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Chinese Medical Journal 2022年第3期135卷 261-267页

作者： Lixi Li Di Zhang Binliang Liu Dan Lv Jingtong Zhai Xiuwen Guan Zongbi Yi Fei Ma Department of Medical Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China

antibody-drug conjugates(ADCs)combine the high specificity of monoclonal antibodies with the high anti-tumor activity of small molecular cytotoxic *** anti-tumor activity of ADCs is mainly achieved by the direct blocking of the receptor by monoclonal antibodies,direct action and bystander effect of cytotoxic drugs,and antibody-dependent cell-mediated cytotoxicity and complement-dependent *** have been used in adjuvant therapy and rescue treatment of human epidermal receptor 2(HER2)-positive breast cancer,greatly improving the prognosis of breast cancer *** ongoing clinical trials of ADC for breast cancer and other solid tumors proved the potential of ADCs will provide more promising treatment options for patients with malignant *** review introduces the mechanism and latest clinical progress of ADC drugs approved for HER2-positive breast cancer to guide clinical practice and conduct research.

关键词： antibody-drug conjugate HER2-positive Breast cancer T-DM1 DS-8201

Resistance to antibody-drug conjugates in breast cancer:mechanisms and solutions

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Cancer Communications 2023年第3期43卷 297-337页

作者： Yu-Fei Chen Ying-ying Xu Zhi-Ming Shao Ke-Da Yu Department of Breast Surgery Fudan University Shanghai Cancer CenterShanghai 200032P.R.China Shanghai Medical College Fudan UniversityShanghai 200032P.R.China Department of Breast Surgery First Affiliated Hospital of China Medical UniversityShenyangLiaoning 110001P.R.China

antibody-drug conjugates(ADCs)are a rapidly developing therapeutic approach in cancer treatment that has shown remarkable activity in breast ***,there are two ADCs approved for the treatment of human epidermal growth factor receptor 2-positive breast cancer,one for triple-negative breast cancer,and multiple investigational ADCs in clinical ***,drug resistance has been noticed in clinical use,especially in trastuzumab ***,the mechanisms of ADC resistance are summarized into four categories:antibodymediated resistance,impaired drug trafficking,disrupted lysosomal function,and payload-related *** overcome or prevent resistance to ADCs,innovative development strategies and combination therapy options are being *** predictive biomarkers for optimal therapy selection may also help to prevent drug resistance.

关键词： antibody-drug conjugate breast cancer drug resistance combination therapy predictive biomarker

antibody-drug conjugates:Recent advances in linker chemistry

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Acta Pharmaceutica Sinica B 2021年第12期11卷 3889-3907页

作者： Zheng Su Dian Xiao Fei Xie Lianqi Liu Yanming Wang Shiyong Fan Xinbo Zhou Song Li School of Pharmaceutical Engineering Shenyang Pharmaceutical UniversityShenyang 110016China National Engineering Research Center for the Emergency drug Beijing Institute of Pharmacology and ToxicologyBeijing 100850China

antibody-drug conjugates(ADCs)are gradually revolutionizing clinical cancer *** antibody-drug conjugate linker molecule determines both the efficacy and the adverse effects,and so has a major influence on the fate of *** ideal linker should be stable in the circulatory system and release the cytotoxic payload specifically in the ***,existing linkers often release payloads nonspecifically and inevitably lead to off-target *** defect is becoming an increasingly important factor that restricts the development of *** pursuit of ADCs with optimal therapeutic windows has resulted in remarkable progress in the discovery and development of novel *** present review summarizes the advance of the chemical trigger,linker-antibody attachment and linker-payload attachment over the last 5 years,and describes the ADMET properties of *** work also helps clarify future developmental directions for the linkers.

关键词： antibody-drug conjugate Linker Chemical trigger Linker-antibody attachment Linker-payload attachment

Therapeutic Evaluation of Monoclonal antibody-Maytansinoid conjugate as a Model of RON-Targeted drug Delivery for Pancreatic Cancer Treatment

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Therapeutic Evaluation of Monoclonal Antibody-Maytansinoid C...

Bispecific antibodies targeting immunomodulatory checkpoints for cancer therapy

浙江省免疫学会第十次学术大会

作者： Hang-Ping Yao Liang Feng Jianwei Zhou Ruiwen Zhang Ming-Hai Wang State Key Laboratory for Diagnosis & Treatment of Infectious Diseases Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases First Affiliated Hospital of Zhejiang University School of Medicine Cancer Biology and Therapeutics Research Center Department of Biomedical Sciences Texas Tech University Health Sciences Center School of Pharmacy Department of Molecular Cell Biology & Toxicology Nanjing Medical University School of Public Health Department of Pharmaceutical Sciences Texas Tech University Health Sciences Center School of Pharmacy

