CCL2

The trial assessed Leukine in 64 subjects with mild to moderate autoimmune pulmonary alveolar proteinosis. Credit: mi_viri / Shutterstock.com. The Japanese Pharmaceuticals and Medical Device Agency (PMDA) has granted approval for Partner Therapeutics’ Leukine (sargramostim) for inhaled use in treating autoimmune pulmonary alveolar proteinosis (aPAP). This is the first regulatory approval of an inhaled recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) product for this indication. In Japan, Leukine is branded as Sargmalin and was licensed to Nobelpharma in 2022 for certain indications. Leukine is a glycosylated recombinant human GM-CSF produced by recombinant DNA technology in yeast. Partner Therapeutics will execute the manufacturing of Sargmalin for Nobelpharma at its facility in Lynnwood, US. See Also: GSK expands Asia-Pacific reach for Trelegy Ellipta with Singapore approval UK MHRA approves Advanz Pharma antibiotic for complex infections The approval is based on the findings from the multicentre, randomised, double-blind, placebo-controlled Phase II PAGE study. It assessed Leukine in 64 subjects with mild to moderate aPAP. Subjects were randomised in a 1:1 ratio to receive either Leukine 125μg or a placebo twice a day for seven days, followed by seven days off, over 12 cycles of two weeks. The trial demonstrated a significant improvement on the primary endpoint, which was the improvement in the alveolar-arterial oxygen gradient from baseline to week 25. Subjects treated with Leukine also showed greater improvements in serum biomarker secondary endpoints, including KL-6, CEA and monocyte chemoattractant protein-1. Partner Therapeutics CEO Robert Mulroy stated: “We are grateful to Nobelpharma for their partnership, as well as their deep commitment to making this treatment available to aPAP patients in Japan. “It has been a pleasure working with their team and we look forward to ensuring the availability of Sargmalin. We also deeply appreciate the commitment of the many patients and doctors who participated in the investigator-initiated clinical trial led by Dr Nakata of Niigata University.”

Treatment will be Marketed by Nobelpharma Co. Ltd. Under the Trade Name Sargmalin® PMDA Approval of Sargmalin is the first regulatory approval of an inhaled recombinant GM-CSF product for aPAP LEXINGTON, Mass., April 3, 2024 /PRNewswire/ -- Partner Therapeutics, Inc. (PTx) announced that its partner Nobelpharma received approval from the Japanese Pharmaceuticals and Medical Device Agency (PMDA) for the inhaled use of Leukine (sargramostim), branded in Japan as Sargmalin, to treat aPAP. PTx licensed rights for certain indications in Japan to Nobelpharma in 2022. Leukine is a glycosylated recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF) produced by recombinant DNA technology in yeast. Leukine is not approved outside Japan for aPAP or as an inhalation therapy. Partner Therapeutics will manufacture Sargmalin for Nobelpharma at its manufacturing facility in Lynnwood, WA. The Sargmalin approval is based on data from the PAGE trial, a phase 2 multicenter, randomized, double-blind, placebo-controlled