Phase I/IIb Study of the Tumor Targeting Human F16IL2 Monoclonal Antibody-cytokine Fusion Protein in Combination With the Anti-PD1 Antibody Nivolumab in Patients With Non-small Cell Lung Cancer

Prospective, open label, non-randomized, phase I/IIb study of F16IL2 in combination with Nivolumab.

开始日期2017-03-09

申办/合作机构

Philogen SpA

NCT03207191 / Completed临床1期

A Phase I Study of the Tumor-targeting Human F16IL2 Monoclonal Antibody-cytokine Fusion Protein in Combination With the Anti-CD33 Antibody BI 836858 in Patients With AML Relapse After Allogeneic Hematopoietic Stem Cell Transplantation

Phase I, open label, single arm, non-randomized, multicenter, prospective dose escalation study in subjects with acute myeloid leukemia relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT).

开始日期2016-12-02

申办/合作机构

Philogen SpA

[+1]

NCT02957032 / Terminated临床1期

A Dose-finding Phase I Study of the Tumor-targeting Human F16IL2 Monoclonal Antibody-cytokine Fusion Protein in Combination With Very Low-dose Cytarabine in Patients With AML Relapse After Allogeneic Hematopoietic Stem Cell Transplantation

Phase I, open label, non-randomized, multicenter, prospective dose escalation study of F16IL2 in combination with very low-dose cytarabine in subjects with acute myeloid leukemia relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT).

开始日期2016-04-13

申办/合作机构

Philogen SpA

100 项与 F16 IL2 fusion protein(Philogen SpA) 相关的临床结果

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100 项与 F16 IL2 fusion protein(Philogen SpA) 相关的转化医学

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100 项与 F16 IL2 fusion protein(Philogen SpA) 相关的专利（医药）

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项与 F16 IL2 fusion protein(Philogen SpA) 相关的文献（医药）

2022-06-28·Blood Advances2区 · 医学

Using stroma-anchoring cytokines to augment ADCC: a phase 1 trial of F16IL2 and BI 836858 for posttransplant AML relapse

2区 · 医学

Article

作者: Schäfers, Michael ; Altvater, Bianca ; Hescheler, Daniel ; Hartmann, Wolfgang ; Berdel, Wolfgang E. ; Gerwing, Mirjam ; Wethmar, Klaus ; Schliemann, Christoph ; Ruhnke, Leo ; Stelljes, Matthias ; Rossig, Claudia ; Neri, Dario ; Röllig, Christoph ; Berdel, Andrew F. ; Scheller, Annika ; Angenendt, Linus ; Lenz, Georg ; Mikesch, Jan-Henrik ; Wermke, Martin ; Rueter, Bjoern ; Matasci, Mattia ; Kessler, Torsten ; Bornhäuser, Martin ; Hemmerle, Teresa

AbstractNatural killer (NK) cells are key effectors in cancer immunosurveillance and posttransplant immunity, but deficiency of environmental signals and insufficient tumor recognition may limit their activity. We hypothesized that the antibody-mediated anchoring of interleukin-2 (IL-2) to a spliced isoform of the extracellular matrix (ECM) glycoprotein tenascin-C would potentiate NK-cell–mediated antibody-dependent cellular cytotoxicity against leukemic blasts. In this novel-novel combination, dose-escalation, phase 1 trial, we enrolled patients with posttransplant acute myeloid leukemia (AML) relapse to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary activity of the antibody-cytokine fusion F16IL2 (10 × 106 to 20 × 106 IU IV; days 1, 8, 15, and 22 of each 28-day cycle) in combination with the anti-CD33 antibody BI 836858 (10-40 mg IV, 2 days after each F16IL2 infusion). Among the 15 patients (median [range] age, 50 [20-68] years) treated across 4 dose levels (DLs), 6 (40%) had received 2 or 3 prior transplantations. The most frequent adverse events were pyrexia, chills, and infusion-related reactions, which were manageable, transient and of grade ≤2. One dose-limiting toxicity occurred at each of DLs 3 (pulmonary edema) and 4 (graft-versus-host disease). Three objective responses were observed among 7 patients treated at the 2 higher DLs, whereas no responses occurred at the 2 starting DLs. Combination therapy stimulated the expansion and activation of NK cells, including those expressing the FcγRIIIA/CD16 receptor. ECM-targeted IL-2 combined with anti-CD33 immunotherapy represents an innovative approach associated with acceptable safety and encouraging biologic and clinical activity in posttransplant AML relapse. This trial was registered at EudraCT as 2015-004763-37.

