药学学报

Classification	Pharmacological approache	Chemical name	Mechanism	Reference
Small molecule inhibitor	ISO-1	(S, R)-3-(4-Hydroxyphenyl)-4, 5-dihydro-5-isoxazole acetic acid methyl ester	Competitive inhibitor Binds to the tautomerase region of MIF, leading to structural changes that block MIF-CD74 binding and thus MIF function	[75]
Ibudilast (also known as AV411)	1, 3-Isobutyryl-2-isopropylpyrazolo (1, 5-a) pyridine	Allosteric inhibitor Blocks catalytic (tautomerase activity) and chemotactic functions of MIF	[76]
4-IPP	4-Iodo-6-phenylpyrmidine	Irreversible inhibitor Covalently adducts MIF at N-terminal proline, altering their structure and preventing function	[77-81]
P425	6, 6'-[(3, 3-Dimethoxy[1, 1'-biphenyl]-4, 4'-diyl)bis(azo)]bis[4-amino-5-hydroxy-1, 3-napthalenedisulphonic acid] tetrasodium salt	Targets an area at the interface of two MIF trimers and inhibits MIF-CD74 interaction and tautomerase activity	[82]
CPSI-1306	2-[3-(2, 4-Difluorophenyl)-4, 5-dihydro-5-isoxazolyl]-1-(4-morpholinyl) ethanone	Competitive inhibitor Binds to the tautomerase region of MIF	[83, 84]
IPG1094	Unknown	Unknown
PROTAC	MD13	8-((2-(2, 6-Dioxopiperidin-3-yl)-1, 3-dioxoisoindolin-4-yl)amino)-N-(4-(7-hydroxy-2-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)phenyl)octanamide	Induces MIF degradation through binding to E3 ligase cereblon	[85]
Anti-MIF antibody	BaxB01, BaxG03, BaxM159	Anti-MIF monoclonal antibody	Reduced cell growth and viability by inhibiting MIF-induced phosphorylation of the central kinases p44/42 mitogen-activated protein kinase	[86]
	Imalumab (also known as BAX69), ON203	Anti-oxMIF monoclonal antibody	Regulate the steady level of circulating oxMIF and total MIF	[32, 87]
Antibody directed against MIF receptors	Milatuzumab	Anti-CD74 monoclonal antibody	Prevents MIF from binding to CD74	[88]

Classification	Pharmacological approache	Chemical name	Mechanism	Reference
Small molecule inhibitor	ISO-1	(S, R)-3-(4-Hydroxyphenyl)-4, 5-dihydro-5-isoxazole acetic acid methyl ester	Competitive inhibitor Binds to the tautomerase region of MIF, leading to structural changes that block MIF-CD74 binding and thus MIF function	[75]
Ibudilast (also known as AV411)	1, 3-Isobutyryl-2-isopropylpyrazolo (1, 5-a) pyridine	Allosteric inhibitor Blocks catalytic (tautomerase activity) and chemotactic functions of MIF	[76]
4-IPP	4-Iodo-6-phenylpyrmidine	Irreversible inhibitor Covalently adducts MIF at N-terminal proline, altering their structure and preventing function	[77-81]
P425	6, 6'-[(3, 3-Dimethoxy[1, 1'-biphenyl]-4, 4'-diyl)bis(azo)]bis[4-amino-5-hydroxy-1, 3-napthalenedisulphonic acid] tetrasodium salt	Targets an area at the interface of two MIF trimers and inhibits MIF-CD74 interaction and tautomerase activity	[82]
CPSI-1306	2-[3-(2, 4-Difluorophenyl)-4, 5-dihydro-5-isoxazolyl]-1-(4-morpholinyl) ethanone	Competitive inhibitor Binds to the tautomerase region of MIF	[83, 84]
IPG1094	Unknown	Unknown
PROTAC	MD13	8-((2-(2, 6-Dioxopiperidin-3-yl)-1, 3-dioxoisoindolin-4-yl)amino)-N-(4-(7-hydroxy-2-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)phenyl)octanamide	Induces MIF degradation through binding to E3 ligase cereblon	[85]
Anti-MIF antibody	BaxB01, BaxG03, BaxM159	Anti-MIF monoclonal antibody	Reduced cell growth and viability by inhibiting MIF-induced phosphorylation of the central kinases p44/42 mitogen-activated protein kinase	[86]
	Imalumab (also known as BAX69), ON203	Anti-oxMIF monoclonal antibody	Regulate the steady level of circulating oxMIF and total MIF	[32, 87]
Antibody directed against MIF receptors	Milatuzumab	Anti-CD74 monoclonal antibody	Prevents MIF from binding to CD74	[88]

Title	Status	Condition	Intervention	NCT number
Anti-MIF intervention
Phase Ⅰ study of anti-MIF antibody in solid tumors	Completed	· Metastatic adenocarcinoma of the colon or rectum · Malignant solid tumors	Biological: anti-MIF antibody	NCT01765790
Study to evaluate ibudilast and TMZ combo treatment in newly diagnosed and recurrent glioblastoma	Active, not recruiting	· Glioblastoma · Recurrent glioblastoma · GBM · Newly diagnosed glioblastoma	Drug: MN-166 Drug: temozolomide	NCT03782415
Phase Ⅱ a study of BAX69 and 5-FU/leucovorin or panitumumab versus standard of care in subjects with metastatic colorectal cancer	Terminated	· Metastatic colorectal cancer	Biological: BAX69 + infusional 5-FU/LV Biological: BAX69 + panitumumab Biological: BAX69 + 5-FU/LV	NCT02448810
Axitinib for the treatment of advanced hepatocellular carcinoma	Completed	· Hepatocellular carcinoma	Drug: axitinib (AG-013736) Other: best supportive care Drug: placebo	NCT01210495
Cardiorespiratory fitness in children and adolescents after cancer treatment	Recruiting	· All types of ediatric cancer	Behavioral: experimental: moderate to high-intensity exercise	NCT04765020
Phase Ⅰ/Ⅱ a two-arm dose-escalation study of BAX69 in subjects with malignant ascites of ovarian cancer	Terminated	· Refractory ovarian cancer with recurrent symptomatic malignant ascites	Biological: BAX69 single-route arm Biological: BAX69 double-route arm	NCT02540356
Anti-CD74 intervention
Effect of expression of CD74 and VEGF on outcome of treatment in patients with malignant pleural mesothelioma	Unknown	· Malignant pleural mesothelioma	Other: CD74, VEGF detection	NCT02761863
Vascularity impact on the treatment outcome in malignant pleural mesothelioma	Completed	· Malignant pleural mesotheliomas	Other: marker CD74 and VEGF	NCT02603315
Phase Ⅰ trial of anti-CD74 (hLL1) antibody therapy in B cell malignancies	Completed	· Non-hodgkin lymphoma · CLL	Drug: hLL1	NCT00504972
Phase Ⅰ/Ⅱ study of different doses and dose schedules of milatuzumab (hLL1) in CLL	Completed	· CLL	Biological: milatuzumab	NCT00603668
Phase Ⅰ study of milatuzumab for GVHD	Terminated	· GVHD (acute or chronic) · AML or ALL · Myelodysplastic syndrome	Drug: milatuzumab	NCT01663766
The humanized monoclonal antibody milatuzumab for refractory CLL	Unknown	· CLL	Drug: milatuzumab	NCT00868478
Veltuzumab and milatuzumab in treating patients with relapsed or refractory B-cell non-hodgkin lymphoma	Completed	· Lymphoma	Biological: milatuzumab Biological: veltuzumab Procedure: correlative/special studies	NCT00989586
MIF involvement in AML	Active, not recruiting	· AML	NA	NCT03918655
An open-label, multicenter, phase Ⅱ study of LDK378 in patients with NSCLC harboring ROS1 rearrangement	Unknown	· NSCLC	Drug: LDK378	NCT01964157
A study of LDK378 in patients with NSCLC harboring ROS1 rearrangement	Unknown	· NSCLC harboring ROS1 rearrangement	Drug: LDK378 (ceritinib)	NCT03399487
A study of hLL1-DOX (milatuzumab-doxorubicin antibody-drug conjugate) in patients with multiple myeloma	Terminated	· Multiple myeloma	Drug: hLL1-DOX	NCT01101594
Phase Ⅰ/Ⅱ study of hLL1 in multiple myeloma	Completed	· Multiple myeloma · Myeloma, plasma-cell · Plasmacytoma	Biological: milatuzumab	NCT00421525
Bortezomib, mitoxantrone, etoposide, and cytarabine in relapsed or refractory AML	Completed	· Adult acute megakaryoblastic leukemia (M7) · Adult acute minimally differentiated myeloid leukemia (M0) · Adult acute monoblastic leukemia (M5a)	Drug: bortezomib Drug: mitoxantrone hydrochloride Drug: etoposide	NCT01127009
Ixazomib, mitoxantrone hydrochloride, etoposide, and intermediate-dose cytarabine in relapsed or refractory AML	Completed	· Recurrent adult AML · Refractory AML	Drug: ixazomib Drug: mitoxantrone hydrochloride Drug: etoposide Drug: cytarabine	NCT02070458
MLN 9708 in induction and consolidation for adults with AML ≥ 60 years of age	Completed	· AML	Drug: MLN9708 Drug: cytarabine Drug: daunorubicin	NCT02582359
Study of STRO-001, an anti-CD74 antibody drug conjugate, in patients with advanced B-cell malignancies	Active, not recruiting	· B-cell lymphoma · Non-hodgkin lymphoma · Multiple myeloma	Drug: STRO-001	NCT03424603

