KAT2B

NEWTON, Mass., March 06, 2024 (GLOBE NEWSWIRE) -- Auron Therapeutics, a biotechnology company focused on developing next-generation targeted therapies by identifying and inhibiting the oncogenic cell states of cancer, today announced that the Company will present an overview of its proprietary AURIGIN™ platform and the first preclinical data from its lead program during two poster sessions at the American Association for Cancer Research (AACR) Annual Meeting 2024. Auron will share data demonstrating the ability of AURIGIN to identify drivers of tumor plasticity, a critical vulnerability of cancer cells that is associated with poor prognosis and treatment-resistance. AURIGIN utilizes a single cell multi-omics atlas of human development and AI machine learning to identify the most relevant genetic targets in cancer cell plasticity. Using AURIGIN to identify disrupted cell states, Auron is developing targeted treatments to revert cancer cells to a normal, quiescent state to stop tumor growth and proliferation. At AACR, Auron will also present in vitro and in vivo data from its first-in-class, novel program targeting KAT2A/B, a histone acetyltransferase identified by AURIGIN that is associated with multiple tumor types. The Company generated preclinical data showing that degradation of KAT2A/B results in potent tumor-growth inhibition in primary models of small cell lung cancer (SCLC), neuroendocrine prostate cancer (NEPC), and acute myeloid leukemia (AML). These data led to the subsequent design of AUTX-703, an orally available, potent and selective KAT2A/B degrader that Auron recently selected as its lead candidate for clinical development. “We are thrilled to present multiple posters at AACR and highlight, for the first time, the novel insights we have learned from our proprietary, internally built AURIGIN platform. We believe AURIGIN has the ability to elucidate many of the most valuable targets driving cancer cell state change, evidenced by our discoveries around KAT2A/B as a driver of multiple tumor types,” said Kate Yen, Ph.D., Founder and Chief Executive Officer of Auron. “This team has executed incredibly, and we look forward to sharing AURIGIN and our lead program data with the broader cancer research community, which we believe can enhance how we target and treat cancer in the future.” Auron’s presentations at the AACR Annual Meeting include: AURIGIN: A comprehensive single-cell OMICs atlas of human development and an AI/ML framework to classify and identify the drivers of tumor plasticity and altered cellular state. Session Category: Bioinformatics / Computational Biology / Systems Biology / Convergent ScienceSession Title: Artificial Intelligence and Machine/Deep Learning 1Session Date and Time: Sunday April 7, 2024, 1:30 – 5:00 p.m. PT Potent and selective degradation of KAT2A and KAT2B induces profound cell state changes and inhibits growth of AML, SCLC and NEPC model systems Session Category: Experimental and Molecular TherapeuticsSession Title: Cancer Treatment: New TechnologiesSession Date and Time: Tuesday April 9, 2024, 1:30 – 5:00 p.m. PT About Auron Therapeutics Auron Therapeutics is a patient-centered, platform-powered, product-driven oncology company. Auron is leading the next generation of targeted cancer therapies by identifying and inhibiting the oncogenic cell states of cancer. Auron pioneered its AURIGIN™ platform, which uses AI and machine learning to compare normal cell states with cancerous cell states to identify novel cancer targets, optimal development models, and biomarkers to facilitate proper patient selection. Using AURIGIN, the Company is building a pipeline of small molecule targeted therapies, led by AUTX-703, which is being developed for the treatment of both solid tumors, including small cell lung cancer and neuroendocrine prostate cancer, and hematologic malignancies, including acute myeloid leukemia. For more information, please visit aurontx.com. Investor Contact: Monique AllaireTHRUST Strategic Communicationsmonique@thrustsc.com Media Contact: Ryan FlinnTHRUST Strategic Communications510-207-7616ryan@thrustsc.com

