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更新于：2025-12-13
DFP-13318
更新于：2025-12-13
概要
基本信息
原研机构 |
非在研机构- |
权益机构- |
最高研发阶段临床2期 |
首次获批日期- |
最高研发阶段(中国)- |
特殊审评- |
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关联
6
项与 DFP-13318 相关的临床试验NCT06337630
A Phase I Study on Tuvusertib (Oral ATR Inhibitor) in Combination With PLX038 (Topo1 Inhibitor) With Dose Expansion Cohorts in Patients With Advanced Solid Tumors
Phase I with a dose finding cohort, followed by expansion cohorts in pre-specified tumor types.
开始日期2025-01-20 |
申办/合作机构  Institut Curie [+2] |
NCT06162351
A Phase II Study to Evaluate the Efficacy and Toxicities of PLX038, in Patients With Locally Advanced or Metastatic Triple-negative Breast Cancer
Single arm phase II study for with primary objective to evaluate the efficacy of PLX038 on response rate for patients with pretreated, metastatic or locally advanced triple negative breast cancer.
开始日期2024-04-17 |
申办/合作机构 Institut Curie [+1] |
NCT06161519
Phase I/II Trial of PLX038 in Primary Central Nervous System Tumors Containing MYC or MYCN Amplifications
Background:
About 90,000 new cases of brain and spinal cord tumors are diagnosed annually in the United States. Most of these tumors are benign; however, about 30% are malignant, and 35% of people with malignant tumors in the brain and spinal cord will die within 5 years. Many of these people have changes in certain genes (MYC or MYCN) that drive the development of their cancers.
Objective:
To test a study drug (PLX038) in people with tumors of the brain or spinal cord.
Eligibility:
People aged 18 years or older with a tumor of the brain or spinal cord. Some participants must also have tumors with changes in the MYC or MYCN genes.
Design:
Participants will be screened. They will have a physical exam and blood tests. They will have imaging scans and a test of their heart function. They may need to have a biopsy: A sample of tissue will be removed from their tumor.
PLX038 is given through a tube attached to a needle inserted into a vein in the arm. All participants will receive PLX038 on the first day of each 21-day treatment cycle. They will take a second drug 3 days later to help reduce the risk of infection; for this drug, participants will be shown how to inject themselves under the skin at home.
Blood tests, imaging scans, and other tests will be repeated during study visits. Hair samples will also be collected during these visits. Some participants may have an additional biopsy.
Study treatment will continue up to 7 months.
Follow-up visits will continue every few months for up to 5 years.
About 90,000 new cases of brain and spinal cord tumors are diagnosed annually in the United States. Most of these tumors are benign; however, about 30% are malignant, and 35% of people with malignant tumors in the brain and spinal cord will die within 5 years. Many of these people have changes in certain genes (MYC or MYCN) that drive the development of their cancers.
Objective:
To test a study drug (PLX038) in people with tumors of the brain or spinal cord.
Eligibility:
People aged 18 years or older with a tumor of the brain or spinal cord. Some participants must also have tumors with changes in the MYC or MYCN genes.
Design:
Participants will be screened. They will have a physical exam and blood tests. They will have imaging scans and a test of their heart function. They may need to have a biopsy: A sample of tissue will be removed from their tumor.
PLX038 is given through a tube attached to a needle inserted into a vein in the arm. All participants will receive PLX038 on the first day of each 21-day treatment cycle. They will take a second drug 3 days later to help reduce the risk of infection; for this drug, participants will be shown how to inject themselves under the skin at home.
Blood tests, imaging scans, and other tests will be repeated during study visits. Hair samples will also be collected during these visits. Some participants may have an additional biopsy.
Study treatment will continue up to 7 months.
Follow-up visits will continue every few months for up to 5 years.
开始日期2024-01-31 |
申办/合作机构 |
100 项与 DFP-13318 相关的临床结果
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100 项与 DFP-13318 相关的转化医学
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100 项与 DFP-13318 相关的专利（医药）
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3
项与 DFP-13318 相关的文献（医药）2024-03-01·BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy
Could a Long-Acting Prodrug of SN-38 be Efficacious in Sacituzumab Govitecan-Resistant Tumors?
Article
作者: Ashley, Gary W ; Bidard, Francois-Clement ; Santi, Daniel V ; Cabel, Luc
We previously proposed that sacituzumab govitecan (SG, Trodelvy®) likely acts as a simple prodrug of systemic SN-38 as well as an antibody drug conjugate (ADC). In the present commentary, we assess whether a long-acting SN-38 prodrug, such as PLX038, might be efficacious in SG-resistant patients. We first describe possible mechanisms of action of SG, with new insights on pharmacokinetics and TROP2 receptor occupancy. We argue that SG is not an optimal conventional ADC and that the amount of systemic SN-38 spontaneously hydrolyzed from the ADC is so high it must have activity. Then, we describe the concept of time-over-target as related to the pharmacology of SG and PLX038 as SN-38 prodrugs. To be clear, we are not in any way suggesting that PLX038 or any SN-38 prodrug is superior to SG as an anticancer agent. Clearly, SG has the benefit over antigen-independent SN-38 prodrugs in that it targets cells with the TROP2 receptor. However, we surmise that PLX038 should be a more efficacious and less toxic prodrug of systemic SN-38 than SG. Finally, we suggest possible mechanisms of SG resistance and how PLX038 might perform in the context of each. Taken together, we argue that-contrary to many opinions-SG does not exclusively act as a conventional ADC, and propose that PLX038 may be efficacious in some settings of SG-resistance.