2021-07-01·Archives of Microbiology4区 · 生物学

Lactococcus-based vaccine against brucellosis: IgG immune response in mice with rOmp16-IL2 fusion protein

4区 · 生物学

Article

作者: Rezaei, Marzieh ; Zarkesh-Esfahani, Sayyed Hamid ; Rabbani-Khorasgani, Mohammad ; Abtahi, Hamid ; Emamzadeh, Rahman

This study was designed to introduce the recombinant Lactococcus lactis MG1363 as a cell factory candidate for production of recombinant Brucella melitensis Omp16-Human IL2 (r-Omp16-IL2) and to suggest it as a promising safe, non-pathogenic mucosal live vaccine against brucellosis. Three groups of BALB/c mice (10 mice per group) were intragastrically administrated with phosphate-buffered saline (PBS), L. lactis harboring the empty pAMJ2008 plasmid and with L. lactis expressing rOmp-IL2. The first two groups were classified as control groups and the third one is indicated as treatment group. Another group was injected by the intraperitoneal (i.p.) route with purified rOmp16-IL2 protein. The total serum IgG of each group was assessed with indirect ELISAs at two days before immunization and also two weeks after the last immunization. Results showed that BALB/c mice intragastrically administrated with L. lactis expressing rOmp-IL2 had dominant IgG response compared to the control (PBS administrated) group (P < 0.05). The level of IgG was significantly increased by intraperitoneally injection of recombinant Omp-IL2 in adjuvant compared to the intragastrically administration of PBS and L. lactis/pAMJ2008 as control groups, and also compared to L. lactis/pAMJ2008-rOmp-IL2 (P < 0.05). Our findings provide the use of L. lactis rOmp16-IL2 as a new promising alternative safe strategy than presently live attenuated vaccines toward developing an oral vaccine or subunit-based vaccine against brucellosis.

2021-03-01·British Journal of Haematology

Phase I study of F16IL2 antibody–cytokine fusion with very low‐dose araC in acute myeloid leukaemia relapse after allogeneic stem cell transplantation

Letter

作者: Altvater, Bianca ; Mikesch, Jan‐Henrik ; Schäfers, Michael ; Rossig, Claudia ; Kessler, Torsten ; Angenendt, Linus ; Hemmerle, Teresa ; Berdel, Wolfgang E. ; Berdel, Andrew F. ; Lenz, Georg ; Schliemann, Christoph ; Neri, Dario ; Stelljes, Matthias

F16IL2, a recombinant fusion protein of a human mono- clonal antibody fragment F16 and rhIL2, binds the A1 domain of tenascin C (TnC), spliced into TnC during angio- genesis and tissue remodeling, which is expressed in the vas- culature of solid and hematol. tumor types, but virtually absent in normal tissues.Targeting, biodistribution of F8 in mouse leukemia models, and therapeutic activity of F8IL2 against syngeneic murine acute myeloid leukemia (AML) models is promising.In combination with low-dose cytarabine, F8IL2 eradicates AML, an effect mediated by natural killer (NK) cells and CD8 +T cells.We report a phase I study (see Supporting Information) combining F16IL2 (Figure S1) with VLDAC in patients with AML relapse after alloHSCT.We observed a significant increase of lymphoid immune cells in peripheral blood and bone marrow at the end of cycle 1, reaching up to 60% of all nucleated cells, most notable in the NK cell compartment, where cell numbers increased up to 40-fold in blood and 26-fold in bone marrow.The patient succumbed to AML 15 mo later. All other patients showed progressive disease and succumbed to AML, Median overall survival (OS) was 776 mo with 25%alive at one year.Patients with AML relapse after multiple lines of therapy and alloHSCT have a dismal prognosis and Thus, the overall response rate (ORR; CR plus CRi) was 40% (4/10). Within all 12 patients with intention to treat, the ORR was 33 3% and both values and median OS compare favorably to DLI.

