الملخص
Approximately 50% of patients with non-small-cell lung cancer (NSCLC) are diagnosed at advanced stages and face a challenging prognosis despite the integration of targeted therapies, immunotherapy, and systemic chemotherapy into current standard care. A key factor in this context is trophoblast cell-surface antigen 2 (TROP2), which is widely expressed in NSCLC and strongly associated with poor patient outcomes. This article examines the latest developments in the application of datopotamab deruxtecan (Dato-DXd, DS-1062), a novel antibody-drug conjugate targeting TROP2, in the treatment of NSCLC. It provides a detailed assessment of Dato-DXd’s technical design, evaluates its efficacy by using recent clinical trial data, and discusses its safety profile.
الملخص
Currently, breast cancer is a common malignancy in female, and previous guidelines recommended that one of the key biomarkers for breast cancer, human epidermal growth factor receptor 2 (HER2), is classified as either positive or negative to guide clinicians’ treatment decisions. While nearly half of breast cancer patients have low HER2 expression (IHC expression is 1+ or 2+ and ISH detection is negative), such patients are insensitive to traditional anti-HER2 targeted therapy. However, novel antibody-drug conjugates (ADCs) provide new targeted therapy options for breast cancer patients with low HER2 expression, challenging the traditional binary concept and arousing research enthusiasm. In the latest ASCO/CAP guidelines for HER2 detection in breast cancer, HER2-low breast cancer has been included as a clinical treatment subgroup. This article will review the definition of HER2-low breast cancer, the progress of drug therapy such as ADC, and the current challenges faced by this subgroup.
الملخص
Since the approval of gemtuzumab ozogamicin, an antibody–drug conjugate (ADC) targeting CD33 in 2000, 13 ADC drugs have been approved by the FDA. Although these drugs have clearly improved the survival of patients with various types of advanced cancers, their significant toxicity has compromised their therapeutic benefits. The adverse reactions of ADC drugs are complex and include on-target and off-target toxicities, where the payload drug is a determining factor. Antibody and linker may also affect the degree of toxicity. Combination therapy becomes an important strategy in anticancer treatment because of its increased efficiency, but treatment-related adverse reactions also increase accordingly. This review comprehensively analyzes the toxicity mechanisms of current ADC drugs and proposes various optimization strategies, including but not limited to optimizing linker molecules, upgrading antibody design, and changing drug administration strategies, to improve the overall safety profile of ADC drugs.
الملخص
Objective Based on the U.S.Food and Drug Administration Adverse Event Reporting System(FAERS)database,data mining was conducted on hematological adverse events related to antibody drug conjugates(ADC),providing reference for the safe use of ADC drugs in clinical practice.Methods The report data from the third quarter of 2011 to the fourth quarter of 2022 were retrieved from the FAERS database.After data cleaning such as deduplication and name standardization,extract hematological adverse events related to ADC,and use report odds ratio method and the information component method for signal detection.Results A total of 101 610 adverse event reports were extracted,with 8 ADC drugs as the primary suspected drugs,and 5 768 ADC related hematological adverse event reports.Among them,3 423 cases of agranulocytosis were involved,and the signal intensity from strong to weak were sacituzumab govitecan(SG),gemtuzumab ozogamicin(GO),brentuximab vedotin(BV),polatuzumab vedotin(PV),enfortumab vedotin(EV),trastuzumab deruxtecan(TD),inotuzumab ozogamicin(IO)and ado-trastuzumab emtansine(TDM-1).There were 2 327 cases hematopoietic cell deficiency,with signals ranging from strong to weak were IO,SG,BV,EV,PV,TD,TDM-1,and GO.Report with clinical outcome of death of ADC drug related hematological adverse events included BV 179(16.84％),TDM-1 102(13.01％),TD 88(27.08％),GO 12(16.90％),IO 8(11.59％),EV 54(24.32％),PV 22(27.16％),and SG 84(21.05％).Adverse event time analysis showed that the number of events on the first day of TD,IO,and SG medication accounts for ≥ 40％of the total number of cases.The median time of hematological adverse events in TD,GO,IO,EV,PV,and SG was within one treatment course(21 days).Conclusion Attention should be paid to the risk of ADC drug-related hematological adverse event,during the clinical medication process,blood cell count changes should be closely monitored,and any abnormalities should be promptly diagnosed and treated.
