The purpose of this research study is to determine if the study drug, flotetuzumab, is safe and tolerable when given to participants with acute myeloid leukemia (AML) that has relapsed after transplant.

开始日期2022-10-20

申办/合作机构

The Sidney Kimmel Comprehensive Cancer Center

[+2]

NCT05063123

/ Withdrawn临床2期IIT

A Phase II Multicenter Study to Assess the Feasibility and Efficacy of the Addition of an Interphase Cycle With Flotetuzumab Prior to Start Conditioning for an Allogeneic HCT in AML With MRD After 2 Cycles of Intensive Chemotherapy

Patients who have measurable residual disease (MRDpos, defined as MRD > 0.1% by flowcytometry or detectable mutant Nucleophosmin 1 (NPM1) by quantitative polymerase chain reaction (qPCR) after two cycles of intensive chemotherapy) prior to start conditioning for an allogeneic Hematopoietic Cell Transplantation (HCT) have a very high risk of relapse after transplantation. Important questions in the field are whether patients with MRD after intensive chemotherapy can be converted to MRD negativity (i.e. undetectable MRD, MRDneg) and whether this conversion impacts on the relapse rate after transplantation. This trial aims to develop effective "interphase" treatment for patients in morphological complete remission (CR) with MRD after at least 2 cycles of intensive chemotherapy and prior to start conditioning for an allogeneic HCT. Flotetuzumab, a bispecific antibody-based molecule against CD3 and CD123 in a dual-affinity re-targeting antibody (DART®) format is a new treatment modality based on immunomodulation. The rationale to use flotetuzumab in this study is: 1) its antileukemic activity reported in R/R AML; 2) its limited extra-medullary (i.e. tissue) toxicity; and 3) its short halflife.

开始日期2022-01-01

申办/合作机构

Hemato-Oncologie voor Volwassenen Nederland

NCT04582864

/ Terminated临床2期IIT

A Phase 2 Trial Evaluating the Efficacy of Flotetuzumab (MGD006) for Relapsed Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) Following Allogeneic Hematopoietic Cell Transplantation (Allo-HCT)

The investigators hypothesize that flotetuzumab for relapsed AML following allo-HCT will be safe, tolerable and may facilitate preferential immune effector cell retargeting of leukemic cells resulting in improved patient outcomes. Furthermore, administration of a donor lymphocyte infusion (DLI) (if available) in combination with flotetuzumab will be safe, tolerable and may provide additional therapeutic efficacy.

开始日期2021-05-20

申办/合作机构

Washington University School of Medicine

[+2]

100 项与 Flotetuzumab 相关的临床结果

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100 项与 Flotetuzumab 相关的转化医学

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100 项与 Flotetuzumab 相关的专利（医药）

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项与 Flotetuzumab 相关的文献（医药）

2025-12-02·EXPERT OPINION ON BIOLOGICAL THERAPY

Current status and future potential of CD123-based targeted therapies for acute leukemia

Review

作者: Aldoss, Ibrahim ; Arslan, Shukaib ; Stein, Anthony ; Aribi, Ahmed

INTRODUCTION:

Acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and blastic plasmacytoid dendritic cell neoplasm (BPDCN) are aggressive hematologic malignancies with poor outcomes, particularly in relapsed/refractory settings. CD123, the interleukin-3 receptor alpha chain, is highly expressed on leukemic blasts and leukemia stem cells, making it an attractive therapeutic target with limited expression on normal hematopoietic cells. CD123-directed therapies - including antibody-drug conjugates (ADCs), bispecific T-cell engagers (BiTEs), and CAR T-cell therapies - are under active investigation.

AREAS COVERED:

This review details the preclinical rationale, clinical development, efficacy, and toxicity of CD123-targeted therapies. It discusses completed and ongoing clinical trials for agents such as tagraxofusp, pivekimab sunirine, flotetuzumab, vibecotamab, and investigational CAR T-cell therapies (e.g. MB-102, UCART123v1.2). Toxicities, including myelosuppression, cytokine release syndrome (CRS), and hepatotoxicity - are characterized in detail, with attention to mitigation strategies. Future directions highlight combination regimens, switchable CAR designs, and biomarker-driven personalization.

EXPERT OPINION:

CD123-targeted therapy represents a promising yet challenging frontier in treating high-risk leukemias. While clinical activity has been demonstrated, especially in BPDCN, therapeutic durability and safety remain hurdles. Precision in antigen targeting, combination strategies, and toxicity management will be critical for successful integration of CD123-directed therapies into standard clinical practice.

2025-01-01·[Rinsho ketsueki] The Japanese journal of clinical hematology

[Novel HLA-mediated mechanisms of GVHD: multifaceted roles of HLA class II in GVHD and GVL].

Review

作者: Morita, Kaoru

HLA class II molecules play a central role in antigen presentation that underlies the pathogenesis of graft versus host disease (GVHD) following allogeneic hematopoietic stem cell transplantation. This review introduces the concept of "neo-self" antigens observed in autoimmune diseases and applies it to chronic GVHD, where DBY/HLA class II complexes trigger pathological B cell activation, complement deposition, and tissue fibrosis. In acute GVHD, non-hematopoietic epithelial cells such as intestinal epithelial cells also contribute to disease by presenting antigens via HLA class II. In acute myeloid leukemia relapse, downregulation of HLA class II on leukemic cells allows immune evasion, but this suppression can be reversed by IFN-γ or flotetuzumab, a CD123×CD3 bispecific antibody, restoring immunogenicity and potentially enhancing the graft versus leukemia (GVL) effect. Collectively, HLA class II molecules function not only in conventional antigen presentation to CD4⁺ T cells but also in neo-self antigen recognition, immune evasion, and tissue-specific disease expression. A deeper understanding of HLA class II biology may pave the way toward therapeutic strategies that separate GVHD from the GVL effect.

2023-04-06·Blood

Flotetuzumab and other T-cell immunotherapies upregulate MHC class II expression on acute myeloid leukemia cells

Article

作者: Ritchey, Julie K. ; Rimando, Joseph C. ; Christopher, Matthew J. ; Bonvini, Ezio ; DiPersio, John F. ; Christ, Stephanie ; Jayasinghe, Reyka ; Rettig, Michael P. ; Chendamarai, Ezhilarasi ; Kim, Miriam Y.

Abstract:

Acute myeloid leukemia (AML) relapse is one of the most common and significant adverse events following allogeneic hematopoietic cell transplantation (HCT). Downregulation of major histocompatibility class II (MHC-II) surface expression on AML blasts may represent a mechanism of escape from the graft-versus-malignancy effect and facilitate relapse. We hypothesized that T-cell immunotherapies targeting AML antigens would upregulate MHC-II surface expression via localized release of interferon gamma (IFN-γ), a protein known to upregulate MHC-II expression via JAK-STAT signaling. We demonstrate that flotetuzumab (FLZ), a CD123 × CD3 bispecific DART molecule, and chimeric antigen receptor expressing T cells targeting CD123, CD33, or CD371 upregulate MHC-II surface expression in vitro on a THP-1 AML cell line with intermediate MHC-II expression and 4 primary AML samples from patients relapsing after HCT with low MHC-II expression. We additionally show that FLZ upregulates MHC-II expression in a patient-derived xenograft model and in patients with relapsed or refractory AML who were treated with FLZ in a clinical trial. Finally, we report that FLZ-induced MHC-II upregulation is mediated by IFN-γ. In conclusion, we provide evidence that T-cell immunotherapies targeting relapsed AML can kill AML via both MHC-independent mechanisms and by an MHC-dependent mechanism through local release of IFN-γ and subsequent upregulation of MHC-II expression.

