HAP1

Nodenza Venture Partners invests in Trellis Bioscience Lead product TRL1068 targets biofilm, estimated to cause 60-70% of antibiotic resistant infections New York, October 22, 2024 – Nodenza Venture Partners (“Nodenza”), today announces its investment in Trellis Bioscience (“Trellis”), a clinical-stage company focused on discovering and developing native human monoclonal antibodies to treat and prevent drug-resistant, life-threatening infectious diseases. Trellis has developed a patented, proprietary technology (CellSpot) to clone genes of rare fully-human therapeutic monoclonal antibodies (mAbs) from memory B-cells of the blood of individual human donors. CellSpot has identified a high-affinity, broad-spectrum native human antibody, TRL1068, which targets and disrupts bacterial biofilm, a physiological factor promoting drug resistance in most clinically relevant multi-drug-resistant bacteria species, both gram positive and gram negative. TRL1068 is being developed for the treatment of chronic prosthetic joint infection (“PJI”), a chronic infection which requires, as standard of the care, the surgical removal of the prostheses with an estimated cost to the US health system of more than $10bn a year. In addition to PJI, it is estimated that biofilm is the cause of 60-70% of antibiotic resistant infections. TRL1068 has been granted Fast Track and QIDP designations and orphan drug designation for PJI and infective endocarditis by the U.S. Food and Drug Administration (FDA). Chronic PJI always forms biofilms on the prosthesis, thereby shielding the bacteria from eradication by antibiotics, being the reason for PJI to be a difficult-to-treat disease. As biofilm cannot be removed by antibiotics or any other non-invasive treatment, the current standard treatment of chronic PJI is a complex two-stage surgical procedure consisting of removal and replacement of the infected prosthesis. This costly and invasive two-stage process substantially and adversely affects quality of life, with increased immobility and morbidity in addition to decreased 5-year survival rates in patients with PJI when compared with non-infected patients that receive a prosthetic joint replacement. In a clinical proof-of-concept trial, published in a peer-reviewed article in the prestigious AAC Journal, TRL1068 has demonstrated the ability to disrupt the bacterial biofilm barrier to antibiotic access, allowing antibiotics to be efficacious without surgical intervention: In 25% of TRL1068-treated patients, biofilm was removed below the limit of detection after only 7 days of treatment, a finding that has never been observed in this patient population.64% of chronic PJI patients treated with an infusion of a single dose of TRL1068 and standard antibiotics had a bacterial biofilm burden below 100 CFU/mL sonication fluid after only 7 days of treatment. Although the sample size is small (n=11), a favourable comparison to historical data where only 15% of PJI patients are below that mark, suggesting that a treatment period 8 times longer, as planned in a Phase 2 study, will be highly efficacious.TRL1068 was well-tolerated across all three dose groups with no drug-related adverse events.The results of this initial exploratory study have provided strong evidence of efficacy across a diverse set of bacterial species, safety, and pharmacokinetic data to guide the design of a pivotal clinical study of TRL1068 for PJI with the goal to treat the infection without the need for a complex replacement surgery. Ross Morton, Managing Partner of Nodenza Venture