study to evaluate Leukine in 64 patients with mild to moderate aPAP led by Sponsor-Investigator Koh Nakata MD, PhD, Project Professor, Division of Pioneering Advanced Therapeutics, Center for Medical Innovation of Niigata University Medical Dental Hospital. Patients were randomly assigned 1:1 to receive either 125 micrograms of Leukine or placebo twice per day for seven days and then off for seven days for twelve two–week cycles. There was a significant improvement (p=0.02) in the primary endpoint of improvement in alveolar–arterial oxygen gradient (A-aDO2) between baseline and week 25. Greater improvements in serum biomarker secondary endpoints KL-6, CEA, and monocyte chemoattractant protein-1 (MCP-1) were observed with Leukine.1 "We are grateful to Nobelpharma for their partnership as well as their deep commitment to making this treatment available to aPAP patients in Japan," said Robert Mulroy, CEO of Partner Therapeutics. "It has been a pleasure working with their team and we look forward to ensuring availability of Sargmalin. We also deeply appreciate the commitment of the many patients and doctors who participated in the investigator-initiated clinical trial led by Dr. Nakata of Niigata University." Investigation of inhaled sargramostim, a recombinant human GM-CSF, in aPAP is based on knowledge that the disease is a progressive lung disorder driven by blockage of GM-CSF signaling due to the production of GM-CSF autoantibodies.1,2 The deficiency of GM-CSF in aPAP patients inhibits their ability to differentiate monocytes into alveolar macrophages, which causes aPAP patients to accumulate surfactant in their lungs. This dysfunction leads to low oxygen levels, difficulty breathing, innate immune deficiency, and, in some cases, serious infection, pulmonary fibrosis, respiratory failure, and death.2 GM-CSF improves lung function by directly acting on alveolar macrophages to promote their maturation and the breakdown of pulmonary surfactant by mature macrophages.3 To date, the standard treatment for aPAP has been Whole Lung Lavage (WLL), a lengthy and invasive procedure where saline is used to wash the lungs of excess surfactant. WLL requires hospitalization, general anesthesia, and mechanical ventilation. While effective in providing short term symptomatic relief, WLL can also have serious complications and does not treat alveolar macrophage dysfunction, the underlying cause of aPAP.4 REFERENCES Tazawa R, Ueda T, Abe M, et al. Inhaled GM-CSF for Pulmonary Alveolar Proteinosis. N Engl J Med. 2019;381(10):923-32. Seymour JF, Presneill JJ. Pulmonary alveolar proteinosis. Progress in the first 44 years. Am J Respir Crit Care Med. 2002;166(2);215-35. Campo I, Carey BC, Paracchini E, Kadija Z, De Silvestri A, Rodi G, et al. Inhaled recombinant GM-CSF reduces the need for whole lung lavage and improves gas exchange in autoimmune pulmonary alveolar proteinosis patients. Eur Respir J 2024;63(1):2301233. McCarthy C, Carey BC and Trapnell BC. Autoimmune pulmonary alveolar proteinosis. Am J Respir Crit Care Med 2022;205(9):1016-1035. ABOUT LEUKINE LEUKINE (sargramostim) is a glycosylated recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF) produced by recombinant DNA technology in yeast. The product is commercially available in the United States and accessible through a named patient program operated by Tanner Pharma Group outside of the United States. LEUKINE is indicated: To shorten time to neutrophil recovery and to reduce the incidence of severe and life-threatening infections and infections resulting in death following induction chemotherapy in adult patients 55 years and older with acute myeloid leukemia (AML). For the mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis and autologous transplantation in adult patients. For the acceleration of myeloid reconstitution following autologous bone marrow or peripheral blood progenitor cell transplantation in adult and pediatric patients 2 years of age and older. For the acceleration of myeloid reconstitution following allogeneic bone marrow transplantation in adult and pediatric patients 2 years of age and older. For treatment of delayed neutrophil recovery or graft failure after autologous or allogeneic bone marrow transplantation in adult and pediatric patients 2 years of age and older. To increase survival in adult and pediatric patients from birth to 17 years of age acutely exposed to myelosuppressive doses of radiation (Hematopoietic Syndrome of Acute Radiation Syndrome [H-ARS]). Important Safety Information for Leukine (sargramostim) Contraindications Do not administer LEUKINE to patients with a history of serious allergic reaction, including anaphylaxis, to human granulocyte-macrophage colony-stimulating factor, sargramostim, yeast-derived products, or any other component of LEUKINE. Warnings and Precautions Serious hypersensitivity reactions, including anaphylactic reactions, have been reported with LEUKINE. If a serious allergic or anaphylactic reaction occurs, immediately discontinue LEUKINE therapy, and institute medical management. Discontinue LEUKINE permanently for patients with serious allergic reactions. LEUKINE can cause infusion-related reactions that may be characterized by respiratory distress, hypoxia, flushing, hypotension, syncope, and/or tachycardia. Observe closely during infusion, particularly in patients with preexisting lung disease; dose adjustment or discontinuation may be needed. LEUKINE should not be administered simultaneously with or within 24 hours preceding cytotoxic chemotherapy or radiotherapy or within 24 hours following chemotherapy. Edema, capillary leak syndrome, and pleural or pericardial effusions have been reported in patients after LEUKINE administration. LEUKINE should be used with caution in patients with preexisting fluid retention, pulmonary infiltrates, or congestive heart failure. Such patients should be monitored. Supraventricular arrhythmia has been reported in uncontrolled studies during LEUKINE administration, particularly in patients with a history of cardiac arrhythmia. Use LEUKINE with caution in patients with preexisting cardiac disease. If absolute neutrophil count (ANC) > 20,000 cells/mm3 or if white blood cell (WBC) counts > 50,000/mm3, LEUKINE administration should be