2022-11-03·Molecular cancer therapeutics
PLX038: A Long-Acting Topoisomerase I Inhibitor With Robust Antitumor Activity in
ATM
-Deficient Tumors and Potent Synergy With PARP Inhibitors
Article
作者: Kumar, Rajesh ; Nguyen, Minh ; Ashworth, Alan ; Ashley, Gary W. ; Sciuto, Linda ; Santi, Daniel V. ; Thomas, Anish ; Pommier, Yves ; Feng, Felix Y. ; Nichols, Samantha ; Diolaiti, Morgan E. ; Fontaine, Shaun D. ; Desai, Parth ; Takahashi, Nobuyuki
Abstract:
Alterations in the ATM gene are among the most common somatic and hereditary cancer mutations, and ATM-deficient tumors are hypersensitive to DNA-damaging agents. A synthetic lethal combination of DNA-damaging agents and DNA repair inhibitors could have widespread utility in ATM-deficient cancers. However, overlapping normal tissue toxicities from these drug classes have precluded their clinical translation. We investigated PLX038, a releasable polyethylene glycol-conjugate of the topoisomerase I inhibitor SN-38, in ATM wild-type and null isogenic xenografts and in a BRCA1-deficient xenograft. PLX038 monotherapy and combination with PARP inhibition potently inhibited the growth of both BRCA1- and ATM-deficient tumors. A patient with an ATM-mutated breast cancer treated with PLX038 and the PARP inhibitor rucaparib achieved rapid, symptomatic, and radiographic complete response lasting 12 months. Single-agent PLX038 or PLX038 in combination with DNA damage response inhibitors are novel therapeutic paradigms for patients with ATM-loss cancers.
2020-01-01·Cancer chemotherapy and pharmacology4区 · 医学
PLX038: a PEGylated prodrug of SN-38 independent of UGT1A1 activity
4区 · 医学
Article
作者: Fontaine, Shaun D ; Santi, Angelo D ; Ashley, Gary W ; Santi, Daniel V ; Reid, Ralph ; Smith, Philip C
PURPOSE:
The purpose of this study was to determine the importance of UGT1A1 activity on the metabolism and pharmacokinetics of a releasable PEG ~ SN-38 conjugate, PLX038A. Irinotecan (CPT-11) is converted to the topoisomerase 1 inhibitor SN-38 by first-pass hepatic metabolism and is converted to its glucuronide SN-38G by UGT1A1. With diminished UGT1A1 activity, the high liver exposure to SN-38 can cause increased toxicity of CPT-11. In contrast, releasable PEG ~ SN-38 conjugates-such as PLX038-release SN-38 in the vascular compartment, and only low levels of SN-38 are expected to enter the liver by transport through the OATP1B1 transporter.
METHODS:
We measured CPT-11 and PLX038A metabolites in plasma and bile, and determined pharmacokinetics of PLX038A in UGT1A-deficient and replete rats.
RESULTS:
Compared to CPT-11, treatment of rats with PLX038A results in very low levels of biliary SN-38 and SN-38G, a low flux through UGT1A, and a low SN-38G/SN-38 ratio in plasma. Further, the pharmacokinetics of plasma PLX038A and SN-38 in rats deficient in UGT1A is unchanged compared to normal rats.
CONCLUSIONS:
The disposition of PEGylated SN-38 is independent of UGT1A activity in rats, and PLX038 may find utility in full-dose treatment of patients who are UGT1A1*28 homozygotes or have metastatic disease with coincidental or incidental liver dysfunction.
6
项与 DFP-13318 相关的新闻（医药）2025-10-25
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肿瘤相关钙信号转导蛋白2（TROP2），又称TACSTD2，是一种在多种实体瘤中高表达的跨膜糖蛋白，其过表达通常与肿瘤的侵袭性、转移能力增强以及患者预后不良密切相关。这些特性使TROP2成为肿瘤靶向治疗，尤其是抗体药物偶联物（ADC）开发的理想靶点。ADC通过将高特异性的单克隆抗体与强效的细胞毒性药物（载荷）通过连接子偶联，实现了对肿瘤细胞的精准打击，同时降低了对正常组织的损伤。近年来，以Sacituzumab govitecan (SG)和Datopotamab deruxtecan (Dato-DXd)为代表的TROP2靶向ADC在多种实体瘤，特别是三阴性乳腺癌（TNBC）和非小细胞肺癌（NSCLC）的治疗中取得了突破性进展，改变了临床实践格局。本综述旨在系统性地梳理和论述TROP2的生物学功能、其在不同癌种中的表达谱与临床意义、TROP2-ADC的设计原理与作用机制、主要在研及已上市药物的临床前与临床数据，并深入探讨TROP2-ADC治疗所面临的挑战，如耐药性机制和毒副作用管理。通过整合现有研究，本文旨在全面展现TROP2靶向ADC作为一类革命性抗肿瘤药物的科学基础、临床价值及当前局限性。关键词
TROP2；抗体药物偶联物；Sacituzumab govitecan；Datopotamab deruxtecan；肿瘤治疗；耐药性；间质性肺病
引言
抗体药物偶联物（ADC）作为一种新兴的靶向治疗策略，被誉为“生物导弹”，它巧妙地结合了单克隆抗体的高度靶向性与小分子化疗药物的强大杀伤力，旨在实现对癌细胞的精准杀灭，并最大限度地减少全身性毒副作用。一个典型的ADC由三个核心部分组成：特异性识别肿瘤表面抗原的抗体、通过化学连接子（Linker）与抗体相连的细胞毒性载荷（Payload），以及发挥最终杀伤作用的载荷。理想的ADC靶点应在肿瘤组织中高度且均一地表达，而在正常组织中表达量极低或不表达，从而为药物提供一个足够宽的治疗窗口。
在众多潜在的ADC靶点中，肿瘤相关钙信号转导蛋白2（TROP2, Trophoblast cell-surface antigen 2），其基因名为TACSTD2，近年来受到了前所未有的关注。TROP2是一种I型跨膜糖蛋白，最初在滋养层细胞中被发现，后续研究证实其在多种上皮来源的恶性肿瘤中广泛过表达，包括乳腺癌、肺癌、胃癌、结直肠癌、胰腺癌、膀胱癌、宫颈癌等[1, 2]。TROP2不仅是一个细胞表面标志物，更深度地参与了肿瘤的多种病理生理过程。研究表明，TROP2的过表达能够通过激活PI3K/Akt、NF-κB/IL-8等信号通路，显著促进肿瘤细胞的增殖、侵袭、迁移和上皮间质转化（EMT），并抑制细胞凋亡[3, 4, 5]。因此，TROP2的高表达水平常常与肿瘤的侵袭性表型、更晚的临床分期以及患者更差的生存预后紧密相连[6, 7, 8, 9]。
基于TROP2在肿瘤生物学中的重要作用及其理想的靶点特性，针对TROP2的ADC药物开发已成为当前肿瘤药物研究的热点领域。以美国FDA批准上市的Sacituzumab govitecan (SG)为代表的TROP2-ADC，已在临床上证明了其在治疗难治性、转移性三阴性乳腺癌（TNBC）和尿路上皮癌中的卓越疗效，并正在向更多癌种拓展[10]。与此同时，Datopotamab deruxtecan (Dato-DXd)等一系列新型TROP2-ADC也展现出强大的抗肿瘤活性和临床潜力。本综述将依据现有已发表的研究成果，详细阐述TROP2的生物学特性及其作为治疗靶点的价值，深入剖析TROP2-ADC的分子设计、多样化的作用机制，系统总结主要TROP2-ADC药物在不同实体瘤中的研究进展，并对治疗过程中出现的毒副作用管理和耐药性等关键挑战进行全面论述。正文1. TROP2的生物学功能及其在肿瘤治疗中的靶点价值1.1 TROP2的分子结构、信号调控与生物学功能
TROP2是一种分子量约为40kDa的单次跨膜糖蛋白，其结构包括一个胞外结构域（ECD）、一个跨膜区和一个短的胞内尾区。胞外结构域是抗体识别和结合的主要区域，而胞内尾区虽然短小且无已知的酶活性，但包含一个磷脂酰肌醇4,5-二磷酸（PIP2）结合位点，这对于其介导下游信号至关重要。TROP2的生物学功能复杂多样，在胚胎发育过程中，它参与调控器官形成，例如在胎儿肺部细胞增殖中发挥作用[11]。然而，在肿瘤细胞中，TROP2的功能被“劫持”，成为驱动恶性进展的关键分子。
多项研究揭示了TROP2参与调控的关键信号通路。在口腔癌中，TROP2被证实可以通过激活PI3K/Akt信号通路来促进肿瘤的转移[3]。在三阴性乳腺癌（TNBC）中，一种名为Uc003xsl.1的长链非编码RNA能够激活NF-κB/IL-8信号轴，进而促进TNBC的进展，而TROP2在此过程中扮演了重要角色[4]。此外，在皮肤鳞状细胞癌中，TROP2同样被发现能够促进细胞的增殖和迁移[5]。更有研究发现，TROP2能够通过抑制p16蛋白的表达来促进口腔癌细胞内的钙离子释放，这可能是一种新的促癌机制[12]。在非小细胞肺癌（NSCLC）的吉非替尼耐药模型中，TROP2被发现能与胰岛素样生长因子2受体（IGF2R）结合，从而诱导对吉非替尼的耐药性，这与上皮间质转化（EMT）过程中的Vimentin上调和E-cadherin下调有关[13, 14]。这些研究共同描绘了TROP2作为一个多效性的信号节点，通过多种途径驱动肿瘤的生长、存活、转移和耐药，从而确立了其作为治疗靶点的坚实生物学基础。1.2 TROP2在多种实体瘤中的广泛表达与临床预后意义
