An open-label, Phase I/II trial to determine the maximum tolerated doseand investigate safety, pharmacokinetics and efficacy of BI 836858 incombination with decitabine in patients with acute myeloid leukemia - -

开始日期2017-11-23

申办/合作机构

Boehringer Ingelheim Italia SpA

EUCTR2015-002892-30-ES / Unknown status临床1/2期

An open-label, Phase I/II trial to determine the maximum tolerated dose and investigate safety, pharmacokinetics and efficacy of BI 836858 in combination with decitabine in patients with acute myeloid leukemia

开始日期2017-07-03

申办/合作机构

Boehringer Ingelheim España SA

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

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100 项与 BI-836858 相关的临床结果

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100 项与 BI-836858 相关的转化医学

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100 项与 BI-836858 相关的专利（医药）

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项与 BI-836858 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: Rueter, Bjoern ; Bornhäuser, Martin ; Berdel, Wolfgang E. ; Altvater, Bianca ; Ruhnke, Leo ; Hescheler, Daniel ; Wermke, Martin ; Matasci, Mattia ; Angenendt, Linus ; Mikesch, Jan-Henrik ; Röllig, Christoph ; Kessler, Torsten ; Hartmann, Wolfgang ; Schäfers, Michael ; Scheller, Annika ; Berdel, Andrew F. ; Schliemann, Christoph ; Lenz, Georg ; Rossig, Claudia ; Hemmerle, Teresa ; Gerwing, Mirjam ; Stelljes, Matthias ; Neri, Dario ; Wethmar, Klaus

Abstract:

Natural 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.

2018-02-09·Oncotarget

Polo-like kinase inhibitor volasertib marginally enhances the efficacy of the novel Fc-engineered anti-CD33 antibody BI 836858 in acute myeloid leukemia

Article

作者: Rueter, Bjoern ; Walsh, Katherine ; Mo, Xiaokui ; Mani, Rajeswaran ; Gopalakrishnan, Bhavani ; Klisovic, Rebecca ; Muthusamy, Natarajan ; Heider, Karl-Heinz ; Blum, William ; Walker, Alison ; Waizenegger, Irene C. ; Vasu, Sumithira ; Bhatnagar, Bhavana ; Cheney, Carolyn ; Bucci, Donna

Acute myeloid leukemia (AML) is the second most common type of leukemia in adults. Incidence of AML increases with age with a peak incidence at 67 years. Patients older than 60 years have an unfavorable prognosis due to resistance to conventional chemotherapy. Volasertib (BI 6727) is a cell-cycle regulator targeting polo-like kinase which has been evaluated in clinical trials in AML. We evaluated effects of volasertib in primary patient samples and NK cells. At equivalent doses, volasertib is cytotoxic to AML blasts but largely spares healthy NK cells. We then evaluated the effect of volasertib treatment in combination with BI 836858 on primary AML blast samples using antibody-dependent cellular cytotoxicity (ADCC) assays. Volasertib treatment of NK cells did not impair NK function as evidenced by comparable levels of BI 836858 mediated ADCC in both volasertib-treated and control-treated NK cells. In summary, volasertib is cytotoxic to AML blasts while sparing NK cell viability and function. Higher BI 836858 mediated ADCC was observed in patient samples pretreated with volasertib. These findings provide a strong rationale to test combination of BI 836858 and volasertib in AML.

2017-10-01·Leukemia1区 · 医学

Novel therapeutic approach to improve hematopoiesis in low risk MDS by targeting MDSCs with the Fc-engineered CD33 antibody BI 836858

1区 · 医学

Article

作者: McGraw, K L ; Wei, S ; Djeu, J ; Lancet, J ; Heider, K-H ; Eksioglu, E A ; Wei, M ; Chen, X ; Rueter, B ; List, A ; Burnette, A ; Basiorka, A A ; Cheng, P ; Komrokji, R

We recently reported that the accumulation of myeloid-derived suppressor cells (MDSC), defined as CD33⁺HLA-DR^-Lin^-, has a direct role in the pathogenesis of myelodysplastic syndrome (MDS). In particular, CD33 is strongly expressed in MDSC isolated from patients with MDS where it has an important role in MDSC-mediated hematopoietic suppressive function through its activation by S100A9. Therefore, we tested whether blocking this interaction with a fully human, Fc-engineered monoclonal antibody against CD33 (BI 836858) suppresses CD33-mediated signal transduction and improves the bone marrow microenvironment in MDS. We observed that BI 836858 can reduce MDSC by antibody-dependent cellular cytotoxicity, which correlated with increases in granule mobilization and cell death. BI 836858 can also block CD33 downstream signaling preventing immune-suppressive cytokine secretion, which correlates with a significant increase in the formation of CFU-GM and BFU-E colonies. Activation of the CD33 pathway can cause reactive oxygen species (ROS)-induced genomic instability but BI 836858 reduced both ROS and the levels of double strand breaks and adducts (measured by comet assay and γH2AX). This work provides the ground for the development of a novel group of therapies for MDS aimed at MDSC and their disease-promoting properties with the goal of improving hematopoiesis in patients.

