The purpose of this study is to determine if IMC-EB10 is safe for participants with leukemia, and also to determine the best dose of IMC-EB10 to give to participants.

开始日期2009-06-01

申办/合作机构

Eli Lilly & Co.

100 项与 IMC-EB10 相关的临床结果

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100 项与 IMC-EB10 相关的转化医学

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100 项与 IMC-EB10 相关的专利（医药）

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项与 IMC-EB10 相关的文献（医药）

2006-05-01·Cancer research1区 · 医学

IMC-EB10, an Anti-FLT3 Monoclonal Antibody, Prolongs Survival and Reduces Nonobese Diabetic/Severe Combined Immunodeficient Engraftment of Some Acute Lymphoblastic Leukemia Cell Lines and Primary Leukemic Samples

1区 · 医学

Article

作者: Huso, David ; Nguyen, Bao ; Kim, Kyu-Tae ; Hicklin, Daniel J. ; Small, Donald ; Witte, Larry ; Piloto, Obdulio ; Li, Yiwen ; Brown, Patrick

Abstract:

The class III receptor tyrosine kinase FLT3 is expressed on the blasts of >90% of patients with B-lineage acute lymphoblastic leukemias (ALL). In addition, it is expressed at extremely high levels in ALL patients with mixed lineage leukemia rearrangements or hyperdiploidy and is sometimes mutated in these same patients. In this report, we investigate the effects of treating ALL cell lines and primary samples with human anti-FLT3 monoclonal antibodies (mAb) capable of preventing binding of FLT3 ligand. In vitro studies, examining the ability of two anti-FLT3 mAbs (IMC-EB10 and IMC-NC7) to affect FLT3 activation and downstream signaling in ALL cell lines and primary blasts, yielded variable results. FLT3 phosphorylation was consistently inhibited by IMC-NC7 treatment, but in some cell lines, IMC-EB10 actually stimulated FLT3 activation, possibly as a result of antibody-mediated receptor dimerization. Through antibody-dependent, cell-mediated cytotoxicity, such an antibody could still prove efficacious against leukemia cells in vivo. In fact, IMC-EB10 treatment significantly prolonged survival and/or reduced engraftment of several ALL cell lines and primary ALL samples in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. This occurred even when IMC-EB10 treatment resulted in FLT3 activation in vitro. Moreover, fluorescence-activated cell sorting and PCR analysis of IMC-EB10-treated NOD/SCID mice surviving 150 days post-leukemic cell injection revealed that FLT3 immunotherapy reduced leukemic engraftment below the level of detection in these assays (<0.001%). Furthermore, in vivo IMC-EB10 treatment did not select for resistant cells, because cells surviving IMC-EB10 treatment remain sensitive to IMC-EB10 cytotoxicity upon retransplantation. In vivo studies involving either partial depletion or activation of natural killer (NK) cells show that most of the cytotoxic effect of IMC-EB10 is mediated through NK cells. Therefore, such an antibody, either naked or conjugated to radioactive isotopes or cytotoxic agents, may prove useful in the therapy of infant ALL as well as childhood and adult ALL patients whose blasts typically express FLT3. (Cancer Res 2006; 66(9): 4843-51)

2005-02-15·Cancer research1区 · 医学

Inhibitory Anti-FLT3 Antibodies Are Capable of Mediating Antibody-Dependent Cell-Mediated Cytotoxicity and Reducing Engraftment of Acute Myelogenous Leukemia Blasts in Nonobese Diabetic/Severe Combined Immunodeficient Mice

1区 · 医学

Article

作者: Huso, David ; Witte, Larry ; Small, Donald ; Levis, Mark ; Li, Yiwen ; Hicklin, Daniel J. ; Li, Hongli ; Wang, Mei-Nai ; Balderes, Paul ; Bassi, Rajiv ; Piloto, Obdulio ; Zhu, Zhenping ; Ludwig, Dale L.

