA silencing therapy on the market for ATTR amyloidosis with cardiomyopathy, a condition in which misfolded proteins build up in the heart and can result in heart failure. If approved, Alnylam could enter a multibillion-dollar market currently dominated by Pfizer. #clinicaltrials #clinicalresults #readout #RNAsilencing #heartmuscledisease #vutrisiran #heartdisease #cardiology #cardio #ATTRcardiomyopathy #patients #PhaseIII #clinicaldata

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72% reduction in cancer cell growth seen when using our newly developed custom electronic signal. This paper describes in detail what the signal is and how to synthesize it and why it works so well against cancer cells. We decided NOT to patent this new method so that the world may benefit from it and use it freely without having to pay for the years of research it took us to accomplish it. Here's the FREE paper: https://lnkd.in/em-hsNjm

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In this position paper, Marc argues that #Oncology is the next therapeutic frontier for the application of value-based agreements. As a country and society, we must move towards value-based health - from therapeutics to the provisioning of healthcare services. Thought leaders like Peter have been discussing the societal value and importance of therapeutics for some time. It's now time to put our money where value is created, not destroyed. #NoPatientLeftBehind

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The countdown is on. Next week, I'm heading to Chicago for the American Society of Clinical Oncology (ASCO) Annual Meeting (#ASCO24). It's one of the most significant events in the oncology world, bringing together a global community of researchers, clinicians, advocates, and patients in the fight against cancer. For me, #ASCO24 is more than just a conference; it's a chance to: - Dive into the Latest Research: Thousands of abstracts will be presented, showcasing cutting-edge advancements across all aspects of cancer care. I'm eager to learn about new therapies, diagnostic approaches, and breakthroughs that can transform patients' lives. Discussing the evolving landscape of cancer treatment is crucial for staying updated on the latest developments and best practices in patient care. - Connect with Experts: Meeting and exchanging ideas with leading oncologists, scientists, and industry innovators is an invaluable experience. It fosters collaboration and fuels inspiration for advancing cancer care. - Share Our Recent Developments: Zephyr AI team will present a poster and share our findings on the "Evaluation of a Novel Machine Learning Method for PARP Inhibitor Sensitivity Prediction Using Real-World Data." Abstract # 5583 / Poster Bd # 454, presented by Emily Vucic et al., June 3rd, 9 am—12 pm: https://lnkd.in/g8wKqB8v In the meantime, what are you most interested in learning about from #ASCO24? Share your thoughts and questions. See you in Chicago!

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Small patient populations make clinical development challenging and financially unfeasible, despite the urgency that exists to address them. That’s why #tRNA, with its unique potential to treat many diseases with the same genetic mutation, is so exciting. We can also take a page from oncology drug development and leverage basket studies to address the statistical and economic barriers to performing clinical trials in small populations and bring the opportunity of new innovation to more patients. Thank you, Anna-Marie MacDonald and Technology Networks team for the opportunity to showcase the enormous potential of #tRNA to transform #raredisease #drugdevelopment.

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