IL-11RA

本文为转化医学网原创，转载请注明出处 作者：Rainbow 导读： 在癌症生物学领域，人们越来越认识到由细胞因子和生长因子介导的自分泌和旁分泌信号在塑造肿瘤行为中起着重要作用，影响细胞增殖、转移倾向以及对化疗药物的敏感性。 3月1日，中山大学黄海、赖义明、李锴文共同通讯在期刊《Journal of Experimental & Clinical Cancer Research》上在线发表题为“Single-cell deconvolution algorithms analysis unveils autocrine IL11-mediated resistance to docetaxel in prostate cancer via activation of the JAK1/STAT4 pathway”的研究论文， 研究结果确定了IL-11/IL-11RA的自分泌环，该环通过JAK1/STAT4通路赋予多西他赛耐药性。pSTAT4-CBP相互作用是前列腺癌细胞中c-MYC转录活性的关键增强子。靶向这一信号轴为克服晚期前列腺癌中的多西他赛耐药性提供了一种潜在的治疗策略。 https://jeccr.biomedcentral.com/articles/10.1186/s13046-024-02962-8 研究背景 01 前列腺癌是肿瘤学中最紧迫的健康问题之一，在全球男性中占据了相当大比例的癌症相关发病率和死亡率。以多西他赛为基础的化疗的出现标志着治疗格局的重大转变，在转移性去势抵抗性前列腺癌中提供了生存优势。然而，多西他赛耐药的出现不可避免地成为一个主要的临床障碍，导致治疗失败和癌症进展。 因此，克服多西他赛耐药对于改善患者预后至关重要，然而驱动这一现象的分子机制仍未完全理解。 在众多信号分子中，IL-11是IL-6家族中的一种细胞因子，因其在肿瘤发生中的恶性作用而受到关注，促进不同癌症类型的肿瘤细胞增殖、侵袭性和药物耐药性。IL-11/IL-11RA相互作用作为这一信号级联的关键，通常最终导致Janus激酶/信号转导子与转录激活子（JAK/STAT）途径的激活，这是一个以细胞存活和增殖为核心作用的轴路。 研究发现 02 研究发现IL-11的自分泌在多西他赛耐药的前列腺癌细胞中显著增加。IL-11 刺激导致 JAK1/STAT4 信号转导的强烈激活。激活后，pSTAT4易位到细胞核，并在c-MYC启动子区域与CBP结合，从而扩增其转录活性。抑制 IL-11/IL-11RA 相互作用或破坏 JAK1/STAT4 通路显著降低了 pSTAT4 核进入及其与CBP的结合，导致c-MYC 表达下调和多西他赛敏感性的恢复。 这项研究描绘了这种耐药机制的分子编排，并揭示了治疗干预的潜在靶点，旨在恢复对这种一线化疗药物耐药的前列腺癌细胞的多西他赛敏感性。 研究结论 03 综上所述， 研究结果确定了IL-11/IL-11RA的自分泌环，该环通过JAK1/STAT4通路赋予多西他赛耐药性。pSTAT4-CBP相互作用是前列腺癌细胞中c-MYC转录活性的关键增强子。靶向这一信号轴为克服晚期前列腺癌中的多西他赛耐药性提供了一种潜在的治疗策略。 参考资料： https://jeccr.biomedcentral.com/articles/10.1186/s13046-024-02962-8 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。 热门·直播/活动 🕓 上海｜3月01日-02日 ▶第三届长三角单细胞组学技术应用论坛暨空间组学前沿论坛将在上海召开，诚邀您的参与！ 点击对应文字 查看详情

Innovent plans to release detailed results from the study at future medical conferences or in journals. Innovent Biologics is hoping that a phase 3 win for its thyroid eye disease (TED) treatment will provide a first shot at the Chinese equivalent of a market that has already been conquered by Amgen’s Tepezza in the U.S. Like Tepezza, Innovent’s candidate IBI311 targets the insulin-like growth factor 1 receptor (IGF-1R). The candidate hit the primary endpoint of the phase 3 Restore-1 trial by showing a greater reduction in eyeball protrusion—known as proptosis—than placebo. The percentage of subjects with a reduction in proptosis of 2 mm or more in one eye without the equivalent increase in proptosis in the other eye was 85.8% among the IBI311 group, compared with just 3.8% among those who received placebo. The candidate also showed “significant” improvement on key secondary endpoints for the trial, including overall response rate, percentage of subjects with a clinical activity score of 0 or 1, and mean change in proptosis from baseline, Innovent said in a Feb. 20 release. No serious adverse events occurred, added the biotech, which plans to release detailed results from the study at future medical conferences or in journals. Lei Qian, vice president of clinical development at Innovent, said the company plans to submit a new drug application to Chinese regulators “as soon as possible” based on the results. TED occurs in 16 out of every 100,000 women and 2.9 in every 100,000 men, according to Innovent. The condition is clearly a tempting target, with Horizon Pharma’s Tepezza quickly securing blockbuster sales. Horizon noticed a drop off in uptake in the drug’s third year on the market, with Amgen making this a top priority when it acquired the biotech in October 2023. Still, as the only approved treatment for TED in the U.S., Tepezza garnered sales of $1.66 billion in its first full year on the market and $1.97 billion in 2022 before stalling out. Amgen also sees an international opportunity for Tepezza. The drug is under review in Japan and the company will file this year for approval in Europe. A subcutaneous version of the treatment is also in development. "There are no targeted drugs approved in the field of TED in China so far, while the treatment costs of overseas targeted drugs are beyond many patients' reach,” Qian explained in Innovent’s release this morning. The clinical success of