Abstract:

Aberrant FLT3 expression and/or mutation plays a significant role in leukemogenesis. This has prompted the development of selective small molecule tyrosine kinase inhibitors against FLT3. However, like most tyrosine kinase inhibitors, those against FLT3 are not completely specific and at the doses required to completely inhibit target, significant toxicities may occur. In addition, tyrosine kinase inhibitors for other kinases have been shown to select for cells that become resistant. To overcome some of these limitations we developed two fully human phage display monoclonal antibodies against FLT3 (IMC-EB10 and IMC-NC7). These antibodies inhibited ligand-mediated activation of wild-type FLT3 and constitutively activated mutant FLT3 and in most cell types affected downstream STAT5, AKT, and mitogen-activated protein kinase activation. In addition to interfering with FLT3 signaling, IMC-EB10 and, to a significantly lesser extent, IMC-NC7 initiated antibody-dependent cell-mediated cytotoxicity on FLT3-expressing cells. When IMC-EB10 was used in vivo to treat nonobese diabetic/severe combined immunodeficient mice given injections of primary FLT3/ITD acute myelogenous leukemia samples or myeloid cell lines with FLT3 expression, it significantly decreased engraftment of leukemic cells and increased survival, respectively. In contrast, IMC-EB10 treatment did not reduce engraftment of normal human CD34+ cord blood cells nor did it show any significant inhibition of normal murine hematopoiesis. Thus, these types of antibodies have the potential to be safe and effective new therapeutic agents for acute myelogenous leukemia and possibly other FLT3-expressing malignancies.

2004-08-15·Blood1区 · 医学

Suppression of leukemia expressing wild-type or ITD-mutant FLT3 receptor by a fully human anti-FLT3 neutralizing antibody

1区 · 医学

Article

作者: Wu, Yan ; Small, Donald ; Li, Yiwen ; Lu, Dan ; Zhang, Haifan ; Pytowski, Bronislaw ; Li, Hongli ; Kussie, Paul ; Zhu, Zhenping ; Hicklin, Daniel J. ; Balderes, Paul ; Piloto, Obdulio ; Wang, Mei-Nai ; Bohlen, Peter ; Witte, Larry ; Bassi, Rajiv ; Ludwig, Dale L.

Abstract:

FMS-like tyrosine kinase 3 (FLT3), a class III receptor tyrosine kinase, is expressed at high levels in the blasts of approximately 90% of patients with acute myelogenous leukemia (AML). Internal tandem duplications (ITDs) in the juxtamembrane domain and point mutations in the kinase domain of FLT3 are found in approximately 37% of AML patients and are associated with a poor prognosis. We report here the development and characterization of a fully human anti-FLT3 neutralizing antibody (IMC-EB10) isolated from a human Fab phage display library. IMCEB10 (immunoglobulin G1 [IgG1], κ) binds with high affinity (KD = 158 pM) to soluble FLT3 in enzyme-linked immunosorbent assay (ELISA) and to FLT3 receptor expressed on the surfaces of human leukemia cell lines. IMC-EB10 blocks the binding of FLT3 ligand (FL) to soluble FLT3 in ELISA and competes with FL for binding to cell-surface FLT3 receptor. IMC-EB10 treatment inhibits FL-induced phosphorylation of FLT3 in EOL-1 and EM3 leukemia cells and FL-independent constitutive activation of ITD-mutant FLT3 in BaF3-ITD and MV4;11 cells. Activation of the downstream signaling proteins mitogen-activated protein kinase (MAPK) and AKT is also inhibited in these cell lines by antibody treatment. The antibody inhibits FL-stimulated proliferation of EOL-1 cells and ligand-independent proliferation of BaF3-ITD cells. In both EOL-1 xenograft and BaF3-ITD leukemia models, treatment with IMC-EB10 significantly prolongs the survival of leukemia-bearing mice. No overt toxicity is observed with IMC-EB10 treatment. Taken together, these data demonstrate that IMC-EB10 is a specific and potent inhibitor of wild-type and ITD-mutant FLT3 and that it deserves further study for targeted therapy of human AML. (Blood. 2004;104:1137-1144)