项与 Flotetuzumab 相关的新闻（医药）

2026-01-16

·中国生物器材网

T细胞衔接器(TCEs)的作用机制、分类、及TCE药物研发概览

本文来源于微信公众：智享药界作者：虎仔奶爸 T细胞接合剂（TCEs）是经过工程改造的免疫治疗分子，旨在通过桥接T细胞及其靶标来引导身体的免疫系统对抗肿瘤或感染细胞，从而引发强烈的细胞毒性反应。2014年，美国FDA批准了blinatumomab，这是一种针对CD3和CD19的TCE，用于治疗急性淋巴细胞白血病。正式开启TCE治疗不同的血液系统恶性肿瘤，如急性髓系白血病、多发性骨髓瘤、非霍奇金淋巴瘤和霍奇金淋巴瘤。截至2023年11月，市场上已有7种临床批准的TCE疗法。基于TCE的疗法仍然有其局限性；然而，改善TCE的特性，以及将基于TCE的疗法与其他形式的治疗相结合，有望找到治疗目前晚期疾病的方法。截至目前，市场上有9种临床批准的TCE疗法，所有这些疗法都用于治疗淋巴增生性疾病。表1. 截止2024年3月获批的用于血液肿瘤的TCE药物此外，2022年1月FDA批准Immunocore公司tebenafusp-tebn（Kimmtrak，gp100 (a melanoma-associated antigen) through ahigh-affinity T cell receptor (TCR) binding domain and an anti-CD3 T-cell-engaging domain），一种双特异性gp100肽HLA导向的CD3 T细胞接合剂，用于治疗HLA-a*02:01阳性的不可切除或转移性葡萄膜黑色素瘤成年患者。 2025年11月FDA批准Amgen公司Tarlatamab-dlle（Imdelltra, DLL3 on tumour cells and CD3 on T cells）用于患有广泛期小细胞肺癌（ES-SCLC）并在基于铂的化疗期间或之后疾病进展的成人。 TCEs作用机制： T细胞接合器（TCE）是一类有前景的免疫疗法，旨在利用T细胞的细胞还原潜力，而不需要识别特定的肽抗原。这些分子通过结合T细胞上的CD3/TCR复合物和癌症细胞表面上的肿瘤相关抗原（TAAs）来工作。这种反式结合促进了T细胞和癌症细胞之间的突触，从而触发细胞毒性。TCE代表了一种现成的精确方法，可以扩大受益于传统免疫疗法的患者群体。2014年，靶向B细胞CD19的双特异性T细胞接合器（BiTE™）blinatumomab（BLICYTO®）获得批准，标志着TCE发展的一个重要里程碑。从那时起，人们对开发针对血液系统和实体恶性肿瘤的各种肿瘤相关靶点的TCE越来越感兴趣。图1. TCEs 作用机制及原理 *TCE分子同时与TAAs和CD3结合，从而形成溶细胞突触。与CD3的结合会引发T细胞细胞毒性作用的激活信号的诱导，包括颗粒酶和穿孔素的释放，最终导致肿瘤细胞溶解。此外，TCE的刺激会触发T细胞室的增殖Fv-Based TCEs。 TCEs疗法优势比较：基于T细胞的癌症免疫疗法通过靶向和动员T细胞来根除恶性细胞，改变了癌症治疗的临床实践。根据作用机制的不同，基于T细胞的癌症免疫疗法主要可分为两类：一类是针对以免疫检查点抑制剂（ICIs）为代表的免疫抑制因子，另一类是以嵌合抗原受体（CAR）T细胞和T细胞结合双特异性抗体（bsAbs）为特征的免疫刺激途径。针对靶细胞重定向T细胞的另一种替代方法是T细胞结合bsAbs，其具有独特的功能，结合癌症细胞上的TAA和T细胞上的细胞表面分子。双特异性T细胞结合子（BiTE）是一种新型的T细胞结合bsAbs亚类，在治疗癌症方面具有很好的临床效果。表2. 三种主要基于T细胞的免疫疗法的比较：ICI、CAR T细胞和BiTE TCEs分类：根据其分子结构的TCE类型。根据其分子结构，TCE可分为三类。免疫球蛋白G样（IgG样）TCE与人体内天然存在的抗体有相似之处。产生IgG样TCE的最流行的方法包括knob-in-a-hole（KiH）、CrossMab和DuoBody。单链可变片段样（scFv样）TCEs试剂基于合成的scFv分子构建，包括例如BiTE、DART和TandAb平台。以及融合了前两者特性的combination结构。图2. 不同结构的TCEs 1. IgG-like TCEs： IgG样TCE是基于天然抗体，即IgG分子开发的。这意味着，与天然抗体类似，它们由两条重链和两条轻链组成。在它们的结构中，我们可以区分Fc，以及通过A铰链连接的两个抗原结合区（Fab），每个区都有一个Fv。与天然mAb相反，在天然mAb中，两种Fv都结合同一类型的抗原，在IgG样TCE中，一种Fv结合TAA，另一种结合CD3分子。 Knobs-into-Holes (KiH): 罗氏开发的KiH技术能够通过交换半分子来生产抗体。这项技术的名字来源于促进针对不同抗原的抗体两半二聚化的机制。KiH背后的原理是基于在两条不同的抗体重链上创建类似拼图的匹配位点，以创建产品。 CrossMab: 基于KiH的原始概念，罗氏在解决轻链失配问题的前提下开发了CrossMab平台。与KiH中重链上的区域类似，这种技术基于交换一侧重链和轻链的区域，以便正确组装重链和重链。重链和轻链的区域可以被修饰，尽管已经表明用轻链的CL交换重链的CH1是最有效的方法。 DuoBody： Genmab开发的Duobody是通过在两种不同的IgG之间交换Fab区来生产BsAbs的平台。Fc片段CH3区的突变可以识别异源半分子，促进异二聚化过程。Duobody技术的核心在于受控Fab臂交换（cFAE）过程。该方法涉及两种不同类型的IgG单克隆抗体的单独表达，每种单克隆抗体在CH3-CH3结构域界面上都有一个匹配的点突变。 2. Fv-Based TCEs：与基于IgG的BsAbs相比，基于Fv的TCE的设计相对简单。这些分子与天然存在的抗体不同，因为它们通常仅由单链抗体组成。scFv在结构和功能上与抗体的Fv区相似。它是重链（VH）和轻链（VL）的一个可变区人工融合的产物。 Bi-Specific T-Cell Engagers (BiTE)： BiTE是一种简单的分子，通过G4S接头连接CD3特异性ScFv和TAA特异性ScFv。除了blinatumomab，使用BiTE平台的BsAbs的其他例子包括CD3 BCMA-AMG420和CD3 CD33-AMG330，目前正在临床试验中进行评估（NCT03836053，NCT02520427）。BiTE平台上的BsAbs很小，半衰期很短，仅约2小时，这意味着需要持续静脉输注给药。 Dual-Affinity Retargeting Antibody (DART) DART是一个类似于BiTE的平台。它是通过将VH和VL序列分别与其他抗体VL和VH序列连接而形成的。此外，半胱氨酸被引入两条多肽链的C末端，形成链间二硫键。MGD024是Macrogenics在DART平台上创建的TCE的一个例子。它靶向CD3和CD123抗原，并研究了其在r/r CD123阳性恶性肿瘤中的应用。