Title	Status	Condition	Intervention	NCT number
Anti-MIF intervention
Phase Ⅰ study of anti-MIF antibody in solid tumors	Completed	· Metastatic adenocarcinoma of the colon or rectum · Malignant solid tumors	Biological: anti-MIF antibody	NCT01765790
Study to evaluate ibudilast and TMZ combo treatment in newly diagnosed and recurrent glioblastoma	Active, not recruiting	· Glioblastoma · Recurrent glioblastoma · GBM · Newly diagnosed glioblastoma	Drug: MN-166 Drug: temozolomide	NCT03782415
Phase Ⅱ a study of BAX69 and 5-FU/leucovorin or panitumumab versus standard of care in subjects with metastatic colorectal cancer	Terminated	· Metastatic colorectal cancer	Biological: BAX69 + infusional 5-FU/LV Biological: BAX69 + panitumumab Biological: BAX69 + 5-FU/LV	NCT02448810
Axitinib for the treatment of advanced hepatocellular carcinoma	Completed	· Hepatocellular carcinoma	Drug: axitinib (AG-013736) Other: best supportive care Drug: placebo	NCT01210495
Cardiorespiratory fitness in children and adolescents after cancer treatment	Recruiting	· All types of ediatric cancer	Behavioral: experimental: moderate to high-intensity exercise	NCT04765020
Phase Ⅰ/Ⅱ a two-arm dose-escalation study of BAX69 in subjects with malignant ascites of ovarian cancer	Terminated	· Refractory ovarian cancer with recurrent symptomatic malignant ascites	Biological: BAX69 single-route arm Biological: BAX69 double-route arm	NCT02540356
Anti-CD74 intervention
Effect of expression of CD74 and VEGF on outcome of treatment in patients with malignant pleural mesothelioma	Unknown	· Malignant pleural mesothelioma	Other: CD74, VEGF detection	NCT02761863
Vascularity impact on the treatment outcome in malignant pleural mesothelioma	Completed	· Malignant pleural mesotheliomas	Other: marker CD74 and VEGF	NCT02603315
Phase Ⅰ trial of anti-CD74 (hLL1) antibody therapy in B cell malignancies	Completed	· Non-hodgkin lymphoma · CLL	Drug: hLL1	NCT00504972
Phase Ⅰ/Ⅱ study of different doses and dose schedules of milatuzumab (hLL1) in CLL	Completed	· CLL	Biological: milatuzumab	NCT00603668
Phase Ⅰ study of milatuzumab for GVHD	Terminated	· GVHD (acute or chronic) · AML or ALL · Myelodysplastic syndrome	Drug: milatuzumab	NCT01663766
The humanized monoclonal antibody milatuzumab for refractory CLL	Unknown	· CLL	Drug: milatuzumab	NCT00868478
Veltuzumab and milatuzumab in treating patients with relapsed or refractory B-cell non-hodgkin lymphoma	Completed	· Lymphoma	Biological: milatuzumab Biological: veltuzumab Procedure: correlative/special studies	NCT00989586
MIF involvement in AML	Active, not recruiting	· AML	NA	NCT03918655
An open-label, multicenter, phase Ⅱ study of LDK378 in patients with NSCLC harboring ROS1 rearrangement	Unknown	· NSCLC	Drug: LDK378	NCT01964157
A study of LDK378 in patients with NSCLC harboring ROS1 rearrangement	Unknown	· NSCLC harboring ROS1 rearrangement	Drug: LDK378 (ceritinib)	NCT03399487
A study of hLL1-DOX (milatuzumab-doxorubicin antibody-drug conjugate) in patients with multiple myeloma	Terminated	· Multiple myeloma	Drug: hLL1-DOX	NCT01101594
Phase Ⅰ/Ⅱ study of hLL1 in multiple myeloma	Completed	· Multiple myeloma · Myeloma, plasma-cell · Plasmacytoma	Biological: milatuzumab	NCT00421525
Bortezomib, mitoxantrone, etoposide, and cytarabine in relapsed or refractory AML	Completed	· Adult acute megakaryoblastic leukemia (M7) · Adult acute minimally differentiated myeloid leukemia (M0) · Adult acute monoblastic leukemia (M5a)	Drug: bortezomib Drug: mitoxantrone hydrochloride Drug: etoposide	NCT01127009
Ixazomib, mitoxantrone hydrochloride, etoposide, and intermediate-dose cytarabine in relapsed or refractory AML	Completed	· Recurrent adult AML · Refractory AML	Drug: ixazomib Drug: mitoxantrone hydrochloride Drug: etoposide Drug: cytarabine	NCT02070458
MLN 9708 in induction and consolidation for adults with AML ≥ 60 years of age	Completed	· AML	Drug: MLN9708 Drug: cytarabine Drug: daunorubicin	NCT02582359
Study of STRO-001, an anti-CD74 antibody drug conjugate, in patients with advanced B-cell malignancies	Active, not recruiting	· B-cell lymphoma · Non-hodgkin lymphoma · Multiple myeloma	Drug: STRO-001	NCT03424603

不同亚细胞定位的巨噬细胞迁移抑制因子促肿瘤功能研究进展

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张欢 ^# , 杨辰 ^# , 尚爽 , 吕晓希 , 花芳 ^*

药学学报 | 综述 2023,58(8): 2085-2097

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药学学报 |综述 2023 , 58 (8) : 2085 -2097

不同亚细胞定位的巨噬细胞迁移抑制因子促肿瘤功能研究进展

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张欢^#, 杨辰^#, 尚爽, 吕晓希, 花芳^*

作者信息

中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 新药作用机制研究与药效评价北京市重点实验室 (BZ0150), 代谢紊乱和肿瘤发生相关机制和靶点发现重点实验室, 北京 100050

通讯作者:

*花芳, Tel: 86-10-83161187, E-mail: huafang@imm.ac.cn

Subcellular localization of macrophage migration inhibitory factor and its diverse biological functions in tumors

Huan ZHANG, Chen YANG, Shuang SHANG, Xiao-xi LV, Fang HUA^*

Affiliations

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study (BZ0150), CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Institute of Meteria Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China

出版时间: 2023-08-12 doi: 10.16438/j.0513-4870.2023-0623

文章导航

摘要

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巨噬细胞迁移抑制因子(macrophage migration inhibitory factor, MIF) 是一种具有酶活性的多效细胞因子, 在多种免疫细胞和肿瘤细胞中均可见到其表达。MIF在炎性反应及肿瘤发生发展过程中发挥多重效应, 不但作为细胞因子参与机体免疫反应和炎性病变, 而且与肿瘤细胞增殖、转移等肿瘤生物学特性密切相关, 从多方面影响肿瘤发生和演进。研究显示, MIF不仅分泌到细胞外以细胞因子的形式发挥作用, 同样也可以定位于细胞浆和细胞核发挥多样化的生物学功能。随着MIF促进肿瘤进展的作用日益被人们所认识, 目前基于MIF的治疗策略已成为肿瘤学研究的热点。本文对不同亚细胞定位的MIF所发挥的促肿瘤功能进行综述, 对MIF肿瘤生物学功能的全面理解将为开发新的靶向MIF的治疗策略提供更为广阔的视野, 为肿瘤治疗指出更具前景的方向。

