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Development of antibody-drug conjugates in cancer:Overview and prospects

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Cancer Communications 2024年第1期44卷 3-22页

作者： Dan-Yun Ruan Hao-Xiang Wu Qi Meng Rui-Hua Xu Department of Clinical Research Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat-sen UniversityGuangzhouGuangdongP.R.China Research Unit of precision diagnosis and Treatment for Gastrointestinal Cancer Chinese Academy of Medical SciencesGuangzhouGuangdongP.R.China Department of Medical Oncology Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat-sen UniversityGuangzhouGuangdongP.R.China

In recent years,remarkable breakthroughs have been reported on antibody-drug conjugates(ADCs),with 15 ADCs successfully entering the market over the past decade.This substantial development has positioned ADCs as one of the fastest-growing domains in the realm of anticancer drugs,demonstrating their efficacy in treating awide array of malignancies.Nonetheless,there is still an unmet clin-ical need forwider application,better efficacy,and fewer side effects of ADCs.An ADC generally comprises an antibody,a linker and a payload,and the combina-tion has profound effects on drug structure,pharmacokinetic profile and efficacy.Hence,optimization of the key components provides an opportunity to develop ADCs with higher potency and fewer side effects.In this review,we comprehen-sively reviewed the current development and the prospects of ADC,provided an analysis of marketed ADCs and the ongoing pipelines globally as well as in China,highlighted several ADC platforms and technologies specific to different pharmaceutical enterprises and biotech companies,and also discussed the new related technologies,possibility of next-generation ADCs and the directions of clinical research.

关键词： companies breakthrough payload

Identification of fangchinoline as a broad-spectrum enterovirus inhibitor through reporter virus based high-content screening

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Virologica Sinica 2024年第2期39卷 301-308页

作者： Qiu-Yan Zhang Jia-Qi Li Qi Li Yang Zhang Zhe-Rui Zhang Xiao-Dan Li Hong-Qing Zhang Cheng-Lin Deng Feng-Xia Yang Yi Xu Bo Zhang The Joint Center of Translational precision Medicine Department of Infections and DiseasesGuangzhou Institute of PediatricsGuangzhou Women and Children's Medical CenterGuangzhou510623China key laboratory of Special Pathogens and Biosafety Wuhan Institute of VirologyCenter for Biosafety Mega-ScienceChinese Academy of SciencesWuhan430071China University of Science and Technology of China Department of Life Sciences and MedicineHefei230026China hunan Normal University School of MedicineChangsha410081China

Hand,foot,and mouth disease(HFMD)is a common pediatric illness mainly caused by enteroviruses,which are important human pathogens.Currently,there are no available antiviral agents for the therapy of enterovirus infection.In this study,an excellent high-content antiviral screening system utilizing the EV-A71-eGFP reporter virus was developed.Using this screening system,we screened a drug library containing 1042 natural compounds to identify potential EV-A71 inhibitors.Fangchinoline(FAN),a bis-benzylisoquinoline alkaloid,exhibits potential inhibitory effects against various enteroviruses that cause HFMD,such as EV-A71,CV-A10,CV-B3 and CV-A16.Further investigations revealed that FAN targets the early stage of the enterovirus life cycle.Through the selection of FAN-resistant EV-A71 viruses,we demonstrated that the VP1 protein could be a potential target of FAN,as two mutations in VP1(E145G and V258I)resulted in viral resistance to FAN.Our research suggests that FAN is an efficient inhibitor of EV-A71 and has the potential to be a broad-spectrum antiviral drug against human enteroviruses.

