DYRK1B

*仅供医学专业人士阅读参考 “吃饭不积极，思想有问题”，这句话奇点糕还挺认可，但如果吃吃吃变成了工作，或许就不是一回事了，这么想的话，好像癌症微环境里经常不务正业，不去吞噬掉癌细胞的巨噬细胞们也情有可原？但为了消灭掉癌症，还是得想办法让巨噬细胞们“吃”起来。 近日，德国马尔堡大学研究团队在Gut期刊发表最新研究成果，首次揭示了调动巨噬细胞有效吞噬“癌王”胰腺癌的治疗靶点——DYRK1B，采用基因敲除或药物抑制手段处理胰腺癌细胞表达的DYRK1B，可将巨噬细胞募集到胰腺癌部位，并下调吞噬检查点（Phagocytosis Checkpoint）即“别吃我”信号CD24表达，使巨噬细胞们有效抗癌[1]。 论文首页截图 众所周知，胰腺癌的免疫微环境抑制性极强，而介导抑制性的元凶之一，就是大量存在的肿瘤相关巨噬细胞（TAMs），这对免疫治疗、化疗等许多治疗手段的起效都极为不利，但如果换个角度来看，以巨噬细胞作为治疗突破口，把它们“扳回来”发挥抗癌作用的话，那其中蕴藏的抗癌潜能可实在是够丰富的。 而马尔堡大学研究团队瞄准的DYRK1B，其全称是“双特异性酪氨酸磷酸化调节激酶1B”，既往研究报告在胰腺癌中的检出率可达10-40%，且DYRK1B可能会帮助癌细胞脱离细胞周期、进入静止状态（quiescence），由此躲避许多常用化疗药物的杀伤[2]，但这次研究还真是它们和巨噬细胞头一回“同屏出现”。 研究者们首先确认，胰腺癌中表达DYRK1B的主要是导管上皮来源癌细胞，且DYRK1B表达水平与患者预后负相关，然而接下来评估敲除Dyrk1b基因的影响时，实验结果相当出人意料：在体外细胞实验中，敲除Dyrk1b使胰腺癌细胞的增殖速率像踩了油门一样快，在TGFβ信号和mTOR激酶的调控下，癌细胞能更快速地完成细胞周期，加速分裂增殖。 但是，敲除Dyrk1b的胰腺癌细胞被植入小鼠体内后，它们形成肿瘤的速度和体积反而远不及正常的胰腺癌细胞；对肿瘤的单细胞测序显示，有海量的巨噬细胞从外部涌入了肿瘤部位，而且表型基本都向着有利于抗癌的M1型TAMs极化。也就是说，敲除Dyrk1b虽然让胰腺癌细胞增殖更快，但也招来了巨噬细胞铺天盖地的追杀，导致强有力的抑癌效应。 敲除Dyrk1b使大量巨噬细胞被募集到肿瘤部位抗癌 那下一个问题就很自然了：敲除胰腺癌细胞的Dyrk1b为什么会激活巨噬细胞呢？研究者们猜测这可能与胰腺癌细胞外分泌物质的改变有关，于是用癌细胞培养上清液处理了巨噬细胞，发现巨噬细胞的基因表达会在两个层面受影响，一方面是M1型TAMs相关基因（如Cd40）的表达上调，另一方面则是炎症相关（如il1a/1b）和M2型TAMs相关基因的表达下调。 此外，敲除癌细胞Dyrk1b后被“吸引”来的巨噬细胞，迁移能力和存活能力也显著提高，这与敲除Dyrk1b改变了癌细胞的多种趋化因子分泌水平有关；而更为关键的是，巨噬细胞们在共培养实验中吞噬癌细胞的能力大幅增强，这主要是因为敲除Dyrk1b会使癌细胞表面的“别吃我”信号CD24水平直接减半，癌细胞就无法靠CD24从巨噬细胞嘴下逃命了。 敲除Dyrk1b可在多个层面影响巨噬细胞，使它们抗癌能力更强 最后研究者们在小鼠实验中证实，以针对DYRK1B的小分子抑制剂（AZ191/KU0063794，后者还可抑制mTOR激酶）配合胰腺癌化疗中常用的吉西他滨，可显著延长胰腺癌模型小鼠的生存时间，研究者们还乐观推测，DYRK1B抑制剂或许也能与现有免疫治疗实现协同增效，在胰腺癌攻坚战中发挥作用，那就看看未来会不会有临床研究的好消息吧。 参考文献： [1]Brichkina A, Ems M, Suezov R, et al. DYRK1B blockade promotes tumoricidal macrophage activity in pancreatic cancer [J]. Gut, 2024, gutjnl-2023-331854. [2]Ewton D Z, Hu J, Vilenchik M, et al. Inactivation of mirk/dyrk1b kinase targets quiescent pancreatic cancer cells[J]. Molecular Cancer Therapeutics, 2011, 10(11): 2104-2114. 本文作者丨谭硕

- CBL-0202 Phase 2 study results met all the primary and secondary endpoints. - 69.9% and 60.9% of participants lost at least 150mL and 200mL of abdominal subcutaneous fat in the treated area after CBL-514 treatment. - Compared with placebo, an average of 312.1mL of subcutaneous fat was reduced in the treated area after CBL-514 treatment. - 42.9% of participants lost at least 150mL of subcutaneous fat in the treated area after only one CBL-514 treatment. TAIPEI, Oct. 2, 2023 /PRNewswire/ -- Caliway Biopharmaceuticals (Caliway) announced the topline results of the CBL-0202 stage 2 phase 2 study met all the primary and secondary efficacy endpoints compared with placebo in the ITT (Intent-to-treat) and PP (per-protocol) analysis population. "According to the study published in the Aesthetic Surgery Journal in 2012, liposuction could remove a mean of the subcutaneous fat volume of 183.3mL," said Vivian Ling, CEO of Caliway, "We are delighted to see that CBL-514 demonstrated the efficacy on subcutaneous fat reduction more effective than liposuction in the CBL-0202 stage 2 phase 2 study, reducing over 300mL of subcutaneous fat averagely." Topline Results from the CBL-0202 Phase 2-stage 2 Study Primary Endpoint 63.9% and 69.6% of participants in the CBL-514 group who lost at least 150 mL of subcutaneous fat in the treated area at 4 weeks and 8 weeks after treatment; while in the placebo group, 17.4% and 0.0% of participants who lost at least 150 mL of subcutaneous fat in the treated area at 4 weeks and 8 weeks after treatment. The percentage of participants who lost at least 150 mL of subcutaneous fat in the treated area at 4 weeks (p<0.001) and 8 weeks (p<0.00001) after CBL-514 treatment was significantly higher than the placebo group and achieved the primary endpoint. Secondary Endpoints 58.3% and 60.9% of participants in the CBL-514 group who lost at least 200 mL of subcutaneous fat in the treated area at 4 weeks and 8 weeks after treatment; while in the placebo group, 8.7% and 0.0% of participants who lost at least 200 mL of subcutaneous fat in the treated area at 4 weeks and 8 weeks after treatment. The percentage of participants who lost at least 200 mL of subcutaneous fat in the treated area at 4 weeks (p< 0.0002) and 8 weeks (p< 0.0001) after CBL-514 treatment was significantly higher than the placebo group. Compared with the placebo group, the LS mean (least square mean) difference of the subcutaneous fat volume change in the treated area at 4 weeks and 8 weeks after CBL-514 treatment were -312.08 mL (p<0.00001) and -276.83 mL (p<0.00005). 