项与 F16 IL2 fusion protein(Philogen SpA) 相关的新闻（医药）

2024-04-07

·佰傲谷BioValley

IL-2/IL-2R研究简史

1976年发现的IL-2，在整个免疫治疗史上，有着不可替代的位置。Rosenberg称之为第一个人类肿瘤有效的免疫治疗方法。IL-2/IL-2R受体里程碑研究 1976年 NCI肿瘤细胞生物学实验室的RobertGallo，使用PHA刺激淋巴细胞产生条件培养基培养骨髓细胞，其中90%的T细胞长达9个月的生存维持。在此之前，原代T细胞无法体外培养，是免疫学发展的巨大瓶颈性技术问题。这个未被纯化的成分称之为T细胞生长因子（TCGF）。条件培养基培养骨髓细胞（文献1）1980年NCI肿瘤细胞生物学实验室的RobertGallo，通过离子交换色谱和凝胶分离，从条件培养基中分离浓缩了TCGF，并且得出了大致的分子量约15KD。纯化IL-2电泳（文献2）1983年日本癌症研究基金会肿瘤研究中心，Junji Hamuro等人，克隆了IL-2的基因，完成了测序工作。人们可以完整的了解这个T细胞生长因子的基因和氨基酸序列等基础信息。但是为什么第一个被克隆的细胞因子成为IL-2而不是IL-1呢？原因是，当初有科学家认为，有另外一个细胞因子刺激了IL-2的产生，那个未知的因子应该是1。IL-2序列（文献3）IL-2受体的发现和克隆 1984年Nature发表了三篇IL-2受体α克隆的文章（文献4，5，6），分别来自于Immunex 公司（2002年Amgen收购），NCI，和日本京都大学。 1986年NIH国立儿童健康与人类发育研究所在Science发表文章（文献7），发现了IL-2另外一个受体p70，1986和1987年还有多篇文章报道IL-2 p70受体。1990年日本东北大学医学院，1991京都大学分别发表文章发现IL-2Rγ（文献8，9）。至此，IL-2受体α，β，γ被发现。之后IL-2和受体的结合，被Stanford的科学家解析。IL-2-IL-2Rα，β，γ复合物结构（文献10）IL-2/IL-2R药物开发重组IL-21983年IL-2基因被克隆，是IL-2药物开发的里程碑式基础研究，1983年和1984年多个实验室进行了IL-2的大肠杆菌表达。 IL-2临床试验统计（文献16）1984年11月，一个33岁黑色素瘤转移的病人接受重组IL-2治疗，肿瘤消退，此后病人无疾病生存29年。1985年Rosenberg在肝癌转移小鼠模型注射重组IL-2，获得很好的治疗效果（文献11）。1985年Rosenberg等在新英格兰医学杂志报道，使用IL-2和LAK细胞进行了25个癌症转移病人的临床研究。Rosenberg 2014年发文评述IL-2是第一个人类肿瘤有效的免疫治疗方法（文献13）。 1991年诺华与linigen联合研发的重组IL-2药物 Proleukin（Aldesleukin，阿地白介素）被FDA批准治疗转移性肾癌，1998年批准治疗转移性黑色素瘤。但是因为半衰期短，治疗窗口窄，毒副作用大，且同时刺激Treg活化，限制了临床使用。新型IL-2开发（PEG化，偏向性IL-2） IL-2R有α（CD25），β（CD122），γ（CD132），其中，α为低亲和力受体，且下游无信号传导，β和γ组成中等亲和力的受体，下游可以通过JAK传导信号，在α参与的情况下，亲和力增强为高亲和力受体。IL-2受体（文献17）从1990s开始，很多的科研单位和企业开始，通过突变改变IL-2和不同受体亚单位亲和力，以增加活力，降低毒性。2000年Bayer 设计了BAY50-4798，选择性结合IL-2Raβγ，减少和IL-2βγ的结合，减少IL-2Rβγ+ NK细胞介导的毒性。但是最终临床治疗和传统IL-2比较，没有改善。BAY50-4798结构及作用（文献14）NKTR-214NKTR-214是由美国Nektar公司开发的一种针对CD122 (IL-2Rβ)抗原的偏向型激动剂,其通过靶向作用于CD8+效应T细胞以刺激肿瘤杀伤T细胞的增殖,从而利用患者自身免疫系统对抗癌症。NKTR-214通过对首个肿瘤免疫药物aldesleukin进行聚乙二醇(PEG)修饰,有效克服了其严重的毒副作用并延长起效时间。THOR-707Synthorx公司（赛诺菲25亿美金收购）产品，通过向宿主细胞转入非天然氨基酸，在该位点实现定点PEG偶联，和IL-2Rα低亲和力，但是和IL-2Rβγ有接近天然的亲和力，选择性激活CD8+T细胞，不激活Treg。