关键词： Hand,foot,and mouth disease(HFMD) Enterovirus EV-A71 High-content screening Fangchinoline(FAN)

Microstructure and mechanical properties stability of pre-hardening treatment in Al-Cu alloys for pre-hardening forming process

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International Journal of Minerals,Metallurgy and Materials 2024年第3期31卷 539-551页

作者： Liping Tang Pengfei Wei Zhili Hu Qiu Pang Hubei Longzhong laboratory Xiangyang 441000China Hubei key laboratory of Advanced Technology for Automotive Components School of Automotive EngineeringWuhan University of TechnologyWuhan 430070China Hubei Engineering Research Center for Green&precision Material Forming Wuhan University of TechnologyWuhan 430070China key laboratory of Metallurgical Equipment and Control Technology of Ministry of Education School of Machinery and AutomationWuhan University of Science and TechnologyWuhan 430081China

The stability of the microstructure and mechanical properties of the pre-hardened sheets during the pre-hardening forming(PHF)process directly determines the quality of the formed components.The microstructure stability of the pre-hardened sheets was in-vestigated by differential scanning calorimetry(DSC),transmission electron microscopy(TEM),and small angle X-ray scattering(SAXS),while the mechanical properties and formability were analyzed through uniaxial tensile tests and formability tests.The results in-dicate that the mechanical properties of the pre-hardened alloys exhibited negligible changes after experiencing 1-month natural aging(NA).The deviations of ultimate tensile strength(UTS),yield strength(YS),and sheet formability(Erichsen value)are all less than 2%.Also,after different NA time(from 48 h to 1 month)is applied to alloys before pre-hardening treatment,the pre-hardened alloys possess stable microstructure and mechanical properties as well.Interestingly,with the extension of NA time before pre-hardening treatment from 48 h to 1 month,the contribution of NA to the pre-hardening treatment is limited.Only a yield strength increment of 20 MPa is achieved,with no loss in elongation.The limited enhancement is mainly attributed to the fact that only a limited number of clusters are transformed into Guinier-Preston(GP)zones at the early stage of pre-hardening treatment,and the formation ofθ''phase inhibits the nucleation and growth of GP zones as the precipitated phase evolves.

关键词： Al-Cu alloy pre-hardened alloy natural aging mechanical properties microstructure

Adrenal pheochromocytoma impacts three main pathways: cysteine-methionine, pyrimidine, and tyrosine metabolism

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第5期25卷 410-421页

作者： Chong LAI Qingling YANG Yunuo ZHANG Renjie GONG Majie WANG Jiankang LI Maode LAI Qingrong SUN Department of Urology the First Afiliated HospitalZhejiang University School of MedicineHangzhou 310003China School of Basic Medical Sciences and Clinical Pharmacy China Pharmaceutical UniversityNanjing 210009China Department of laboratory Medicine the First Afiliated HospitalZhejiang University School of MedicineHangzhou 310003China laboratory of Behavioral Neuroscience Ningbo Kangning HospitalNingbo Institute of Microcirculation and HenbaneSchool of MedicineNingbo UniversityNingbo 315201China Xi'an key laboratory of Stem Celland Regenerative Medicine Institute of Medical ResearchNorthwestern Polytechnical UniversityXi'an 710072China Department of Pathology Research Unit of Intelligence Classification of Tumor Pathology and Precision TherapyChinese Academy of Medical Sciences Key Laboratory of Disease Proteomics of Zhejiang ProvinceZhejiang University School of MedicineHangzhou 310058China

Pheochromocytomas and paragangliomas(PPGLs)cause symptoms by altering the circulation levels of catecholamines and peptide hormones.Currently,the diagnosis of PPGLs relies on diagnostic imaging and the detection of catecholamines.In this study,we used ultra-performance liquid chromatography(UPLC)/quadrupole time-of-flight mass spectrometry(Q-TOF MS)analysis to identify and measure the perioperative differential metabolites in the plasma of adrenal pheochromocytoma patients.We identified differentially expressed genes by comparing the transcriptomic data of pheochromocytoma with the normal adrenal medulla.Through conducting two steps of metabolomics analysis,we identified 111 differential metabolites between the healthy group and the patient group,among which 53 metabolites were validated.By integrating the information of differential metabolites and differentially expressed genes,we inferred that the cysteine-methionine,pyrimidine,and tyrosine metabolism pathways were the three main metabolic pathways altered by the neoplasm.The analysis of transcription levels revealed that the tyrosine and cysteine-methionine metabolism pathways were downregulated in pheochromocytoma,whereas the pyrimidine pathway showed no significant difference.Finally,we developed an optimized diagnostic model of two metabolites,L-dihydroorotic acid and vanylglycol.Our results for these metabolites suggest that they may serve as potential clinical biomarkers and can be used to supplement and improve the diagnosis of pheochromocytoma.

