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SHANGHAI, March 28, 2024 /PRNewswire/ -- GenFleet Therapeutics, a clinical-stage biotechnology company focusing on cutting-edge therapies in oncology and immunology, today announced it has entered into a clinical trial collaboration and supply agreement with BeiGene Switzerland GmbH to start a combination study of GFH009 (CDK9 inhibitor) and BRUKINSA® (zanubrutinib, BTK inhibitor) in a multicenter phase Ib/II trial treating diffuse large B cell lymphoma (DLBCL). The first patient was dosed in the trial led by prominent Henan Cancer Hospital and Fudan University Shanghai Cancer Center. Under the terms of the agreement, GenFleet will conduct an open-label, single-arm and multi-center (10 hospitals in China) study of the combination therapy to evaluate the safety and efficacy among relapsed/refractory DLBCL patients. BeiGene will provide clinical drug supplies of BRUKINSA®(zanubrutinib) for this trial. This study will be the first combination trial conducted by a Chinese biotech to combine CDK9 inhibitor and BTK inhibitor targeting DLBCL. China's National Cancer Center reports that around 100,000 patients are newly diagnosed non-Hodgkin's lymphoma per year in China, with DLBCL patients accounting for 40-50% of new cases. Currently, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) is the standard of care in the first line setting for DLBCL globally, but 30-40% of DLBCL patients ultimately progressing into relapsed/refractory stage need more effective treatments. The trials of GFH009 treating peripheral T-cell lymphoma and acute myeloid leukemia have entered into phase II stage in China and the U.S. respectively. Numerous patients achieved complete or partial response, and significant downregulation of anti-apoptotic proteins such as MYC, MCL1 were observed among patients. Preclinical research demonstrated GFH009's anti-proliferation effects on various tumor cell lines; the expression level of apoptosis markers including cleaved caspase-3 (CC3) and cleaved PARP increased dose-dependently with GFH009 treatment. According to academic publications, the treatment of CDK9 inhibitor in combination with BTK inhibitor resulted in accelerated induction of cleaved CC3 (the key protein in the cancer-cell killing mechanism of cytotoxic T lymphocytes). "We are delighted to reach this agreement to move forward the innovative combinational therapy. We appreciate BeiGene's recognition of GenFleet's R&D capabilities and GFH009's clinical potential. GFH009 has shown a promising activity in monotherapy trial and BRUKINSA®(zanubrutinib) has been approved in scores of markets worldwide; we hope to explore more innovative therapies for relapsed/refractory DLBCL patients with our mutual efforts." stated Jiong Lan, Ph.D, Chief Executive Officer of GenFleet. References： 1.Development and validation of a sensitive UPLC–MS/MS analytical method for GFH009 in rat plasma and its application to toxicokinetics studies, Biomedical Chromatography, 2023 2. Epidemiology of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) in the United States and Western Europe: population-level projections for 2020–2025, Leukemia & Lymphoma, 2021 3. Current status and progress of lymphoma management in China, International Journal of Hematology, 2018 About GFH009 & CDK9 As a family of serine & threonine kinases, the cyclin-dependent kinase (CDK) family plays an important role in cell cycle regulation and transcription; CDK9 activity is inversely correlated with the overall survival rate of patients with multiple tumors. Data from phase I trial and the preclinical research of GFH009 were posted at the 2002 Annual Meeting of the American Society of Hematology. GFH009 monotherapy is well tolerated with preliminary clinical activity in patients with relapsed/ refractory lymphomas. According to preclinical research, GFH009 reduces the expression of downstream oncogenes required for rapid cellular division and protein expression through specific, short-lived inhibition of CDK9. With more than 100 times selectivity over other CDK subtypes, this depletion via GFH009 inhibition of CDK9 likely deprives oncogene-addicted cancer cells of crucial