IBI311’s comes a month after mazdutide, a GLP-1/glucagon receptor agonist that Innovent licensed from Eli Lilly, demonstrated weight loss abilities in a phase 3 trial. Qian aligned these recent wins with the Chinese approval of its hypercholesterolemia injection Sintbilo in August 2023 as proof of the strength of Innovent’s late-stage strategy. “With the approval of Sintbilo, the NDA acceptance of mazdutide and the endpoints met in phase 3 study of IBI311, Innovent is strategically establishing its innovative commercial and late-stage portfolio in the fields of cardiovascular and metabolic diseases, endocrinology and ophthalmology,” Qian added. Innovent isn’t the only biotech looking to stake out a piece of TED territory. Last month, Kriya Therapeutics announced plans to get a gene therapy into the clinic for the condition next year, while Lassen Therapeutics has already dosed the first patient in a phase 1 trial of an interleukin-11 receptor targeted at TED.

Proceeds will fund Phase 2 study in thyroid eye disease (TED) with LASN01 and continue development of LASN500 in Investigational New Drug (IND) enabling studies The Phase 1 study for LASN01 in healthy volunteers has been completed and patient cohorts in idiopathic pulmonary fibrosis (IPF) and TED are enrolling The IND for LASN01 Phase 2 program in the US has received Food and Drug Administration (FDA) clearance and one site is currently active SAN DIEGO--(BUSINESS WIRE)-- Lassen Therapeutics, a clinical stage biotech company developing first-in-class antibody therapeutics, LASN01, targeting interleukin-11 receptor (IL-11R) as a potential treatment for fibro-inflammatory diseases such as TED and IPF, and a highly potent, first-in-class monoclonal antibody, LASN500, targeting the interleukin-18 binding protein (IL-18BP) as a potential treatment for cancer, today announced the closing of an oversubscribed Series B financing which raised $85 million. Frazier Life Sciences co-led the financing along with new investor Longitude Capital. The syndicate also included new investors BVF Partners and Catalio Capital Management as well as existing investors, Alta Partners and Longwood Capital. Concurrent with this financing, Brian Liu, M.D. from Longitude Capital and Matthew Hobson, Ph.D. from Catalio Capital Management have joined the Board of Directors. Proceeds from this financing will support the LASN01 clinical program and advance IND-enabling activities for LASN500. The clinical program for LASN01 is focused primarily in TED with a cohort in IPF in the Phase 1 program. Lassen recently presented data using orbital fibroblast cells from TED patients demonstrating that LASN01 suppresses multiple markers associated with TED disease progression including hyaluronan production, cell proliferation, and other markers such as procollagen. Recent accomplishments and future activities with use of proceeds in the LASN01 program include: Expansion of the Phase 1 study in IPF and TED: The Phase 1 study in healthy volunteers has been completed and demonstrated a favorable safety profile, pharmacokinetics, and target engagement, leading to expansion of the program to patient cohorts in IPF and TED; both cohorts are currently enrolling patients with the first patient dosed in TED. Initiation and expansion of the Phase 2 program in TED in the US and ex-US: Lassen has received US IND clearance from the FDA as well as Clinical Trial Authorisation (CTA) from the Medicine and Healthcare Products Regulatory Agency (MHRA). One site is active with additional sites being activated in the US and ex-US. Development of subcutaneous formulation: Process development work to create a subcutaneous presentation of LASN01 has been initiated. “I am very pleased with the recent advancements at Lassen, particularly in successfully concluding the Series B financing round which will facilitate the continued development of our two pipeline products,” said Maria Fardis, Ph.D., Chief Executive Officer of