interrupted, or the dose reduced by half. Monitor complete blood counts (CBC) with differential twice per week. Discontinue LEUKINE therapy if tumor progression, particularly in myeloid malignancies, is detected during LEUKINE treatment. Treatment with LEUKINE may induce neutralizing anti-drug antibodies. Use LEUKINE for the shortest duration needed. Avoid administration of solutions containing benzyl alcohol (including LEUKINE for injection reconstituted with Bacteriostatic Water for Injection, USP [0.9 % benzyl alcohol]) to neonates and low birth weight infants. Drug Interactions Avoid the concomitant use of LEUKINE and products that induce myeloproliferation. Monitor for clinical and laboratory signs of excess myeloproliferative effects. Adverse Reactions Adverse events occurring in >10% of patients receiving LEUKINE in controlled clinical trials and reported at a higher frequency than in placebo patients are: In recipients of autologous bone marrow transplantation (BMT)–asthenia, malaise, diarrhea, rash, peripheral edema, urinary tract disorder In recipients of allogeneic BMT–abdominal pain, chills, chest pain, diarrhea, nausea, vomiting, hematemesis, dysphagia, GI hemorrhage, pruritus, bone pain, arthralgia, eye hemorrhage, hypertension, tachycardia, bilirubinemia, hyperglycemia, increased creatinine, hypomagnesemia, edema, pharyngitis, epistaxis, dyspnea, insomnia, anxiety, high glucose, low albumin In patients with AML–fever, weight loss, nausea, vomiting, anorexia, skin reactions, metabolic laboratory abnormalities, edema ABOUT PARTNER THERAPEUTICS Partner Therapeutics, Inc. (PTx), an integrated biotechnology company, focuses on development and commercialization of late-stage therapeutics to improve health outcomes in treatment of cancer and other serious diseases. The company believes in delivering products and supporting medical teams with the purpose of achieving superior outcomes for patients and their families. Visit . SOURCE Partner Therapeutics, Inc.

*仅供医学专业人士阅读参考众所周知，部分免疫细胞具有免疫记忆。因此，人体在遇到相同抗原刺激时，免疫系统可做出更快速和强烈的反应，这也是疫苗起效的主要机制[1]。不过，最近几年，我们对于免疫细胞记忆能力的认知，不断被刷新。4年前，匹兹堡大学和康奈尔大学的研究人员，在《科学》杂志上发表一篇研究论文，我至今记忆犹新[2]。这个研究首次发现，巨噬细胞等髓样先天免疫细胞，竟然也会形成抗原特异性的免疫记忆。我没想到的是，免疫记忆这种一直被认为是免疫细胞专属的能力，大脑里的一种非免疫细胞竟然也有。近日，由哈佛医学院Francisco J. Quintana领衔的研究团队，在《自然》杂志上发表一项重磅研究成果[3]。他们发现，中枢神经系统内的星形胶质细胞同样具有免疫记忆，而且这种免疫记忆能力受到表观遗传调控。具体来说，在受到炎症刺激后，星形胶质细胞内的一部分亚群将转变为表达组蛋白乙酰转移酶p300和ATP-柠檬酸裂解酶（ACLY）的亚群（p300+ ACLY+）。当再次受到炎症刺激时，ACLY可产生乙酰辅酶A，为组蛋白乙酰转移酶p300使组蛋白发生乙酰化提供底物，提高了炎症相关基因的染色质可及性，从而产生更快速和剧烈的炎症反应。研究人员同时通过实验证实，星形胶质细胞的这一免疫记忆很可能与中枢神经系统自身免疫性疾病，如多发性硬化症相关，且p300和ACLY基因的失活可以改善实验性自身免疫性脑脊髓炎（EAE，多发性硬化症的实验模型）小鼠的炎症反应，将来有可能针对ACLY-p300通路开发这类疾病的新疗法。论文首页截图前期已有研究表明，多发性硬化症和EAE与星形胶质细胞关系密切[4]。为了研究最初的炎症刺激是否会影响随后的星形胶质细胞反应，研究人员对两组小鼠分别脑室内注射IL-1β和TNF（两者可触发星形胶质细胞发生类似于在多发性硬化症和EAE中检测到的反应[5]）1次和2次（2次间隔1周），然后在IL-1β+TNF刺激后一天对两组小鼠脑部的星形胶质细胞进行RNA测序分析。研究结果显示，相比于1次注射IL-1β+TNF的小鼠，2次注射IL-1β+TNF小鼠脑组织中的星形胶质细胞呈现更强的促炎表型，NF-κB相关促炎通路被明显激活。同时，研究人员还通过染色体可及性测序（ATAC-seq）发现，第二次注射IL-1β+TNF后星形胶质细胞中炎症基因的染色质可及性增加，且这一现象与组蛋白乙酰转移酶p300介导的表观遗传调控相关。小鼠脑组织星形胶质细胞在第二次注射IL-1β+TNF时表现出比第一次时更强的促炎表型，并与组蛋白乙酰转移酶p300介导的表观遗传调控相关紧接着，研究人员在体外培养的小鼠脑原代星形胶质细胞中再次验证了这一点。