TROP2作为ADC靶点的另一个关键优势在于其在多种上皮源性实体瘤中的广泛高表达，这为TROP2-ADC的“泛癌种”应用潜力提供了依据。
乳腺癌：TROP2在乳腺癌中，尤其是在预后最差、治疗选择有限的三阴性乳腺癌（TNBC）亚型中，呈现出高水平表达。研究显示，高达85%的高级别乳腺癌病例为TROP2阳性[15]。TROP2的高表达与TNBC的不良预后显著相关，使其成为该亚型极具吸引力的治疗靶点[7, 16]。TROP2靶向ADC，如SG和Dato-DXd，已在TNBC治疗中显示出革命性的疗效，甚至在脑转移这种棘手的临床场景中也观察到了活性[10, 17]。
肺癌：在非小细胞肺癌（NSCLC）中，TROP2的过表达同样普遍，并且是预测患者不良预后的独立因素[8, 18]。一项研究发现，TROP2的高表达与NSCLC患者接受免疫检查点抑制剂治疗的预后不良相关，提示TROP2可能参与了免疫抑制微环境的形成[19]。另一项研究则观察到TROP2与PD-L1的表达在肺癌中可能存在负相关关系，这为TROP2-ADC与免疫疗法的联合应用提供了复杂的背景和潜在的理论依据[20]。值得注意的是，TACSTD2基因的上调也被发现是肺部感染过程中的一种早期反应，这提示其在炎症和组织修复中也可能扮演一定角色[21]。
消化系统肿瘤：TROP2在消化系统肿瘤中也扮演着重要角色。在胃癌中，TROP2的高表达与TNBC类似，同样普遍存在[16]。在结直肠癌（CRC）中，TROP2的表达与肿瘤的侵袭性表型相关，且其高表达与转移性结直肠癌（mCRC）患者的预后不佳有关[22, 23]。针对胃癌，有研究利用TROP2抗体修饰的黑磷纳米片来增强光热治疗的效果，展示了靶向TROP2策略的多样性[24]。在胰腺癌中，TROP2同样高表达，使其成为ADC的有效靶点[25, 26]。在胆管癌（CCA）中，TROP2的表达也相当广泛，研究显示，使用SG能够有效抑制源自患者的胆管癌类器官（PDO）的生长，为TROP2-ADC治疗CCA提供了临床前证据[27, 28]。一项针对多种消化系统癌症的分析指出，TROP2的高表达与胃肠道印戒细胞癌（SRCC）、血管侵犯（VI）和神经侵犯（PNI）等恶性临床病理特征显著相关，进一步凸显了其作为预后不良标志物和治疗靶点的价值[29]。
妇科肿瘤：在妇科恶性肿瘤领域，TROP2的表达也为ADC治疗开辟了新途径。宫颈癌组织中普遍高表达TROP2、CEACAM5和CD138等ADC靶点，为开发针对这些靶点的ADC提供了理论基础[30]。在卵巢癌中，尽管不同ADC靶点的表达存在显著差异，但TROP2仍是一个重要的潜在靶点[31]。SG已被证明能够有效抑制卵巢癌的生长[32]，而Dato-DXd也在TROP2阳性的卵巢癌患者中显示出临床活性[33]。此外，在子宫内膜癌中，TROP2是ADC药物开发的重要靶点之一[34, 35, 36]，SG在罕见的子宫浆液性癌中也显示出靶向TROP2的潜力[37]。外阴鳞状细胞癌（VSCC）中也普遍表达TROP2，且其表达水平与特定的分子亚型相关[38, 39]。
泌尿系统肿瘤及其他：在膀胱癌中，TROP2和NECTIN4（另一种重要的ADC靶点）均呈现高表达，为单药或联合靶向治疗提供了机会[40]。TROP2在膀胱癌的各个亚型中均有广泛表达，并且其表达与EpCAM相关[41, 42]。在乳腺外佩吉特病（EMPD）中，TROP2的高表达同样与不良预后相关，提示TROP2-ADC可能成为一种新的治疗选择[43, 44]。
综上所述，TROP2在众多实体瘤中的高表达率及其与不良预后的强关联性，共同奠定了其作为广谱抗肿瘤ADC靶点的坚实基础，驱动了大量靶向TROP2的药物研发活动。2. TROP2靶向ADC的设计原理与抗肿瘤作用机制
TROP2-ADC的成功依赖于其各个组成部分的精心设计，包括抗体、连接子和载荷，以及它们协同作用所产生的独特抗肿瘤机制。2.1 TROP2-ADC的核心组成与关键技术
抗体部分：ADC的“导航系统”是其抗体部分。目前开发的TROP2-ADC主要采用人源化单克隆抗体，如SG和Dato-DXd所使用的抗体，以降低免疫原性并延长半衰期。为了进一步优化药物特性，研究人员正在探索多种新型抗体形式。例如，开发新型人源化抗TROP2抗体IMB1636 [45]，以及基于此抗体构建的ADC药物hIMB1636-MMAE [46]。纳米抗体（Nanobody）由于其分子量小、组织穿透性强、生产成本低等优点，也成为TROP2靶向治疗的新选择。已有研究开发了靶向TROP2的纳米抗体药物偶联物，并在胰腺癌模型中显示出抗肿瘤活性[26]。此外，双特异性抗体，如同时靶向TROP2和T细胞表面CD3分子的F7AK3，能够招募T细胞直接杀伤肿瘤细胞，代表了一种不同的免疫治疗策略[47]。
连接子与偶联技术：连接子的设计对于ADC的成败至关重要。它必须在血液循环中保持稳定，以防止载荷过早释放导致全身毒性；同时，在进入靶细胞后，又能被特异性地切断以释放活性载荷。目前TROP2-ADC多采用可裂解连接子，如SG中的CL2A连接子和Dato-DXd中的四肽连接子，它们可以在肿瘤细胞内的酸性环境或特异性酶（如组织蛋白酶B）作用下断裂。此外，药物-抗体比（DAR）和偶联位点也显著影响ADC的均一性、稳定性及药代动力学。传统的随机偶联技术产生的ADC混合物不均一，而定点特异性偶联技术能够生产出DAR均一的ADC。例如，新型定点特异性TROP2 ADC gsADC 3b就显示出良好的稳定性[48]。
载荷/弹头：载荷是ADC的“弹头”，其效力直接决定了ADC的杀伤能力。针对TROP2的ADC主要采用了两类高效载荷：
·拓扑异构酶I（TOP1）抑制剂：这是目前最成功的TROP2-ADC载荷类型。Sacituzumab govitecan (SG)的载荷是SN-38，是化疗药伊立替康的活性代谢物。Datopotamab deruxtecan (Dato-DXd)的载荷是Deruxtecan (DXd)，一种新型、高效的TOP1抑制剂。TOP1抑制剂通过嵌入DNA并稳定TOP1-DNA复合物，导致DNA单链和双链断裂，激活DNA损伤应答（DDR），最终诱导细胞周期G2/M期阻滞、复制应激和细胞凋亡[49]。DXd的效力据称是SN-38的数倍，并且具有较高的细胞膜渗透性，这为其强大的旁观者效应奠定了基础[50]。