该药物被设计用于降低细胞因子释放综合征（CRS）的发生率，CRS是其前身flotetuzumab的常见不良事件，同时保持抗肿瘤活性。目前正在一项1期首次人体剂量递增研究中对其进行评估（CP-MGD024-01；NCT05362773）。 3. TandAb： TandAbs平台是一种四价抗体分子，每种抗原都有两个结合位点。同二聚体分子是由两条肽链反向配对形成的。AFM11靶向CD3和CD19，是Affimed在TandAb平台上开发的BsAb。AFM11的安全性和有效性已在两项开放标签、多中心、剂量递增的1期研究中进行了评估，这两项研究分别针对r/r CD19阳性B细胞非霍奇金淋巴瘤（NHL）患者（AFM11-101）和CD19阳性的B前体费城染色体阴性（Ph-）ALL患者（AFM13-102）。最常见的是神经系统不良反应，一些患者严重，以及剂量限制治疗引起的不良事件（TEAE）。在ALL中，尽管短暂，但该药物显示出活性迹象，而在NHL患者中没有观察到活性。由于AFM11治疗存在重大健康风险，终止了进一步的临床开发。 4. Combination-Based TCEs 组合型TCE利用了IgG样和Fv样基团的平台优势。这些药物具有IgG样TCE特有的Fc区和Fv样TCE典型的Fcvs。HLE-BiTE是组合型TCE的领先例子。它是安进公司通过将Fc片段连接到原始构建体的ScFv末端而开发的第二代BiTE。这种修改将其半衰期延长至7天。它被应用于安进的AMG701 BsAb，一种针对CD3和BCMA的抗体。一项针对（NCT03287908）的1期首次人体研究表明，在重度预处理r/r MM患者中，其安全性可控制，活性令人鼓舞，药代动力学特征良好，支持进一步评估AMG 701。在研的TAA靶点： TCEs通常靶向细胞外蛋白，TCEs的理想靶点应在肿瘤细胞表面表达，而不是在健康细胞上表达，以防止靶向非肿瘤毒性。由于靶抗原丢失和下调是癌症最常见的逃避机制之一，靶抗原也应在肿瘤细胞存活中发挥重要作用。例如，CD19和CD20是在B细胞上广泛表达的相对稳定的细胞表面抗原。因此，在正在进行的临床试验中，大多数靶向表面抗原包括CD19、CD20和BCMA（B细胞成熟抗原）。靶向实体瘤抗原（如PSMA（前列腺特异性膜抗原）、EpCAM（上皮细胞粘附分子）、CEA（癌胚抗原）和GPC3（glypican-3））的TCE的开发标志着将该技术扩展到血液系统恶性肿瘤之外的重大进展。这些BiTE旨在解决实体瘤带来的独特挑战，与血液学癌症相比，实体瘤包括更复杂和免疫抑制的肿瘤微环境。目前有200多种TCE抗体正在进行临床试验。大约一半的双特异性抗体靶向CD20、CD19和BCMA。尽管如此，新的靶点也进入了早期临床试验。图3. 目前在研的TAA靶点TCEs药物研究概况 TCEs 存在挑战：优化TCEs几何结构： TCE的大小和结构是影响其疗效和药代动力学（PK）特性的关键因素。通常，TCE被设计成具有小而灵活的结构，以允许T细胞和肿瘤细胞之间的紧密接近，从而提高突触形成的效率。这种格式的一个例子是BiTE™，由串联单链可变片段（scFv）组成，其中两个scFv通过一个短的柔性接头连接。然而，由于其大小和形式（没有Fc尾部），BiTE™会迅速从体内清除，因此需要频繁给药。为了应对这些挑战，各种修饰，如聚乙二醇化、白蛋白结合结构域的掺入或与抗体Fc区的融合，已被用于延长TCE的半衰期，而不会损害其结合特性和疗效。除了大小，TCE的结构在决定T细胞和肿瘤细胞之间的突触距离方面也起着重要作用，这对T细胞活化和肿瘤细胞杀伤至关重要。TAA结合臂的定位、靶向表位和接头长度等几个因素有助于有效的免疫突触形成。已经表明，T细胞和抗原呈递细胞之间有效形成突触的最佳膜距离约为15nm。该距离对应于天然TCR肽-MHC复合物的大小，并与IgG1抗体的Fab臂跨度相匹配。最近，已证实该距离也是TCE活性的理想距离。事实上，抗TAA和抗CD3臂靠得更近的TCE配置显示出增强的T细胞活化和优异的肿瘤细胞杀伤能力。因为接头长度、表位定位和TCE灵活性独立影响细胞溶解潜力，使预测和合理设计变得复杂。亲和力和效价： TCE亲和力和化合价的微调是优化的关键组成部分。与单价对应物相比，通过结合多个TAA结合结构域来增加对肿瘤靶点的化合价可以增强TCE的亲和力，这可以导致更有效的肿瘤杀伤，以及在以低和异质TAA表达为特征的肿瘤环境中的活性。二价TAA结合可在不影响活性的情况下降低单个TAA结合物的亲和力，潜在地避免与可溶性抗原的相互作用，导致下沉效应和减少暴露。具有靶向TAA的双Fab结构域和用于CD3的单Fab结构区（2+1形式）的TCE已在临床前研究和癌症患者中证明了抗肿瘤功效。这种2+1格式的例子是CD20特异性的glofitamab（COLUMVI™；罗氏）和STEAP1特异性的沙鲁利他明（安进）。 CD3及细胞因子释放综合征（CRS）越来越多的证据表明，TCE结合的CD3特定结构域可以显著影响T细胞活化、信号强度和整体治疗方案。CD3是由CD3ε、CD3δ、CD3γ和CD3ζ链组成的多亚基复合物，与TCR（T细胞受体）相关。每个亚基在信号转导中起着不同的作用，它们的可及性和方向各不相同。研究表明，不同的CD3结合抗体（如OKT3、UCHT1、L2K、SP34）结合CD3ε链上的不同表位，这些差异会影响TCR信号传导，从而不同地影响细胞毒性和细胞因子释放，当整合到TCE中时，可能会导致更好的治疗方案。TCE对T细胞上CD3/TCR复合物的亲和力是优化疗效和安全性之间平衡的另一个关键因素，特别是在治疗细胞因子释放综合征（CRS）方面，这是TCE疗法的一个显著副作用。CRS发生在T细胞过度活化时，由促炎细胞因子的释放引发，如白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）、干扰素-γ（IFN-γ）和粒细胞-巨噬细胞集落刺激因子（GM-CSF），可引起全身炎症反应。事实上，患者特征，如TAA密度、转移性疾病和肿瘤负荷，也可能在影响CRS中发挥关键作用，较高的肿瘤负荷与CRS严重程度的增加之间存在潜在的相关性。这一观察结果得到了旨在降低CRS风险的临床策略的支持，例如在开始TCE治疗之前使用单克隆抗体来灭活肿瘤。这些策略包括在用靶向CD20的TCE治疗B细胞恶性肿瘤之前服用B细胞耗竭剂obinutuzumab（Gazyva®，罗氏）。可能影响CRS的其他因素包括基线免疫状态和患者T细胞健康状况。处于临床阶段的TCEs ：激活特定的T细胞亚群是通过减少激活的T细胞数量和降低CRS相关毒性来提高TCE治疗指数的另一种选择。CD8+T细胞主要负责介导对呈递来源于感染或突变的肽的细胞的细胞毒性，并在抗癌免疫反应中发挥关键作用。研究表明，在体外使用常规双特异性TCE，CD8+T细胞对癌症细胞的重定向杀伤是有效的。虽然CD4+T辅助细胞可以支持CD8+T细胞功能并表现出细胞溶解活性，包括在TCE诱导的刺激后，但它们的激活会导致细胞因子分泌和CRS相关的不良反应。表2. 已批准或处于临床试验第2阶段/第3阶段的TCE列表表3. 目前正在开发和最近停产的临床和临床前条件TCE列表