项与 IMC-EB10 相关的新闻（医药）

2022-06-12

·生物制药小编

CD20之外，其余10个血液瘤双抗热门靶点

2022年6月8日，罗氏宣布Lunsumio® (mosunetuzumab)获得欧盟附加条件上市许可，成为全球第一个上市的CD3/CD20双抗，获批是基于其phase I/II GO29781 study（NCT02500407），CR为60%，ORR为80%。除此之外，Roche还手握另外一个基于2:1 CrossMab 的CD3/CD20双抗，Glofitamab (RO7082859)。具体可以阅读：Roche 2022有望上市抗体药，多为免疫靶点。血液肿瘤除去CD20之外，尚有10个热门靶点，就其TCE双抗项目进展稍作梳理。01GPRC5D（多发性骨髓瘤）GPRC5D(GPCR class C group 5 member D)分子量39kDa，孤儿G蛋白偶联受体，通常只在毛囊中表达。GPRC5D在多发性骨髓瘤中过表达，且不太可能从细胞膜上脱落，可以避免因脱落引起的疗效下降。Talquetamab（JNJ-64407564）Janssen Talquetamab（GPRC5D/CD3），采用Genmab的Duobody双抗技术平台构建（immunoglobulin G4 proline, alanine, alanine，IgG4PAA)。临床前数据，可以有效激活T细胞（非NK细胞），杀伤原代多发性骨髓瘤病人细胞。Blood Adv . 2021T细胞效应分子，显著升高，包括TNF-α、IFN-γ、IL-2、颗粒酶B等。Blood Adv . 2021可以检索到7项多发性骨髓瘤临床实验在开展，包括单药治疗复发或难治性多发性骨髓瘤NCT04634552（2期），NCT03399799（1期）。今年ASCO上University Medical Center Utrecht的Monique C. Minnema报道了NCT03399799数据，ORR可达70%，PR 57%。国内目前驯鹿、启源等开展了GPRC5D CAR-T。02FLT3（急性髓系白血病)FLT3（FMS-like tyrosine kinase 3）分子量140-160KD，是一种1型跨膜蛋白，受体酪氨酸激酶。FLT3通过与其配体结合，促进造血细胞的增殖和分化。FLT3在急性髓系白血病（AML）中过表达，并在大约30%的AML患者中检测到其突变，导致AML患者预后不良。因为FLT3本身是酪氨酸激酶，所以小分子抑制剂是开发重点，全球有几十个药物在开发，安斯泰来制药吉瑞替尼片国内已经上市。礼来的LY3012218(IMC-EB10)是一种靶向FLT3的人单抗，因为缺乏活性，已经停止开发。AMG427AMG427，是Amgen的CD3/FLT3双抗，目前在AML的1期临床（NCT03541369）CLN-049 CLN-049 是CULLINAN ONCOLOGY（Nasdaq：CGEM）开发的CD3/FLT3双抗，目前在进行R/R-AML的1期临床（NCT05143996）。03CLEC12A（急性髓系白血病)CLEC12A（C-type lectin domain family 12 member A），是一种31kda髓系抑制受体，一种重要的炎症负调控因子。在AML中特异性表达，在约90%的AML患者中观察到，与AML患者预后不良密切相关但在正常的造血干细胞和祖细胞中不表达。MCLA-117Merus N.V.开发的CD3/CLEC12A，采用低亲和力CD3抗体臂和高亲和力CLEC12A抗体臂。Merus N.V官网临床前的数据显示可以有效激活并扩增病人T细胞，并有效杀伤病人AML细胞Merus N.V官网目前开展了一项AML临床（NCT03038230）。04CD123（急性髓系白血病)CD123是IL-3Rα，75KD的1型跨膜蛋白，它在白血病干细胞中过表达，但在正常造血干细胞中低表达或不表达。CD123与IL-3结合，可导致各种血液癌的生存和增殖，如AML、ALL和HL，在AML，CD123表达与病人不良预后相关。Flotuzumab (MGD-006)靶向CD123XCD3，采用MacroGenics的DART技术。目前开展了AML的2期临床（NCT04582864）。SAR440234（Sanofi-Aventis）CD123XCD3，2022年赛诺菲已经终止了AML临床研究（NCT03594955）JNJ-63709178杨森开发CD123 x CD3 DuoBody 双抗，NCT02715011在2021年完成，未继续。APVO436（Aptevo）靶向CD123XCD3，采用ADAPTIR Technology ，包含4个scFV，融合突变的Fc（没有ADCC和CDC活性）https://aptevotherapeutics.com/adaptir/NCT03647800，Study of APVO436 in Patients With AML or MDS，phase1，部分队列有CR。Vibecotamab/XmAb14045（Xencor）靶向CD123XCD3，采用scFv-Fab。目前在进行AML 和 MDS的2期临床（NCT05285813），与诺华的合作已经终止。05 CD33（急性髓系白血病)又名Siglec-3，调节免疫细胞功能，如吞噬、细胞因子的释放和凋亡，在急性髓系白血病中过表达。据报道，在接受化疗的AML患者中，CD33高表达患者的OS率为42.9%，而CD33低表达患者的OS率为67.5%。AMG330AMG330, 一个短效BiTE CD33/CD3双抗。不过目前Amgen已经终止了两项临床开发（ NCT02520427，NCT04478695）.AMG673Amgen的AMG673作为另外一个 CD33/CD3双抗，也被终止了临床开发（NCT03224819）JNJ-67371244杨森的JNJ-67371244，是基于Duobody的IgG样双抗，目前处于激活未招募状态。（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。huCD33-Bi Specific(Y-mAbs Therapeutics)Y-mAbs Therapeutics开发的CD33/CD3双抗，目前开始进行R/R-AML 1期临床研究（NCT05077423）。06CD38(多发性骨髓瘤)CD38是45KD的2型跨膜蛋白，在多发性骨髓瘤细胞中过表达，但在正常淋巴细胞和髓系细胞中低表达。单抗达雷妥尤单抗注射液说明书已在国内上市，治疗单药治疗复发和难治性多发性骨髓瘤成年患者。ISB 1342Ichnos Sciences开发的CD38/CD3双抗，目前在1期临床NCT03309111 Study of ISB 1342, a CD38/CD3 Bispecific Antibody, in Subjects With Previously Treated Multiple Myeloma。XmAb968 (CD38 x CD3)Ichnos Sciences SA NCT03309111 Study of ISB 1342, a CD38/CD3 Bispecific Antibody, in Subjects With Previously Treated Multiple MyelomaY150武汉友之友开发的CD38/CD3双抗，目前开始多发性骨髓瘤1期临床，NCT05011097 A Phase I Clinical Trial of Y150 in the Treatment of Relapsed or Refractory Multiple Myeloma07 CD30(霍奇金淋巴瘤)CD30是一种120-kDa的I型跨膜蛋白，属于肿瘤坏死因子受体家族。