项与 BI-836858 相关的新闻（医药）

2021-03-20

·生物制药小编

CD33：AML最具潜力的靶点；单抗，双抗，三抗，ADC均有布局

▲限时免费参会名额倒计时🔥，1600+已报名急性髓细胞性白血病(AML)是一种以髓系祖细胞的分化阻滞和克隆增殖为特征的疾病。长期以来一直采用蒽环类和阿糖胞苷化疗来治疗年轻患者，其次是造血干细胞移植治疗中、高风险患者。老年患者（≥60岁）和表现不佳的患者死亡率较高，老年患者5年总生存率总生存率约为10%。寻找一个可成药的靶点，对于AML的治疗至关重要。如慢性髓细胞性白血病（CML），伊马替尼可以抑制ABL酪氨酸激酶的活性，特异性地抑制ABL的表达和BCR-ABL细胞的增殖，从而治疗CML。但是AML异质性很强，几个突变（如IDH1/2 和 FLT3）都不太容易成药。 CD33：AML最具潜力的靶点 CD33是67KD糖基化跨膜蛋白，属于Siglec家族。在交联或者配体结合后激活，介导抑制信号，调节细胞内钙动员、细胞粘附、白血病细胞凋亡、髓系细胞成熟和细胞因子的产生等。 Siglec家族（文献6）在分化过程中，成熟粒细胞上CD33降低，但在巨噬细胞、单核细胞和树突状细胞上保留。CD33在非造血组织中的表达有限，但在AML细胞中高表达。此外，现已证实在白血病祖细胞也表达CD33，使该分子成为一个非常有潜力的AML的治疗靶点。 ADC药物 Gentuzumab ozogamicin Gentuzumab ozogamicin (Mylotarg, CMA-676; Wyeth Laboratories, Philadelphia, Pennsylvania)，是人IgG4 CD33单克隆抗体（hP67.6）偶联calicheamicin衍生物，DAR为2-3，包含约50%裸抗。 2017年9月被FDA批准用于成人新确诊的CD33阳性急性髓细胞白血病（AML）、成人复发或难治性AML和2岁及儿科患者的AML。 Vadastuximab Talirine Vadastuximab talirine (SGN-CD33A, 33A) 由Seagen Inc.开发。CD33单克隆抗体通过蛋白酶可切割的linker偶联pyrrolobenzodiazepine 二聚体（破坏DNA修复，诱导肿瘤细胞死亡）。 FDA于2016年12月暂停或部分暂停了4个1期试验，此前6名患者发生了4起致命事件。临床搁置于2017年3月解除，但2017年6月19日，所有与vadastuximab相关的临床试验均停止，因为死亡人数过多。 AVE9633 AVE9633是CD33 IgG1单抗与DM-4偶联。因为未观察到明显的临床活性，2009年赛诺菲已经终止了AVE9633的临床研究（NCT00543972）。 IMGN779 IMGN779 (ImmunoGen, Inc., Waltham, Massachusetts)，由CD33单克隆抗体偶联indolinobenzodiazeprine pseudodimers（烷化剂）。进行了一项临床研究（NCT02674763）。已有50例患者接受IMGN779，没有剂量限制毒性（DLT）。治疗不良事件包括发热性中性粒细胞减少，鼻出血，恶心，腹泻，疲劳，腹痛和低钾血症。总的来说，24例可测量的循环blasts患者中有19例（79%）的blasts计数减少。初步结果安全有效。单克隆抗体药物 Lintuzumab Lintuzumab由Actinium Pharmaceuticals开发，是一种人源化抗体，与表达CD33的AML细胞结合，通过CDC或者ADCC直接诱导细胞死亡。一项临床211名60岁以上AML患者接受低剂量环他滨和Lintuzumab或安慰剂。在第一个28天的周期中，每周服用600毫克，然后又每隔一周服用一次。两组之间的总体生存率没有差异，亚组分析也没有从治疗中受益的患者。临床未获得明显进展。该药剂已进一步发展为放射性同位素Lintuzumab-Ac225,在临床研究(NCT03441048) ,依然未发现明显的疗效。 BI 836858 全人IgG1抗CD33抗体，增强与FcɣRIIIa的结合，以强其ADCC活性。Phase1b的初步结果报告了31例接受BI836858治疗的结果，五例患者获得CR/完全反应另有4例达到形态无白血病状态。双特异性抗体 AMG330（Amgen） AMG330是一种CD33/CD3双特异性T细胞接合(BiTE)抗体结构，将细胞毒性T细胞导向到CD33表达的AML细胞，杀死靶细胞。临床前显示有效，目前在1期临床（NCT02520427）。强生的BiTE JNJ-67371244也在1期临床（NCT03915379). AMV564（Amphivena Therapeutics） CD33/CD3双抗，采用了Tandem技术，分子量106KD，半衰期8.72-19.2小时。对复发/难治性AML患者进行了1、3+3剂量爬坡研究。初步结果，19名患者持续静脉输液超过14天，未见DLTs或治疗相关等级≥3不良事件。在100μg/天的队列中，1例患者获得完全反应， 1例有PR，2例有稳定的疾病。目前研究还在进行（NCT03144245：Study of AMV564 in Patients With AML）三特异性抗体（TriKE） 161533 TriKE（GT Biopharma） 161533 TriKE （CD16/IL-15/CD33）通过靶向CD33阳性的恶性细胞以及CD33髓系衍生抑制细胞(MDSC)，增强自然杀伤细胞功能，诱导靶向CD33的抗肿瘤反应。目前正在进行1/2期临床研究，NCT03214666，GTB-3550 (CD16/IL-15/CD33) Tri-Specific Killer Engager (TriKE™) for High Risk Heme Malignancies。小编总结 AML是一种恶性程度高的血液肿瘤，高表达CD33。目前单抗，双抗，三抗，ADC均有企业布局，Mylotarg已经被FDA批准。虽然和所有药物开发类似，困难重重，但是CD33依旧是AML最具潜力的开发靶点。参考文献 1.Amadori S, Suciu S, Selleslag D, et al. Gemtuzumab ozogamicin versus best supportive care in older patients with newly diagnosed acute myeloid leukemia unsuitable for intensive chemotherapy: results of the randomized phase III EORTC-GIMEMA AML-19 trial. J Clin Oncol. 2016;34(9): 972-979. 2.Kovtun Y, Noordhuis P, Whiteman KR, et al. IMGN779, a Novel CD33-targeting antibody–drug conjugate with DNAalkylating activity, exhibits potent antitumor activity in models of AML. Mol Cancer Ther. 2018;17(6):1271-1279. 3.Atallah EL, Orozco JJ, Craig M, et al. A Phase 2 study of actinium-225 (225Ac)-lintuzumab in older patients with untreated acute myeloid leukemia (AML) - interim analysis of 1.5 μci/Kg/dose. Blood. 2018;132(suppl 1):1457-1457. 4.Blum W, Ruppert AS, Mims AS, et al. Phase 1b dose escalation study of BI 836858 and azacitidine in previously untreated AML: results from beatAMLS2. Blood. 2018;132(suppl 1):4053-4053. 5.Joseph E.Maakaron, et al，CD33-Targeted Therapies: Beating the Disease or Beaten to Death?，The Journal of Clinical Pharmacology，DOI: 10.1002/jcph.1730 6.Huan Cao and Paul R. Crocker，Evolution of CD33-related siglecs: regulating host immune functions and escaping pathogen exploitation? Immunology, 132, 18–26 版权声明：本文转自生物制药小编，如不希望被转载的媒体或个人可与我们联系，我们将立即删除【关于药融圈】药融圈围绕我国生物医药产业链，针对生物医药大数据、技术和资本投资、药融园(产业园)等开展系列系统性工作，促进我国生物医药产业健康发展，完善产业链，共同面对全球合作和竞争。点分享点点赞点在看