Aberrant expression of the RON receptor tyrosine kinase,a member of the MET proto-oncogene family,contributes significantly to pancreatic cancer tumorigenesis and *** we validate RON as a target for pancreatic cancer therapy using a novel anti-RON antibody Zt/g4-drug maytansinoid conjugates(Zt/g4-DMl) as a model for RON-targeted drug delivery to kill pancreatic cancer *** pancreatic cancer cell lines overexpressing RON,Zt/g4-DM1 rapidly induced receptor endocytosis,arrested cell cycle at G2/M phase,reduced cell viability,and subsequently caused massive cell *** in vitro observations help to establish a correlation between the number of the cell surface RON receptors and the efficacy of Zt/g4-DM1 in reduction of cell *** mice,Zt/g4-DM1 pharmacokinetics in the linear dose range fitted into a two-compartment model with clearance in 0.21 ml/day/kg and terminal half-life at 6.05 *** results helped to confirm a concentration-activity relationship for the BxPC-3 and other pancreatic cancer cell xenograft model with a tumoristatic dose at 3.02 mg/***/g4-DM1 was effective in vivo against various xenograft PDAC growth but efficacy varied with individual cell *** of Zt/g4-DM1 with gemcitabine had a complete inhibition of xenograft pancreatic cancer *** conclude from these studies that increased RON expression in pancreatic cancer cells is a suitable targeting moiety for anti-RON ADC-directed drug delivery and anticancer ***/g4-DM1 is highly effective alone or in combination with chemotherapeutics in inhibition of pancreatic cancer xenograft growth in preclinical *** findings justify the use of humanized Zt/g4-DM1 for targeted pancreatic cancer therapy in the future.

关键词： receptor tyrosine kinase antibody-drug conjugate pancreatic cancer pharmacokinetics xenograft tumor model therapeutic efficacy combination therapy

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Cancer Biology & Medicine 2023年第3期20卷 181-195页

作者： Tiancheng Zhang Youpei Lin Qiang Gao Department of Liver Surgery and Transplantation and Key Laboratory of Carcinogenesis and Cancer Invasion(Ministry of Education)Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghai 200032China Key Laboratory of Medical Epigenetics and Metabolism Institutes of Biomedical SciencesFudan UniversityShanghai 200032China State Key Laboratory of Genetic Engineering Fudan UniversityShanghai 200433China

Advances in antibody engineering have led to the generation of more innovative antibody drugs,such as bispecific antibodies(bs Abs).Following the success associated with blinatumomab,bs Abs have attracted enormous interest in the field of cancer *** specifically targeting two different antigens,bs Abs reduce the distance between tumor and immune cells,thereby enhancing tumor killing *** are several mechanisms of action upon which bs Abs have been *** experience on checkpoint-based therapy has promoted the clinical transformation of bs Abs targeting immunomodulatory ***(PD-1×CTLA-4)is the first approved bs Ab targeting dual inhibitory checkpoints,which confirms the feasibility of bs Abs in *** this review we analyzed the mechanisms by which bs Abs targeting immunomodulatory checkpoints and their emerging applications in cancer immunotherapy.

关键词： antibody-drug conjugate bispecific antibody immunotherapy tumor microenvironment clinical trials

Advances in preclinical evaluation of experimental antibody-drug conjugates

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Cancer drug Resistance 2021年第4期4卷 745-754页

作者： Scott K.Lyons Dennis Plenker Lloyd C.Trotman Cold Spring Harbor Laboratory Cold Spring HarborNY 11724USA

The ability to chemically modify monoclonal antibodies with the attachment of specific functional groups has opened up an enormous range of possibilities for the targeted treatment and diagnosis of cancer in the *** the number of such antibody-based drug candidates has increased,so too has the need for more stringent and robust preclinical evaluation of their in vivo performance to maximize the likelihood that time,research effort,and money are only spent developing the most effective and promising candidate molecules for translation to the *** with the development of antibody-drug conjugate(ADC)technology,several recent advances in preclinical research stand to greatly increase the experimental rigor by which promising candidate molecules can be *** include advances in preclinical tumor modeling with the development of patient-derived tumor organoid models that far better recapitulate many aspects of the human disease than conventional subcutaneous xenograft *** models are amenable to genetic manipulation,which will greatly improve our understanding of the relationship between ADC and antigen and stringently evaluate mechanisms of therapeutic ***,tumor development is often not visible in these in vivo *** discuss how the application of several preclinical molecular imaging techniques will greatly enhance the quality of experimental data,enabling quantitative pre-and post-treatment tumor measurements or the precise assessment of ADCs as effective *** our opinion,when taken together,these advances in preclinical cancer research will greatly improve the identification of effective candidate ADC molecules with the best chance of clinical translation and cancer patient benefit.