2025-07-15

·ioncology

EHA 2025科学报告丨单克隆抗体与细胞免疫治疗——下一轮对决

编者按日前，EHA 2025科学会议报告正式发布，涵盖恶性血液学与非恶性血液学两大部分！报告全面回顾了在EHA 2025大会上展示的最重要科学进展与临床见解，为全球血液学专业人士提供了深入了解血液学各大领域最新动态的机会。本期特整理恶性血液学报告中关于单克隆抗体与细胞免疫治疗的精粹内容，旨在为广大同行提供有价值的临床与科研洞见。精选演讲概览双抗原靶向的双特异性抗体治疗多发性骨髓瘤双特异性抗体（也称为T细胞衔接器，TCE）在血液学肿瘤学中取得了重要进展，但大多数患者最终会复发并发展出耐药性。与其他治疗方法一样，靶向多个抗原提供了一种有前景的策略，以克服耐药机制。在今年的EHA大会上介绍了1期RedirecTT-1试验，该试验探索了双重TCE治疗方案，结合了塔奎妥单抗（αGPTC5D）和特克立单抗（αBCMA）。作为单药治疗，每种药物在三类药物暴露后复发/难治性（R/R）多发性骨髓瘤（MM）和髓外疾病（EMD）患者中的总有效率（ORR）约为40%。EMD通常与较差的预后相关。三类药物暴露的患者（IMiD、蛋白酶体抑制剂、αCD38）的中位总生存期（OS）仅为7.2个月[1]。初步数据显示，双重靶向治疗能带来更高的ORR以及更深、更持久的缓解，这可能是通过减轻抗原相关逃逸来实现的。在试验的第二阶段，观察到78.9%的ORR和54.4%的完全缓解（CR）率，许多患者的缓解随着时间的推移而持续加深。中位无进展生存期（PFS）为15.4个月，12个月的OS率为74.5%。在安全性方面，1-2级细胞因子释放综合征（CRS）的发生率为77.8%，通常发生在递增剂量治疗期间。免疫效应细胞相关神经毒性综合征（ICANS）的发生率为12.2%，大多数为1-2级，出现了两例3/4级病例。其他常见的不良事件（AEs）包括细胞减少症和感染。总体而言，结果表明，该组合治疗的疗效超过了单药治疗，并且未加重不良事件。与使用两个独立抗体不同，另一项正在进行的1期临床试验[2]评估了JNJ-5322，这是一种三特异性抗体，具有对BCMA和GPRC5D的高亲和力，以及对CD3的低亲和力[3]。该研究旨在确定安全性、推荐2期剂量（RP2D）和初步疗效。研究人群包括BCMA暴露患者（17.7%）、GPRC5D暴露患者（3.4%）和BCMA/GPRC5D未暴露患者（80.3%）。RP2D被确定为5 mg的递增剂量给药，之后每4周给予100 mg。在接受50-300 mg治疗的BCMA/GPRC5D暴露组，ORR为55%，CR率为30%。在BCMA/GPRC5D未暴露的患者中，ORR和CR率分别为100%和70.4%。在RP2D剂量下，12个月PFS为95%。通过预防性使用托珠单抗，仅20%的患者在RP2D剂量下出现1级CRS。不同患者群体中的反应率CAR-T在复发/难治性B-ALL中的影响——挑战与新进展肿瘤负荷影响CAR-T细胞治疗的总生存期（OS）和毒性，这可能是由于在高负荷环境中扩增不足，或是反映了输注时机不理想[4-7]。正如在今年的EHA大会上讨论的那样，桥接至CAR-T治疗是一个重要的考虑因素[8-9]，但经验表明，强化化疗不太可能带来获益，反而可能增加感染率。尽管细胞能够持久存在，但复发依然是一个挑战，特别是在CD19抗原丢失风险高的患者以及治疗前存在高白血病负荷的患者中。对于这一患者群体，CAR-T治疗后的干细胞移植（SCT）是一种选择。为了应对毒性和复发风险，正在探索自体CAR-T在早期治疗中的应用。此外，正在开发新的平台以延长治疗效益，包括如用双特异性抗体预加载CAR细胞和探索自然杀伤（NK）CAR等策略[10]。淋巴瘤中的装甲CAR白介素（IL）-18是已知的T细胞生长因子，能够改善治疗性T细胞产品的活性和增殖。实际上，一项针对1例患有滤泡性淋巴瘤和弥漫性大B细胞淋巴瘤（FL/DLBCL）患者的首次人体试验，使用了huCART19-IL18细胞，在3百万个细胞的微剂量下实现了持续的完全缓解（CR）[11-12]。随后一项针对接受过αCD19 CAR-T细胞治疗的B细胞淋巴瘤患者的1期临床试验（NCT04684563）结果在大会上进行了展示，表明在所有亚型中，3个月的初步总有效率（ORR）为80%，而在曾接受过基于CD28的CAR-T细胞产品的患者中，反应率达到了100%[12-13]。这项研究揭示了几个发现，包括（初步）确认了IL-18 CAR-T细胞治疗的高疗效，但也指出这种CAR-T细胞疗法的成功取决于先前CAR类型的选择，即4-1BB与CD28之间的差异。目前，后续的试验正在进行中（NCT05989204）。huCART19-IL18治疗后3个月的反应下一代CAR-T在淋巴瘤中的应用：双重特异性应对肿瘤逃逸淋巴瘤中CD19 CAR-T的耐药性可能源于淋巴瘤细胞上抗原密度低或异质性。BCMA，通常在多发性骨髓瘤（MM）中作为靶点，也显示出作为B细胞淋巴瘤抗原的潜力。在EHA 2025大会上，Sonia Guedan博士介绍了ARI-0003，这是一种双重靶向BCMA/CD19的CAR-T产品，专为治疗非霍奇金淋巴瘤（NHL）而开发[14]。它通过共同转导两个CAR载体（CD19和BCMA，比例约为4:1）而制成，从而增强了T细胞的增殖、功能性和抗肿瘤效能，并在临床前Burkitt淋巴瘤模型中延长了生存期。在临床前淋巴瘤模型中，它的表现优于CD19 CAR（ARI-0001），并为CD19 CAR-T细胞治疗后复发的患者提供了有前景的治疗方案。目前，ARI-0003在NHL患者中的首次人体1期临床试验正在进行中。Burkitt淋巴瘤小鼠的生存情况T细胞衔接器与CAR-T细胞治疗在AML中的应用异基因造血干细胞移植（SCT）的成功——主要归功于其移植物抗白血病效应——为在急性髓性白血病（AML）中使用T细胞激活剂（TCE）和CAR-T细胞治疗提供了强有力的理论依据[15]。Marion Subklewe教授对这一主题进行了深入概述。截至目前，共有27项关于TCE在AML中应用的临床试验，主要靶向谱系限制性抗原（如CD33、CD123、CLL1、FLT3），但也包括与白血病相关的抗原（如CD70和Wt1）。尽管观察到反应，但通常不持久，且靶向白血病以外的毒性仍然是一个挑战[16-25]。TCE目前正在作为联合治疗的一部分进行探索，包括在临床前和临床研究中与维奈克拉（venetoclax）和阿扎胞苷（azacitidine）的联合使用，这些药物不会损害T细胞功能[26]。AML中的新型TCE靶点包括CD38、csGRP78、ILT3-CD3，以及源自组织蛋白酶 G/HLA-A02.01 的前导序列肽[27-30]。其他策略包括桥接至异基因造血干细胞移植（SCT）[31-32]，或通过使用抗体构建体的靶向共刺激来增强TCE的疗效。许多限制TCE疗效的障碍也妨碍了CAR-T细胞治疗在AML中的广泛成功，包括T细胞固有的功能障碍和免疫抑制的肿瘤微环境（TME）[33]。进一步的挑战包括CAR-T细胞与AML微环境中白血病母细胞之间的相互作用及促炎细胞因子的释放，这可能有导致耐药性的发生。AML的快速进展性也给自体制造带来了后勤问题。与B细胞急性淋巴细胞白血病（ALL）80-90%的反应率相比，AML中的CAR-T细胞研究仅报告了30-50%的疾病反应。为了克服这些障碍，新的策略集中在通过细胞因子分泌“装甲”CAR-T细胞、改善骨髓归巢（“自驾”CARs）或通过开关信号限制毒性。值得注意的是，CLEAR-AML研究正在探讨一种靶向CD371、分泌IL-18的CAR-T细胞产品，并已显示出有前景的疗效[34]。门诊CAR-T疗法：家是最好的选择CRS和ICANS是CAR-T细胞输注后常见的不良事件，并且可能导致高达88%的再入院率。然而，临床经验表明，如果采取早期干预策略以预防和管理CRS、ICANS及巨噬细胞激活综合征，门诊管理是可行且安全的。Alexandra Martínez-Roca博士在演讲中强调，照护者与患者的关系对于门诊CAR-T细胞治疗的成功至关重要。照护者在门诊监测中发挥着关键作用，因此他们必须充分了解相关信息。对患者和照护者的教育对于确保治疗过程中安全性至关重要。重要的是，并非每个患者都适合门诊治疗，基于临床、后勤和社会心理标准仔细选择患者至关重要[35]。建立门诊CAR-T细胞治疗项目CAR-T细胞图谱或有助于揭示CAR-T调控机制CAR -T细胞在癌症免疫治疗领域引发了革命性的变化。然而，尽管初期反应通常良好，但维持长期疗效仍然是一个挑战，尤其是在多发性骨髓瘤（MM）中[36]。更好地理解潜在的分子机制可能推动治疗进步。Juan R. Rodríguez-Madoz博士在报告中介绍了一种新开发的CD19 CAR-T细胞图谱，旨在揭示与细胞持久性和扩增相关的机制[37-38]。该CAR-T细胞图谱的第一版包含来自100多位患有不同血液系统疾病的患者的415,000个细胞数据，涵盖了靶向不同抗原（如CD19、BCMA、APRIL）的CAR-T细胞产品。该图谱使研究人员能够识别耐药性和应答机制。例如，输注产品的记忆表型与更好的治疗反应相关。此外，图谱还可以用于生成基于数据的新假设——例如与年龄或性别相关的差异——并能检测与治疗毒性相关的细胞。当前的研究旨在验证已识别的机制。双特异性抗体 vs. CAR-T治疗R/R MM新的治疗方式正在改变接受过多种前期治疗的复发/难治性多发性骨髓瘤（R/R MM）患者的治疗格局。