Data presented at International Society for Stem Cell Research conference shows unparalleled level of consistency across manufacturing of multiple human cell products World leading stem cell biologists call the technology “a watershed moment for biology” and “a true disruptive innovation in stem cell biology, much as CRISPR has been for genetics” bit.bio’s ioCells are already being used and enable large-scale experiments that underpin preclinical research and drug development The consistency of the cells is enabling scientific breakthroughs and applications ranging from biohybrid devices, novel targets for neurodegeneration, and cultured meat. CAMBRIDGE, England & BOSTON--(BUSINESS WIRE)-- bit.bio, a synthetic biology company focused on human cells, has achieved a milestone in the manufacture of human cells. Based on their opti-oxTM 1- based transcription factor reprogramming technology, bit.bio has reached a new level of precision and consistency of their induced pluripotent stem cells (iPSC)-derived cell products. The data that will be presented at the International Society for Stem Cell Research (ISSCR) conference show an unparalleled level of consistency with regards to multiple human cell products for research use. Samples of cells were selected from different manufacturing lots and time periods and different users carried out the opti-ox reprogramming step to manufacture the mature cell types. Analysis of the samples show fewer than 1% differentially expressed genes in bulk-mRNA sequencing experiments between manufacturing lots. This achievement sets a new standard for the manufacture of human cells. Commenting on the data, Dr Marius Wernig, Professor in the Departments of Pathology and Chemical and Systems Biology and Co-Director of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University and bit.bio SAB member said: “Out of 20,000 genes, not a single one is differentially expressed across three independently produced batches of bit.bio’s glutamatergic neurons. This seems like a watershed moment for biology. The team at bit.bio has achieved a level of consistency that is outside of the realm of what was thought possible. It is another proof point that transcription-factor based programming of cells can solve the challenges that have restricted the use of stem cell-derived cells in drug development and cell therapy.” Human stem cell pioneer Roger Pedersen, Senior Research Scientist at Stanford University School of Medicine and chair of bit.bio’s SAB said: “These new results are both compelling and biologically fascinating. bit.bio's opti-ox approach seems to remove interfering sources of stochasticity, thereby enabling deterministic reprogramming of iPSCs into somatic cells of any lineage. The homogeneity achieved by opti-ox is amazing, and I would never have thought such a high level of control over differentiation was possible. This is a true disruptive innovation in stem cell biology, much as CRISPR has been for genetics.” Bertie Göttgens, Professor and Director, University of Cambridge Stem Cell Institute commented: “bit.bio is an integral partner within the Cambridge Stem Cell community, where they have pushed the boundaries of what the field thought was possible with regards to consistent differentiation of human stem cells. From what I have seen, the data are astonishing. If this can be generalised to other cell types, these data will be seen as a landslide moment for the human stem cell field, which demonstrate that it is possible to industrialise the manufacture of human cells.” The consistency and scale of manufacturing achieved, with billions of cells now being produced on a daily basis, has opened doors to the creation of human cell standards. This has the