关键词

巨噬细胞迁移抑制因子 / 亚细胞定位 / 肿瘤 / 肿瘤微环境 / 靶向治疗

Abstract

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Macrophage migration inhibitory factor (MIF) is an enzyme-active pleiotropic cytokine that is expressed in various immune cells and tumor cells. MIF plays diverse roles in inflammation and tumor progression. It acts as a cytokine involved in immune response and inflammatory lesions. Additionally, MIF is closely associated with tumor proliferation, metastasis, and other tumor hallmarks, exerting a multifaceted influence on tumor occurrence and progression. MIF not only functions by being secreted into the extracellular space as a cytokine but can also be localized within the cytoplasm and nucleus, exhibiting diverse biological functions. As MIF in promoting tumor progression becomes increasingly recognized, MIF-based therapeutic strategies have become a hot research topic in oncology. Here, we provide a comprehensive review of MIF with different subcellular localization about their pro-tumoral functions. A better understanding of MIF in tumor biology will bring broader perspectives for the development of novel MIF targeting strategies and give promising direction for future tumor treatments.

Key words

macrophage migration inhibitory factor / subcellular localization / tumor / tumor microenvironment / targeted therapy

引用本文

张欢, 杨辰, 尚爽, 吕晓希, 花芳. 不同亚细胞定位的巨噬细胞迁移抑制因子促肿瘤功能研究进展. 药学学报, 2023 , 58 (8) : 2085 -2097 . DOI: 10.16438/j.0513-4870.2023-0623

Huan ZHANG, Chen YANG, Shuang SHANG, Xiao-xi LV, Fang HUA. Subcellular localization of macrophage migration inhibitory factor and its diverse biological functions in tumors[J]. Acta Pharmaceutica Sinica, 2023 , 58 (8) : 2085 -2097 . DOI: 10.16438/j.0513-4870.2023-0623

正文

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巨噬细胞迁移抑制因子(macrophage migration inhibitory factor, MIF) 是一种具有酶活性的多功能细胞因子。自从20世纪90年代初首次被克隆以来, MIF与疾病的关联、功能多样性, 以及其受体、相互作用蛋白和下游信号通路传导一直受到学术界的广泛关注。尽管目前对MIF的认识已经取得一定进展, 但仍有许多未知问题亟待回答。大量证据表明, MIF与肿瘤密切相关, MIF高表达于某些实体肿瘤如结直肠癌^{[1, 2]}、胃癌^[3]、非小细胞肺癌^[4]、卵巢癌^[5]、胰腺癌^[6]、黑色素瘤^[7]和神经母细胞瘤^[8]等, 并且其表达与高肿瘤负担、转移风险增加和不良预后有关。既往研究已经充分关注到MIF作为分泌型细胞因子所发挥的生物学功能以及其在疾病中的作用, 然而近些年的研究发现, MIF不仅可以以细胞因子的形式分泌到细胞外液, 还可以被包裹在外泌体囊泡内进而递送至内环境中; 此外, MIF还可以作为非分泌型蛋白存在于细胞浆和细胞核。MIF定位的多样性提示其生物学活性和生理、病理功能同样具有多样性^[9-12]。本综述对定位于不同亚细胞区域的MIF发挥的多样化肿瘤生物学功能及促肿瘤机制进行总结; 并对目前靶向MIF的抗肿瘤药物研发状况进行归纳。以期在全面了解MIF促肿瘤作用及机制前提下, 为寻找更有效的MIF靶向策略提供思路。

1 MIF家族及其结构和分布

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1.1 MIF家族

MIF最初发现于1966年, 是迟发型超敏反应中活化的T细胞产生的细胞因子, 当时发现在抗原存在的情况下, 分枝杆菌致敏的动物淋巴组织中炎性细胞的迁移受到抑制, MIF也因此而得名^[13]。MIF基因位于人类基因组第22号染色体(22q11.23) 上, 包含3个外显子(107、172和66 bp) 和2个内含子(188和94 bp)^[14] (图 1A)。MIF是一种由115个氨基酸组成的12.5 kDa蛋白, 根据X射线晶体学数据显示, MIF由2个反向平行的α螺旋和4个β链形成的一个β片层组成, 且MIF以同源三聚体的形式发挥生物学功能^{[14, 15]} (图 1B和C)。D-多巴色素互变异构酶(D-dopachrome tautomerase, D-DT) 是一种新发现的细胞因子, 是巨噬细胞迁移抑制因子蛋白超家族的第二个成员, 又称为MIF-2, 于1997年被首次发现, D-DT与MIF具有34%的氨基酸序列同源性, 也以同源三聚体结构形式发挥生物学功能。多项研究表明, D-DT在某些方面与MIF具有相似的生物学活性^[16-18]。

1.2 MIF的细胞表达类型及其多态性

MIF广泛表达于各种类型的细胞, 包括免疫细胞、上皮细胞、内皮细胞、神经细胞、肿瘤细胞, 并在各种炎性疾病、自身免疫性疾病以及肿瘤发生、发展过程中发挥重要作用^[19-22]。研究显示, MIF等位基因的高表达与这些疾病的发病率和严重程度密切相关, 目前已经发现200余种MIF基因多态性, 其中在MIF基因启动子区域存在两个重要的与MIF功能相关的基因多态性: MIF启动子上游第173位核苷酸存在G/C突变的单核苷酸多态性(single nucleotide polymorphism, SNP), 以及MIF启动子上游第794位存在5~8次CATT微卫星重复序列多态性(图 1A)^[23]。其中, MIF基因启动子存在6~8次CATT微卫星重复序列和第173位核苷酸为C的G/C SNP多态性是与MIF高表达相关的基因变异; 而CATT重复5次和第173位核苷酸为G的G/C SNP多态性则是MIF低表达相关的基因变异, 这些多态性与宿主疾病易感性以及疾病严重程度有关。在多数情况下, 高表达的MIF等位基因在炎性疾病、自身免疫病和肿瘤的进展中起着关键作用, 有助于促进疾病的发展进程, 因此MIF基因多态性可能成为判断相关疾病严重程度的一个有潜力标志物^[24-27]。

目前已经有证据表明MIF存在两种免疫学上不同的构象异构体: 氧化型MIF (oxidized macrophage migration inhibitory factor, oxMIF) 是一种与疾病相关的结构异构体, 主要存在于炎症疾病患者的血浆和组织, 以及肿瘤组织和相应的转移瘤中; 而还原型MIF (reduced macrophage migration inhibitory factor, redMIF) 存在于健康个体的血浆、细胞和组织中^[28]。这是由于肿瘤和炎症性疾病的微环境中巨噬细胞、中性粒细胞和其他免疫细胞有助于活性氧和促炎介质的产生, 在这些氧化条件下, 肿瘤细胞以及内皮细胞、上皮细胞和其他免疫细胞分泌的MIF可以转化为oxMIF^[29]。与redMIF相比, oxMIF增加了氧化还原修饰, 最主要的修饰位点在CALC基序远端的第3个Cys (Cys-80), 它作为一个开关, 通过氧化修饰将redMIF转化为oxMIF。抗oxMIF抗体可以结合oxMIF亚型三聚体核心通道表位, 阻断多条MIF相关信号通路, 有效减少肿瘤细胞增殖、迁移、侵袭、血管生成等^[30]。有证据表明抗oxMIF抗体也能诱导细胞凋亡, 改变免疫细胞功能和迁移能力^{[31, 32]}。oxMIF与redMIF在疾病与健康状态下的不同分布情况对于开发靶向MIF药物具有重要意义, 靶向oxMIF药物不仅可以起到良好的疾病治疗作用, 同时可以避免对正常组织和细胞产生毒性。此外, 对于oxMIF与redMIF结构的深入分析对于进一步开发靶向oxMIF药物如小分子抑制剂等具有重要价值。因此, oxMIF作为MIF的一种可靶向的亚型有望在炎性疾病和癌症中成为潜在的治疗新靶点。