关于新药物的最佳使用顺序和应用方式仍有许多未解答的问题，包括：哪种治疗方式在某些患者群体中更具优势？哪种疗法提供更好的安全性和更高的疗效？是否有特定的患者群体从某种方法中获益更多？哪种治疗应当更早开始，其使用是否会阻碍另一种治疗方法的使用？在EHA 2025大会上，Elena Zamagni博士、Philippe Moreau博士和Paula Rodriguez-Otero博士共同参与了一场名为“BCMA双特异性抗体 vs. CAR-T在多发性骨髓瘤中的应用”的辩论，尝试解答部分这些问题。在辩论开始前，观众被要求选择他们在临床实践中更倾向使用的治疗方法：CAR-T还是双特异性抗体治疗。约50%的观众表示对于选择其中任何一种治疗方法感到不确定，凸显了决策过程中的持续不确定性[39-41]。Philippe Moreau博士支持使用BCMA双特异性抗体治疗R/R MM患者。目前，有两种针对BCMA的双特异性抗体（特立妥单抗和埃纳妥单抗）和一种针对GPRC5D的双特异性抗体（塔奎妥单抗）可用于重度预处理的R/R MM患者的治疗。BCMA在B淋巴细胞成熟过程中优先表达，而在正常细胞中则不表达或低水平表达。另一方面，GPRC5D在健康组织中的作用不太清楚，但与其他癌症相比，它在多发性骨髓瘤中呈高表达。双特异性抗体的优势在于易于获取且可快速使用，适合社区医院和门诊环境。它们也适合体弱、老年或有肾脏问题的患者，这使得其在实际应用中具有更大的潜力。然而，双特异性抗体也面临一些挑战。首先，约三分之一的患者对它们没有反应，且耐药的原因尚不清楚。另一个挑战是，如何将双特异性抗体与CAR-T疗法联合使用尚不明确。此外，还有靶点丢失的风险，例如BCMA或GPRC5D水平的下降。优化治疗方案也是一个挑战。一些研究人员正在探索将双特异性抗体作为桥接治疗的使用，但仍然存在感染风险，可以通过静脉注射免疫球蛋白（Ig）进行管理。未来，降低成本和开发新疗法（如cevostamab和FCRH5）也是研究的重点。接下来，Paula Rodriguez-Otero博士阐述了其支持CAR-T细胞治疗的观点。在FDA目前已批准的六种CAR T细胞治疗中，有四种用于多发性骨髓瘤。最近批准并且疗效较好的治疗是cilta-cel（cilta-cabtagene autoleucel），用于复发/难治性多发性骨髓瘤患者。在其关键性临床试验CARTITUDE-1中，cilta-cel显示了43.9个月的中位无进展生存期（PFS），并在长期随访中达到60.7个月的中位总生存期（OS）。CARTITUDE-4测试了cilta-cel在早期治疗中的应用，并显示其优于标准治疗方案。CAR-T细胞治疗的优势包括：更长的停药间期、改善早期治疗中的T细胞适应性，从而提高了CAR-T疗效；在早期疾病阶段有更多桥接治疗选择；以及更少的难治性或侵袭性疾病。当前CAR-T治疗的挑战包括：其对急需治疗或难以获得治疗的患者适用性有限；制造延迟；以及在欧洲的供应有限，这仍然是一个重大障碍。总之，辩论的参与者一致认为，患者的选择需要因人而异，两种疗法对特定患者群体、疾病分期和实际考虑因素都有各自的优势。参考文献：（上下滑动查看更多）1. 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Bajel et al, First-in-Human Study of the CD123 NK Cell Engager SAR443579 in Relapsed or Refractory Acute Myeloid Leukemia, B-Cell Acute Lymphoblastic Leukemia or High Risk-Myelodysplasia: Updated Safety, Pharmacokinetics Efficacy, and Pharmacodynamics. Abstract 3474, presented at ASH 2023.26. Haenel G, et al. Combining venetoclax and azacytidine with T-cell bispecific antibodies for treatment of acute myeloid leukemia: a preclinical assessment. Leukemia. 2024;38(2):398-402.27. Zhong X, Ma H. Targeting CD38 for acute leukemia. 2022:12:1007783. Front Oncol.28. Zeng X, et al. A novel bispecific T-cell engager using the ligand-target csGRP78 against acute myeloid leukemia. Cell 2024;81(1):371. Mol Life Sci.29. Lin et al. Preclinical Characterization of NGM936, a Novel Bispecific T Cell Engager Targeting ILT3 for the Treatment of Acute Myeloid Leukemia With Monocytic Differentiation. Abstract 4082, presented at ASH 2022.30. Shi et al. AML Immunotherapy Using a Novel Tcrm-Based Bispecific Antibody That Targets a Leader Sequence Peptide Derived from Cathepsin G. Abstract 1415, presented at ASH 2023.31. Volta L, et al. A single-chain variable fragment-based bispecific T-cell activating antibody against CD117 enables T-cell mediated lysis of acute myeloid leukemia and hematopoietic stem and progenitor cells. Hemasphere. 2024;8(11):e70055.32. Rasouli M. An Immunotherapy For Rapid Bone Marrow Conditioning And Leukemia Depletion That Allows Efficient Hematopoietic Stem Cell Transplantation. Oral Abstract s129 at EHA2025.33. Ghorashian S. CAR T cell therapy in AML. Oral presentation p141-2 at EHA2025.34. Geyer et al., CD371-Targeted CAR T Cells Secreting Interleukin-18 Exhibit Robust Expansion and Disease Clearance in Patients with Refractory Acute Myeloid Leukemia. ASH 2024 #207035. Martínez Roca A. Outpatient CAR-T therapy. Oral presentation p213-3 at EHA2025.36. Rodriguez-Madoz J, et al. A functional CAR-T cell atlas to unravel regulatory mechanisms of CAR-T cells. Oral presentation s276 at EHA2025.37. Bai Z, et al. Single-cell CAR T atlas reveals type 2 function in 8-year leukaemia remission. 2024;634(8034):702-711.38. Li X, et al. A single-cell atlas of CD19 chimeric antigen receptor T cells. Cancer Cell. 2023;41(11):1835-1837.39. Zamagni E. BCMA bsAb vs CAR T in MM. Thematic Debate p552-0 at EHA2025.40. Moreau P. BCMA bsAb vs CAR T in MM. Thematic Debate p552-1 at EHA2025.41. Rodríguez-Otero P. BCMA bsAb vs CAR T in MM. Thematic Debate p552-2 at EHA2025（来源：《肿瘤瞭望–血液时讯》编辑部）声明凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