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100 项与 BI-836858 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
急性髓性白血病	临床2期	美国	Boehringer Ingelheim GmbH	2016-06-16
急性髓性白血病	临床2期	德国	Boehringer Ingelheim GmbH	2016-06-16
急性髓性白血病	临床2期	意大利	Boehringer Ingelheim GmbH	2016-06-16
急性髓性白血病	临床2期	西班牙	Boehringer Ingelheim GmbH	2016-06-16
骨髓增生异常综合征	临床2期	美国	Boehringer Ingelheim GmbH	2015-01-22
骨髓增生异常综合征	临床2期	德国	Boehringer Ingelheim GmbH	2015-01-22
复发性急性髓细胞白血病	临床1期	美国	Boehringer Ingelheim GmbH	2012-09-13

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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


NCT02632721 (CTgov)	临床1/2期	急性髓性白血病	49	BI 836858+Decitabine (Phase I Dose Escalation: BI 836858 20 mg + Decitabine (Intensive))	構範廠膚構選襯蓋鏇艱(築夢網壓獵膚蓋鬱顧壓) = 鏇築構網淵鏇顧淵顧鬱壓夢願夢艱醖淵憲選構 (窪繭齋鏇鬱選遞簾願築, 願顧顧鹽蓋淵顧衊繭衊 ~ 遞網餘憲鏇衊齋鏇憲選) 更多	-	2024-03-19
				BI 836858+Decitabine (Phase I Dose Escalation: BI 836858 40 mg + Decitabine (Intensive))	構範廠膚構選襯蓋鏇艱(築夢網壓獵膚蓋鬱顧壓) = 鬱選網願選膚遞簾廠範壓夢願夢艱醖淵憲選構 (窪繭齋鏇鬱選遞簾願築, 築淵壓衊憲鑰築齋鹹顧 ~ 憲窪窪範襯鹹廠衊壓範) 更多