Partners, said: “Antibiotic resistance is a significant and growing global threat, with insufficient investment to identify urgently needed new approaches. Trellis stands out with its truly novel and innovative approach to address antibiotic resistance. Through the application of its unique CellSpot technology, Trellis has the potential to be at the forefront of innovation in this critical field. CellSpot and TRL1068 align perfectly with Nodenza Venture Partners’ strategy of identifying and investing in disruptive technologies and therapies with the potential to deliver exceptional benefits to patients. We believe that Trellis has the potential to generate a multi-fold return on for Nodenza.” Stefan Ryser, Ph.D, President & CEO of Trellis Bioscience, commented: “Nodenza’s deep expertise of the pharmaceutical and biotech industry, and their recognition of the novelty of biofilm disruption, makes it an ideal investment partner for Trellis Bioscience as we prepare to advance TRL1068 rapidly through the clinic. The positive data generated to date give us confidence in the potential for a successful clinical study that may result in early FDA marketing authorisation given the five times higher mortality of the PJI standard of care surgery versus an aseptic prostheses replacement as well as the lack of new mechanisms to tackle the specific challenges of prosthetic joint infection. Nodenza has also recognized the enormous potential of TRL1068 beyond PJI as it addresses the broader global threat of antibiotic resistance.” Contacts: Nodenza Venture Partners Ross Morton, Managing Partnerinfo@nodenza.com Mo Advisory PRmo@mopradvisory.comMo Noonan / Jonathan Birt Notes to Editors About Nodenza Venture PartnersNodenza Venture Partners provides financial and operational support to early-stage and pre-commercial biotech and medtech companies and products designed to bring exceptional patient benefit. Our bi-modal investment strategy combines early-stage opportunities – advancing new treatment modalities through active IND to phase 2 - with pre-commercial targets supporting their transition from scientific to commercial companies delivering strong upside potential. Established by a team of experienced life sciences entrepreneurs, founders and leaders, our approach leverages Nodenza’s extensive expertise in the creation and growth of new companies, as well as late-stage product development and launch. For more information visit us at https://www.nodenza.com Trellis BioscienceTrellis Bioscience is a clinical-stage company focused on discovering and developing native human monoclonal antibodies to treat and prevent drug-resistant, life-threatening infectious diseases. Antibodies are the immune system's most potent natural weapon against disease. Trellis's innovative proprietary technology CellSpot™ overcomes technical obstacles that have long hindered exploiting the full human antibody repertoire. This ideal source of drugs focuses on the selection of elite antibodies that bind highly conserved target epitopes with high affinity. To learn more, visit trellisbio.com. Attachment Nodenza Trellis Investment Final