关键词： Pheochromocytoma and paraganglioma(PPGL) Metabolomics Gene set variation analysis L-Dihydroorotic acid Vanylglycol

The spatial transcriptomic landscape of human gingiva in health and periodontitis

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Science China(Life Sciences) 2024年第4期67卷 720-732页

作者： Zongshan Shen Ran Zhang Yunjia Huang Jiayao Chen Mengjun Yu Chunhua Li Yong Zhang Lingling Chen Xin Huang Jichen Yang Zhengmei Lin Songlin Wang Bin Cheng Hospital of Stomatology Guangdong Provincial Key Laboratory of StomatologyGuanghua School of StomatologySun Yat-sen UniversityGuangzhou 510055China Beijing laboratory of Oral Health Capital Medical UniversityBeijing 100050China Department of Oral Pathology Peking University School and Hospital of Stomatology&National Center of Stomatology&National Clinical Research Center for Oral Diseases&National Engineering Research Center of Oral Biomaterials and Digital Medical DevicesBeijing 100050China Research Unit of precision Pathologic diagnosis in Tumors of the Oral and Maxillofacial Regions Chinese Academy of Medical SciencesBeijing 100050China BGI-Qingdao BGI-ShenzhenQingdao 266555China

The gingiva is a key oral barrier that protects oral tissues from various stimuli.A loss of gingival tissue homeostasis causes periodontitis,one of the most prevalent inflammatory diseases in humans.The human gingiva exists as a complex cell network comprising specialized structures.To understand the tissue-specific pathophysiology of the gingiva,we applied a recently developed spatial enhanced resolution omics-sequencing(Stereo-seq)technique to obtain a spatial transcriptome(ST)atlas of the gingiva in healthy individuals and periodontitis patients.By utilizing Stereo-seq,we identified the major cell types present in the gingiva,which included epithelial cells,fibroblasts,endothelial cells,and immune cells,as well as subgroups of epithelial cells and immune cells.We further observed that inflammation-related signalling pathways,such as the JAK-STAT and NF-κB signalling pathways,were significantly upregulated in the endothelial cells of the gingiva of periodontitis patients compared with those of healthy individuals.Additionally,we characterized the spatial distribution of periodontitis risk genes in the gingiva and found that the expression of IFI16 was significantly increased in endothelial cells of inflamed gingiva.In conclusion,our Stereo-seq findings may facilitate the development of innovative therapeutic strategies for periodontitis by mapping periodontitis-relevant genes and pathways and effector cells.

关键词： spatial transcriptomics gingiva periodontal disease periodontitis risk genes

Tumor necrosis factor-stimulated gene-6 ameliorates early brain injury after subarachnoid hemorrhage by suppressing NLRC4 inflammasome-mediated astrocyte pyroptosis

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Neural Regeneration Research 2024年第5期19卷 1064-1071页

作者： Mingxiang Ding Lei Jin Boyang Wei Wenping Cheng Wenchao Liu Xifeng Li Chuanzhi Duan Neurosurgery Center Department of Cerebrovascular SurgeryThe National Key Clinical SpecialtyThe Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular DiseaseGuangdong Provincial Key Laboratory on Brain Function Repair and RegenerationThe Neurosurgery Institute of Guangdong ProvinceZhujiang HospitalSouthern Medical UniversityGuangzhouGuangdong ProvinceChina Department of Cerebrovascular Intervention Zhongshan City People’s HospitalZhongshanGuangdong ProvinceChina

