PO.ET07.01 · 实验与分子治疗
ACSL4介导的铁死亡及其在增强抗体药物偶联物疗效中的潜在作用
ACSL4 mediated ferroptosis and its potential role in enhancing the efficacy of antibody-drug conjugates
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
目的：虽然通常认为抗体药物偶联物（ADC）保留了其载荷的药代动力学/药效学（PK/PD）特性，但偶联在多大程度上改变其作用机制仍未被充分探究。本研究探讨了ADC偶联是否能从根本上重编程载荷药理学，并阐明了其在常规递送优势之外对抗肿瘤疗效和免疫激活的下游影响。
实验设计：使用MORAb-202（一种由临床获批的艾立布林（eribulin）连接至叶酸受体α（FRα）靶向抗体组成的ADC），我们在具有不同FRα表达的异种移植模型中开展了瘤内药代动力学/药效学（PK/PD）和药物代谢组学分析。通过液相色谱-质谱法定量瘤内释放的艾立布林浓度和磷脂图谱。我们比较了MORAb-202和游离艾立布林对铁死亡、免疫原性细胞死亡（ICD）和肿瘤免疫浸润的影响。在人外周血单个核细胞共植入模型中，作为单药及与pembrolizumab联用测试了治疗疗效。
结果：以AUC值计，ADC偶联的艾立布林实现了比游离艾立布林高出20倍以上的瘤内滞留。代谢组学分析显示，MORAb-202强力诱导铁死亡，其特征为ACSL4上调、GPX4耗竭、脂质过氧化和花生四烯酸重塑。与游离艾立布林不同，MORAb-202触发了ICD，表现为HMGB1表达以及总/活化/PD-1⁺ T细胞和树突状细胞募集的增强。此外，游离艾立布林诱导的铁死亡反应是可逆的，而ADC偶联的艾立布林则诱导不可逆且持续的反应。MORAb-202与pembrolizumab的联用使肿瘤控制超越了任一单药。
结论：ADC偶联重编程了载荷的药效学，诱导出游离载荷即使在临床等效剂量下也无法实现的铁死亡和ICD。这凸显了ADC制剂特有的药效学阈值。这些发现强调了进行瘤内PK/PD评估的必要性，并将铁死亡相关的脂质重塑确定为一种新的ADC机制，支持在精准肿瘤学中与免疫治疗进行合理联用。
查看英文原文 English abstract
Purpose: While antibody-drug conjugates (ADCs) are generally assumed to preserve the pharmacokinetic/pharmacodynamic (PK/PD) properties of their payloads, the extent to which conjugation alters their mechanism of action remains underexplored. This study investigated whether ADC conjugation can fundamentally reprogram payload pharmacology and clarified the downstream consequences for antitumor efficacy and immune activation beyond conventional delivery advantages.
Experimental Design: Using MORAb-202, an ADC consisting of the clinically approved eribulin linked to a folate receptor alpha (FRalpha)-targeting antibody, we performed intratumoral pharmacokinetic/pharmacodynamic (PK/PD) and pharmacometabolomic analyses in xenograft models with varying FRalpha expression. Intratumoral concentrations of released eribulin and phospholipid profiles were quantified by liquid chromatography-mass spectrometry. We compared effects of MORAb-202 and free eribulin on ferroptosis, immunogenic cell death (ICD), and tumor immune infiltration. Therapeutic efficacy was tested as monotherapy and in combination with pembrolizumab in a human peripheral blood mononuclear cells co-implantation model.
Results: ADC-conjugated eribulin achieved >20-fold higher intratumoral retention of eribulin compared to the free eribulin in AUC value. Metabolomics analysis revealed that MORAb-202 robustly induced ferroptosis, characterized by ACSL4 upregulation, GPX4 depletion, lipid peroxidation, and arachidonic acid remodeling. Unlike free eribulin, MORAb-202 triggered ICD, evidenced by HMGB1 expression and enhanced recruitment of total/activated/PD-1⁺ T cells and dendritic cells. Furthermore, ferroptosis responses induced by free eribulin were reversible, whereas ADC-conjugated eribulin induced irreversible and sustained responses. The combination of MORAb-202 with pembrolizumab enhanced tumor control beyond either monotherapy.
Conclusions: ADC conjugation reprograms payload's pharmacodynamics, inducing ferroptosis and ICD unattainable with free payload, even at clinically equivalent doses. This highlights a pharmacodynamic threshold unique to the ADC formulation. These findings stress the need for intratumoral PK/PD evaluation and identify ferroptosis-linked lipid remodeling as a novel ADC mechanism, supporting rational combination with immunotherapy in precision oncology.
利益披露 Disclosure
S. Koganemaru,
Eisai Inc. ).
Amgen ).
Bristol Myers Squibb ).
Daiichi-Sankyo ).
GSK ).
BeiGene ).
AbbVie ).
Incyte ).
ONO Pharmaceutical ).
MSD ).
H. Fuchigami,
Eisai Inc. ).
H. Tsugawa, None..
H. Shinohara, None.
Y. Kuboki,
Taiho ).
Astelas ).
Lilly ).
Takeda ).
Daiichi-Sankyo ).
Astrazeneca ).
Boehringer Ingelheim ).
Chugai ).
Genmab ).
Incyte ).
Abbvie ).
Amgen ).
Merk ).
Hengrui ).
Novartis ).
ONO Pharmaceutical ).
Noile-Immune Biotech Inc ).
Kyowa Kirin ).
BMS ).
Biontech ).
T. Uenaka,
Eisai Co., Ltd. Employment.
T. Doi,
PRA Health Sciences ).
MSD ).
Daiichi-Sankyo ).
Amgen ).
Taiho ).
GSK ).
Ono Pharmaceutical ).
Janssen pharmaceutical ).
Boehringer Ingelheim ).
Pfizer ).
Bristol Myers Squibb ).
Abbvie ).
RIN Institute ).
Chugai Pharmaceutical ).
Shionogi ).
Bayer ).
Kyowa Kirin ).
Takeda ).
Oncolys Bio Pharma ).
Rakuten Medical ).
M. Yasunaga,
Eisai Inc ).
Daiichi-Sankyo ).
Taiho ).
Shimadzu ).
Ajinomoto ).
Sysmex ).
Dojin ).
Johnson and Johnson ).
Lilly ).