survival signals, leading to senescence and death. GFH009 also exhibits strong anti-proliferative activities in multiple human cell lines, effectively inhibits the growth of tumor in various xenograft models and significantly improves survival of tumor bearing animals. GFH009 has been granted with both fast track and orphan drug designation from the FDA for the treatment of adult patients with relapsed/refractory (r/r) peripheral T-cell lymphomas (PTCL) and r/r acute myeloid leukemia (AML). GenFleet received IND approval in 2020 for the GFH009 monotherapy to proceed into phase I trial treating patients with r/r hematological malignancies. In 2022, GenFleet and SELLAS Life Sciences Group (Nasdaq: SLS) entered into an exclusive license agreement across all therapeutic and diagnostic uses worldwide outside of Greater China (the Chinese mainland, Hong Kong, Macau and Taiwan). About BRUKINSA® (zanubrutinib) BRUKINSA®(zanubrutinib) is a small molecule inhibitor of BTK designed to deliver complete and sustained inhibition of the BTK protein by optimizing bioavailability, half-life, and selectivity. With differentiated pharmacokinetics compared with other approved BTK inhibitors, BRUKINSA has been demonstrated to inhibit the proliferation of malignant B cells within a number of disease-relevant tissues. About GenFleet Therapeutics GenFleet Therapeutics, a clinical-stage biotechnology company focusing on cutting-edge therapies, is dedicated to serving significant global unmet medical needs in oncology and immunology. Based on the deep understanding of disease biology and translational medicine, GenFleet's proprietary and fully integrated R&D platform highlights multiple cutting-edge products with novel mechanisms and global IP. Since its inception in 2017, GenFleet has built up industry-leading capabilities and expertise in developing novel drug candidates - both small molecules and biologics. Its pipeline includes over 10 programs, many of which have entered multi-regional clinical trials across China (including Taiwan), the United States, Europe and Australia. To date, GenFleet has over 5 clinical studies encompassing IND stage to phase II studies and completed co-development partnerships with numerous publicly listed companies worldwide. GenFleet is expected to progress additional programs into the clinic, as well as transition from a clinical stage biotech company into a commercial stage biopharmaceutical company in the next 3-5 years. View original content: SOURCE GenFleet Therapeutics

Strong CSL Behring portfolio growth especially Ig FINANCIAL HIGHLIGHTS 4 Revenue $8.05 billion, up 11% at CC3 NPAT $1.90 billion1, up 17% NPAT $1.94 billion1 at CC3, up 20% NPATA $2.02 billion1,2 , up 11% NPATA $2.06 billion1,2 at CC3, up 13% NPATA1,2 earnings per share $4.182, up 11% NPATA1,2 earnings per share $4.26 at CC3 up 13% Interim dividend 5 of US$1.19 per share Converted to Australian currency, the interim dividend is approximately A$1.81 per share, up 12% Guidance reaffirmed – FY24 NPATA2,4 anticipated to be in the range of approximately $2.9 billion to $3.0 billion2 at CC3 MELBOURNE, Australia, Feb. 13, 2024 /PRNewswire/ -- CSL Limited (ASX:CSL; USOTC:CSLLY) today announces a reported net profit after tax of $1.90 billion1 for the 6 months ended 31 December 2023, up 20% on a constant currency basis3. Underlying profit (NPATA) was $2.02 billion1,2, up 13% on a constant currency basis to $2.06 billion1,2,3. Dr. Paul McKenzie, CSL's Chief Executive Officer and Managing Director said, "Our strong first-half result for the 2024 financial year was driven by CSL Behring's exceptional performance across its portfolio, especially immunoglobulins. The plasma initiatives we have implemented are starting to drive gross margin recovery. "CSL Seqirus achieved solid growth in a challenging season. Its portfolio of differentiated products outperformed the market. "For CSL Vifor we are well prepared for the transitioning iron market." PERFORMANCE CSL Behring Total revenue was $5,238 million, up 14%3 when compared to the prior comparable period. Immunoglobulin (Ig) product sales of $2,757 million, increased 23%3 with strong growth recorded across all geographies driven