42.9% of participants lost at least 150 mL of subcutaneous fat in the treated area after one CBL-514 treatment. Overall, the safety and tolerability profiles of CBL-514 demonstrated in the study were favorable and consistent with previous clinical studies of CBL-514. Major TEAEs were ISRs (injection site reactions) that were mild and moderate, and most TEAEs were resolved before the end of the study visit. About the CBL-0202 Stage 2 Study The CBL-0202 stage 2 study (NCT04897412) is a randomized, single-blind, placebo-controlled phase 2 study to evaluate the efficacy, safety, and tolerability of CBL- 514 injection for abdominal subcutaneous fat reduction approved by the U.S. Food and Drug Administration (FDA) and Australian Therapeutic Goods Administration (TGA). CBL-514 will be administered via injection into the subcutaneous adipose layer on the abdomen. The trial randomized 76 participants across the U.S. and Australia in a 2:1 ratio to receive CBL-514 or a placebo. Each participant will receive up to 4 treatments of allocated CBL-514 or placebo administered on the abdomen once every 4 weeks and complete the two follow-up visits after the last treatment. The maximum dose is 600 mg per treatment, depending on the level of subcutaneous fat accumulation on the participant's abdomen. The primary efficacy endpoint of the CBL-0202 -stage 2 phase 2 study is the percentage of participants who lost at least 150 mL of abdominal subcutaneous fat as measured by ultrasound at 4 weeks and 8 weeks follow-up visits after treatment compared with placebo. The critical secondary efficacy endpoints include the percentage of participants who lost at least 200 mL of abdominal subcutaneous fat as measured by ultrasound at 4 weeks and 8 weeks follow-up visits after treatment compared with placebo, and reduction of subcutaneous fat volume over the treated area as measured by ultrasound from Baseline to follow-up visits compared with placebo. About Fat Reduction The current methods for fat reduction include non-invasive products and invasive surgery, such as liposuction and abdominal contour surgery. The efficacies of non-invasive products often take more than twelve weeks to show, and are generally poor with the limited treatment body area. The potential moderate to severe side effects of non-invasive products include tissue necrosis, nerve damage, scar tissue fibrosis, and paradoxical adipose hyperplasia (PAH). Though the efficacy of surgery is more significant compared to approved non-surgery local fat reduction products, the surgery still comes with severe side effects and a high risk of death. According to the American Society of Plastic Surgeons' report, more than 60% of people are reluctant to undergo local fat reduction due to the fear of the side effects. The medical needs for local fat reduction remain unmet. About CBL-514 CBL-514, a first-in-class small-molecule drug, is an injection lipolysis drug that can induce adipocytes apoptosis and lipolysis to reduce subcutaneous adiposity in treatment areas in animal studies without causing any systematic side effects on the central nervous system, cardiovascular system, and respiratory system. Caliway's nonclinical studies showed that CBL-514 inhibits the cell survival kinase DYRK1b, upregulates the apoptosis mediators caspase 3 and Bax/Bcl-2 ratio, and then induces dose-dependent adipocyte apoptosis in vivo and in vitro. Caliway is investigating multiple indications for CBL-514, including non-invasive fat reduction (reducing subcutaneous fat), Dercum's disease, cellulite, and lipoma treatment. About Caliway Biopharmaceuticals Caliway Biopharmaceuticals (Caliway), is a Taiwan-based, clinical-stage biopharmaceutical company driven to breakthrough drug discovery of novel small-molecule therapeutics to help patients suffering from illness or life-threatening diseases. In Caliway, we aim to become an innovative pharmaceutical leader in medical aesthetics and inflammatory disease. For more information, please visit: SOURCE Caliway Biopharmaceuticals