相比于第一次受到刺激时，第二次受到IL-1β+TNF刺激的星形胶质细胞炎症相关基因表达活跃（IL6、CCL2和NOS2），并导致共培养的神经元死亡。此外，研究人员还发现，在首次IL-1β+TNF刺激后，星形胶质细胞的促炎表型在7天后恢复到基础水平。根据以上的研究结果，p300介导的表观遗传调控可能在星形胶质细胞对炎症刺激的免疫记忆中起到关键作用。为了验证这一点，研究人员使用CRISPR-Cas9技术沉默了小鼠星形胶质细胞中p300的表达，发现p300表达被沉默后，星形胶质细胞组蛋白3第27位赖氨酸（H3K27）的乙酰化及NF-κB相关促炎基因的转录受到抑制，从而减轻了星形胶质细胞的促炎反应。这一结果也在随后的染色质免疫共沉淀测序及体外原代星形胶质细胞实验中再次得到验证。p300表达被沉默后，H3K27乙酰化受到抑制，从而减轻了星形胶质细胞的促炎反应以上实验证实，p300介导的组蛋白乙酰化可通过表观遗传方式，调控星形胶质细胞的免疫记忆促炎反应，而p300使组蛋白乙酰化需要乙酰辅酶A作为底物[6]。用于组蛋白乙酰化的乙酰辅酶A主要由两种酶产生：ACLY和乙酰辅酶A合成酶2（ACSS2）[6, 7]。为了确定参与星形胶质细胞免疫记忆表观遗传调控的乙酰辅酶A的来源，研究人员测定了1次和2次IL-1β+TNF刺激后这两种酶的表达情况。结果显示，IL-1β+TNF的再次刺激仅使星形胶质细胞中ACLY的表达增加，而ACSS2表达无明显变化。紧接着，研究人员使用CRISPR-Cas9技术，分别沉默了星形胶质细胞中ACLY和ACSS2的表达，发现仅在ACLY被沉默后，H3K27乙酰化被抑制，星形胶质细胞的免疫记忆所致炎症反应减少。ACLY提供p300使组蛋白乙酰化需要的底物乙酰辅酶A，进而调控星形胶质细胞的免疫记忆接下来，研究人员在小鼠EAE模型中（由MOG诱导[8]）再次发现了星形胶质细胞中免疫记忆现象的存在，这种免疫记忆同样由ACLY和p300介导，前者提供底物乙酰辅酶A，后者使H3K27乙酰化，从而通过表观遗传方式调控再次炎症刺激时星形胶质细胞的炎症反应。研究人员还通过FIND-seq技术，对EAE小鼠和正常小鼠中ACLY-p300-、ACLY+p300-、ACLY-p300+和ACLY+p300+的星形胶质细胞亚群进行分析。实验分析表明，EAE小鼠中ACLY+p300+的星形胶质细胞亚群数量较正常小鼠增加，同时ACLY+p300+星形胶质细胞与先前实验中具有免疫记忆的星形胶质细胞的转录特征十分相似，而ACLY+p300-和ACLY-p300+亚群的转录特征，则是星形胶质细胞建立免疫记忆的一种过渡状态。最后，研究人员在培养的人胎儿星形胶质细胞中，验证了具有免疫记忆的星形胶质细胞是否与多发性硬化症的发病机制相关。在第二次受到IL-1β+TNF刺激后，人胎儿星形胶质细胞表现出增强的促炎反应，且这种增强的促炎反应可被p300抑制剂C646所拮抗。此外，17名多发性硬化症患者和12名正常对照人群的单细胞分析显示，多发性硬化症患者中ACLY+p300+星形胶质细胞亚群数目明显更多，且显示出与EAE小鼠ACLY+p300+星形胶质细胞相似的转录特征，表现出组蛋白乙酰化活跃和炎症相关基因表达增加。这些发现明确了ACLY和p300介导的表观遗传调控导致的星形胶质细胞免疫记忆在多发性硬化症发病机制中的潜在作用。具有免疫记忆的星形胶质细胞与多发性硬化症的发病机制相关总的来说，本研究发现了星形胶质细胞获得免疫记忆的表观遗传调控机制，其与ACLY和p300介导H3K27乙酰化密切相关，并可能与多发性硬化症等自身免疫性疾病的发病机制相关，具备成为潜在治疗靶点的临床价值。参考文献1.Wendeln AC, Degenhardt K, Kaurani L, Gertig M, Ulas T, Jain G, Wagner J, Hasler LM, Wild K, Skodras A et al: Innate immune memory in the brain shapes neurological disease hallmarks. Nature 2018, 556(7701):332-338.2.Dai H, Lan P, Zhao D, Abou-Daya K, Liu W, Chen W, Friday AJ, Williams AL, Sun T, Chen J et al: PIRs mediate innate myeloid cell memory to nonself MHC molecules. Science 2020, 368(6495):1122-1127.3.Lee HG, Rone JM, Li Z, Akl CF, Shin SW, Lee JH, Flausino LE, Pernin F, Chao CC, Kleemann KL et al: Disease-associated astrocyte epigenetic memory promotes CNS pathology. Nature 2024, 627(8005):865-872.4.Wheeler MA, Clark IC, Tjon EC, Li Z, Zandee SEJ, Couturier CP, Watson BR, Scalisi G, Alkwai S, Rothhammer V et al: MAFG-driven astrocytes promote CNS inflammation. Nature 2020, 578(7796):593-599.5.Rothhammer V, Borucki DM, Tjon EC, Takenaka MC, Chao CC, Ardura-Fabregat A, de Lima KA, Gutierrez-Vazquez C, Hewson P, Staszewski O et al: Microglial control of astrocytes in response to microbial metabolites. Nature 2018, 557(7707):724-728.6.Pietrocola F, Galluzzi L, Bravo-San Pedro JM, Madeo F, Kroemer G: Acetyl coenzyme A: a central metabolite and second messenger. Cell Metab 2015, 21(6):805-821.7.Wellen KE, Hatzivassiliou G, Sachdeva UM, Bui TV, Cross JR, Thompson CB: ATP-citrate lyase links cellular metabolism to histone acetylation. Science 2009, 324(5930):1076-1080.8.Chierzi S, Kacerovsky JB, Fok AHK, Lahaie S, Shibi Rosen A, Farmer WT, Murai KK: Astrocytes Transplanted during Early Postnatal Development Integrate, Mature, and Survive Long Term in Mouse Cortex. J Neurosci 2023, 43(9):1509-1529.责任编辑丨BioTalker