Dose-escalation Sequention Cohort Study of Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GNR-084 in Patients With Refractory or Relapse Acute Lymphoblastic B-cell Precursor Leukemia.

It is an open-label dose-escalating study in sequential cohorts to assess safety and pharmacokinetics of GNR-084.

开始日期2020-10-15

申办/合作机构

Generium ZAO

100 项与 GNR-084 相关的临床结果

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100 项与 GNR-084 相关的转化医学

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100 项与 GNR-084 相关的专利（医药）

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项与 GNR-084 相关的文献（医药）

2022-10-20·Blood

A novel CD19/CD22/CD3 trispecific antibody enhances therapeutic efficacy and overcomes immune escape against B-ALL

Article

作者: Liu, Lei ; Li, Shuhong ; Liu, Ze-lin ; Zhao, Lijun ; Wen, Feiqiu ; Qi, Xuexiu ; Wei, Xiaoyi ; Liu, Dong ; Wang, Feng ; Cao, Yu J. ; Zhang, Ji-shuai

Abstract:

The bispecific T-cell engager (BiTE) blinatumomab against CD19 and CD3 has emerged as the most successful bispecific antibody (bsAb) to date; however, a significant proportion of patients do not respond to the treatments or eventually experience relapse after an initial response, and the recurrence rate increases significantly due to escape or downregulation of the CD19 antigen. To enhance antitumor efficacy and overcome potential immune escape, we developed a novel approach to design a CD19/CD22/CD3 trispecific antibody (tsAb) by site-specifically fusing anti-CD19 scFv (FMC63) and anti-CD22 nanobody (Nb25) to the defined sites of the CD3 antigen-binding fragment (Fab, SP34). This strategy allows for the optimal formation of immune synapses mediated by CD19/CD22/CD3 between target cells and T cells. Optimized tsAb can be superior for inducing T-cell−specific cytotoxicity and cytokine production against CD19+ and/or CD22+ tumor cells compared to other tsAb formats, and demonstrated significantly enhanced antitumor efficacy and the ability to overcome immune escape compared with the corresponding bsAbs alone or in combination, as well as with blinatumomab. In addition, tsAb treatment can lead to the long-term elimination of primary B-ALL patient samples in the PDX model and significantly prolong survival. This novel approach provides unique insight into the structural optimization of T-cell−redirected multispecific antibodies using site-specific recombination, and may be broadly applicable to heterogeneous and resistant tumor populations as well as solid tumors.

2022-02-01·Frontiers of medicine3区 · 医学

Preclinical characterization and comparison between CD3/CD19 bispecific and novel CD3/CD19/CD20 trispecific antibodies against B-cell acute lymphoblastic leukemia: targeted immunotherapy for acute lymphoblastic leukemia

3区 · 医学

Article

作者: Zhou, Yuebo ; Xu, Wenqian ; Wang, Jin ; Wang, Sisi ; Peng, Lijun ; Leung, Stewart ; Mi, Jian-Qing ; Zhu, Ziyan ; Yan, Xiaoqiang ; Kong, Yushan

The CD19-targeting bispecific T-cell engager blinatumomab has shown remarkable efficacy in patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia. However, several studies showed that blinatumomab has a short plasma half-life due to its low molecular weight, and thus its clinical use is limited. Furthermore, multiple trials have shown that approximately 30% of blinatumomab-relapsed cases are characterized by CD19 negative leukemic cells. Here, we design and characterize two novel antibodies, A-319 and A-2019. Blinatumomab and A-319 are CD3/CD19 bispecific antibodies with different molecular sizes and structures, and A-2019 is a novel CD3/CD19/CD20 trispecific antibody with an additional anti-CD20 function. Our in vitro, ex vivo, and in vivo experiments demonstrated that A-319 and A-2019 are potent antitumor agents and capable of recruiting CD3 positive T cells, enhancing T-cell function, mediating B-cell depletion, and eventually inhibiting tumor growth in Raji xenograft models. The two molecules are complementary in terms of efficacy and specificity profile. The activity of A-319 demonstrated superior to that of A-2019, whereas A-2019 has an additional capability to target CD20 in cells missing CD19, suggesting its potential function against CD19 weak or negative CD20 positive leukemic cells.

2021-11-11·Blood1区 · 医学

BTK inhibitors, irrespective of ITK inhibition, increase efficacy of a CD19/CD3-bispecific antibody in CLL

1区 · 医学

Article

作者: Ahn, Inhye E. ; Rader, Christoph ; Sun, Clare ; Baptista, Maria Joao ; Kendall, Ellen K. ; Gaglione, Erika M. ; Mhibik, Maissa ; Blackburn, Amy ; Eik, David ; Qi, Junpeng ; Keyvanfar, Keyvan ; Wiestner, Adrian

Abstract:

Bruton tyrosine kinase inhibitors (BTKis) are a preferred treatment of patients with chronic lymphocytic leukemia (CLL). Indefinite therapy with BTKis, although effective, presents clinical challenges. Combination therapy can deepen responses, shorten treatment duration, and possibly prevent or overcome drug resistance. We previously reported on a CD19/CD3-bispecific antibody (bsAb) that recruits autologous T-cell cytotoxicity against CLL cells in vitro. Compared with observations with samples from treatment-naïve patients, T cells from patients being treated with ibrutinib expanded more rapidly and exerted superior cytotoxic activity in response to the bsAb. In addition to BTK, ibrutinib also inhibits interleukin-2 inducible T-cell kinase (ITK). In contrast, acalabrutinib, does not inhibit ITK. Whether ITK inhibition contributes to the observed immune effects is unknown. To better understand how BTKis modulate T-cell function and cytotoxic activity, we cultured peripheral blood mononuclear cells (PBMCs) from BTKi-naive and ibrutinib- or acalabrutinib-treated CLL patients with CD19/CD3 bsAb in vitro. T-cell expansion, activation, differentiation, and cytotoxicity were increased in PBMCs from patients on treatment with either BTKi compared with that observed for BKTi-naïve patients. BTKi therapy transcriptionally downregulated immunosuppressive effectors expressed by CLL cells, including cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and CD200. CTLA-4 blockade with ipilimumab in vitro increased the cytotoxic activity of the bsAb in BTKi-naïve but not BTKi-treated PBMCS. Taken together, BTKis enhance bsAb-induced cytotoxicity by relieving T cells of immunosuppressive restraints imposed by CLL cells. The benefit of combining bsAb immunotherapy with BTKis needs to be confirmed in clinical trials.

项与 GNR-084 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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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
前体B细胞急性淋巴细胞白血病	临床2期	俄罗斯	Generium ZAO	2020-10-15
难治性 B 细胞急性淋巴细胞白血病	临床2期	俄罗斯	Generium ZAO	2020-10-15
急性髓性白血病	临床1期	俄罗斯	Generium ZAO	-