- CBL-0201DD Phase 2 study met the primary and all secondary endpoints. - 64.5% of painful lipomas showed complete clearance or dimensions reduction of more than 50% after CBL-514 treatments. - 54.8% of painful lipomas showed complete clearance or dimension reduction of more than 50% after one CBL-514 treatment. - The pain score of CBL-514 treated painful lipoma was decreased by 4.7 points. - CBL-514 is the first and only drug to demonstrate clinically and statistically significant efficacy in lipoma size reduction, complete clearance, and pain improvement of greater than 4.0 points. TAIPEI, Sept. 13, 2023 /PRNewswire/ -- Caliway Biopharmaceuticals (Caliway), a Taiwan-based biopharmaceutical company focusing on breakthrough medical aesthetics and inflammatory medicine discovery of small-molecule therapeutics, today announced that all the primary and secondary efficacy endpoints were met in the analysis of the ITT (Intent-to-treat) population and PP (per-protocol) population from the CBL-0201DD Phase 2 study (NCT05387733), evaluating CBL-514's efficacy and safety on participants with Dercum's Disease lipomas. In addition, CBL-514 demonstrated good safety and tolerance profiles, with no systemic adverse events reported. Dercum's disease is a rare disease currently without approved or effective treatment, leading to the clinical need remaining unmet. According to a published study by Emma Hansson, MD in 2011, liposuction may reduce pain in Dercum's disease by 3 points (evaluated by the Visual Analog Scale) at 3 months after liposuction compared to baseline. "The topline results of CBL-0201DD study demonstrated that CBL-514 is the first and only product to show clinically meaningful and statistically significant in painful lipomas complete clearance or dimensions reduction of more than 50%, while also demonstrating significant pain improvement by 4.7 points," said Vivian Ling, CEO of Caliway. Topline Results from the CBL-0201DD Study In the CBL-0201DD Phase 2 study, 12 participants with at least 4 painful and well-defined lipomas were recruited and randomized to 2 dose groups of CBL-514, with 6 participants per group. Each enrolled participant will receive up to 2 courses of their allocated dose of CBL-514 administered into selected lipomas, which the injection volume per lipoma will be based on the lipoma size, determined by ultrasound. Primary Endpoint Painful lipomas dimension in the high-dose group was reduced by 51.3% (p<0.0001) and 54.7% (p<0.0001) at 4 and 8 weeks after CBL-514 treatments. Painful lipomas dimension in the low-dose group was reduced by 40.0% (p=0.0002) and 34.7% (p<0.0001) at 4 and 8 weeks after CBL-514 treatments. Secondary Endpoints 90.3% of painful lipomas in the high-dose group showed dimensions reduction after CBL-514 treatments compared to baseline. 64.5% of painful lipomas in the high-dose group showed complete clearance or dimensions reduction of more than 50% after CBL-514 treatments compared to baseline. 38.7% of painful lipomas in the high-dose group showed complete clearance after CBL-514 treatments compared to baseline. The mean absolute change in pain score of painful lipomas in the high-dose group, evaluated by the Comparative Pain Scale, was decreased by 4.7 points (p<0.0001) after CBL-514 treatments compared to baseline. The results in painful lipomas in the low-dose group showed statistical significance in primary and all secondary endpoints. Detailed efficacy and safety topline results from the CBL-0201DD study will be published in the journal for rare diseases. Based on the promising results, Caliway is currently planning for CBL-0202DD Phase 2b study IND application to further investigate CBL-514's efficacy in treating Dercum's disease. About Dercum's Disease Dercum's