免疫疗法临床结果临床2期细胞疗法

2024-07-30

·SYNAPSE

MacroGenics Provides Update on Corporate Progress and 2021 Financial Results

ROCKVILLE, Md., Feb. 24, 2022 (GLOBE NEWSWIRE) -- MacroGenics, Inc. (NASDAQ: MGNX), a biopharmaceutical company focused on developing and commercializing innovative antibody-based therapeutics for the treatment of cancer, today provided an update on its recent corporate progress and reported financial results for the year ended December 31, 2021. “We are excited about our 2022 plans for our B7-H3-directed programs for the potential treatment of multiple solid tumors. We believe we are well-positioned to be a leader in this promising field and are prioritizing our efforts around B7-H3. First, I am pleased to share that later this quarter, we plan to meet with the U.S. Food and Drug Administration (FDA) to discuss the design of a potential registration-directed study of MGC018 in patients with metastatic castration-resistant prostate cancer (mCRPC). Second, we expect to initiate a study of MGC018 in combination with lorigerlimab, our bispecific DART molecule targeting PD-1 and CTLA-4, in the coming weeks. And third, during the second half of this year, we intend to provide an update from a study of our second B7-H3 targeted molecule, enoblituzumab, being evaluated in combination with two of our checkpoint molecules in front-line squamous cell carcinoma of the head and neck (SCCHN). Beyond these B7-H3 programs, we are advancing several of our other clinical-stage molecules and have a variety of ongoing preclinical activities intended to expand our pipeline of differentiated investigational product candidates for the potential treatment of cancer,” said Scott Koenig, M.D., Ph.D., President and CEO of MacroGenics. Updates on Proprietary Programs B7-H3 Programs: MacroGenics is developing two investigational, clinical product candidates that target B7-H3, an antigen with broad expression across multiple solid tumor types and a member of the B7 family of molecules involved in immune regulation. Recent highlights for these two molecules include: MGC018is an antibody-drug conjugate (ADC) that targets B7-H3. MacroGenics presented encouraging preliminary clinical results from an ongoing Phase 1/2 study of MGC018 in patients with solid tumors at the American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) meetings in 2021. The Phase 1/2 study expansion cohorts are fully enrolled for patients with mCRPC (n=40) and smaller cohorts of patients (n=approximately 20 each) with non-small cell lung cancer (NSCLC), melanoma and triple negative breast cancer (TNBC), while the Company continues to recruit patients for the SCCHN cohort. MacroGenics plans to meet with FDA later this quarter to discuss its development strategy in mCRPC. In addition, the Company intends to provide an update on clinical data from the dose expansion cohorts in the second half of 2022 as the data further mature. Finally, beyond monotherapy, the Company expects to initiate a combination study of MGC018 with lorigerlimab across multiple indications in the coming weeks. Enoblituzumab is an Fc‐engineered, monoclonal antibody (mAb) that targets B7‐H3. MacroGenics continues to recruit patients into its Phase 2 study of enoblituzumab in combination with retifanlimab, the Company's investigational, anti-PD-1 antibody that was licensed to Incyte, in front-line patients with SCCHN who are PD-L1 positive and with tebotelimab in SCCHN patients who are PD-L1 negative. The Company expects to complete enrollment of the PD-L1 positive patient cohort during the first half of this year and provide an update on this cohort during the second half of the year. I-Mab, MacroGenics’ partner in Greater China, announced in December that the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA) approved its Investigational New Drug (IND) submission for the initiation of a Phase 2 trial in China for enoblituzumab in combination with pembrolizumab in patients with solid tumors, including NSCLC, urothelial carcinoma and other selected cancers. DART Molecules for Immune Checkpoint Blockade: MacroGenics is studying multiple investigational, PD-1-directed programs to provide further differentiation from existing PD-1-based treatment options and enable combination opportunities across the Company’s portfolio. Recent highlights include: Lorigerlimab (formerly MGD019)is a bispecific, tetravalent DART molecule targeting PD-1 and CTLA-4. MacroGenics is conducting a Phase 1/2 dose expansion study in cohorts of patients with microsatellite stable colorectal cancer (MSS CRC), mCRPC, melanoma and checkpoint-naïve NSCLC. The Company anticipates sharing data from this ongoing study in the second half of 2022. As described above, MacroGenics expects to initiate a dose escalation study of MGC018 in combination with lorigerlimab in the coming weeks. Tebotelimab is a bispecific, tetravalent DART molecule targeting PD-1 and LAG-3. Tebotelimab was evaluated in a Phase 1/2 dose expansion study in several tumor types and is currently being studied in combination with enoblituzumab in SCCHN. The Company expects to provide an update on potential future development plans for tebotelimab in the second half of 2022. MacroGenics' partner in Greater China, Zai Lab, recently informed the Company that it has decided to discontinue development of tebotelimab for indications it was enrolling in its territory and is evaluating future development plans in other indications. Bispecific CD123 × CD3 DART molecule: MacroGenics has prioritized the development of MGD024, its investigational, next-generation CD123 × CD3 DART molecule, and will discontinue the development of flotetuzumab. Recent updates of these DART molecules include: MGD024is a next-generation, humanized CD123 × CD3 DART molecule designed to minimize cytokine-release syndrome, while maintaining anti-tumor cytolytic activity, and permitting intermittent dosing through a longer half-life. In November, MacroGenics announced submission of an IND application for MGD024 to FDA. At the American Society of Hematology (ASH) Annual Meeting in December, MacroGenics presented preclinical data from the combination of MGD024 with standard-of-care agents used to treat CD123-positive hematological malignancies. The Company expects to initiate a Phase 1 dose escalation study of MGD024 in patients with CD123-positive neoplasms, including acute myeloid leukemia (AML), pending IND clearance by FDA. Flotetuzumab is the Company’s first-generation, investigational, bispecific CD123 × CD3 DART molecule. An interim efficacy threshold from the single-arm study evaluating flotetuzumab in patients who were refractory to induction therapy was met with manageable safety. However, the Company has recently decided to prioritize the development of MGD024 and discontinue development of flotetuzumab, in view of the Company’s belief that MGD024 may offer certain advantages over flotetuzumab, including easier dose administration and a more facile means to combine with other