Findings To Be Presented During the European Society of Gene & Cell Therapy 30th Annual Meeting BRUSSELS--(BUSINESS WIRE)-- Be Biopharma Inc. (“Be Bio”), a company pioneering the discovery and development of Engineered B Cell Medicines (BCMs), will present research from preclinical studies during the European Society of Gene & Cell Therapy (ESGCT) 30th Annual Meeting. In an oral presentation on Friday, October 27, from 11:00 to 13:00 CEST, Be Bio demonstrates that BCMs are capable of producing a variety of therapeutic protein classes using precision gene editing. The data include durable in vivo production of the human clotting factor IX, prevention of tumor growth in a patient-derived xenograft model via a CD19xCD3 bispecific antibody, and engraftment without preconditioning in immunocompetent non-human primates (NHPs). Also being presented are findings from a preclinical study showing BCMs are capable of producing highly active acid sphingomyelinase, the gene defective in Niemann-Pick disease, and correct the disease phenotype in knockout cells. “The data we are presenting give further evidence that our precision B cell engineering platform enables the expression of diverse therapeutic proteins and represents a promising approach for a new class of medicines with potentially broad therapeutic utility,” said Rick Morgan, Ph.D., chief scientific officer, Be Biopharma. “These data highlight the therapeutic modularity and unique advantages of our BCM platform.” Today’s gene and cell therapies are potentially transformative medicines which can treat previously intractable diseases. However, there are barriers to the broad adoption of these therapies as current platforms struggle with drawbacks including inability to titrate dose and reliance on toxic preconditioning, among other challenges. Terminally differentiated human plasma cells (PCs) derived from genetically engineered B cells -- termed B Cell Medicines, or BCMs -- potentially offer natural longevity1, capacity for high levels of protein secretion (thousands of Ig molecules/cell/sec)2, ability to engraft without preconditioning, and the ability to redose. Study Summary: “Development of an ex vivo precision gene engineered B cell medicine platform and demonstration of engraftment without preconditioning in non-human primates” BCMs are produced via a CRISPR/Cas9 engineering platform that achieves gene knockouts with greater than 90% efficiency as well as targeted HDR-mediated gene insertions at frequencies as high as 60%. A BCM prototype engineered to express firefly luciferase with a phenotype of >90% CD27+CD38+ was injected via IV into immunodeficient mice, demonstrating rapid bone-marrow-homing and durable engraftment (>100 days). Further illustrating the modularity of the BCM platform, B cells were engineered to produce either lysosomal storage disease (LSD) enzyme acid sphingomyelinase (ASM), clotting factor IX (FIX), or an anti-CD19/CD3 bispecific T cell engager. These examples demonstrated that BCMs can produce proteins with specific activity much higher than standard recombinant proteins (ASM), are stably expressed for over 4 months in vivo (FIX) and show efficacy in tumor treatment (anti-CD19/CD3 scFv). In order to assess engraftment in an immunocompetent model, an ex vivo method was developed to engineer, expand and differentiate non-human primate (NHP) peripheral blood B lymphocytes into PCs. Using zirconium-89-oxine cell radiolabeling and high sensitivity PET/CT tracking, ex vivo expanded and differentiated autologous PCs demonstrated rapid homing and engraftment in PC niches in unconditioned NHPs. Details for the oral presentation of this study are as follows: Title: “Development of an ex vivo precision gene engineered B cell medicine platform and demonstration of engraftment without preconditioning in non-human primates” Lead Author: Hanlan Liu, Ph.D., MBA, Senior VP, Pipeline and Non-clinical Development, Be Biopharma Presenter: Rick Morgan, Ph.D., Chief Scientific Officer, Be Biopharma Oral Presentation #: OR-77 Date/Time: Friday, October 27, 11:00-13:00 CEST Session: 11a: Gene editing: Towards clinical trials The study was funded and conducted through a collaborative research and development agreement with the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health. Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Study Summary: “Development of an ex vivo precision gene engineered B cell medicine that produces highly active and sustained levels of acid sphingomyelinase for the treatment of Niemann-Pick disease” Niemann-Pick disease (NPD) is an autosomal recessive lysosomal storage disease caused by acid sphingomyelinase (ASM) deficiency. Sphingomyelin accumulates in multiple organs leading to organ failure, and in the severest form causes death early in life. Currently, the only treatment which is approved in NPB, a subset of NPD, is an enzyme replacement therapy (ERT) requiring an intensive dose escalation phase followed by Q2W maintenance intravenous infusions. This study evaluated the potential of engineering B cells to produce therapeutic levels of ASM, thus offering a potential new treatment for NPD. In this study, primary human B cells were expanded, engineered by CRISPR/Cas9 genome editing with an AAV-delivered template for homology-directed repair (HDR) to insert a constitutive promoter followed by the ASM gene, SMPD1, into a safe harbor locus, which showed up to 30% HDR. BCMs were subsequently expanded and differentiated in vitro. Engineered BCMs secreted ASM up to ~150 ng/1e6 cells/24hr as measured by ELISA. HAP1 SMPD1 knockout cells exposed to supernatant from SMPD1-engineered BCMs restored ASM activity. Liquid chromatography–mass spectrometry analysis demonstrated that HAP1 SMPD1 knockout cells treated with supernatant from SMPD1-engineered BCMs mitigated the accumulation of lyso-sphingomyelin and that BCM-produced ASM was approximately 10-fold more active than recombinant ASM made from CHO cells. Details for the poster presentation of this study are as follows: Title: “Development of an ex vivo precision gene engineered B cell medicine that produces highly active and sustained levels of acid sphingomyelinase for the treatment of Niemann-Pick disease” Lead Author: Monika Musial-Siwek, Ph.D., Director Protein Science, Be Biopharma Co-Presenters: Timothy Mullen, Ph.D., Senior Scientist, Be Biopharma Anja Hohmann, Ph.D., Senior Director, Cell Engineering, Be Biopharma Poster #: P579 Poster Session: October 25, 17:00 to 18:15, and October 26 from 20:30 to 21:30 CEST About B Cells – A New Class of Cellular Medicines Imagine what could “Be?” In nature, a single B cell engrafts in the bone marrow and can produce thousands of proteins per second at constant levels over decades. B cells are nature’s exquisite medicine factories, manufacturing proteins to fight disease and maintain health. Unleashing the power of B cells is driving a new class of cellular medicines – Engineered B Cell Medicines (BCMs). BCMs have the potential to be durable, allogeneic, redosable and administered without toxic conditioning. The promise of BCMs could transform therapeutic biologics with broad application — across protein classes, patient populations and therapeutic areas. About Be Biopharma Be Biopharma (“Be Bio”) is pioneering Engineered B Cell Medicines (BCMs) to dramatically improve the lives of patients who are living with cancer, rare diseases and other serious conditions. With eyes locked on the patient, our team of purpose-driven scientists, technologists, manufacturing experts and business