potential to address the lack of reproducibility that has plagued the life sciences industry. By using reliable and standardised human cells, researchers worldwide can accelerate their studies and enhance the reliability of their findings. Thore Graepel, SVP of Computational biology at Altos Laboratories and bit.bio SAB member said: “I have never seen such consistency in biological data before. The data has made me rethink what level of consistency is possible in cell biology. Like in other application areas of machine learning, the quality of training data is of crucial importance and bit.bio’s cell products have the potential to super-charge AI models of biological systems.” Sir David Klenerman, Professor of Biochemistry University of Cambridge, 2020 Breakthrough Prize in Life Sciences recipient 2022 who is best known for his work on next-generation sequencing of DNA as the technological basis for Illumina, said: “This is a significant technological step forward, removing the cell-to-cell variation that has been a problem in the field.” Cells produced using the opti-ox technology have already been used in a range of research applications, including the identification of novel targets for neurodegenerative diseases such as Alzheimer’s,2,3. They have been used for the generation of biohybrid implant devices aiming to restore paralysed limb function4, and 3D printing of brain models5. The ability to produce cells at an industrial scale allows large-scale experimentation, such as high-throughput screening - for example, underpinning bit.bio’s partnership with leading contract research organisation Charles River Laboratories. This means scientists can now conduct experiments on a significantly larger scale in human models, leading to faster discoveries and a deeper understanding of cellular mechanisms. In addition, bit.bio is developing their technology for use in the field of cell therapy. Large scale manufacturing of human cells based on the ability to precisely reprogram iPSC into specific somatic cell types will enable off the shelf regenerative medicines that are available to millions of patients as mainstay treatments. Rahul Singhvi, CEO National Resilience stated: “This is an important breakthrough for the manufacture of human cells. The data are impressive and have set a new bar of what is possible. We are excited to support bit.bio in the development of their cell therapy pipeline.” Loïc Vincent, CSO Affini-T Therapeutics said: “A scalable source of consistent human cells will have a transformational impact on research, drug discovery, and cell therapy. It can tackle major challenges such as the reproducibility of scientific research all the way to scale up challenges for cell therapies and regenerative medicine. bit.bio's preclinical data show extraordinary consistency. The fact that this has been achieved across multiple cell types is also astonishing. bit.bio’s genomic safe harbour technology, opti-ox, is really pushing the boundaries.” Outside of medicine, the extraordinary scale enabled by opti-ox has enabled the manufacture of trillions of fat and muscle cells in a porcine background for cultured meat applications. Meatable held their first tasting in Singapore this year7 and is due to launch its first products by the end of the year. Meatable co-founder and CEO Krijn de Nood said: “Meatable is creating a world in which we can enjoy meat that is innocent. At the heart of our approach and enabling this dream is opti-ox. It allows us to manufacture at scale, and in the future reach price parity with meat derived from farmed animals. Whilst it is surprising to see these levels of consistency in the data, it is also what we experience on a daily basis. We found that opti-ox enables the manufacture of cells at all levels of scale, from the smallest experiment to the largest industrial bioreactor.” “The beauty of the data and how consistently bit.bio can produce human