·其他类型的载荷：为了应对耐药性和拓宽应用，研究人员也在探索其他类型的载荷。微管蛋白抑制剂MMAE（单甲基澳瑞他汀E）被用于构建hIMB1636-MMAE [46]。一种极具潜力的新型载荷是α-鹅膏蕈碱（Amanitin），它是一种RNA聚合酶II抑制剂，其作用机制与DNA损伤药物完全不同，可能对传统化疗耐药的肿瘤有效。一款靶向TROP2的新型Amanitin ADC在胰腺癌模型中就显示出高效低毒的特性[25]。2.2 TROP2-ADC的多重抗肿瘤作用机制
TROP2-ADC的抗肿瘤活性并非单一机制的结果，而是多种机制协同作用的体现。
直接细胞毒性作用：这是ADC最基本的作用机制。ADC通过抗体部分与肿瘤细胞表面的TROP2结合，随后整个复合物通过内吞作用被细胞吞入。在细胞内，ADC被转运至溶酶体。有研究指出，改善ADC的溶酶体运输效率可以显著提高其效力[51]。在溶酶体中，连接子被降解，释放出高浓度的细胞毒性载荷。载荷随后作用于其靶点（如DNA或微管），最终导致肿瘤细胞死亡。
旁观者效应（Bystander Effect）：肿瘤组织往往具有高度异质性，并非所有癌细胞都表达TROP2。旁观者效应是指当ADC释放的载荷具有细胞膜渗透性时，它可以从TROP2阳性的靶细胞中扩散出来，进入并杀死邻近的TROP2阴性或低表达的肿瘤细胞。这一效应极大地扩展了ADC的杀伤范围，对于治疗异质性肿瘤至关重要。Dato-DXd的载荷DXd就具有很强的膜渗透性，因此表现出显著的旁观者效应。一项研究在TROP2过表达的癌肉瘤模型中证实了Dato-DXd的旁观者效应[52]。
免疫原性细胞死亡（Immunogenic Cell Death, ICD）：传统的化疗药物通常诱导耐受性的细胞死亡，而某些药物，包括一些ADC载荷，可以诱导ICD。ICD的特征是垂死的癌细胞会释放一系列损伤相关分子模式（DAMPs），如钙网蛋白（CRT）的暴露、ATP的释放和HMGB1的释放。这些信号能够吸引并激活树突状细胞（DC），从而启动适应性抗肿瘤免疫反应。最近的研究表明，Datopotamab deruxtecan能够诱导具有ICD特征的细胞死亡，这提示TROP2-ADC不仅能直接杀伤肿瘤，还可能通过调动宿主免疫系统来协同抗肿瘤，为ADC与免疫疗法的联合提供了理论基础[53]。
其他创新机制：除了传统的ADC模式，研究人员还在探索基于TROP2靶向的其他治疗策略。例如，将TROP2靶向抗体与放射性核素（如177Lu）偶联，形成放射性免疫偶联物（RIC）。这种177Lu标记的ADC能同时通过靶向放射治疗和ADC的细胞毒性双重机制杀伤肿瘤，在实体瘤模型中显示出优于传统RIC的潜力[54]。3. 主要TROP2-ADC药物的临床前与临床研究进展
基于对TROP2靶点的深入理解，一系列TROP2-ADC药物被开发出来，并在临床试验中取得了令人瞩目的成果。3.1 Sacituzumab Govitecan (SG, Trodelvy®)
SG是首个获批上市的TROP2-ADC，由人源化抗TROP2抗体、可裂解的CL2A连接子和拓扑异构酶I抑制剂SN-38组成，DAR约为7.6。
在乳腺癌中的应用：SG的成功首先在转移性三阴性乳腺癌（TNBC）中得到验证。基于ASCENT研究的阳性结果，SG获批用于治疗既往已接受至少两种系统治疗（其中至少一种用于转移性疾病）的不可切除的局部晚期或转移性TNBC患者。其疗效显著优于标准化疗。此外，SG在新辅助治疗领域也显示出潜力，一项研究评估了其用于TNBC新辅助治疗的有效性[55]。
在其他癌种中的拓展：SG的适应症正在不断扩大。在小细胞肺癌（SCLC）中，SG与PD-1抑制剂帕博利珠单抗（pembrolizumab）的联合治疗显示出改善患者生存的希望[56]。在食管腺癌中，TROP2的表达水平被发现可以预测SG的治疗疗效[57]。此外，SG在治疗TROP2阳性的子宫浆液性癌和卵巢癌中也显示出抗肿瘤活性[37, 32]。这些数据表明，SG作为一种广谱抗癌药物具有巨大潜力，其应用范围远不止于乳腺癌和尿路上皮癌[58]。3.2 Datopotamab Deruxtecan (Dato-DXd, DS-1062)
Dato-DXd是另一款备受瞩目的TROP2-ADC，它由人源化抗TROP2抗体、一种稳定的可被肿瘤特异性蛋白酶切割的四肽连接子和高效的TOP1抑制剂Deruxtecan (DXd)组成，DAR约为4。其独特的设计赋予了它高稳定性和强大的旁观者效应。
在非小细胞肺癌（NSCLC）中的突破：Dato-DXd在NSCLC治疗领域取得了重大进展。TROPION-Lung01研究表明，对于经治的晚期NSCLC患者，Dato-DXd相比于多西他赛能够显著改善无进展生存期（PFS），尤其是在非鳞癌患者中获益更为明显[59]。基于这些数据，Dato-DXd有望成为NSCLC后线治疗的新标准[60]。药代动力学（PK）模型研究为Dato-DXd的剂量选择提供了指导，推荐的临床剂量为6 mg/kg [61]。
在乳腺癌及其他实体瘤中的潜力：Dato-DXd在HER2阴性乳腺癌，包括脑转移患者中也显示出令人鼓舞的抗肿瘤活性[62]。其活性被证实依赖于肿瘤细胞的TROP2表达水平[63]。此外，Dato-DXd在TROP2阳性的晚期宫颈癌、卵巢癌以及罕见的癌肉瘤中均观察到了临床疗效，进一步证实了其广谱抗癌的潜力[64, 33, 52]。一款名为ESG401的ADC，其结构与Dato-DXd相同，也在多项实体瘤中显示出疗效[65]。3.3 新型及在研的TROP2靶向疗法
除了SG和Dato-DXd，众多新型TROP2-ADC及其他靶向策略也正在积极开发中，旨在改善疗效、克服耐药或降低毒性。
·OBI-992：这是一款新型TROP2-ADC，临床前研究表明其在多种癌症模型中具有强大的抗肿瘤活性[66, 67]。更有头对头比较研究提示，OBI-992在某些模型中的表现可能优于Dato-DXd，显示出成为“best-in-class”药物的潜力[68]。