2 分泌型MIF在肿瘤中的作用

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大多数细胞因子存在一个N端信号肽, 通过常规的内质网-高尔基体途径分泌。MIF作为一种独特的细胞因子, 其分泌方式区别于其他大部分细胞因子, MIF通过非常规蛋白分泌(unconventional protein secretion, UPS) 的替代途径释放^[33]。分泌型MIF通过多种受体, 包括与同源受体CD74以及CXC型趋化因子受体2 (C-X-C motif chemokine receptor 2, CXCR2)、CXC型趋化因子受体4 (CXCR4)、CXC型趋化因子受体7 (CXCR7) 等非同源受体相互作用介导多条信号转导通路, 通过促进肿瘤增殖、诱导凋亡抵抗、促进侵袭转移、诱导血管新生、诱发炎症以及维持免疫抑制性微环境等方式促进肿瘤的发生和发展^[34] (图 2)。

2.1 分泌型MIF促进肿瘤增殖、抵抗细胞死亡

多项研究表明, 分泌型MIF可以促进胃癌、肝癌、膀胱癌、黑色素瘤等多种肿瘤细胞增殖并抑制其死亡, 是肿瘤细胞存活的关键促进因子^{[8, 35-38]}。这一功能主要由免疫细胞或基质细胞来源的外源性MIF和肿瘤细胞自分泌的MIF快速触发丝/苏氨酸蛋白激酶B (AKT) 信号通路来实现。在这条信号通路中分泌型MIF首先与肿瘤细胞表面CD74受体特异性结合, 随后启动共受体CD44向细胞膜的募集, 引起两种蛋白胞质结构域磷酸化以启动下游信号转导, 进而通过蛋白酪氨酸激酶SRC和磷脂酰肌醇-3-激酶(phosphatidylinositol-3 kinase, PI3K) 引起AKT信号通路激活, 最终导致促凋亡蛋白BAD和BAX的磷酸化失活, 使细胞能够抵抗凋亡^[35-37]。分泌型MIF还可以通过与肿瘤细胞表面CD74受体结合引起丝裂原激活蛋白激酶/细胞外调节蛋白激酶(mitogen-activated protein kinase/extracellular regulated protein kinases, MAPK/ERK) 信号通路的激活以及抑制p53活性与功能, 进而促进肿瘤增殖和抵抗细胞死亡^{[8, 38]}。鉴于分泌型MIF通过与CD74受体结合介导多种信号转导通路促进多种肿瘤细胞增殖和抵抗细胞死亡, 靶向MIF/CD74信号通路有望成为肿瘤治疗的新策略。

2.2 分泌型MIF促进肿瘤侵袭和转移

外源性MIF及肿瘤自分泌产生的MIF还可以促进肿瘤侵袭和转移, 这种促转移作用已在胰腺导管腺癌、口腔鳞状细胞癌、乳腺癌等多种癌症中报道^{[6, 39, 40]}。Wang等^[6]阐明了MIF/AKT/ERK/cyclin D1/MMP-2信号转导通路驱动胰腺导管腺癌转移的机制。他们发现分泌型MIF通过与肿瘤细胞表面特异性受体CD74结合引起上述信号通路的激活, 增强细胞周期蛋白D1 (cyclin D1) 和基质金属蛋白酶2 (matrix metalloproteinase-2, MMP-2) 的活性和表达来促进肿瘤细胞侵袭和转移。在口腔鳞状细胞癌的一项研究中发现, MIF通过增加MMP-2以及MMP-9的表达促进肿瘤细胞侵袭和转移^[39]。此外研究还证实, 分泌型MIF通过调节高迁移率族蛋白B1/Toll样受体4 (high mobility group protein 1/Toll-like receptor 4, HMGB1/TLR4) 轴在体内促进乳腺癌细胞迁移和乳腺癌肺转移。分泌型MIF触发肿瘤细胞生成活性氧自由基(reactive oxygen species, ROS) 并磷酸化膜蛋白caveolin-1, 进而诱导HMGB1由细胞核逐步释放至细胞外基质中, 激活肿瘤细胞表面TLR4信号转导通路, 引起核因子κB (nuclear factor kappa-B, NF-κB) 磷酸化, 进而促进MMP-2的表达^[40]。综上所述, 分泌型MIF可以通过增加肿瘤细胞中促肿瘤转移蛋白的表达增强肿瘤细胞的侵袭和转移能力。

2.3 分泌型MIF促进并维持肿瘤免疫抑制微环境

研究发现肿瘤来源的分泌型MIF在髓系来源抑制细胞(myeloid-derived suppressor cells, MDSCs) 以及肿瘤相关巨噬细胞(tumor-associated macrophages, TAMs) 的募集中发挥重要作用^[41]。在实体瘤中肿瘤分泌的MIF与巨噬细胞表面的CD74和CXCR7受体相互作用激活下游信号通路, 有效地使肿瘤微环境内TAMs向免疫抑制、促血管生成和促肿瘤的M2表型极化, 促进肿瘤免疫抑制性微环境(tumor microenvironment, TME) 的形成^{[42, 43]}。研究发现, A549R、H460R等顺铂耐药细胞株与TAMs共培养可以通过SRC/CD155/MIF信号转导通路促进肿瘤相关巨噬细胞M2极化, 而M2型TAMs反过来又可以增强肿瘤细胞中MIF的表达^[4]。肿瘤分泌的MIF以CXCR2受体依赖的方式诱导中性粒细胞向肿瘤微环境中募集, 促进中性粒细胞向促肿瘤表型发生转化, 进而促进并维持肿瘤免疫抑制微环境^[44]。TAMs、MDSCs及中性粒细胞在肿瘤微环境中的聚集会诱导肿瘤免疫抑制性微环境的形成, 减少T细胞的浸润以及抑制T细胞的活化, 进而抑制其发挥抗肿瘤生物学功能^[41]。值得注意的是, 最新的一项研究发现CD36⁺肿瘤相关成纤维细胞(cancer-associated fibroblasts, CAFs) 也可以分泌MIF为肝癌提供免疫抑制微环境^[45]。在肝癌中, CD36⁺ CAFs通过脂质过氧化/p38/CEBPs轴介导MIF表达和分泌, 以MIF和CD74依赖的方式招募CD33⁺ MDSCs, 进而抑制T细胞介导的肿瘤免疫, 促进免疫抑制微环境形成。分泌型MIF在肿瘤免疫抑制微环境形成中发挥的重要作用提示, MIF在肿瘤免疫治疗领域可能有巨大的潜在应用价值。

2.4 分泌型MIF促进肿瘤血管新生

大量研究表明, 外源性以及肿瘤自分泌MIF通过与特异性受体CD74结合激活MAPK信号通路, 刺激肿瘤细胞过度表达多种促血管生成因子包括白细胞介素-8 (interleukin-8, IL-8)、碱性成纤维细胞生长因子(fibroblast growth factor-basic, bFGF) 和血管内皮生长因子(vascular endothelial growth factor, VEGF) 等促进肿瘤血管新生^[46]。血管内皮生长因子是目前研究最多的血管生成因子之一, 研究表明MIF和VEGF在肝癌患者血清和癌组织中的表达与正常对照组相比均呈显著正相关^[47], MIF和VEGF表达之间的这种密切关系在胶质母细胞瘤中也有报道^[48]。Bucala团队^[49]证明了MIF和肿瘤血管生成之间更直接的联系, 对B细胞淋巴瘤荷瘤小鼠给予抗MIF单克隆抗体与对照组相比, 实验组显著减少了肿瘤血管生成数量而且减少了新生血管的直径。分泌型MIF在促肿瘤血管生成中的重要作用进一步丰富了MIF的促肿瘤生物学功能。

2.5 分泌型MIF诱发炎症促进肿瘤进展

炎症和癌症之间有着错综复杂的关系, 先前大量研究已经表明炎症会促进肿瘤的发生和进展^[50]。分泌型MIF作为一种促炎细胞因子, 可以直接或间接地调节炎性细胞中其他促炎分子如IL-2、IL-6、IL-8、肿瘤坏死因子α (tumor necrosis factor alpha, TNFα)、干扰素γ (interferon gamma, IFNγ) 和IL-1β的分泌, 这些炎症因子的分泌不仅可以进一步放大炎症, 还可以通过受体介导的方式激活NF-κB等信号转导通路, 促进癌症的发生和进展^{[51, 52]}。因此, 分泌型MIF的促肿瘤作用在一定程度上依赖于其促进癌症相关慢性炎症的能力。