disease is a rare disorder with a strong tendency to recurrence that is characterized by the development of painful lipomas primarily located on the trunk region, and the extremities close to the trunk. The pain is chronic (>3 months), symmetrical, often disabling, and resistant to traditional analgesics. The main symptoms of Dercum's disease, according to the early reports, are obesity, painful adipose tissue, and numerous psychiatric manifestations, including sleep disturbances, depression, and anxiety. The etiology of Dercum's disease remains unknown. There is no approved drug nor recommended standard treatment for Dercum's disease yet. The current treatment options, including surgical removal, liposuction, electrotherapy, and inflammation inhibitors, are symptomatic, and the efficacies are limited with numerous adverse events. The clinical need for Dercum's disease remains unmet. According to the Global Dercum's Disease Market Research Report, the global Dercum's disease treatment market size in 2021 was $11.3 billion. With a compound annual growth rate (CAGR) of 6.76%, the global market of Dercum's disease treatment in 2030 is estimated to expand to $19.95 billion. About the CBL-0201DD Phase 2 Study The CBL-0201DD study is a randomized, open-label, Phase 2 trial (NCT05387733) evaluating the efficacy and safety of CBL-514 injections in subjects with Dercum's disease. To determine the optimal CBL-514 dose for Dercum's disease treatment, the study enrolled twelve Dercum's disease patients with at least four painful lipomas and randomized 1:1 to two groups to receive one of two doses of CBL-514 injections. Each subject would receive up to two courses of their allocated dose of CBL-514 administered into selected lipomas, and the injection volume per lipoma will be based on the lipoma size, determined by ultrasound. The efficacy of CBL-514 on each lipoma was evaluated at Week 4 and Week 8 after the last treatment. The primary endpoint is the change of lipoma dimensions measured by ultrasound following CBL-514 treatment. The secondary endpoints include the percentage of lipomas with dimensions change and/or complete clearance measured by ultrasound, and the improvement of pain of individual lipomas following CBL-514 treatment. About CBL-514 CBL-514, a first-in-class small-molecule drug, is an injection lipolysis drug that can induce adipocytes apoptosis and lipolysis to reduce subcutaneous adiposity in treatment areas in animal studies without causing any systematic side effects on the central nervous system, cardiovascular system, and respiratory system. Caliway's nonclinical studies showed that CBL-514 inhibits the cell survival kinase DYRK1b, upregulates the apoptosis mediators caspase 3 and Bax/Bcl-2 ratio, and then induces dose-dependent adipocyte apoptosis in vivo and in vitro. Caliway is investigating multiple indications for CBL-514, including non-invasive fat reduction (reducing subcutaneous fat), Dercum's disease, cellulite, and lipoma treatment. About Caliway Biopharmaceuticals Caliway Biopharmaceuticals (Caliway), is a Taiwan-based, clinical-stage biopharmaceutical company driven to breakthrough drug discovery of novel small-molecule therapeutics to help patients suffering from illness or life-threatening diseases. In Caliway, we aim to become an innovative pharmaceutical leader in medical aesthetics and inflammatory disease. For more information, please visit: Disclaimer This article and related information on this site contain forward-looking statements. The forward-looking information requires the Company to make numerous assumptions and is subject to inherent risks, uncertainties, and other factors that are beyond the control of the Company which may cause actual results, performance or achievements to be materially different from future results, performance or achievements expressed or implied by such forward-looking statements. The Company undertakes no obligation to timely inform, update, or revise the information on this site if circumstances should change. SOURCE Caliway Biopharmaceuticals