by global plasma supply and patient demand. PRIVIGEN® / INTRAGRAM® (Immune Globulin Intravenous (Human), 10% Liquid) sales grew 27%3 as the momentum from the prior year continued in improving product availability and patient diagnosis rates. HIZENTRA® (Immune Globulin Subcutaneous (Human), 20% Liquid) sales were up 18%3 driven by patient diagnosis rates. HIZENTRA® continues to be the clear market leader for subcutaneous immunoglobulin. Underlying demand for Ig continues to be strong due to significant patient needs in core indications – namely Primary Immune Deficiency, Secondary Immune Deficiency and Chronic Inflammatory Demyelinating Polyneuropathy (CIDP). Albumin sales of $613 million, were up 8%3. Sales were strong in emerging markets with solid growth in the US and Europe. Growth in China was modest, tempered by competitive pressure. Haemophilia product sales of $662 million increased 8%3. IDELVION®, CSL Behring's novel long-acting recombinant factor IX product achieved growth of 7%3 and continues to be the market leader in key markets. HEMGENIX®, the first and only gene therapy for haemophilia B was successfully launched in the US in FY23 and patient referrals have been accelerating. The haemophilia A market continued to be competitive resulting in a modest decline in sales for AFSTYLA®, a novel recombinant factor VIII product. Plasma-derived haemophilia products, however, achieved growth of 8% driven by HUMATE® / HAEMATE®, therapies for the treatment of patients with von Willebrand disease. Specialty products sales of $976 million, were up 6%3 led predominately by demand for KCENTRA® and HAEGARDA®. KCENTRA® (4 factor prothrombin complex concentrate) recorded sales growth of 12%3, as it continues to further penetrate the warfarin reversal market in the US. HAEGARDA®, our therapy for patients with Hereditary Angioedema, increased 9%, driven by the continued shift from on-demand to prophylaxis treatment and a strong performance in the UK and Europe. Garadacimab (Anti-FXIIa) for HAE, was filed for regulatory approval in the US and EU. Plasma Collections Plasma collections remain strong. The cost of collections, which includes donor compensation and labour, continued to trend down. A new roll out plan for the RIKA plasmapheresis devices was developed. Deployment across the US fleet is expected over the next 18 months. In addition, results from an individualised nomogram trial conducted by our supplier have been submitted for regulatory approval. CSL Seqirus Total revenue of $1,804 million, was up 2%3 driven by the adjuvanted influenza vaccine FLUAD®, which increased by 14%3. This growth was achieved against a backdrop of reduced rates of immunisation and highlights the strength of CSL Seqirus' differentiated product portfolio. During the period: Self-amplifying mRNA vaccine for COVID was approved by Japan's Ministry of Health, Labour and Welfare aQIVc, a next generation influenza vaccine combining adjuvant technology with cell-based manufacturing, enrolled its last patient in the Phase III clinical study in January 2024. CSL Vifor Total revenue was $1,011 million. The prior comparable period included only 5 months revenue following the acquisition of Vifor Pharma in August 2022. During the period: Preparations were made for the transitioning iron market There was strong performance from the long-acting erythropoiesis-stimulating agent, MIRCERA® TAVNEOS® was successfully launched in multiple European countries While the strategic potential of the business remains strong, we have dampened our near-term growth aspirations for CSL Vifor. Expense Performance Research and development (R&D) expenses were $669 million8 , up 11%3 when compared to the prior comparable period. The increase in expenses reflects higher costs associated with the progression of the R&D portfolio and investment in R&D infrastructure. Selling and marketing expenses (S&M) were $707 million8, up 2%3 in comparison to the prior comparable period. An additional month of CSL Vifor and an increase in labour costs accounts for the increase in S&M expenses while other S&M expenses were held in line with the prior comparable period. General and administrative (G&A) expenses were $323 