·SKB264 (MK-2870)：这是一款由科伦博泰开发的TROP2-ADC，其载荷为一种新型的拓扑异构酶I抑制剂。临床前数据显示其活性优于IMMU-132（SG的早期代号）[69]，目前正在全球范围内进行多项临床试验。
·其他ADC：如前所述，hIMB1636-MMAE（载荷为MMAE）和靶向TROP2的Amanitin ADC等，通过采用不同的载荷来探索新的抗癌机制和克服耐药的可能性[46, 25]。
·非ADC策略：除了ADC，靶向TROP2的CAR-T细胞疗法也成为研究热点。TROP2 CAR-T细胞在临床前模型中显示出强大的杀伤活性，并被认为是克服ADC耐药的一种潜在策略[70, 71]。然而，其在TNBC等实体瘤中的应用也伴随着潜在的脱靶毒性风险，需要进一步优化[72]。此外，靶向TROP2的适配体-药物偶联物、免疫毒素（Fab-PE24）以及用于肿瘤成像的分子探针和单域抗体等也都在积极研发中，展现了TROP2靶点开发的多样化前景[73,74, 75, 76]。4. TROP2-ADC治疗的挑战与应对策略
尽管TROP2-ADC取得了巨大成功，但其在临床应用中仍面临着毒副作用管理和耐药性两大核心挑战。4.1 毒副作用及其管理
ADC的治疗窗口虽然相比传统化疗有所拓宽，但并非没有毒性。TROP2-ADC相关的常见不良事件（AEs）主要包括血液学毒性、胃肠道反应和一些特殊的“类效应”毒性。
·间质性肺病/肺炎（ILD/Pneumonitis）：这是与Deruxtecan系列ADC（包括T-DXd和Dato-DXd）相关的一个特别值得关注的严重不良事件。尽管发生率不高，但可能危及生命。一项关键研究揭示了其潜在机制：ADC可能通过Fcγ受体被肺泡巨噬细胞非特异性摄取，随后在肺部释放细胞毒性载荷，引发炎症反应和组织损伤[77]。因此，对接受Dato-DXd治疗的患者进行严密监测，早期识别并积极干预ILD/肺炎至关重要，这已成为临床实践中的标准操作规程[78]。
·血液学与胃肠道毒性：以SG为代表的ADC，其常见毒性主要包括中性粒细胞减少、贫血等血液学毒性，以及恶心、呕吐、腹泻等胃肠道反应。这些毒性通常是可预测且可管理的，通过支持性治疗（如使用粒细胞集落刺激因子G-CSF）和剂量调整，大部分患者可以耐受治疗[79]。4.2 耐药性机制与克服策略
随着TROP2-ADC的广泛应用，获得性耐药已成为一个不可避免的临床难题。其机制复杂多样，主要可分为靶点相关耐药和载荷相关耐药。
·耐药机制：研究发现，SG的耐药可能与TROP2（TACSTD2）基因的表达下调或功能丧失性突变有关，导致药物无法有效结合靶细胞。此外，作为载荷SN-38和DXd作用靶点的TOP1基因发生突变，也可能导致药物无法有效抑制其功能，从而产生耐药[80]。其他机制，如药物外排泵（如ABCG2）的上调、溶酶体功能障碍、细胞凋亡通路缺陷等，也可能参与耐药的形成。例如，COX-2的上调被发现与TROP2相关，并能促进结肠癌的耐药[81]。
·克服策略：
1.联合用药：联合治疗是克服耐药、增敏增效的重要策略。由于TOP1抑制剂主要通过制造DNA单链断裂发挥作用，这会激活DNA损伤应答（DDR）通路。因此，TROP2-ADC与DDR通路抑制剂的联合具有很强的协同作用。例如，与PARP抑制剂（PARPi）联合，可以形成“合成致死”效应，显著增强抗肿瘤活性[82]。同样，与ATR抑制剂联合也能产生协同作用[83]。
2.表观遗传调控：通过表观遗传学手段上调靶点表达是另一种有前景的策略。研究表明，使用表观遗传药物可以上调TROP2以及与药物敏感性相关的基因SLFN11的表达，从而增强SG的治疗效果[84]。
3.开发新疗法：当患者对一种TROP2-ADC耐药时，更换为另一种具有不同作用机制或载荷的药物可能有效。例如，对于SG耐药的肿瘤，或许可以尝试使用基于Amanitin的ADC。PLX038作为一种新型药物，也被提出可能对SG耐药的肿瘤有效[85]。此外，如前所述，开发TROP2 CAR-T细胞疗法是绕过ADC内化和载荷递送障碍的根本性策略，有望为ADC耐药患者提供新的治疗希望[70]。抑制自噬通路也被发现在胰腺癌中能增强TROP2-ADC的疗效，提示调控细胞自噬可能是克服耐药的新方向[86]。4.3 诊断与生物标志物
精准的患者选择是实现ADC个体化治疗的关键。
·TROP2表达检测：目前，免疫组化（IHC）是临床上评估TROP2表达水平的标准方法。然而，不同的抗体克隆、染色方案和判读标准可能导致结果存在较大差异，给患者分层带来挑战[87]。开发标准化的检测方法和可靠的抗体至关重要，例如TrMab-6就是一种被用于检测TROP2表达的单克隆抗体[88, 89]。定量检测HER2和TROP2双靶点表达的方法也正在开发中，以指导更复杂的治疗决策[90]。
·液体活检：循环肿瘤DNA（ctDNA）作为一种非侵入性的检测手段，在监测肿瘤动态变化和预测治疗反应方面显示出巨大潜力。一项研究表明，通过DNADX ctDNA测试监测TROP2等基因的改变，可以与接受SG治疗的乳腺癌患者的生存结局相关联，提示ctDNA有望成为指导TROP2-ADC治疗的动态生物标志物[91]。总结
综上所述，肿瘤相关钙信号转导蛋白2（TROP2）凭借其在多种实体瘤中的广泛高表达以及在驱动肿瘤恶性进展中的关键作用，已成为抗体药物偶联物（ADC）领域一个极其成功和充满希望的靶点。从生物学基础来看，TROP2通过调控PI3K/Akt、NF-κB等多个核心信号通路，深度参与肿瘤细胞的增殖、侵袭和转移，其高表达水平普遍预示着更差的临床预后，这为靶向治疗提供了坚实的理论依据。
TROP2-ADC的设计和开发体现了现代药物工程的精髓。通过优化抗体、连接子和载荷，研究人员成功地将高效的细胞毒性药物（如拓扑异构酶I抑制剂SN-38和Deruxtecan）精准递送至肿瘤部位。这些药物不仅通过直接杀伤TROP2阳性细胞发挥作用，更借助强大的旁观者效应清除邻近的异质性肿瘤细胞，并通过诱导免疫原性细胞死亡来潜在地激活宿主的抗肿瘤免疫，形成了多维度的抗癌机制。
以Sacituzumab govitecan和Datopotamab deruxtecan为代表的TROP2-ADC，已经在包括三阴性乳腺癌、非小细胞肺癌、泌尿系统肿瘤在内的多个癌种中取得了突破性的临床成功，显著改善了难治性、晚期患者的生存结局，并正在向更多的实体瘤适应症中拓展。与此同时，一系列具有不同载荷、不同抗体形式或创新偶联技术的新型TROP2-ADC和TROP2靶向疗法（如CAR-T）正处在积极的研发管线中，预示着该领域的持续繁荣。