NCT04009681，A Study Evaluating Safety and TherapeuticActivity of THOR-707 in Adult Subjects With Advanced or Metastatic Solid Tumors(THOR-707-101)，Phase1/2SHR-1916 12月25日恒瑞偏向性IL-2，SHR-1916获批临床。SHR-1916是恒瑞医药自主研发的全新PEG修饰和位点突变的IL-2分子，可以通过激活JAK1/JAK3/STAT5信号通路，促进CD8⁺T和NK细胞增殖，发挥抗肿瘤作用。Immunocytokine（抗体-IL2偶联）通过靶向肿瘤抗原抗体将IL-2携带至肿瘤局部，是另外一种策略，可以增加半衰期，增强靶向性，降低毒性。hu14.18-IL2hu14.18-IL2（EMD273063），由EMD Serono研发，是一种抗GD2免疫因子，由抗GD2抗体14.18（抗体）和两分子的IL-2（免疫因子）融合而成的蛋白，主要用于治疗黑色素瘤。临床研究：NCT00590824，Pilothu14.18-IL2 in Resectable Recurrent Stage III or Stage IV Melanoma，phase2 在一些高复发风险的黑色素瘤患者中，使用IC治疗的患者出现了长时间的无瘤生存。 L19-IL2Philogen S.p.A.公司研发，L19靶向细胞外基质（ECM）纤维连接蛋白异构体B-FN的的结构域B（ED-B）。NCT02957019，A PhaseI/II Study of the Tumor-targeting Human L19-IL2 Monoclonal Antibody-cytokineFusion Protein in Combination With Rituximab in Relapsed or Refractory DiffuseLarge B-cell Lymphoma (DLBCL)NCT04362722，IntratumoralAdministration of Daromun in Non-melanoma Skin Cancer Patients (DUNCAN)，phase2Philogen S.p.A.还开发了F16IL2，有多个临床在开展，但是进度未更新。RO6874281RO6874281，来自于Roche，是IL-2突变体与靶向FAP的单抗融合而成的双特异性蛋白，其中靶向肿瘤胶质抗原FAP的单抗用于将蛋白相对准确地定位到肿瘤部位，IL-2突变体部分则偏向性地结合和调控肿瘤微环境中的T细胞表面的IL-2Rβγ二聚体，从而激活微环境中的抗肿瘤免疫效果。 NCT03875079（Metastatic Melanoma），NCT03063762（Metastatic Renal Cell Carcinoma），NCT02627274（联用Trastuzumab or Cetuximab），NCT03386721（实体瘤，联用Atezolizumab），NCT03193190（PDAC）IL-2R抗体阻断性抗体用于炎症性疾病，非阻断性抗体用于肿瘤免疫治疗。阻断性抗体Zinbryta(daclizumab)AbbVie，Inc.和Biogen适用为有多发性硬化症(MS)的复发型成年患者的治疗白介素-2受体阻断抗体7例严重不良反应，主要为脑炎和脑膜炎，这才紧急启动撤市程序。 IL-2R alpha嵌合体抗体Basiliximab/巴利昔单抗/舒莱Novartis预防首次肾移植术后的急性器官排斥国内注册号：S20171040非阻断性抗体RG6292非阻断性CD25抗体，选择性清除Treg。详细内容可阅读：Roche 新型CD25抗体选择性清除调节性T细胞，增强抗肿瘤免疫参考文献Morgan DA, Ruscetti FW, GalloRC: Selective in vitro growth of T lymphocytes from normal human bone marrows.Science 1976, 193: 1007e1008J.W. Mier, R.C. Gallo,Purification and some characteristics of human T-cell growth factor fromphytohemagglutinin-stimulated lymphocyte-conditioned media, Proc.Natl. Acad.Sci. USA (1980)aniguchi T,et al: Structure andexpression of a cloned cDNA for human interleukin-2. Nature 1983, 302:305e310Cosman, D.et al, (1984).Cloning, sequence and expression of human interleukin-2 receptor. Nature 312,768–771.Leonard, W.J.,etal.