2.6 外泌体中的MIF促进肿瘤耐药以及远处转移

外泌体是一种可由多种细胞分泌、大小为30~150 nm的细胞外囊泡, 肿瘤来源的外泌体富含多种生物活性分子包括蛋白质、核酸、脂质等, 可以用于细胞通讯并激活靶细胞中的信号转导通路, 越来越多的证据表明肿瘤来源的外泌体参与了肿瘤生长、转移和耐药^[53]。目前, 已经发现MIF在替莫唑胺(temozolomide, TMZ) 耐药脑胶质瘤细胞外泌体中表达上调。TMZ敏感细胞通过摄取外泌体中MIF下调组织金属蛋白酶抑制因子3 (tissue inhibitors of metalloproteinase 3, TIMP3), 进一步激活PI3K/AKT信号通路促进敏感细胞增殖和抑制细胞凋亡, 从而在脑胶质瘤细胞间传递TMZ耐药特性^[54]。另有研究显示, 人胰腺导管癌细胞释放的外泌体中高表达MIF, 其通过血液运输到肝脏, 肝脏Kupffer细胞选择性摄取富含MIF的外泌体, 引起转化生长因子-β (transforming growth factor-β, TGF-β) 分泌增加, 通过TGF-β信号转导通路促进肝星形细胞合成连接蛋白, 纤连蛋白的沉积促进MDSCs和中性粒细胞在肝脏浸润, 这在肝脏创造出一个转移前生态位, 有利于胰腺导管癌细胞发生肝转移^[10]。此外, MIF同样高表达于非小细胞肺癌的外泌体中, 但其在肿瘤中的功能还没有相关报道^[55]。目前, 关于外泌体中MIF如何介导肿瘤细胞增殖、抵抗死亡、转移、侵袭等方面的研究还较少, 尚需进一步的探索。但可以预见的是, 外泌体中存在MIF为MIF可以进入目的细胞内发挥相应的生物学功能提供了基础。

3 定位于细胞浆的MIF在肿瘤中的作用

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与抗原刺激后分泌的其他细胞因子不同, MIF不断表达并储存在细胞内, 目前研究已经发现细胞内MIF同样具有生物学活性并且发挥重要生物学功能, 其中细胞浆内的MIF既可以作为酶参与多种物质的催化过程, 而且可以作为分子伴侣调节其他蛋白的结构和功能, 还可以直接与其他蛋白相互作用激活相应的信号转导通路(图 3)。

3.1 定位于细胞浆的MIF可发挥多种酶活性

研究显示, 细胞浆内的MIF具有两种进化上保守的酶活性即互变异构酶活性和巯基-蛋白氧化还原酶(thiol-protein oxidoreductase, TPOR) 活性, 它们由不同的催化中心所介导。MIF的互变异构酶活性具有催化苯丙酮酸、对羟基苯丙酮酸和D-多巴色素互变异构的能力, 这种活性需要MIF的N端脯氨酸作为催化残基^{[56, 57]}。而TPOR活性是通过位于MIF中心的保守的半胱氨酸(Cys)-丙氨酸(Ala)-亮氨酸(Leu)-半胱氨酸(Cys) 即CALC基序介导的^[58]。目前, 尚未有研究发现MIF两种酶活性与疾病之间的关联, 但不可否认的是, 针对MIF酶活性位点设计的小分子抑制剂在肿瘤中显示出一定的治疗效果, 这提示研究者MIF酶活性位点对于MIF发挥其他生物学活性可能同样具有重要作用。

3.2 定位于细胞浆的MIF可充当分子伴侣

大量研究表明, MIF作为分子伴侣参与多种蛋白质的折叠和组装过程, 对于相应蛋白结构和功能的维持发挥重要作用^[59]。细胞浆内MIF调节Cu/Zn超氧化物歧化酶1 (superoxide dismutase 1, SOD1) 的折叠, 防止错误折叠突变体SOD1的积累, MIF这一功能依赖于其分子伴侣样活性, 且其分子伴侣样活性与其两种酶催化活性无关^[60-62]。在多发性骨髓瘤细胞的细胞浆内MIF以同源三聚体的形式作为SOD1的分子伴侣, 防止SOD1错误折叠突变体的形成和聚集以维持SOD1的正常结构和功能, 进而抑制过量ROS的产生以保证线粒体的正常功能活动, 这对于肿瘤细胞抵抗由于过量ROS积累所引起的细胞凋亡至关重要^[63]。MIF也参与NLRP3炎症体的激活过程, 其中MIF作为NLRP3的分子伴侣稳定蛋白结构和促进NLRP3与波形蛋白的相互作用^[11]。还有文献报道, MIF可以结合胰岛β细胞分泌颗粒中的胰岛素, 显著增加胰岛素六聚体的比例并且改变胰岛素的生物学活性, 进一步表明MIF作为分子伴侣在蛋白质折叠和构象维持中发挥重要作用^[64]。目前, 尚未有研究明确阐明MIF作为分子伴侣在肿瘤发生和发展中的作用, MIF是否作为分子伴侣影响更多种肿瘤相关蛋白的组装和折叠进而影响肿瘤发生发展进程具有重要研究价值。

3.3 MIF在细胞浆内通过蛋白-蛋白相互作用发挥促肿瘤作用

细胞浆内MIF可通过蛋白-蛋白相互作用(protein-protein interaction, PPI) 发挥调控功能。MIF特异性与细胞内蛋白Jun激活区域-连接蛋白1 (c-Jun activation domain-binding protein-1, JAB1) 相互作用, 通过抑制核转录因子激活蛋白1 (activator protein 1, AP-1) 的转录激活作用以及促进细胞周期蛋白依赖性激酶抑制剂p27^Kip1的降解, 促进肿瘤增殖和抵抗细胞死亡^[65]。此外, 细胞浆内MIF可以帮助肿瘤细胞逃避生长抑制因子, 从而促进肿瘤进展, MIF在细胞浆内直接与p53相互作用, 通过稳定p53与E3泛素连接酶MDM2的结合直接降低p53水平, 导致细胞凋亡相关蛋白p21和BAX表达量降低, 从而抑制p53所引起的细胞周期阻滞和细胞凋亡, 促进肿瘤细胞增殖和抵抗死亡^{[66, 67]}。除以上两种蛋白外, MIF还可以与细胞浆内多种蛋白发生相互作用如核糖体蛋白S19、硫氧还蛋白互作蛋白等^{[68, 69]}, 进一步挖掘这些蛋白相互作用在肿瘤中的作用以及寻找更多MIF相互作用蛋白仍具有重要研究意义。

4 定位于细胞核的MIF在肿瘤中的作用

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在正常生理条件下, MIF主要位于细胞胞浆内, 少量位于细胞核。而在一些应激条件下如高水平DNA复制应激会诱导MIF发生核易位, 研究发现MIF乙酰化与其核易位密切相关, MIF第78位赖氨酸(K78) 乙酰化可以减弱MIF与凋亡诱导因子(apoptosis inducing factor, AIF) 之间的相互作用, 从而抑制MIF核易位, 这一过程受到组蛋白去乙酰化酶6 (histone deacetylase 6, HDAC6) 的调节^[70]。研究表明, 进入细胞核内的MIF具有核酸酶活性, 而且可以与一些细胞核内蛋白如p53蛋白发生相互作用, 促进肿瘤细胞增殖和抵抗细胞死亡^{[71, 72]}。

4.1 MIF在细胞核内具有核酸酶活性

2016年, Wang等^[12]发现MIF可以作为一种核酸酶在细胞核内发挥生物学功能。MIF由AIF招募到细胞核, 裂解基因组DNA以应对氧化应激和细胞DNA损伤。值得注意的是, MIF核酸酶活性位点不同于其互变异构酶和巯基-蛋白氧化还原酶活性位点, MIF的第一个α螺旋中的谷氨酸对其核酸酶活性至关重要^[12]。此前已有文献报道, 甲基硝基亚硝胍可以诱导MIF的核易位, 其中甲基硝基亚硝胍本身可以引起细胞DNA损伤, 说明MIF的核定位与基因组DNA损伤密切相关^[73]。