关键词： antibody-drug conjugate tumor preclinical organoid CRISPR preclinical imaging theranostic

Enfortumab vedotin and pembrolizumab as monotherapies and combination treatment in locally advanced or metastatic urothelial carcinoma:A narrative review

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Monoclonal antibody-based cancer therapies

当代泌尿学（英文） 2023年第4期17卷 271-279页

作者： Maria A.Bantounou Josip Plascevic Lewis MacDonald Man Chun Wong Neasa O'Connell Helen F.Galley School of Medicine Medical Sciences and NutritionUniversity of AberdeenAberdeenUK

Background:Bladder cancer is the 10th most common cancer *** majority of bladder cancers are urothelial carcinomas(UCs),which,if locally advanced or metastatic,carry poor long-term *** cells can evade the immune system by express-ing the programmed cell death ligand 1 protein(PD-L1).Programmed cell death ligand 1 protein binds to programmed cell death protein 1(PD-1)onT cells,inhibiting their antitumor *** tumor cells also overexpress nectin-4,a cell adhesion polypeptide that con-tributes to metastasis,worsening *** platinum-based chemotherapy treatments are *** review aimed to assess novel treatments for locally advanced or metastatic UC that specifically target PD-L1 or nectin-4,namely,the PD-1 inhibitor pembrolizumab and the anti-nectin-4 antibody-drug conjugate enfortumab vedotin(EV).Materials and methods:Relevant English-language peer-reviewed articles and conference abstracts from the last 5 years were iden-tified through MEDLINE and EMBASE database searches.A narrative review was performed,with key results outlined below.Results:Pembrolizumab was demonstrated to be superior to chemotherapy as a second-line treatment for platinum-unresponsive participants in the KEYNOTE-045 trial,resulting in its Food and drug Administration(FDA)*** vedotin therapy re-sulted in superior outcomes compared with chemotherapy in the EV-301 trial,resulting in FDA approval for its use for patients with locally advanced or metastatic UC who had previously undergone treatment with platinum-based chemotherapy and PD-1/PD-L1 *** preliminary results for pembrolizumab and EV combination therapy have led to FDA approval in patients with locally advanced or metastatic UC who are not eligible for platinum chemotherapy.Conclusions:Pembrolizumab and EV represent novel treatment options for patients with locally advanced or metastatic UC with doc-umented superior outcomes and tolerability as compare

关键词： antibody-drug conjugate Bladder Checkpoint inhibitor Review Urothelial carcinoma

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Chinese Journal of Chemical Engineering 2021年第2期34卷 301-307页

作者： Yingnan Si Arin L.Melkonian Keegan C.Curry Yuanxin Xu Maranda Tidwell Mingming Liu Ahmed F.Zaky Xiaoguang(Margaret)Liu Department of Biomedical Engineering University of Alabama at Birmingham(UAB)1825 University BlvdBirminghamAL 35294USA Department of Medicine UAB17202nd Ave S.BirminghamAL 35294USA Chinese Medicine Hospital 98 Shengcheng StreetShouguang 262700China Department of Anesthesiology and Perioperative Medicine UAB62519th Street SouthBirminghamAL 35294USA

Targeted therapy has been widely demonstrated as an effective strategy to treat cancers,the leading cause of death in the *** minireview summarizes the technical platforms and methodologies utilized to develop and engineer therapeutic monoclonal antibodies and antibody-drug ***,the USA FDA approved monoclonal antibody(mAb)-based targeted therapies are *** the representative innovative chimeric,humanized and fully human anti-cancer antibodies and antibody-drug conjugates are ***,the past and predictive market trend of therapeutic antibodies is discussed.

关键词： Monoclonal antibody antibody-drug conjugate Anti-cancer therapy Market

Strategies to enhance monoclonal antibody uptake and distribution in solid tumors

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Cancer Biology & Medicine 2021年第3期18卷 649-664页

作者： Brandon M.Bordeau Joseph P.Balthasar Department of Pharmaceutical Science University at BuffaloBuffaloNY 14214USA

Despite the significant resources dedicated to the development of monoclonal antibody(m Ab)therapies for solid tumors,the clinical success,thus far,has been *** efficacy of m Ab in solid tumors likely relates to unique aspects of tumor *** tumors have an aberrant vasculature and a dense extracellular matrix that slow both the convective and diffusive transport of m Abs into and within *** m Abs that are directed against cellular antigens,high antigen expression and rapid antigen turnover can result in perivascular cells binding to and eliminating a significant amount of extravasated m Ab,limiting m Ab distribution to portions of the tumor that are distant from functional *** preclinical investigations have reported strategies to improve m Ab uptake and distribution;however,to our knowledge,none have translated into the ***,we provide an overview of several barriers in solid tumors that limit m Ab uptake and distribution and discuss approaches that have been utilized to overcome these barriers in preclinical studies.

关键词： Solid tumors antibody uptake and distribution monoclonal antibody antibody-drug conjugate