million8, down 7%3 due to favourable foreign exchange differences and efficiencies generated from the centralisation of the group's Enabling Functions. Depreciation and amortisation (D&A) expense (excluding acquired intellectual property) was $297 million, up 1%3. Net finance costs were $234 million9, up 32%3. The increase in net finance costs was due to the debt associated with the acquisition of Vifor Pharma and higher interest rates. Financial position Cashflow from operations was $1,069 million, up 9%. The increase was driven by higher profitability and overall growth in sales. This was partly offset by higher payments for income tax and interest. Cash outflow from investing was $702 million, down significantly when compared to the prior comparable period as payment for the acquisition of Vifor Pharma was made in the prior period. CSL's balance sheet remains in a strong position with net assets of $19,162 million. Current assets increased by 10% to $10,146 million. The main driver was an increase in receivables due to the increase in sales and the seasonality of CSL Seqirus. Non-current assets increased by 1% to $27,158 million in comparison to the previous year. Current liabilities increased by 2% to $4,718 million. The increase in interest-bearing liabilities and borrowings (bank debt) was offset by the decrease in trade and other payables and current tax liabilities. Non-current liabilities decreased by 3% to $13,424 million. The decrease was due to the reclassification of certain bank borrowings as current, coupled with repayment across the Group's debt portfolio including the private placement senior notes. Outlook (at FY23 exchange rates) Commenting on CSL's outlook, Dr. McKenzie said, "For FY24, I am pleased to reaffirm our previous guidance. CSL's underlying profit, NPATA is expected be in the range of approximately $2.9 billion to $3.0 billion at constant currency3, representing growth over FY23 of approximately 13-17%[6]" "CSL is in a strong position to deliver annualised double-digit earnings growth over the medium term. "The strong growth in our immunoglobulins franchise is expected to continue as patient demand remains strong. "We have a number of initiatives underway in plasma collections that are improving efficiencies and processing times, supporting continued expansion in CSL Behring's gross margin. "Our transformational gene therapy product for haemophilia B patients, HEMGENIX®, is attracting significant interest from patients and health care professionals and patient referrals have accelerated. We expect more patients dosed in the second half of this financial year. "CSL Seqirus has performed well in a challenging season. However, due to the seasonality of this business we anticipate it to post a loss in the second half of the fiscal year. "For CSL Vifor, we are operating within an evolving iron market. While there are challenges for near-term growth, we are well positioned for iron competition in the EU and further geographic expansion. Our focus remains on unlocking value by leveraging capabilities across the CSL group", Dr. McKenzie concluded. In compiling the company's financial forecasts for FY24, a number of key variables that may have a significant impact on guidance have been identified and these have been included in the endnote[7]. FURTHER INFORMATION Additional details about CSL's results are included in the company's 4D statement, investor presentation slides and webcast, all of which can be found on CSL's website A glossary of medical terms can also be found on the website. 1 Attributable to CSL shareholders 2 Statutory net profit after tax (NPAT) before impairment and amortisation of acquired intellectual property, business acquisition and integration costs and the unwind of the inventory fair value uplift. 3 Constant currency (CC) removes the impact of exchange rate movements, facilitating the comparability of operational performance. For further detail refer to CSL's Financial Statements for the Half Year ended December 2023 (Directors Report). 4 All figures are expressed in US dollars unless otherwise stated. 