Subarachnoid hemorrhage is associated with high morbidity and mortality and lacks effective treatment.Pyroptosis is a crucial mechanism underlying early brain injury after subarachnoid hemorrhage.Previous studies have confirmed that tumor necrosis factor-stimulated gene-6(TSG-6)can exert a neuroprotective effect by suppressing oxidative stress and apoptosis.However,no study to date has explored whether TSG-6 can alleviate pyroptosis in early brain injury after subarachnoid hemorrhage.In this study,a C57BL/6J mouse model of subarachnoid hemorrhage was established using the endovascular perforation method.Our results indicated that TSG-6 expression was predominantly detected in astrocytes,along with NLRC4 and gasdermin-D(GSDMD).The expression of NLRC4,GSDMD and its N-terminal domain(GSDMD-N),and cleaved caspase-1 was significantly enhanced after subarachnoid hemorrhage and accompanied by brain edema and neurological impairment.To explore how TSG-6 affects pyroptosis during early brain injury after subarachnoid hemorrhage,recombinant human TSG-6 or a siRNA targeting TSG-6 was injected into the cerebral ventricles.Exogenous TSG-6 administration downregulated the expression of NLRC4 and pyroptosis-associated proteins and alleviated brain edema and neurological deficits.Moreover,TSG-6 knockdown further increased the expression of NLRC4,which was accompanied by more severe astrocyte pyroptosis.In summary,our study revealed that TSG-6 provides neuroprotection against early brain injury after subarachnoid hemorrhage by suppressing NLRC4 inflammasome activation-induced astrocyte pyroptosis.

关键词： astrocyte early brain injury inflammasome NLRC4 pyroptosis subarachnoid hemorrhage tumor necrosis factor-stimulated gene-6(TSG-6)

Neoadjuvant nivolumab with or without platinum-doublet chemotherapy based on PD-L1 expression in resectable NSCLC(CTONG1804):a multicenter open-label phase II study

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Signal Transduction and Targeted therapy 2024年第1期9卷 249-258页

作者： Si-Yang Liu Song Dong Xue-Ning Yang Ri-Qiang Liao Ben-Yuan Jiang Qun Wang Xiao-Song Ben Gui-Bin Qiao Jun-Tao Lin Hong-Hong Yan Li-Xu Yan Qiang Nie Hai-Yan Tu Bin-Chao Wang Jin-Ji Yang Qing Zhou Hong-Rui Li Ke Liu Wendy Wu Si-Yang Maggie Liu Wen-Zhao Zhong Yi-Long Wu Guangdong Lung Cancer Institute Guangdong Provincial Key Laboratory of Translational Medicine in Lung CancerGuangdong Provincial People’s Hospital(Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina Department of Thoracic Surgery Zhongshan HospitalFudan UniversityShanghaiChina Department of Thoracic Surgery Guangdong Provincial People’s Hospital(Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina Department of Pathology Guangdong Provincial People’s Hospital(Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina Fujian key laboratory of Advanced Technology for Cancer Screening and early diagnosis FuzhouChina Berry Oncology Corporation FuzhouChina Chinese Thoracic Oncology Group(CTONG) GuangzhouChina Department of Hematology The First Affiliated HospitalJinan UniversityGuangzhouChina

This prospective multicenter phase II study evaluated the clinical efficacy of neoadjuvant nivolumab-exclusive(N)and nivolumab–chemotherapy(N/C)combinations based on PD-L1 expression.Eligible patients exhibited resectable clinical stage IIA–IIIB(AJCC 8th edition)NSCLC without EGFR/ALK alterations.Patients received either mono-nivolumab(N)or nivolumab+nabpaclitaxel+carboplatin(N/C)for three cycles based on PD-L1 expression.The primary endpoint was the major pathological response(MPR).key secondary endpoints included the pathologic complete response(pCR),objective response rate(ORR),and event-free survival(EFS).Baseline PD-L1 expression and perioperative circulating tumor DNA(ctDNA)status were correlated with pCR and EFS.Fifty-two patients were enrolled,with 46 undergoing surgeries.The MPR was 50.0%(26/52),with 25.0%(13/52)achieving pCR,and 16.7%and 66.7%for patients with PD-L1≥50%in N and N/C groups,respectively.Thirteen(25.0%)patients experienced grade 3 or higher immune-related adverse events during neoadjuvant treatment.Patients with post-neoadjuvant ctDNA negativity was more likely to have pCR(39.1%)compared with those remained positive(6.7%,odds ratio=6.14,95%CI 0.84-Inf,p=0.077).With a median follow-up of 25.1 months,the 18-month EFS rate was 64.8%(95%CI 51.9–81.0%).For patients with ctDNA–vs.ctDNA+,the 18m-EFS rate was 93.8%vs 47.3%(HR,0.15;95%CI 0.04,0.94;p=0.005).Immunochemotherapy may serve as an optimal neoadjuvant treatment even for patients with PD-L1 expression≥50%.ctDNA negativity following neoadjuvant treatment and surgery could help identify superior pathological and survival benefits,which requires further confirmation in a prospective clinical trial(NCT04015778).