cells using our forward programming technology is mind-boggling” said Mark Kotter, CEO of bit.bio. “The team has developed solid processes and we haven’t had a single failed manufacturing run in the past two years. This is paving the way for groundbreaking research and future cell-based therapies. We are excited to collaborate with researchers and industry partners to unlock the full potential of human cells." Hermann Hauser KBE, Serial Entrepreneur and Venture Capitalist, e.g behind Acorn Computers, ARM, Solexa/Illumina and chair of the bit.bio Board said: “When I joined bit.bio I sensed that bit.bio’s opti-ox technology has the potential to create a category leader in the human cell space. The consistency that we detected in bit.bio’s products is astonishing. This is the bottom line if one gets everything right in a manufacturing process. I am proud of this fantastic achievement by the team.” bit.bio's human cell manufacturing technology is set to reshape the future of scientific research and biomedicine. By ensuring reliability, scalability, and reproducibility, bit.bio is driving forward the frontiers of cellular biology and transforming the possibilities of what can be achieved. Data for multiple cell types - glutamatergic neurons, sensory neurons and GABAergic neurons - will be presented at ISSCR, showing the approach may be generalisable to any human cell type. Notes to editors About the data This new data will be showcased in 4 posters and a talk at ISSCR TALK: Industrialising Cellular Reprogramming: Leveraging opti-ox™ Technology to Manufacture Human Cells with Unprecedented Consistency Marius Wernig and Mark Kotter Innovation Showcase - Thursday, 15 June 12:00 – 1:00pm, ET. ISSCR Transcription factor-mediated cellular reprogramming has emerged as a groundbreaking paradigm in developmental biology, challenging traditional theories and opening new avenues for further scientific innovations. Prof Wernig will discuss his pioneering work on cellular reprogramming, which opened up a new paradigm for cell identity, in which cellular states are driven by transcriptional events. His laboratory developed the first across germ layer reprogramming protocols highlighting the potential generalisability of this concept. His group demonstrated how transcription factor combinations are able to dictate cellular states and sub-cell identities. Based on this new paradigm, he developed new cellular models for translational research and outlined how reprogrammed cells could be used for therapeutic applications. Despite the benefits of cellular reprogramming, several challenges associated with conventional vector-based methods of transgene expression impact the efficiency, consistency and purity of the resulting cell populations, all of which need to be addressed for its potential to be truly realised in regenerative medicine. As Dr Kotter will outline, these challenges can be addressed by expressing reprogramming cassettes via genomic safe harbour (GSH) sites. GSH-mediated optimised inducible over-expression (opti-ox) enables highly controlled, consistent and scalable manufacturing of human iPSC-derived cells. Further, he will discuss how bit.bio has generalised this paradigm to generate cells from all three germ layers. The integration of opti-ox technology ensures increased precision and inducible control of transcription factor expression, setting a new standard for consistency in cell manufacturing. This breakthrough enables the manufacture of trillions of highly defined cells with unprecedented consistency offering the potential to transform the field of regenerative medicine and accelerate advancements in cell-based therapies. ○ POSTER: Generation Of Highly Pure, Consistent And Functional Inhibitory Gabaergic Neurons From Human Ipscs Using opti-ox Technology | Presenter Gianmarco Mastrogiovanni, Team leader ○ POSTER: Optimised and scalable reprogramming of human iPSCs to generate