5 For shareholders with an Australian registered address, the interim dividend of US$1.19 per share (approximately A$1.81) is expected to be paid on 3 April 2024. For shareholders with a New Zealand registered address the interim dividend of US$1.19 per share (approximately NZ$1.94) is expected to be paid on 3 April 2024. The exchange rates will be fixed at the record date of 12 March 2024. All other shareholders will be paid in US$. CSL also offers shareholders the opportunity to receive dividend payments in US$ by direct credit to a US bank account. 6 % growth rates excludes the one-off gain from the sale of property in FY23 (NPATA $44m). 7 Key variables that could cause actual results to differ materially include: the success and timing of research and development activities; decisions by regulatory authorities regarding approval of our products as well as their decisions regarding label claims; competitive developments affecting our products; the ability to successfully market new and existing products; difficulties or delays in manufacturing; ability to collect plasma; trade buying patterns and fluctuations in interest and currency exchange rates; legislation or regulations that affect product production, distribution, pricing, reimbursement, access or tax; acquisitions and divestitures; research collaborations; litigation or government investigations; and CSL's ability to protect its patents and other intellectual property. 8 Underlying results are adjusted to exclude amortisation of acquired intellectual property ($132 million), business acquisition and integrations costs and the unwind of the inventory fair value uplift. 9 At reported currency For further information, please contact: Investors: Bernard Ronchi Director, Investor Relations CSL Limited P: +61 3 9389 3470 E: [email protected] Stephen McKeon Director, Investor Relations CSL Limited P: +61 402 231 696 E: [email protected] Media: Jimmy Baker Communications CSL Limited P: +61 450 909 211 E: [email protected] SOURCE CSL Limited

导读：激活信号协整剂 3 （ASCC3） 已被确定为损害宿主免疫防御的致癌因子。然而，致癌的潜在机制及其对抗肿瘤免疫反应的影响仍不清楚。近日，复旦大学附属中山医院丁建勇、蒋家好联合在期刊《Journal for Immuno Therapy of Cancer》发表题为“ASCC3 promotes the immunosuppression and progression of non-small cell lung cancer by impairing the type I interferon response via CAND1-mediated ubiquitination inhibition of STAT3”的研究论文，研究表明ASCC3可通过CAND1稳定STAT3通路，重塑肿瘤微环境，诱导抗PD-1治疗耐药，促进NSCLC进展。它是一种可靠的预后指标，可以作为NSCLC联合治疗的靶点。https://jitc-bmj-com.libproxy1.nus.edu.sg/content/11/12/e007766研究背景 01 肺癌是全球癌症相关死亡的主要原因，非小细胞肺癌（NSCLC）占大多数病例。许多无症状患者在晚期被诊断为非小细胞肺癌，限制了手术联合放化疗等常规治疗的有效性。在NSCLC中发现了体细胞突变、拷贝数变异和染色体重排，包括EGFR/KRAS突变和ALK或ROS1重排，并开发了靶向这些基因改变的小分子抑制剂。这些药物可抑制肿瘤细胞增殖并调节免疫反应，从而改善 NSCLC 患者的预后。免疫疗法，尤其是免疫检查点抑制剂，在治疗晚期非小细胞肺癌方面显示出良好的疗效。尽管取得了这些进展，但挑战依然存在，包括对各种治疗方案的耐药性发展，这阻碍了NSCLC的综合管理。远处转移是导致晚期NSCLC患者治愈率和生存率低的主要因素。因此，进一步了解NSCLC发展背后的机制并确定提高治疗效果的有效策略至关重要。先前的研究表明，激活信号协整合器3（ASCC3）是一种具有解旋酶活性的蛋白质，与DNA损伤修复和免疫调节有关，它可能参与多种实体瘤的发展。然而，尚未研究 ASCC3 在肺癌中的作用。单细胞RNA测序分析揭示了非小细胞肺癌组织、原发肿瘤和转移中的差异表达基因，其中一些与NSCLC转移有关，通过直接影响肿瘤细胞的恶性特征或参与肿瘤进展相关的信号通路。我们发现ASCC3在NSCLC中也上调，重要的是，在远处转移中观察到更高的表达水平。作为解旋酶家族的一员，ASCC3 被认为参与 DNA 损伤修复和癌症进展。此外，ASCC3 已被证明可以调节免疫相关基因的表达，影响免疫细胞浸润和甲状腺癌复发。通过基因本体论 （GO） 和京都基因和基因组百科全书 （KEGG） 对我们的 RNA 测序数据的分析，我们发现 ASCC3 参与信号转导和转录激活因子 （STAT） 信号传导以及 I 型干扰素 （IFN） 相关通路。进一步的机制研究表明，ASCC3调控STAT3信号通路。STAT3 是恶性肿瘤行为和抗肿瘤免疫反应的关键调节因子，是许多致癌信号通路的聚集点。探索影响 STAT3 表达和激活的因素将增强我们对支撑肿瘤进展的复杂机制的理解，并促进新的治疗策略。研究进展 02 我们测试了ASCC3在一些NSCLC细胞系中的表达，并证实在某些细胞系中表达高于正常细胞系人支气管上皮细胞（HBE）（图2A）。用 ASCC3-shRNA 慢病毒转染 ASCC3 表达水平最高的 H1299 和 H460 细胞。在验证转染效率（图2B，C）后，使用为后续实验选择的shRNA（称为shASCC3与shNC）生成了两个稳定转染的细胞系。菌落形成和CCK8检测表明，ASCC3敲除抑制NSCLC细胞的增殖（图2D-G）。伤口愈合和Transwell试验对ASCC3敲低细胞的迁移显示出显著的抑制作用（图2H-M）。同样，Matrigel Transwell测定显示，ASCC3敲低损害了H1299和H460细胞的侵袭（图2N，O）。此外，皮下植入H1299-shNC/shASCC3细胞的裸鼠的体内测定（图2P）显示，与shNC肿瘤相比，shASCC3皮下肿瘤中ASCC3的表达显著下调（图 2Q），并且ASCC3敲低抑制了NSCLC的生长（图 2R）。总体而言，这些结果表明，ASCC3促进了NSCLC的进展，并且ASCC3敲低可以抑制这一过程。ASCC3的高表达促进了NSCLC在体外和体内的进展研究结论 03 图8总结了本研究的主要发现。NSCLC 中的 ASCC3 过表达有助于免疫抑制 TME，并赋予免疫治疗耐药性。从机制上讲，ASCC3 通过抑制 Ub 介导的 STAT3 降解来招募 CAND1 以稳定 STAT3 信号传导，从而损害肿瘤细胞中的 I 型 IFN 反应并促进对抗肿瘤免疫细胞的耐药性。此外，敲低ASCC3联合抗PD-1治疗可显著提高ASCC3高表达NSCLC患者免疫治疗的敏感性和疗效。本研究主要发现的示意图综上所述，本研究揭示了ASCC3在重塑TME和促进NSCLC进展中的关键作用，我们提供了一种可以靶向改善抗PD-1治疗疗效和NSCLC患者预后的新分子。参考资料：https://jitc-bmj-com.libproxy1.nus.edu.sg/content/11/12/e007766识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。