4.2 细胞核内MIF核酸酶活性介导基因组不稳定性和突变促进肿瘤进展

近期一项研究表明, 细胞核定位MIF借助其核酸酶活性在乳腺癌细胞应对高水平DNA复制应激中发挥关键作用。在S期, MIF进入细胞核, 通过与聚腺苷二磷酸核糖聚合酶1 (poly ADP-ribose polymerase 1, PARP1) 相互作用被募集到DNA复制位点, MIF识别和切割Y型dsDNA 3'端的错配核苷酸, 以抵抗肿瘤细胞在S期遭受的高水平DNA复制应激。MIF核酸酶活性对核酸酶活性缺乏的DNA聚合酶介导的DNA链延长和保真至关重要, 可以防止肿瘤细胞DNA损伤和基因组不稳定, 而MIF较不活跃的校对活性还可以产生足够数量的突变以促进肿瘤发展^[72]。早期研究显示, MIF纯合缺失增加了B细胞淋巴瘤等多种类型肿瘤的发生, 表明MIF对正常细胞和癌细胞基因组稳定性的作用可能具有不同的致癌后果, 这与正常细胞中的基因组不稳定性被认为是肿瘤发生的关键驱动因素的观点一致^[74]。除DNA高水平复制、DNA损伤应激之外是否有其他刺激因素可以引起MIF的核易位, MIF在细胞核内除核酸酶活性以及与核内蛋白发生相互作用外, 是否还有更多的生物学功能具有非常广阔的探索空间。

5 靶向MIF的抗肿瘤药物研发进展

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鉴于MIF在肿瘤进展中的病理作用日益被人们所认识, 基于靶向MIF的治疗策略已经成为肿瘤学的研究热点。目前, 主要通过3种策略对MIF进行靶向: ①通过抗MIF、抗MIF受体的中和抗体, 或小分子化合物抑制MIF作为分泌型细胞因子对下游信号的激活作用; ②通过小分子化合物抑制MIF酶活性; ③通过PROTAC策略, 促进MIF降解。基于上述几种策略的MIF靶向药物已经在肿瘤等相关疾病中显示出治疗潜力(图 4、表 1^{[32, 75-88]}和表 2)。

5.1 靶向MIF的小分子抑制剂

ISO-1是首个MIF小分子拮抗剂, 其通过与底物竞争互变异构酶位点来抑制其活性, 并抑制MIF与下游信号通路蛋白之间的结合。最近一项研究表明, ISO-1在体外对胰腺癌细胞的增殖、迁移和侵袭具有明显的抑制作用, 且在体内异种移植瘤模型中显示出良好的抑制肿瘤生长的作用^[75]。异丁司特(AV411) 是一种非选择性的变构抗炎药。近期一项研究显示, 异丁司特通过阻断MIF和CD74之间的相互作用阻断下游信号通路, 并最终导致单核细胞趋化蛋白-1 (monocyte chemotactic protein 1, MCP-1) 分泌减少, 抑制单核细胞和MDSCs向肿瘤微环境募集, 阻碍肿瘤免疫抑制微环境形成, 在动物水平显示出抑制神经胶质母细胞瘤增殖的效果^[76]。4-IPP是一种不可逆的MIF抑制剂, 研究表明4-IPP可以通过抑制NF-κB途径显著降低骨肉瘤细胞的增殖和转移^[77]。在结肠腹膜癌的研究中发现, 4-IPP通过阻断MIF/CD74/AMPK信号转导通路诱导肿瘤细胞死亡^[78]。也有研究显示, 在体内异种移植瘤模型中, 4-IPP联合放疗对胶质母细胞瘤具有明显的抑制作用^[79]。4-IPP还可以通过阻断MIF/CXCR4信号转导通路抑制转移性神经母细胞瘤的增殖以及抑制其向骨髓转移^[80]。4-IPP也可以通过阻断MIF/CD74内化, 进而激活c-Jun氨基末端激酶(c-Jun N-terminal kinase, JNK), 抑制甲状腺肿瘤细胞增殖并诱导其凋亡^[81]。P425是一种新型的磺化偶氮化合物, 通过疏水作用与MIF结合, 阻断MIF/CD74复合物的形成^[82]。CPSI-1306是一种低分子量异恶唑啉, 可以与MIF互变异构酶活性位点结合并抑制其活性, CPSI-1306可以抑制MIF介导的血管生成因子表达, 最大限度抑制肿瘤生长和进展, 在膀胱癌中具有一定的治疗意义^[83]。此外在三阴性乳腺癌的研究中发现, CPSI-1306在体外对三阴性乳腺癌细胞的生长具有抑制作用。在体内研究中, CPSI-1306能降低原位小鼠乳腺癌模型中肿瘤生长和转移^[84]。IPG1094为全球首款获批临床的靶向MIF的小分子抑制剂, 可以阻断髓系细胞上受体CD74所介导的下游信号, 在实体瘤中可以有效抑制肿瘤免疫抑制微环境的形成, 促进抗肿瘤免疫反应, 有效抑制肿瘤生长, 目前正在进行成年健康受试者治疗实体肿瘤以及多发性骨髓瘤的I期临床试验(NCT05112159)。

5.2 靶向MIF降解的PROTAC分子

MD13是最近开发的针对MIF互变异构酶活性位点设计的靶向MIF的PROTAC, 可以特异性降解肿瘤细胞内的MIF。在体外细胞实验中, MD13显著抑制A549细胞的增殖, 其机制可能是通过阻断MAPK通路, 导致细胞周期阻滞于G2/M期, MD13在体外成球实验中也表现出抗肿瘤细胞增殖作用^[85]。

5.3 抗MIF单克隆抗体

BaxG03、BaxB01和BaxM159是抗MIF的重组人源化单克隆抗体, BaxB01与MIF的氧化还原酶结构域结合, 而BaxG03和BaxM159则与MIF的C端结合, 通过阻断MIF与CD74的结合抑制下游信号通路发挥抗肿瘤作用, 3种中和抗体的体内外实验均显示出抑制前列腺癌增殖的能力^[86]。Imalumab是一种完全人源化的抗MIF单克隆抗体, 特异性与oxMIF相互作用。临床前研究已经发现imalumab具有显著的组织穿透和凋亡途径激活作用, 已经用于恶性肿瘤如转移性结直肠癌患者的Ib/IIa期临床试验, 但因之后研究停滞不前被迫终止^[32]。ON203是第二代抗oxMIF单抗, 临床前研究显示在前列腺癌小鼠异种移植模型中, ON203显示出优于imalumab的疗效, 其在实体瘤中的治疗潜力值得进一步开展临床评估^[87]。

5.4 抗MIF受体单克隆抗体

MIF的同源受体CD74在大多数肿瘤中过度表达, 目前已成为肿瘤治疗的重要靶点, milatuzumab是第一个进入临床试验的抗CD74抗体, 目前正在研究用于治疗非霍奇金淋巴瘤、慢性淋巴细胞白血病和多发性骨髓瘤, 临床研究显示milatuzumab和硼替佐米联合应用可提高多发性骨髓瘤患者的生存率^[88]。

6 总结与展望

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大量研究表明, MIF与肿瘤细胞增殖、侵袭、迁移、肿瘤免疫抑制性微环境形成、血管新生以及炎症促肿瘤等密切相关, 从多方面影响肿瘤的发生和演进, 因此, 靶向MIF的药物研发对于肿瘤治疗具有重要意义。MIF既可以作为细胞因子存在于细胞外, 同时又以酶或者分子伴侣的形式存在于细胞浆, 还可以定位于细胞核发挥核酸酶活性, MIF多样的亚细胞定位与其多样的生物学功能密切相关。然而, 细胞外、细胞浆、细胞核内的MIF具有什么内在联系？细胞内外不同的应激因素在决定MIF亚细胞定位方面具有怎么样的作用和生物学意义？定位于不同亚细胞结构的MIF在结构和表型上有什么样的区别？这些问题都需要进一步的研究和探索。