agents. Margetuximab is an Fc-engineered mAb that targets the HER2 oncoprotein, which is expressed by certain breast, gastroesophageal and other solid tumor cells. MARGENZA® (margetuximab-cmkb) was launched in March 2021 by MacroGenics and its commercial partner, Eversana Life Science Services, LLC, for the treatment of adult patients with metastatic HER2-positive breast cancer, in combination with chemotherapy, who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. In January 2022, Zai Lab announced that the China NMPA accepted the New Drug Application (NDA) for margetuximab for the treatment of the same HER2-positive breast cancer indication. Zai Lab recently informed MacroGenics that they have decided to discontinue enrollment of Module B of the MAHOGANY study in gastric cancer based on their review of both the clinical data and the changing treatment landscape. MacroGenics previously announced in November 2021 that the Company had decided to discontinue enrollment of Module A of the MAHOGANY study. Selected Partnered Program Updates: IMGC936is an investigational ADC that targets ADAM9, a cell surface protein over-expressed in several solid tumor types, and is being developed jointly under a 50/50 collaboration with ImmunoGen, Inc. Under the collaboration, ImmunoGen is leading clinical development of IMGC936 in a Phase 1 clinical trial evaluating safety and pharmacokinetics in multiple solid tumors and has indicated they anticipate disclosing initial data in 2022. Teplizumab is an investigational, anti-CD3 monoclonal antibody acquired from MacroGenics by Provention Bio, Inc. under an asset purchase agreement in 2018 for which MacroGenics is entitled to receive future milestone payments and royalties on net sales. Provention is developing teplizumab for the treatment of type 1 diabetes (T1D). On February 22, 2022, Provention announced that it had resubmitted the Biologics License Application (BLA) for teplizumab for the delay of clinical T1D in at-risk individuals. The BLA resubmission followed Provention’s Type B meeting with FDA earlier in the year. 2021 Financial Results Cash Position: Cash, cash equivalents and marketable securities as of December 31, 2021, were $243.6 million, compared to $272.5 million as of December 31, 2020. Revenue: Total revenue, consisting primarily of revenue from collaborative agreements, was $77.4 million for the year ended December 31, 2021, compared to total revenue of $104.9 million for the year ended December 31, 2020. Revenue for the year ended December 31, 2021 included $12.3 million net sales of MARGENZA. R&D Expenses: Research and development expenses were $214.6 million for the year ended December 31, 2021, compared to $193.2 million for the year ended December 31, 2020. The increase was primarily related to development, manufacturing and clinical trial costs related to MGC018, as well as other preclinical molecules and increased clinical expenses related to enoblituzumab and lorigerlimab. These increases were partially offset by decreased development and manufacturing costs related to retifanlimab for Incyte and decreased clinical costs and BLA support for margetuximab. SG&A Expenses: Selling, general and administrative expenses were $63.0 million for the year ended December 31, 2021, compared to $42.7 million for the year ended December 31, 2020. The increase was primarily related to the MARGENZA launch, as well as labor-related costs and legal expenses. Net Loss: Net loss was $202.1 million for the year ended December 31, 2021, compared to net loss of $129.7 million for the year ended December 31, 2020. Shares Outstanding: Shares outstanding as of December 31, 2021 were 61,307,428.Cash Runway Guidance: MacroGenics anticipates that its cash, cash equivalents and marketable securities as of December 31, 2021, plus anticipated and potential collaboration payments, and product revenues should enable it to fund its operations through 2023. Such guidance does not reflect anticipated expenditures related to the potential late-stage development of MGC018 in mCRPC or further expansion of studies currently ongoing. Conference Call Information MacroGenics will host a conference call today at 4:30 p.m. (ET) to discuss financial results for the year ended December 31, 2021 and provide a corporate update. To participate in the conference call, please dial (877) 303-6253 (domestic) or (973) 409-9610 (international) five minutes prior to the start of the call and provide the Conference ID: 1067087. The listen-only webcast of the conference call can be accessed under "Events & Presentations" in the Investor Relations section of the Company's website at http://ir.macrogenics.com/events.cfm. A replay of the webcast will be available shortly after the conclusion of the call and archived on the Company's website for 30 days following the call. MACROGENICS, INC.SELECTED CONSOLIDATED BALANCE SHEET DATA(Amounts in thousands) December 31, 2021 December 31, 2020 Cash, cash equivalents and marketable securities $ 243,616 $ 272,531 Total assets 335,245 378,743 Deferred revenue 20,646 11,382 Total stockholders' equity 239,618 295,884 MACROGENICS, INC.CONSOLIDATED STATEMENTS OF OPERATIONS AND COMPREHENSIVE LOSS(Unaudited) (Amounts in thousands, except share and per share data) Year Ended December 31, 2021 2020 2019 Revenues: Revenue from collaborative and other agreements $ 63,294 $ 97,764 $ 62,024 Product revenue, net 12,349 — — Revenue from government agreements 1,804 7,119 2,164 Total revenues 77,447 104,883 64,188 Costs and expenses: Cost of product sales 2,651 — — Research and development 214,577 193,201 195,309 Selling, general and administrative 63,014 42,742 46,064 Total costs and expenses 280,242 235,943 241,373 Loss from operations (202,795 ) (131,060 ) (177,185 ) Other income 680 1,321 25,374 Net loss (202,115 ) (129,739 ) (151,811 ) Other comprehensive income: Unrealized gain (loss) on investments (54 ) (23 ) 19 Comprehensive loss $ (202,169 ) $ (129,762 ) $ (151,792 ) Basic and diluted net loss per common share $ (3.37 ) $ (2.47 ) $ (3.16 ) Basic and diluted weighted average common shares outstanding 59,944,717 52,442,389 48,082,728 About MacroGenics, Inc. MacroGenics (the Company) is a biopharmaceutical company focused on developing and commercializing innovative monoclonal antibody-based therapeutics for the treatment of cancer. The Company generates its pipeline of product candidates primarily from its proprietary suite of next-generation antibody-based technology platforms, which have applicability across broad therapeutic domains. The combination of MacroGenics' technology platforms and protein engineering expertise has allowed the Company to generate promising product candidates and enter into several strategic collaborations with global pharmaceutical and biotechnology companies. For more information, please see the Company's website at www.macrogenics.com. MacroGenics, the MacroGenics logo, MARGENZA and DART are trademarks or registered trademarks of MacroGenics, Inc.