الملخص
Antibody-drug conjugate (ADC) has the characteristics of low toxicity and high efficiency, and plays an important role in cancer treatment. However, due to the complexity of its structure, it brings difficulties in pharmacokinetic (PK) bioanalysis. This study established an analytical method for the detection of ADC (RC108) in cynomolgus monkey plasma by ligand-binding assay (LBA) and liquid chromatography tandem mass spectrometry (LC-MS/MS), which was used to analyze and quantify the total antibody, bound antibody and free drug in cynomolgus monkey plasma. Based on the LBA method, rabbit anti-RC108 Fab and mouse anti-MMAE (monomethyl auristatin E) mAb were pre-coated in 96-well plates as the total antibody and antibody binding reagents, respectively. The samples to be tested were added, and then the detection reagents were added in turn. Goat anti-human IgG (H+L)-HRP, chromogenic solution tetramethylbenzidine (TMB), H2SO4 terminate the reaction, read data at 450 nm/630 nm wavelength of microplate reader; LC-MS/MS analysis method quantifies MMAE concentration, and refer to relevant regulations for methodological validation. The analytical method for quantifying total antibody, bound antibody and free drug of RC108 drug obtained good accuracy and precision, and the selectivity, dilution linearity, hook effect, parallelism and stability were verified. Meet the requirements of biological analysis. Finally, a bioanalytical method for the determination of the concentration of the test substance RC108 (total antibody, conjugated antibody, free MMAE) in cynomolgus monkey plasma with high sensitivity and high throughput was established by LBA and LC-MS/MS method. Subsequent non-clinical research on PK research in cynomolgus monkeys will provide technical support.
الملخص
Antibody-drug conjugates (ADCs) are a class of targeted biological agents that link cytotoxic drugs to monoclonal antibodies through linkers. The monoclonal antibody targets tumor cells and transports small-molecule cytotoxic drugs for specific delivery and minimal off-target side effects. September 30, 2022, 14 anti-tumor ADC drugs have been approved for marketing in the world, and four ADCs have been approved in China. With the improvement of the clinical accessibility of ADC drugs, clinicians urgently need to understand the molecular characteristics and mechanisms of ADCs, and clarify the indications for rational use of drugs. Patients' survival mainly depends on the appropriate dose and course of treatment and also on proper management of adverse reactions. In view of this, on the basis of the "Expert Consensus on the Clinical Application of Antibody-drug Conjugates for the Treatment of Malignant Tumors (2020 edition)", Professional Committee on Clinical Research of Oncology Drugs, Chinese Anti-Cancer Association fully combines the existing clinical research evidence and the feasibility of current ADC drugs in China to update the consensus content. This consensus aims to provide a systematic overview of ADC drugs, so as to provide practical and effective suggestions and references for clinicians to apply and manage ADC drugs more accurately.
الملخص
Acute myeloid leukemia (AML) has highly heterogeneous clinical manifestations and poor prognosis, and traditional chemotherapy is the main treatment. In recent years, with the in-depth development of next-generation sequencing technology, the treatment of AML is gradually exploring the precise targeted therapy in the direction of molecular biology and immunophenotype. The advent of various small-molecule inhibitors and immune-targeted drugs has brought hope to patients who cannot tolerate intensive chemotherapy or with relapsed/refractory AML. Compared with traditional chemotherapy, targeted therapy has the advantages of significant curative effect and fewer adverse effects. This article reviews the latest research progress of targeted drug therapy for AML.
الموضوعات
Humans , Leukemia, Myeloid, Acute/drug therapy , Immunotherapy , Immunotherapy, Adoptive , Antineoplastic Combined Chemotherapy Protocols/therapeutic useالملخص
Click chemistry has been proven to be very useful in drug delivery. Due to the availability of a large number of click reactions with a various characteristics, selection of appropriate chemistry for a given application is often not a trivial task. This review is written for pharmaceutical researchers who are interested in click chemistry applications and yet may not be click chemistry experts. For this, the review gives an overview of available click reactions organized by application types. Further, the general understanding of click reactions being fast and high yielding sometimes overshadows the need to analyze reaction kinetics in assessing suitability of a given reaction for certain applications. For this, we highlight the need to analyze the relationship among reaction kinetics, concentration effects, and reaction time scales, knowing that lack of such analysis could easily lead to failures. Further, possible issues such as chemical stability with various click reagents are also discussed to aid experimental designs. Recent examples and extensive references are also provided to aid in-depth understanding of technical details. We hope this review will help those interested in using click chemistry in drug delivery to select the appropriate reactions/reagents and minimize the number of pitfalls.