builders collaborate to create a bold new class of cell therapies. Be Bio was founded in October 2020 by Longwood Fund and B cell engineering pioneers David Rawlings, M.D., and Richard James, Ph.D., from Seattle Children’s Research Institute. Be Bio is backed by ARCH Venture Partners, Atlas Venture, RA Capital Management, Alta Partners, Longwood Fund, Bristol Myers Squibb, Takeda Ventures, Seattle Children’s Research Institute and others. Since our founding, Be Bio’s investors have committed over $180 million to enable the Company to re-imagine medicine based on the power of B cell therapy. For more information, please visit us at Be.Bio and our LinkedIn page. 1 Landsverk et al (2017) J Exp Med 2 Hibi and Dosch (1986) J Immunol; Eyer et al (2017) Nat Biotech

皱皮木瓜（Chaenomeles speciosa），又名贴梗海棠，为蔷薇科木瓜海棠属落叶灌木。皱皮木瓜花朵艳红，贴生枝干之上，鲜艳夺目。陆游“千点猩红蜀海棠，谁怜雨里作啼妆” 皱皮木瓜（Chaenomeles speciosa），又名贴梗海棠，为蔷薇科木瓜海棠属落叶灌木。皱皮木瓜花朵艳红，贴生枝干之上，鲜艳夺目。陆游“千点猩红蜀海棠，谁怜雨里作啼妆”中所指便是贴梗海棠。除观赏价值外，皱皮木瓜还兼具食用价值与药用价值，其干果富含齐墩果酸和熊果酸，具有抗菌抗炎、抗病毒、抗氧化等作用。构建皱皮木瓜高质量基因组，解析皱皮木瓜药用成分生物合成途径，可为调控其重要药用成分的生物合成、提高药用木瓜品种提供新见解、新途径。 近日，华中农大药用植物学梅之南教授团队联合南京农业大学、中南民族大学、国药集团中联药业有限公司、武汉碳码生物科技有限公司以及北卡罗莱纳州立大学等单位科研人员在园艺一区（1/36）Horticulture Research上联合发表题为“A Telomere-to-telomere Reference Genome Provides Genetic Insight into the Pentacyclic Triterpenoid Biosynthesis in Chaenomeles speciosa”的研究论文。该研究通过HiFi和Hi-C测序，构建了首个皱皮木瓜T2T参考基因组，并结合比较基因组解析皱皮木瓜的三萜生物合成机制，为了解蔷薇科植物驯化和植物进化提供了宝贵的资源。 皱皮木瓜为二倍体植物，原产于中国，广泛栽培于世界各地。基于基因组survey，研究团队评估了皱皮木瓜基因组大小约为650.4 Mb。随后进行PacBio HiFi和Hi-C测序，利用Hifiasm组装出两套单体型，Hap1和Hap2。Hap1的基因组大小为592.84 Mb，包含230个contigs (N50为25.57 Mb)，125个scaffold (N50为36.12 Mb)，GC含量为37.41%。Hap2基因组大小为608.28 Mb，包含97个contigs (N50为29.34 Mb)， 42个scaffold (N50为36.92 Mb)， GC含量为37.25%。Hap1和Hap2，在基因组大小和基因数量方面具有相似性，同时具有良好的共线性。此外，两个单倍型基因组之间的单核苷酸多态性(SNP)、插入-缺失(InDels)和结构变异(SV)存在明显差异，为了解皱皮木瓜遗传多样性提供了大量信息来源。基于Hap1和Hap2，研究团队组装了T2T水平的皱皮木瓜基因组。其基因组全长650.4Mb，contig N50为35.5Mb。其中，632.3 Mb被锚定在17条染色体上，有12条染色体仅有1条contig组成，在11条染色体两端鉴定到端粒，17条染色体上均鉴定到着丝粒。BUSCO评估结果、LAI评分、二三代数据比对结果均证实了组装基因组良好的完整性和准确性。 图1 皱皮木瓜的基因组调查与组装 研究团队使用从头注释和同源注释的方法来鉴定重复序列，49.5%的皱皮木瓜基因组序列被预测为重复序列，约312.9 Mb。序列分析表明，重复序列主要由TE组成。其中，LTR最为丰富，占整个基因组的36.3%，包括Gypsy元件(22.7%)、Copia元件(7.3%)和其它序列。 基于从头注释、同源注释和转录组注释，共在皱皮木瓜中基因组中预测到45515个高置信度的蛋白编码基因，其中93%的基因都能得到功能注释。共鉴定到685个tRNA、4205个rRNA、274个snRNA和739个snoRNA。 表1 皱皮木瓜基因组组装数据统计 研究团队选择11个物种与皱皮木瓜进行比较基因组学分析。基因家族聚类分析表明11个物种中普遍存在6958个基因家族，皱皮木瓜存在5658个特有基因家族。GO富集分析表明这些特有基因主要参与辅因子代谢、辅酶代谢和蛋氨酸代谢过程。KEGG富集分析表明，物种特有基因主要参与碳代谢、丙酮酸代谢、半乳糖代谢和萜类物质生物合成。系统进化发育分析表明，皱皮木瓜和苹果、杜梨、西洋梨被聚类在一起，它们可能由同一祖先进化而来。皱皮木瓜和苹果的分化时间约为10.0个百万年前，苹果族与桃亚属的祖先在约10.92个百万年前分化，蔷薇科物种在约98.81个百万年前分化。基因家族收缩扩张分析表明，皱皮木瓜有320个基因家族发生扩张，与苹果扩张基因家族数量相似；有158个基因家族发生收缩，约为苹果收缩基因家族的50%。皱皮木瓜收缩的基因家族主要富集于脂质转运、信号转导过程等，扩张的基因家族与单萜类、二苯乙烯庚烷类、姜辣素、亚油酸、类黄酮、倍半萜类和三萜类的生物合成有关。 六种蔷薇科物种的系统发育分析表明，西洋梨、苹果、皱皮木瓜同属一个分支，约46个百万年前从同一祖先分化而来。这三个物种共同经历了一次四倍化事件，导致它们的染色体数量加倍，达到16条。WGD分析显示，Ks分布在0.2~0.3处出现了显著峰值，这一事件可能与西洋梨、苹果、皱皮木瓜中近期发生的四倍化事件有关。 图2 皱皮木瓜基因组同源聚类和系统发育分析 图3 皱皮木瓜的WGD特征、共线性和染色体进化 齐墩果酸和熊果酸是羟基五环三萜烯酸，《中国药典》中以齐墩果酸和熊果酸含量作为木瓜中药材质量控制的重要指标。植物五环三萜类化合物主要由甲羟戊酸途径和戊糖磷酸途径合成。本研究将皱皮木瓜与其它七个物种中涉及甲羟戊酸途径的四个基因家族进行比较，发现皱皮木瓜基因组中存在11个β-香树素合酶基因，其中10个基因分布在9号染色体上的两个基因簇中。基因簇1的长度从12,157,281 bp到12,428,418 bp，包含8个β-香树素合酶基因，9个其它基因和64个LTR反转录转座子。基因簇2的长度从31,206,028 bp到31,327,645 bp，包括2个β-香树素合酶基因，5个其它基因和29个LTR反转录转座子。 基因家族的鉴定进一步揭示了2个角鲨烯合酶的成员、12个角鲨烯2,3-氧化环化酶的成员、11个β-香树素合酶的成员和9个β-香树脂醇28-单加氧酶的成员。与其它蔷薇科物种相比，角鲨烯合酶、β -amyrin合酶和β-香树脂醇28-单加氧酶基因家族在皱皮木瓜基因组中显著扩张，这可能是该物种具有高含量的齐墩果酸和熊果酸的原因。 图4 皱皮木瓜中齐墩果酸、熊果酸的生物合成途径和β-香树素合酶基因簇 本研究通过HiFi和Hi-C测序构建了首个木瓜属植物皱皮木瓜的T2T基因组，通过比较基因组分析确定了皱皮木瓜扩张和收缩的基因家族与植物代谢或生物过程的关联，鉴定了与齐墩果酸和熊果酸生物合成途径相关的基因家族，为了解植物五环三萜类物质的生物合成提供了宝贵的资源，为了解蔷薇科植物驯化提供了新的见解。