Lassen. “The proceeds allow us to advance LASN01 Phase 1 and 2 clinical programs and develop a subcutaneous formulation for LASN01. This antibody has significant potential as a treatment for fibro-inflammatory disorders including TED. Our data in orbital fibroblasts have been highly encouraging and paired with our Phase 1 single and multiple ascending dose safety data, support advancement of LASN01 in Phase 2 for TED.” “We are very excited about Lassen and the opportunity to develop two first-in-class programs, one in fibro-inflammatory disorders and the other in cancer, along with the management team’s ability to expeditiously execute these programs in pursuit of new therapeutic options for patients,” said Brian Liu, M.D. Managing Director at Longitude Capital. “We are encouraged by the progress of LASN01, the lead program at Lassen which is entering Phase 2 and is a first-in-class antibody that binds to a novel target, an important differentiator in a broad set of fibro-inflammatory indications addressing serious unmet medical needs.” About LASN01 LASN01 is a first-in-class monoclonal antibody targeting the receptor for IL-11 (IL-11R). IL-11 is a central mediator of fibro-inflammatory disorders and blocking its activity has the potential to offer a novel modality for treatment of thyroid eye disease (TED) and other fibro-inflammatory diseases. In preclinical studies, LASN01 led to the suppression of cell proliferation, hyaluronan secretion, and procollagen from primary TED orbital fibroblasts. These results indicate that LASN01 has the potential to be a new therapeutic agent for the treatment of TED. Please refer to (NCT 05331300) for additional details related to this clinical trial. About LASN500 LASN500 is a highly potent, first-in-class monoclonal antibody targeting the IL-18 binding protein (IL-18BP). IL-18BP is elevated at the tumor site in multiple cancer indications and blockade of this protein allows for elevation of IL-18 at the tumor site, which is expected to provide a better safety profile. About Lassen Therapeutics Lassen Therapeutics is a clinical-stage biotech company developing first-in-class antibodies as potential treatments for fibro-inflammatory disorders, such as thyroid eye disease (TED), and cancer. The company’s lead candidate, LASN01, is a first-in-class monoclonal antibody targeting IL-11 receptor (IL-11R) and is currently being evaluated for the treatment of TED and idiopathic pulmonary fibrosis (IPF). Lassen is also developing LASN500, a highly potent, first-in-class monoclonal antibody targeting the IL-18 binding protein (IL-18BP) for cancer. For more information, please visit and follow us on LinkedIn. About Frazier Life Sciences Frazier Life Sciences invests globally in private and publicly-traded companies that discover, develop and commercialize innovative biopharmaceuticals. Frazier Life Sciences' funds comprise over $3.3 billion in capital raised, including venture funds focusing on company creation and private companies, and public funds focused on small and mid-cap public companies. Since 2005, over 60 Frazier Life Sciences portfolio companies, many of which were created or seeded by Frazier, have completed IPOs or M&As. The Frazier Life Sciences team consists of over 40 professionals with deep experience in biopharmaceuticals, primarily located in Palo Alto, CA (headquarters), San Diego, Seattle, Boston, New York, and London. About Longitude Capital Longitude Capital is a leading healthcare venture capital firm that invests in transformative biotechnology, medical technology, and health solutions companies seeking to improve clinical outcomes, enhance patient quality of life, and drive efficiency of healthcare delivery. Founded in 2006, Longitude Capital invests in both privately held and publicly traded companies through a variety of investment approaches. Longitude Capital has offices in Menlo Park, CA, Greenwich, CT, and Boston. For more information, please visit or LinkedIn.