然而，TROP2-ADC的临床应用也伴随着明确的挑战。以间质性肺病为代表的严重毒副作用要求临床医生具备高度的警惕性和专业的管理能力。同时，获得性耐药机制的阐明，如靶点丢失和载荷靶点突变，以及开发相应的克服策略，如合理的联合用药和序贯治疗，是决定TROP2-ADC长期临床价值的关键。精准的生物标志物，包括标准化的TROP2表达检测和动态的液体活检监测，对于实现患者的精准筛选和个体化治疗至关重要。
总而言之，TROP2靶向ADC的崛起是精准肿瘤学发展历程中的一个里程碑。它不仅为众多束手无策的晚期癌症患者带来了新的生命曙光，也深刻地改变了多个癌种的治疗范式。尽管挑战依然存在，但基于现有坚实的科学证据和临床数据，TROP2-ADC已经确立了其作为现代抗癌药物库中基石之一的重要地位。参考文献
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抗体药物偶联物
2024-03-25
SAN FRANCISCO, March 25, 2024 (GLOBE NEWSWIRE) -- ProLynx Inc. announced that the first patient was included in TOPOLOGY by investigator Dr. Delphine Loirat, with a Phase II clinical trial investigating PLX038 (PEG~SN-38) for locally-advanced or metastatic triple-negative breast cancer (TNBC). Patients will have been previously treated with at least two therapies, including the antibody-drug conjugate (ADC) sacituzumab govitecan (SG; Trodelvy). The TOPOLOGY trial is run by Institut Curie (Paris and Saint Cloud, France), with principal investigator Prof. Francois-Clement Bidard .
PLX038 is a long-acting prodrug of the topoisomerase 1 (Top1) inhibitor, SN-38, which is also the active component of anti-cancer agents irinotecan and the ADC SC. Top1 inhibitors cause DNA breaks and kill tumors that are unable to repair the damage. Previously, Curie researchers showed that about one-third of TNBC patients have defects in DNA damage repair, and should respond to an effective SN-38-based therapy (Coussy et al., 2020). In PLX038, SN-38 is covalently bound to a circulating nanoparticle and is slowly released to provide free SN-38 with a long half-life, low Cmax, and high exposure – important facets for optimal safety and efficacy. Importantly, in preclinical studies PLX038 was shown to accumulate and be retained in solid tumors, where it slowly releases its SN-38.
SG is an anti-TROP2 ADC with an SN-38 payload that was recently approved for use in advanced TNBC. However, the rapid spontaneous linker hydrolysis in SG releases a large amount of SN-38 cargo systemically, which may in part contribute to its efficacy and also in part be responsible for systemic side effects. Unfortunately, the median progression-free survival after SG therapy is only ~6 months due to resistance, and there are limited rescue therapies available.
ProLynx co-founder and President Daniel V. Santi commented, “Although the active SN-38 payload of PLX038 and SG is the same, the anti-tumor mechanisms of the prodrugs are quite different; and, some mechanisms of resistance may also quite be different (Santi et al., Biodrugs,2024). Taken together, it is reasonable to believe that PLX038 may be effective in SG-resistant tumors.”