nociceptor sensory neurons for the study of pain mechanisms and neuropoathies | Presenter Dario Pacitti | Senior Scientist ○ POSTER: Modelling neurodegeneration using a human isogenic system: A next generation approach to study frontotemporal dementia and amyotrophic lateral sclerosis | Presenter Will Bernard​ | Director, Cell Type Development ○ POSTER: Rapid and consistent generation of functional microglia from reprogrammed hiPSCs to study mechanisms in neurodegeneration and neuroinflammation | Presenter Malathi Raman Srivastava​ | Snr Product Manager References: Matthias Pawlowski, Daniel Ortmann, Alessandro Bertero, Joana M. Tavares, Roger A. Pedersen, Ludovic Vallier, Mark R.N. Kotter 2017. Inducible and Deterministic Forward Programming of Human Pluripotent Stem Cells into Neurons, Skeletal Myocytes, and Oligodendrocytes, Stem Cell Reports, VOLUME 8, ISSUE 4, P803-812, APRIL 11, 2017. (16)X0005-7 Julie Qiaojin Lin, Deepak Khuperkar, Sofia Pavlou, Stanislaw Makarchuk, Nikolaos Patikas, Flora CY Lee, Julia M Zbiegly, Jianning Kang, Sarah F Field, David MD Bailey, Joshua L Freeman, Jernej Ule, Emmanouil Metzakopian, Marc-David Ruepp, Giovanna R Mallucci 2023. HNRNPH1 regulates the neuroprotective cold-shock protein RBM3 expression through poison exon exclusion, The EMBO Journal, 30 May 2023. Pavlou, S., Foskolou, S., Patikas, N. et al 2023. CRISPR-Cas9 genetic screen leads to the discovery of L-Moses, a KAT2B inhibitor that attenuates Tunicamycin-mediated neuronal cell death. Nature Scientific Reports 13, 3934 2023. Amy E. Rochford, Alejandro Carnicer-Lombarte, Malak Kawan, Amy Jin, Sam Hilton, Vincenzo F. Curto, Alexandra L. Rutz, Thomas Moreau, Mark R.N. Kotter, George G. Malliaras and Damiano G Barone 2023. Functional neurological restoration of amputated peripheral nerve using biohybrid regenerative bioelectronics, Science Advances, 22 Mar 2023, Vol 9, Issue 12, Zhou, L., Wolfes, A.C., Li, Y., Chan, D.C., Ko, H., Szele, F.G. and Bayley, H., 2020. Lipid‐bilayer‐supported 3D printing of human cerebral cortex cells reveals developmental interactions. Advanced Materials, 32(31), p.2002183. Press release, 11 May, 2023: Meatable holds its world-first tasting in Singapore with aim to launch in 2024. View source version on businesswire.com: Contacts April Six on behalf of bit.bio bitbio@aprilsix.com +44 7875 468942 Source: bit.bio View this news release online at:

综上，本研究揭示了白介素1β通过诱导NNT乙酰化抑制肿瘤细胞铁死亡并介导免疫治疗抵抗的新机制，明确了炎症微环境可通过重塑肿瘤代谢降低免疫治疗疗效，拓宽了对炎症微环境在肿瘤代谢重编程及抗肿瘤免疫中作用的 中山大学肿瘤防治中心徐瑞华教授团队在国际知名期刊Molecular Cell发表了题为“白介素1β（IL-1β）诱导NNT乙酰化促进肿瘤细胞铁硫簇稳态介导免疫治疗抵抗”的研究成果。该成果揭示了白介素1β可通过诱导肿瘤细胞线粒体内膜蛋白NNT乙酰化从而调控铁硫簇稳态，进而抑制肿瘤细胞铁死亡并介导免疫治疗抵抗，阻断IL-1β-NNT乙酰化轴可显著提高免疫治疗疗效。 肿瘤免疫治疗是肿瘤治疗领域的革命性突破。近年来，徐瑞华教授团队在临床实验中证实，相比于单纯化疗，食管癌患者更能从“PD-1抗体+化疗”模式中获益，进一步的转化研究证实也只是部分病人能够真正获益（Cancer Cell，2023），然而仍有相当比例的“冷肿瘤”对此类免疫疗法响应较差。肿瘤微环境的免疫抑制状态是导致免疫检查点阻断剂治疗失败的重要原因之一，因此，深入探索肿瘤微环境抑制抗肿瘤免疫的作用方式和调控机制将为肿瘤免疫治疗提供潜在的新靶点和新策略。 炎-癌转化理论是癌症起源的经典假说。早在1863年，Rudolf Virchow发现肿瘤组织中含有大量的炎性细胞浸润，提出肿瘤起源于慢性炎症的猜想。既往研究表明，炎症参与肿瘤的多个阶段，炎症微环境也被公认是肿瘤的特征之一。白介素1β是一种重要的促炎细胞因子，其基因多态性与胰腺癌、乳腺癌、肺癌和胃癌等多种肿瘤的发生发展密切相关。以往针对白介素1β的研究，绝大部分聚焦于其对肿瘤微环境中免疫细胞或炎症细胞的调控，而白介素1β对肿瘤细胞的直接作用及其在抗肿瘤免疫中的意义仍不明确。 炎癌转化假说（引自Immunity. 2019 Jul 16;51(1):27-41） 肿瘤代谢重编程与肿瘤恶性增殖、转移及免疫治疗抵抗密切相关。徐瑞华教授团队一直致力于研究胃肠道肿瘤的临床诊治策略与基础转化研究，近期的研究发现，靶向叶酸代谢关键酶MTHFD2破坏氧化还原稳态抑制结直肠癌恶性进展（JNCI，2019）；肿瘤甲硫氨酸代谢以m6A依赖的方式增强免疫检查点转录水平从而促进免疫逃逸，展现了代谢调控在肿瘤发生发展中的重要作用（Gut，2023）。 徐瑞华教授团队在本次研究中发现，白介素1β可显著诱导胃癌细胞中NNT K1042位点乙酰化修饰的上调。NNT定位于线粒体内膜，在质子动力势的驱动下催化NADP+生成NADPH，其对线粒体NADPH的贡献占比近50%。机制研究表明，白介素1β通过诱导乙酰基转移酶PCAF进入至线粒体介导NNT K1042乙酰化，该位点的乙酰化可增强NNT与其底物NADP+的亲和力从而增强催化活性，进而促进NADPH的合成并维持铁硫簇稳态，抑制PD-1抗体治疗引发的肿瘤细胞铁死亡。 研究示意图 综上，本研究揭示了白介素1β通过诱导NNT乙酰化抑制肿瘤细胞铁死亡并介导免疫治疗抵抗的新机制，明确了炎症微环境可通过重塑肿瘤代谢降低免疫治疗疗效，拓宽了对炎症微环境在肿瘤代谢重编程及抗肿瘤免疫中作用的认知。更为重要的是，该研究为白介素1β中和抗体联合免疫治疗在临床中的应用提供了理论基础，且IL-1β-NNT乙酰化轴可作为免疫治疗预后的预测标志物。 中山大学肿瘤防治中心徐瑞华教授、鞠怀强研究员为论文的通讯作者。中山大学肿瘤防治中心博士后韩轶、张燕宇和潘艺芊为论文的共同第一作者。研究工作也得到了中山大学肿瘤防治中心黄蓬教授、袁庶强副主任医师、刘泽先研究员、曾昭蕾副研究员、吴其年副主任医师和南方医科大学杨魏教授及郑晓君副研究员等合作者的大力支持。