鉴于细胞不断产生和释放MIF, 如何靶向MIF治疗相关疾病有以下问题值得思考: ①用抗MIF中和抗体抑制细胞外MIF对细胞内MIF的产生会有什么影响; ②能否在不影响血浆分泌型MIF的前提下开发特定靶向细胞浆或细胞核MIF的药物用于治疗相关疾病; ③如果能确定介导MIF发生氧化修饰的酶, 是否可从靶向该酶的角度实现对oxMIF的靶向？④鉴于MIF的多样化促肿瘤作用, 直接利用PROTAC策略促进MIF降解、降低MIF的总体水平可能是一种更为全面、有效的治疗方向; ⑤利用脂质体载体、聚合物载体、无机纳米载体、外泌体等形式将抗MIF抗体递送进入细胞也是MIF靶向药物研发具有潜力的方向。深入理解MIF既是细胞因子又是细胞内效应因子, 进而差异化地对MIF特定功能进行靶向, 将有助于对肿瘤等疾病设计更精准、有效的治疗策略。

作者贡献: 张欢、杨辰负责文献检索、文章撰写和图表绘制; 尚爽、吕晓希对文章内容和绘图进行建议和指导; 花芳提出文章总体构思, 指导文章撰写、并对文章结构、逻辑、文字和图表质量进行最终把关。

利益冲突: 所有作者无任何经济利益或版权冲突。

基金

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国家自然科学基金资助项目(82273947)
北京市自然科学基金项目(7232257)
中国医学科学院医学与健康科技创新工程(2022-I2M-JB-011)
中国医学科学院中央级公益性科研院所基本科研业务费(2018PT350004)
北京高校卓越青年科学家计划(BJJWZYJH01201910023028)

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2023年第58卷第8期

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doi: 10.16438/j.0513-4870.2023-0623

接收时间：2023-05-13
首发时间：2025-11-21
出版时间：2023-08-12

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收稿日期：2023-05-13
修回日期：2023-06-07

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国家自然科学基金资助项目(82273947)

北京市自然科学基金项目(7232257)

中国医学科学院医学与健康科技创新工程(2022-I2M-JB-011)

中国医学科学院中央级公益性科研院所基本科研业务费(2018PT350004)

北京高校卓越青年科学家计划(BJJWZYJH01201910023028)

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*花芳, Tel: 86-10-83161187, E-mail: huafang@imm.ac.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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Classification	Pharmacological approache	Chemical name	Mechanism	Reference
Small molecule inhibitor	ISO-1	(S, R)-3-(4-Hydroxyphenyl)-4, 5-dihydro-5-isoxazole acetic acid methyl ester	Competitive inhibitor Binds to the tautomerase region of MIF, leading to structural changes that block MIF-CD74 binding and thus MIF function	[75]
Ibudilast (also known as AV411)	1, 3-Isobutyryl-2-isopropylpyrazolo (1, 5-a) pyridine	Allosteric inhibitor Blocks catalytic (tautomerase activity) and chemotactic functions of MIF	[76]
4-IPP	4-Iodo-6-phenylpyrmidine	Irreversible inhibitor Covalently adducts MIF at N-terminal proline, altering their structure and preventing function	[77-81]
P425	6, 6'-[(3, 3-Dimethoxy[1, 1'-biphenyl]-4, 4'-diyl)bis(azo)]bis[4-amino-5-hydroxy-1, 3-napthalenedisulphonic acid] tetrasodium salt	Targets an area at the interface of two MIF trimers and inhibits MIF-CD74 interaction and tautomerase activity	[82]
CPSI-1306	2-[3-(2, 4-Difluorophenyl)-4, 5-dihydro-5-isoxazolyl]-1-(4-morpholinyl) ethanone	Competitive inhibitor Binds to the tautomerase region of MIF	[83, 84]
IPG1094	Unknown	Unknown
PROTAC	MD13	8-((2-(2, 6-Dioxopiperidin-3-yl)-1, 3-dioxoisoindolin-4-yl)amino)-N-(4-(7-hydroxy-2-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)phenyl)octanamide	Induces MIF degradation through binding to E3 ligase cereblon	[85]
Anti-MIF antibody	BaxB01, BaxG03, BaxM159	Anti-MIF monoclonal antibody	Reduced cell growth and viability by inhibiting MIF-induced phosphorylation of the central kinases p44/42 mitogen-activated protein kinase	[86]
	Imalumab (also known as BAX69), ON203	Anti-oxMIF monoclonal antibody	Regulate the steady level of circulating oxMIF and total MIF	[32, 87]
Antibody directed against MIF receptors	Milatuzumab	Anti-CD74 monoclonal antibody	Prevents MIF from binding to CD74	[88]

Classification

Pharmacological approache

Chemical name

Mechanism

Reference

Small molecule inhibitor

ISO-1

(S, R)-3-(4-Hydroxyphenyl)-4, 5-dihydro-5-isoxazole acetic acid methyl ester

Competitive inhibitor
Binds to the tautomerase region of MIF, leading to structural changes that block MIF-CD74 binding and thus MIF function

[75]

Ibudilast (also known as AV411)

1, 3-Isobutyryl-2-isopropylpyrazolo (1, 5-a) pyridine

Allosteric inhibitor
Blocks catalytic (tautomerase activity) and chemotactic functions of MIF

[76]

4-IPP

4-Iodo-6-phenylpyrmidine

Irreversible inhibitor
Covalently adducts MIF at N-terminal proline, altering their structure and preventing function

[77-81]

P425

6, 6'-[(3, 3-Dimethoxy[1, 1'-biphenyl]-4, 4'-diyl)bis(azo)]bis[4-amino-5-hydroxy-1, 3-napthalenedisulphonic acid] tetrasodium salt

Targets an area at the interface of two MIF trimers and inhibits MIF-CD74 interaction and tautomerase activity

[82]

CPSI-1306

2-[3-(2, 4-Difluorophenyl)-4, 5-dihydro-5-isoxazolyl]-1-(4-morpholinyl) ethanone

Competitive inhibitor
Binds to the tautomerase region of MIF

[83, 84]

IPG1094

Unknown

PROTAC

MD13

8-((2-(2, 6-Dioxopiperidin-3-yl)-1, 3-dioxoisoindolin-4-yl)amino)-N-(4-(7-hydroxy-2-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)phenyl)octanamide

Induces MIF degradation through binding to E3 ligase cereblon

[85]

Anti-MIF antibody

BaxB01, BaxG03, BaxM159

Anti-MIF monoclonal antibody

Reduced cell growth and viability by inhibiting MIF-induced phosphorylation of the central kinases p44/42 mitogen-activated protein kinase

[86]

Imalumab (also known as BAX69), ON203

Anti-oxMIF monoclonal antibody

Regulate the steady level of circulating oxMIF and total MIF

[32, 87]

Antibody directed against MIF receptors

Milatuzumab

Anti-CD74 monoclonal antibody

Prevents MIF from binding to CD74

[88]