100 项与 Flotetuzumab 相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
D11306	Flotetuzumab	-	DB15223

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
急性双表型白血病	临床2期	-	City of Hope National Medical Center	2020-10-20
急性白血病	临床2期	-	City of Hope National Medical Center	2020-10-20
复发性急性淋巴细胞白血病	临床2期	-	City of Hope National Medical Center	2020-10-20
Blastic浆细胞样树突状细胞肿瘤	临床2期	-	City of Hope National Medical Center	2020-10-20
CD123阳性血液肿瘤	临床2期	-	City of Hope National Medical Center	2020-10-20
慢性期慢性髓性白血病	临床2期	-	City of Hope National Medical Center	2020-10-20
毛细胞白血病	临床2期	-	City of Hope National Medical Center	2020-10-20
费城染色体阳性慢性粒细胞白血病	临床2期	-	City of Hope National Medical Center	2020-10-20
复发性霍奇金淋巴瘤	临床2期	-	City of Hope National Medical Center	2020-10-20
难治性成人急性淋巴细胞白血病	临床2期	-	City of Hope National Medical Center	2020-10-20

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临床结果

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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


NCT05506956 (CTgov)	临床1期	CD123阳性急性髓性白血病	3	Flotetuzumab	鏇艱鏇壓積築鹽窪膚遞 = 獵憲顧襯鑰顧築鹽糧餘衊繭鹹鏇艱鑰窪顧衊築 (餘選艱範鏇蓋醖鏇鏇鑰, 壓膚廠網鑰遞淵範築鏇 ~ 窪選餘繭簾鹽糧鬱窪鹹) 更多	-	2025-09-12
NCT04582864 (CTgov)	临床2期	复发性急性髓细胞白血病 \| 骨髓增生异常综合征	11	Donor lymphocyte infusion+Flotetuzumab	鏇觸醖願廠構廠窪繭構 = 積鏇艱餘顧膚鬱遞蓋襯願壓網顧蓋夢顧糧鬱糧 (簾壓壓蓋構願蓋淵壓願, 衊夢積齋鏇構鑰膚遞願 ~ 獵鹹艱廠鹹網遞淵構繭) 更多	-	2024-12-06
EHA2024	临床1/2期	急性髓性白血病	243	Magrolimab	艱淵淵鏇憲遞簾廠鹹繭(廠膚繭鹽簾製觸簾顧醖) = 顧顧顧廠鹽窪繭範鏇範鑰網鏇製鹹蓋壓構選膚 (淵範廠鑰淵鏇願糧簾鑰, 0.28 ~ 0.54) 更多	-	2024-05-14
EHA2024	临床1/2期	急性髓性白血病	243	Durvalumab	艱餘顧襯選網遞鑰餘餘(襯築簾齋艱廠窪選觸膚) = 鹽鑰艱鑰鑰餘憲範鹹鹹範簾齋艱鹽衊憲淵壓顧 (糧窪壓鹹繭夢願夢遞顧 )	-	2024-05-14
NCT02152956 (VOYAGE, Pubmed \| Circulation \| Blood) 人工标引	临床1/2期	难治性急性髓细胞白血病	88	Flotetuzumab	鏇餘壓構憲簾窪餘鏇網(廠構糧鬱艱簾選衊糧衊) = 繭襯願鹽遞艱鏇蓋餘觸製蓋醖齋製構鏇築醖積 (衊鬱醖顧構積簾糧願鏇 ) 更多	积极	2021-02-11