Curie investigator Francois-Clement Bidard added, “As with our earlier preclinical study of the correlation of efficacy of irinotecan with BRCAness and SFLN11 biomarkers, TOPOLOGY will assess association of PLX038 efficacy with homologous recombination defects, and biomarkers such as SFLN11 expression and RB1 loss. If confirmed in TOPOLOGY, these biomarkers will allow pre-selection of patients most likely to respond to the drug.”
ProLynx is a San Francisco biotechnology company developing proprietary systems to improve the pharmacokinetics and efficacy of important therapies ( ).
Institut Curie, France’s leading cancer center, combines a renowned research center and hospital which treats all types of cancer. Institut Curie has 3 sites (Paris, Saint-Cloud and Orsay) with over 3,700 health professionals working on treatment, research and teaching ( ) Information on this clinical trial is available at clinicaltrials.gov, NCT06162351.
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BD@ProLyninc.com
临床2期抗体药物偶联物
2024-02-05
SAN FRANCISCO, Feb. 05, 2024 (GLOBE NEWSWIRE) -- ProLynx Inc. announced today that the first patient was treated with PLX038 (PEGylated SN-38) in a Phase I/II clinical trial for primary CNS tumors driven by MYC or MYCN amplifications. National Institutes of Health’s NCI investigators Dr. Marta Penas-Prado and Dr. Mark Gilbert are conducting the trial.
MYC genes regulate expression of genes involved in cell division. High levels of MYC drive oncogenesis in many cancers and induce DNA changes leading to the formation of “topoisome complexes”. MYC and MYCN amplifications are seen in multiple primary tumors of the central nervous system (CNS). This includes 30% of relapsed medulloblastomas, and MYCN-amplified ependymoma, characterized by aggressive clinical behavior and treatment resistance. The MYC or MYCN-induced topoisome contains high levels of topoisomerases that should be susceptible to topoisomerase inhibitors.
PLX038 is a long-acting prodrug of the topoisomerase 1 inhibitor, SN-38 – the active metabolite of irinotecan and sacituzumab govitecan. PLX038 is unique as the SN-38 is covalently bound to a circulating nanomolecule and is slowly released to provide free SN-38 with a long half-life, low Cmax and very high exposure – important for optimal safety and efficacy. Importantly, in preclinical studies, PLX038 was shown to accumulate in CNS tumors, where it slowly releases SN-38.
The NCI trial will assess whether PLX038 is safe and efficacious in primary CNS tumors driven by MYC or MYCN amplifications. The Phase I trial will confirm the recommended Phase II dose. The Phase II trial will test PLX038 in 3 independent cohorts: 1) newly diagnosed MYCN-amplified ependymoma, 2) recurrent ependymoma or medulloblastoma with MYCN or MYC amplification, and 3) other recurrent primary CNS tumors with MYC or MYCN amplifications.
Notably, the Phase II trial will incorporate on-treatment tumor biopsies to investigate biomarkers of response and resistance, including SLFN11, MYC, MYCN and Top1, 2a, and 2b expression. This data could prospectively identify patients most responsive to the drug. Additionally, working collaboratively with The Office of Patient-Centered Outcomes (OPCORe), researchers will collect patient-reported outcomes (PROs) to measure the impact of therapy, including toxicity, symptom severity and interference with daily activities, and physical functioning.
ProLynx co-founder, Daniel V. Santi, stated, “We are excited to work with NCI investigators to bring novel treatments to patients with rare CNS cancers, in hope of improving their outcomes.” He added, “Conventional short-acting topoisomerase 1 inhibitors have clinical activity in certain CNS tumors. Accordingly, we are optimistic that a long-acting SN-38 will result in increased efficacy and safety.”
Additional information on this clinical trial is available at clinicaltrials.gov, through identifier number NCT06161519. For patients interested in enrolling in this clinical trial, please call NCI’s toll-free number: 1-800-4-Cancer (1-800-422-6237) (TTY: 1-800-332-8615); visit the website: and/or email: NCIMO_referrals@mail.nih.gov.
ProLynx is a San Francisco biotechnology company developing proprietary systems to improve the pharmacokinetics/efficacy of important drugs ( ).
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| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| 漏斗胸 | 临床2期 | 法国 | 2024-04-17 | |
| 三阴性乳腺癌 | 临床2期 | 法国 | 2024-04-17 | |
| 中枢神经系统肿瘤 | 临床2期 | 美国 | 2024-02-05 | |
| 肿瘤 | 临床2期 | 美国 | 2022-08-10 | |
| 晚期恶性实体瘤 | 临床1期 | 美国 | 2016-03-01 |
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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 |
|---|
临床1/2期 | 10 | (Phase I Arm 1 Level 1, PLX038 (PEGylated SN38) 1.3 g/m^2 and Rucaparib 400 mg) | 齋醖夢鹽遞齋鹽顧構鹽 = 網壓積選壓選憲襯遞範 鏇鑰鬱鏇餘餘廠築襯齋 (積齋齋獵鬱蓋觸積淵鹹, 醖製襯襯窪範鹹餘簾醖 ~ 鑰構鹹範築鹹膚鹽膚衊) 更多 | - | 2024-01-03 | ||
(Phase I - Arm 1 Level 1A, PLX038 (PEGylated SN38) 1.3 g/m^2 and Rucaparib 300 mg) | 齋醖夢鹽遞齋鹽顧構鹽 = 廠衊範壓鹽獵齋觸壓製 鏇鑰鬱鏇餘餘廠築襯齋 (積齋齋獵鬱蓋觸積淵鹹, 鑰簾憲鏇觸構鑰顧網廠 ~ 淵糧膚鬱範鬱遞鬱構夢) 更多 |
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