关键词： chemotherapy NSCLC treatment

A retrospective analysis of mature T-and NK-cell lymphomas

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Cancer Biology & Medicine 2024年第3期21卷 223-229页

作者： Junlei Jia Xiaohui Wang Zheng Song Shen Meng Yue Fei Jingwei Yu Xia Liu Xue Han Lanfang Li Lihua Qiu Zhengzi Qian Shiyong Zhou Wenchen Gong Bin Meng Xiubao Ren Xianhuo Wang Huilai Zhang National key laboratory of Druggability Evaluation and Systematic Translational Medicine and Department of LymphomaTianjin Medical University Cancer Institute&HospitalNational Clinical Research Center for CancerTianjin's Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjinThe Sino-US Center for Lymphoma and Leukemia ResearchTianjin 300060China Department of Radiation Oncology Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinan 250117China Department of Pathology Department of Immunology/Biotherapy Tianjin Medical University Cancer Institute&HospitalNational Clinical Research Center for CancerTianjin's Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjinTianjin 300060China

Mature T-and natural killer(NK)-cell lymphomas are heterogeneous groups of malignant lymphoid neoplasms arising from T and NK cells. The incidence of mature T-and NK-cell lymphomas is 2.1 per 100,000 people, according... 详细信息

关键词： lymphoma neoplasms killer

Allergic Phenotypes and Sarcopenia:Evidence from Observational Studies and Mendelian Randomization Analysis

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Phenomics

Phenomics 2024年第1期4卷 46-50页

作者： Zhenwei Tang Guowei Zhou Yi Xiao Hong Liu Xiang Chen Minxue Shen Department of Dermatology Xiangya HospitalCentralSouth University110 Xiangya RoadChangsha 410008HunanChina hunan key laboratory of Skin Cancer and Psoriasis HunanEngineering Research Center of Skin Health and DiseaseCentral South UniversityChangsha 410008HunanChina Department of Dermatology Second AfliatedHospitalZhejiang University School of MedicineHangzhou 310009ZhejiangChina Furong laboratory Changsha 410008HunanChina Department of Social Medicine and Health Management Xiangya School of Public HealthCentral South UniversityChangsha 410008HunanChina

Commonly afected in early-life population,the impact of allergic phenotypes on mid-or late-life health is less discussed.This study is to explore the association of allergic phenotypes including atopic dermatitis(AD),asthma,eosinophils count(EC),and sarcopenia.We conducted observational studies and mendelian randomization(MR)analysis based on UK Biobank(UKB),the China Health and Retirement Longitudinal Study(CHARLS)and data from genome-wide association study(GWAS).Based on the UKB data,AD,asthma and EC were positively correlated with pre-sarcopenia and decreased skeletal muscle mass index and hand grip in fully adjusted model.Asthma and EC were signifcantly associated with sarcopenia while AD was marginally associated(p=0.095).Based on the CHARLS cohort,asthma signifcantly added 109.4%risk for pre-sarcopenia in adjusted model(relative risk=2.094;p=0.002),respectively.Both asthma(β=0.100,p=0.006)and EC(β=0.023,p=0.017)exerted signifcantly casual efects on pre-sarcopenia.However,as for sarcopenia,merely EC exhibited a signifcantly casual efect(β=0.005,p=0.048).Signifcant casual efects of AD(β=–0.027,p=0.003),asthma(β=–0.029,p=0.027)and EC(β=–0.041,pdiagnosis.The fndings of our study will raise the awareness of preventing aging-related disorders or geriatric syndromes among allergic populations.

关键词： Sarcopenia Atopic dermatitis Asthma Aging Eosinophils