(1984).Molecular cloning and expression of cDNAs for the human interleukin-2 receptor.Nature 311, 626–631.Nikaido, T., et al (1984).Molecular cloning of cDNA encoding human interleukin-2 receptor. Nature 311,631–635.Sharon, M., et al. (1986).Novel interleukin-2 receptor subunit detected by cross-linking underhigh-affinity conditions. Science 234, 859–863.Takeshita, T., et al. (1990).An associated molecule, p64, with high-affinity interleukin 2 receptor. Int.Immunol. 2, 477–480.Saito, Y.,et al. (1991).Biochemical evidence for a third chain of the interleukin-2 receptor. J. Biol.Chem. 266, 22186–22191.X. Wang, M. Rickert, K.C.Garcia, Structure of the quaternary complex of interleukin-2 with Its α, ß, andγc Receptors. Science (80-) 310 (2005) 1159 LP–1163Lafreniere R, Rosenberg SA.1985. Successful immunotherapy of murine experimental hepatic metastases withlymphokine activated killer cells and recombinant interleukin 2. Cancer Res45(8):3735–3741.Rosenberg SA, et al. 1985.Observations on the systemic administration of autologous lymphokine-activatedkiller cells and recombinant interleukin-2 to patients with metastatic cancer.N Engl J Med 313(23):1485–1492.Rosenberg SA. 2014. IL-2: thefirst effective immunotherapy for human cancer. J Immunol 192(12):5451–5458.Shanafelt AB, et al. 2000. AT-cell-selective interleukin 2 mutein exhibits potent antitumor activity and iswell tolerated in vivo. Nat Biotechnol 18(11):1197–1202.Carnemolla B, Borsi L, Balza Eet al (2002) Enhancement of the antitumor properties of interleukin-2 byits targeted delivery to the tumor blood vessel extracellular matrix. Blood99(5):1659– 1665Alexy Orozco Valencia，et al，Interleukin-2 as immunotherapeutic in the autoimmune diseases，International Immunopharmacology 81 (2020) 1062962Rosanne Spolski，et al，Biology and regulation of IL-2: from molecular mechanisms to human therapy，Nat Rev Immunol . 2018 Oct;18(10):648-659.本周好文推荐如需转载请联系佰傲谷并在醒目位置注明出处···