它通过NF-κB和MAPK通路，在淋巴细胞活化和增殖中发挥关键作用，具有抗凋亡和促存活作用。它在造血系统恶性肿瘤中过表达，包括霍奇金淋巴瘤(HL)和NHL，并与这些细胞存活相关。目前Seagen的CD30-ADC药物Adcetris® (brentuximab vedotin)，2011年批准上市。目前还没有TCE双抗开发。AFM13Affimed Therapeutics开发的NK细胞四价双特异性抗体（CD30/CD16A）。J Hematol Oncol . 2015 Aug 1;8:96.AACR 2022, MD Anderson Yago Nieto, MD, PhD报道了NCT04074746初步结果 89% ORR，62%CR。08 CD22(急性淋巴细胞白血病)CD22是一种140-kda的I型跨膜蛋白，是BCR的抑制性共受体，调节B细胞的过度刺激。CD22在多种B细胞淋巴瘤中过表达，如CLL、ALL和NHL，但在未成熟的B细胞和浆细胞上表达水平较低，是B细胞白血病良好的治疗靶点。2017年Pfizer/Wyeth的CD22-ADC药物Besponsa® (inotuzmab ozogamicin)获批上市，治疗复发/难治性(R/R)B细胞急性淋巴细胞白血病。JNJ-75348780杨森开发的CD22/CD3双抗，目前开始了CLL和NHL的1期临床（NCT04540796），同时也在国内开始了相关临床（JXSL2200017，JXSL2200016）09CD19( B 细胞急性淋巴细胞白血病和NHL)CD19是一种95kda的I型跨膜蛋白，是BCR的共受体，调节细胞生长。它在大多数B细胞恶性肿瘤中过表达，如ALL、非霍奇金淋巴瘤(NHL)和慢性淋巴细胞白血病(CLL)。CD19的过表达促进了这些B细胞恶性肿瘤的增殖和存活。博纳吐单抗（Blinatumomab）是第一个CD19/CD3单抗，2019年Amgen在中国上市了该产品，治疗成人复发或难治性前体 B 细胞急性淋巴细胞白血病。TNB-486TeneoTwo Inc开发，NCT04594642，A Study of TNB-486 in Subjects With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma，Phase1GNR-084AO GENERIUM，NCT04601584，GNR-084 Safety and Pharmacological Characteristics in Refractory or Relapse B-cell Precursor ALL， Phase1/2CLN-978 (NexGem)Cullinan 开发的CD19 X CD3 X HSA trispecific抗体，在CD19/CD3 BiTE双抗前，加了一个Vhh HSA抗体。目前尚未进入临床。https://www.cullinanoncology.com/ui/uploads/2022/05/nexgem-aacr-2022-poster-final-revised.pdf10 BCMA（多发性骨髓瘤）B细胞成熟抗原(BCMA)，随着传奇生物的Carvykti(西达基奥仑赛)上市，该靶点广为人知，是多发性骨髓瘤不可多得的优质靶点。BCMA是肿瘤坏死因子受体超家族成员17(TNFRSF17)，是一种20kda的III型跨膜蛋白。BCMA与其配体结合，如增殖诱导配体和B细胞激活因子，促进B细胞的存活。成熟靶点，辉瑞、新基、杨森、再生元等均有布局，上海岸迈等国内企业也已进入临床阶段。Elranatamab (PF-06863135) Elranatamab 是辉瑞开发的CD3/BCMA双抗，目前在进行多发性骨髓瘤1期临床。NCT05228470 Study Of Elranatamab (PF-06863135) Monotherapy in Chinese Participants With Refractory Multiple MyelomaCC-93269 Celgene 开发，NCT03486067 Study of CC-93269, a BCMA x CD3 T Cell Engaging Antibody, in Participants With Relapsed and Refractory Multiple MyelomaTeclistamab Janssen开发， NCT03145181 Dose Escalation Study of Teclistamab, a Humanized BCMA*CD3 Bispecific Antibody, in Participants With Relapsed or Refractory Multiple Myeloma (MajesTEC-1)REGN5458Regeneron开发，NCT03761108 First in Human (FIH) Study of REGN5458 in Patients With Relapsed or Refractory Multiple MyelomaTNB-383BTeneoOne Inc.开发，NCT03933735 A Study of TNB-383B in Participants With Relapsed or Refractory Multiple MyelomaEMB-06 上海岸迈开发， NCT04735575 A Ph1/2 Study of EMB-06 in Participants With Relapsed or Refractory Myeloma参考资料 Roche官网新闻：https://www.roche.com/media/releases/med-cor-2022-06-08临床实验进展：https://clinicaltrials.gov/Christie P M Verkleij et al，Preclinical activity and determinants of response of the GPRC5DxCD3 bispecific antibody talquetamab in multiple myeloma，Blood Adv . 2021 Apr 27;5(8):2196-2215.https://merus.nl/app/uploads/2019/02/MCLA-117-Merus-SITC2016.pdfMichael J. Slade, Geoffrey Uy，CD123 bi-specific antibodies in development in AML: What do we know so far?Best Practice & Research Clinical Haematology (2020）Jingjing Wu et al，AFM13: a first-in-class tetravalent bispecific anti-CD30/CD16A antibody for NK cell-mediated immunotherapy，J Hematol Oncol . 2015 Aug 1;8:96佰傲谷知识周边