Title	Status	Condition	Intervention	NCT number
Anti-MIF intervention
Phase Ⅰ study of anti-MIF antibody in solid tumors	Completed	· Metastatic adenocarcinoma of the colon or rectum · Malignant solid tumors	Biological: anti-MIF antibody	NCT01765790
Study to evaluate ibudilast and TMZ combo treatment in newly diagnosed and recurrent glioblastoma	Active, not recruiting	· Glioblastoma · Recurrent glioblastoma · GBM · Newly diagnosed glioblastoma	Drug: MN-166 Drug: temozolomide	NCT03782415
Phase Ⅱ a study of BAX69 and 5-FU/leucovorin or panitumumab versus standard of care in subjects with metastatic colorectal cancer	Terminated	· Metastatic colorectal cancer	Biological: BAX69 + infusional 5-FU/LV Biological: BAX69 + panitumumab Biological: BAX69 + 5-FU/LV	NCT02448810
Axitinib for the treatment of advanced hepatocellular carcinoma	Completed	· Hepatocellular carcinoma	Drug: axitinib (AG-013736) Other: best supportive care Drug: placebo	NCT01210495
Cardiorespiratory fitness in children and adolescents after cancer treatment	Recruiting	· All types of ediatric cancer	Behavioral: experimental: moderate to high-intensity exercise	NCT04765020
Phase Ⅰ/Ⅱ a two-arm dose-escalation study of BAX69 in subjects with malignant ascites of ovarian cancer	Terminated	· Refractory ovarian cancer with recurrent symptomatic malignant ascites	Biological: BAX69 single-route arm Biological: BAX69 double-route arm	NCT02540356
Anti-CD74 intervention
Effect of expression of CD74 and VEGF on outcome of treatment in patients with malignant pleural mesothelioma	Unknown	· Malignant pleural mesothelioma	Other: CD74, VEGF detection	NCT02761863
Vascularity impact on the treatment outcome in malignant pleural mesothelioma	Completed	· Malignant pleural mesotheliomas	Other: marker CD74 and VEGF	NCT02603315
Phase Ⅰ trial of anti-CD74 (hLL1) antibody therapy in B cell malignancies	Completed	· Non-hodgkin lymphoma · CLL	Drug: hLL1	NCT00504972
Phase Ⅰ/Ⅱ study of different doses and dose schedules of milatuzumab (hLL1) in CLL	Completed	· CLL	Biological: milatuzumab	NCT00603668
Phase Ⅰ study of milatuzumab for GVHD	Terminated	· GVHD (acute or chronic) · AML or ALL · Myelodysplastic syndrome	Drug: milatuzumab	NCT01663766
The humanized monoclonal antibody milatuzumab for refractory CLL	Unknown	· CLL	Drug: milatuzumab	NCT00868478
Veltuzumab and milatuzumab in treating patients with relapsed or refractory B-cell non-hodgkin lymphoma	Completed	· Lymphoma	Biological: milatuzumab Biological: veltuzumab Procedure: correlative/special studies	NCT00989586
MIF involvement in AML	Active, not recruiting	· AML	NA	NCT03918655
An open-label, multicenter, phase Ⅱ study of LDK378 in patients with NSCLC harboring ROS1 rearrangement	Unknown	· NSCLC	Drug: LDK378	NCT01964157
A study of LDK378 in patients with NSCLC harboring ROS1 rearrangement	Unknown	· NSCLC harboring ROS1 rearrangement	Drug: LDK378 (ceritinib)	NCT03399487
A study of hLL1-DOX (milatuzumab-doxorubicin antibody-drug conjugate) in patients with multiple myeloma	Terminated	· Multiple myeloma	Drug: hLL1-DOX	NCT01101594
Phase Ⅰ/Ⅱ study of hLL1 in multiple myeloma	Completed	· Multiple myeloma · Myeloma, plasma-cell · Plasmacytoma	Biological: milatuzumab	NCT00421525
Bortezomib, mitoxantrone, etoposide, and cytarabine in relapsed or refractory AML	Completed	· Adult acute megakaryoblastic leukemia (M7) · Adult acute minimally differentiated myeloid leukemia (M0) · Adult acute monoblastic leukemia (M5a)	Drug: bortezomib Drug: mitoxantrone hydrochloride Drug: etoposide	NCT01127009
Ixazomib, mitoxantrone hydrochloride, etoposide, and intermediate-dose cytarabine in relapsed or refractory AML	Completed	· Recurrent adult AML · Refractory AML	Drug: ixazomib Drug: mitoxantrone hydrochloride Drug: etoposide Drug: cytarabine	NCT02070458
MLN 9708 in induction and consolidation for adults with AML ≥ 60 years of age	Completed	· AML	Drug: MLN9708 Drug: cytarabine Drug: daunorubicin	NCT02582359
Study of STRO-001, an anti-CD74 antibody drug conjugate, in patients with advanced B-cell malignancies	Active, not recruiting	· B-cell lymphoma · Non-hodgkin lymphoma · Multiple myeloma	Drug: STRO-001	NCT03424603

Title

Status

Condition

Intervention

NCT number

Anti-MIF intervention

Phase Ⅰ study of anti-MIF antibody in solid tumors

Completed

· Metastatic adenocarcinoma of the colon or rectum
· Malignant solid tumors

Biological: anti-MIF antibody

NCT01765790

Study to evaluate ibudilast and TMZ combo treatment in newly diagnosed and recurrent glioblastoma

Active, not recruiting

· Glioblastoma
· Recurrent glioblastoma
· GBM
· Newly diagnosed glioblastoma

Drug: MN-166
Drug: temozolomide

NCT03782415

Phase Ⅱ a study of BAX69 and 5-FU/leucovorin or panitumumab versus standard of care in subjects with metastatic colorectal cancer

Terminated

· Metastatic colorectal cancer

Biological: BAX69 + infusional 5-FU/LV
Biological: BAX69 + panitumumab
Biological: BAX69 + 5-FU/LV

NCT02448810

Axitinib for the treatment of advanced hepatocellular carcinoma

Completed

· Hepatocellular carcinoma

Drug: axitinib (AG-013736)
Other: best supportive care
Drug: placebo

NCT01210495

Cardiorespiratory fitness in children and adolescents after cancer treatment

Recruiting

· All types of ediatric cancer

Behavioral: experimental: moderate to high-intensity exercise

NCT04765020

Phase Ⅰ/Ⅱ a two-arm dose-escalation study of BAX69 in subjects with malignant ascites of ovarian cancer

Terminated

· Refractory ovarian cancer with recurrent symptomatic malignant ascites

Biological: BAX69 single-route arm
Biological: BAX69 double-route arm

NCT02540356

Anti-CD74 intervention

Effect of expression of CD74 and VEGF on outcome of treatment in patients with malignant pleural mesothelioma

Unknown

· Malignant pleural mesothelioma

Other: CD74, VEGF detection

NCT02761863

Vascularity impact on the treatment outcome in malignant pleural mesothelioma

Completed

· Malignant pleural mesotheliomas

Other: marker CD74 and VEGF

NCT02603315

Phase Ⅰ trial of anti-CD74 (hLL1) antibody therapy in B cell malignancies

Completed

· Non-hodgkin lymphoma
· CLL

Drug: hLL1

NCT00504972

Phase Ⅰ/Ⅱ study of different doses and dose schedules of milatuzumab (hLL1) in CLL

Completed

· CLL

Biological: milatuzumab

NCT00603668

Phase Ⅰ study of milatuzumab for GVHD

Terminated

· GVHD (acute or chronic)
· AML or ALL
· Myelodysplastic syndrome

Drug: milatuzumab

NCT01663766

The humanized monoclonal antibody milatuzumab for refractory CLL

Unknown

· CLL

Drug: milatuzumab

NCT00868478

Veltuzumab and milatuzumab in treating patients with relapsed or refractory B-cell non-hodgkin lymphoma

Completed

· Lymphoma

Biological: milatuzumab
Biological: veltuzumab
Procedure: correlative/special studies

NCT00989586

MIF involvement in AML

Active, not recruiting

· AML

NCT03918655

An open-label, multicenter, phase Ⅱ study of LDK378 in patients with NSCLC harboring ROS1 rearrangement

Unknown

· NSCLC

Drug: LDK378

NCT01964157

A study of LDK378 in patients with NSCLC harboring ROS1 rearrangement

Unknown

· NSCLC harboring ROS1 rearrangement

Drug: LDK378 (ceritinib)

NCT03399487

A study of hLL1-DOX (milatuzumab-doxorubicin antibody-drug conjugate) in patients with multiple myeloma

Terminated

· Multiple myeloma

Drug: hLL1-DOX

NCT01101594

Phase Ⅰ/Ⅱ study of hLL1 in multiple myeloma

Completed

· Multiple myeloma
· Myeloma, plasma-cell
· Plasmacytoma

Biological: milatuzumab

NCT00421525

Bortezomib, mitoxantrone, etoposide, and cytarabine in relapsed or refractory AML

Completed

· Adult acute megakaryoblastic leukemia (M7)
· Adult acute minimally differentiated myeloid leukemia (M0)
· Adult acute monoblastic leukemia (M5a)

Drug: bortezomib
Drug: mitoxantrone hydrochloride
Drug: etoposide

NCT01127009

Ixazomib, mitoxantrone hydrochloride, etoposide, and intermediate-dose cytarabine in relapsed or refractory AML

Completed

· Recurrent adult AML
· Refractory AML

Drug: ixazomib
Drug: mitoxantrone hydrochloride
Drug: etoposide
Drug: cytarabine

NCT02070458

MLN 9708 in induction and consolidation for adults with AML ≥ 60 years of age

Completed

· AML

Drug: MLN9708
Drug: cytarabine
Drug: daunorubicin

NCT02582359

Study of STRO-001, an anti-CD74 antibody drug conjugate, in patients with advanced B-cell malignancies

Active, not recruiting

· B-cell lymphoma
· Non-hodgkin lymphoma
· Multiple myeloma

Drug: STRO-001

NCT03424603