免疫疗法并购细胞疗法

2021-02-25

·GlobeNewswire

Top Aces Corp. Demonstrates Advanced Adversary Training Capabilities to USAFE

MESA, Ariz., Feb. 25, 2021 (GLOBE NEWSWIRE) -- On February 24th, 2021, Top Aces Corp. (Top Aces), together with Huntington Ingalls Industries, was contracted by the United States Air Force in Europe (USAFE) for fast jet adversary support at the Ramstein Air Base in Germany. Top Aces provided a 4-ship of A-4N Skyhawks to fly in USAFE’s Joint All Domain Command and Control Exercise (JADC2) in conjunction with its Advanced Battle Management System (ABMS). Operating out of the Wittmundhafen Air Base, Top Aces has served the German Armed Forces with advanced adversary training for the past 6 years. “Top Aces has built a reputation for safety, credibility and operational excellence in Germany, and we are very proud to extend our services to other NATO countries in support of USAFE training,” said Rolf Brandt, Senior Program Manager – German Operations at Top Aces. All 8 mission runs were successfully completed “on time, on target” during the exercise lead by Reic “Junior” Ferner, a Top Aces Pilot with more than 5,000 hours of combined fighter experience in the Luftwaffe and with Top Aces. Top Aces has effectively and affordably trained air force leaders throughout the world. Its mission-critical training enhances the operational readiness of combat forces by providing a realistic threat representative experience – all while prolonging its customers’ front-line fleet life and generating cost savings. “Top Aces is honored to support USAFE today and looks forward to the upcoming ADAIR (Adversary Air) Utility Assessment, where we will participate with our new radar-equipped A-4N AAF (Advanced Aggressor Fighter),” said Top Aces Corp. President Russ Quinn. Featuring a state-of-the-art Active Electronically Scanned Array (AESA) radar, Top Aces’ proprietary Advanced Aggressor Mission System (AAMS) allows its aircraft to simulate the capabilities of modern-day opponents in air-to-air combat. With flight testing and certification of the AAMS complete, Top Aces plans to start demonstrating this revolutionary new technology to its customers this summer. About Top Aces The purpose of Top Aces Corp. is to prepare the next generation of air combat leaders with advanced adversary training services. When Top Aces’ first F-16 fighters arrived at its facilities in Mesa, Arizona in early 2021, it made history as the first commercial company in the world to offer the supersonic F-16. Top Aces’ modern aggressor fleet, innovative technology, and very experienced pilots and staff provide highly professional and credible adversary air training. For further information, please visit . Media contact: Russ Quinn President, Top Aces Corp. media@topaces.com +1 480-792-6200 Photos accompanying this announcement are available at

100 项与 F16 IL2 fusion protein(Philogen SpA) 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
转移性Merkel细胞癌	临床1期	奥地利	Philogen SpA	2013-10-25
乳腺癌	临床1期	意大利	Philogen SpA	2008-06-01
非小细胞肺癌	临床1期	意大利	Philogen SpA	2008-06-01
转移性Merkel细胞癌	临床前	西班牙	Philogen SpA	2013-10-25
血管肉瘤	临床前	欧洲	Philogen SpA	-
梅克尔细胞癌	临床前	波兰	Philogen SpA	-
转移性Merkel细胞癌	药物发现	英国	Philogen SpA	2013-10-25
转移性Merkel细胞癌	药物发现	法国	Philogen SpA	2013-10-25
转移性Merkel细胞癌	药物发现	丹麦	Philogen SpA	2013-10-25

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临床结果

适应症

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01131364 (Pubmed) 人工标引	临床1/2期	实体瘤 \| 转移性乳腺癌	29	doxorubicin+F16-IL2 (Combination therapy with escalating doses)	(鑰積鬱窪積築淵製鬱廠) = 鏇築範繭窪鹽鬱簾鹽選觸淵網獵鏇積淵鬱蓋淵 (範遞鹹遞淵範蓋壓鬱壓 )	积极	2015-01-01
				doxorubicin+F16-IL2 (received the drug combination at the RD)	(鑰積鬱窪積築淵製鬱廠) = 襯艱鹹憲願襯衊選遞廠觸淵網獵鏇積淵鬱蓋淵 (範遞鹹遞淵範蓋壓鬱壓 )