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100 项与 IMC-EB10 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
难治性急性髓细胞白血病	临床1期	美国	Eli Lilly & Co.	2009-06-01
复发性急性髓细胞白血病	临床1期	美国	Eli Lilly & Co.	2009-06-01

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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


NCT00887926 (CTgov)	临床1期	复发性急性髓细胞白血病 \| 难治性急性髓细胞白血病	25	IMC-EB10 (IMC-EB10 5 to 30 mg/kg)	網糧繭鏇壓鬱範糧簾顧 = 廠襯醖網構艱窪鑰糧鏇網鹹壓憲構鬱觸廠鬱鑰 (淵遞醖構鏇窪獵選選夢, 齋繭鬱憲遞衊鏇齋簾憲 ~ 顧鑰衊簾廠壓淵窪衊願)	-	2019-09-11
NCT00887926 (CTgov)	临床1期	复发性急性髓细胞白血病 \| 难治性急性髓细胞白血病	25	IMC-EB10 (Cohort 1 - 5mg/kg IMC-EB10)	壓襯廠憲窪艱鏇製衊獵(鹹網鏇範獵構蓋壓襯廠) = 醖餘膚夢獵顧齋築遞願糧鬱願蓋觸製憲觸衊糧 (顧鑰衊築餘廠網鹹艱鬱, 25) 更多	-	2019-09-11
NCT00887926 (ASCO2015)	临床1期	复发性急性髓细胞白血病	24	LY3012218	糧衊選齋網簾獵築餘觸(憲簾衊壓衊鑰製觸蓋選) = dose limiting toxicity 淵夢網齋獵壓鏇齋簾繭 (鏇蓋淵衊壓窪鏇醖選選 ) 更多	不佳	2015-05-20