الملخص
Objective To retrospectively evaluate the clinical efficacy and safety of brentuximab vedotin(BV) combined with chemotherapy in the treatment of malignant lymphoma. Methods We collected the data of 32 lymphoma patients with CD30-positive status, including 14 cases of Hodgkin's lymphomas, 2 cases of diffuse large B-cell lymphomas, and 16 cases of mature T/NK cell lymphomas. Chemotherapy combined with BV was administered to all patients for a minimum of two cycles. The efficacy of the treatment was evaluated according to Lugano criteria every two cycles. Results Complete response rate and overall response rate after four cycles of treatment were 22% and 50%, respectively. Sixteen cases (50.0%) had grades 1 and 2 toxicity, and 16 cases (50.0%) had grade 3 toxicity or higher. The most common adverse events were neutropenia (50.0%), pneumonia (46.9%), and anemia (43.8%). The most common grade 3 or higher adverse events were pneumonia (18.8%) and febrile neutropenia (12.5%). Four patients discontinued brentuximab vedotin because of severe adverse events. Conclusion BV is effective in treating relapsed and refractory CD30- positive Hodgkin's lymphoma and peripheral T-cell lymphoma, and its overall safety is acceptable.
الملخص
Multiple myeloma (MM) is an incurable plasma cell malignancy with a typical course characterized by response to initial treatment and eventual resistance. Despite major advances in the clinical treatment of multiple myeloma driven by the introduction of new drugs (e.g., proteasome inhibitors and immunomodulators), MM remains incurable. Nevertheless, subsequent cycles of remission and relapse continue as long as new treatments are available to patients. With the development of many new treatments, the approval of 12 new drugs over the past 15 years, and the promising trend of clinical trials, the treatment landscape has dramatically changed and patient survival has improved. This article reviews the progress of new treatments for MM.
الملخص
The incidence of breast cancer currently ranks first among malignant tumors in women.Breast cancer exhibits high heterogeneity and can be classified into four molecular subtypes:luminal A,luminal B,human epidermal growth factor receptor 2(HER2)overexpression and triple-negative.However,previous molecular subtype classifications have limited treatment options for patients with HER2 low expression.In recent years,with the rapid development of antibody-drug conjugates(ADCs),new treatment options have emerged for breast cancer patients with HER2 low expression.This has also led to updates in the criteria for determining HER2 expression status in both domestic and international guidelines,based on immunohistochemistry(IHC)and in situ hybridization(ISH)testing,categorizing HER2 expression as HER2-positive(IHC 3+ or IHC 2+/ISH+),HER2 low expression(IHC 1+ or IHC 2+/ISH-),and HER2-negative(IHC 0).ADCs are immunotherapeutics composed of a linker that conjugates a monoclonal antibody with a cytotoxic payload.In the field of breast cancer,several large clinical trials have demonstrated clinical benefits of ADCs targeting HER2,such as trastuzumab emtansine(T-DM1),trastuzumab deruxtecan(T-DXd)and sacituzumab govitecan targeting trophoblast cell surface antigen 2(TROP2),in various molecular subtypes of breast cancer.With the phaseⅢ DESTINY-Breast03 trial and others,T-DXd has been found to have superior efficacy compared to T-DM1 in advanced HER2-positive breast cancer patients(approximately two times higher complete response rate,and four times longer median progression-free survival).T-DXd has now replaced T-DM1 as the recommended second-line therapy for HER2-positive breast cancer and as a second-line treatment option after local treatment for brain metastasis.The phase Ⅲ DESTINY-Breast04 trial confirmed that breast cancer patients with HER2 low expression can also benefit from T-DXd,further reshaping the treatment landscape for advanced breast cancer and supporting the need to redefine molecular subtypes of HER2-negative breast cancer.The phase Ⅲ ASCENT trial demonstrated that sacituzumab govitecan significantly improved survival and quality of life in triple-negative breast cancer(TNBC)patients,and the phase Ⅱ NeoSTAR study suggested its potential as neoadjuvant therapy in TNBC.Based on evidence,T-DM1,T-DXd and sacituzumab govitecan have been approved for marketing in both foreign and Chinese markets.Other ADC drugs,such as HER3-DXd,Dato-DXd and China-developed RC48,are also undergoing extensive clinical trials in the field of breast cancer and other tumors.Furthermore,there are several other ADCs targeting different molecular targets in active development.This article aimed to review the new advances related to ADCs therapy for breast cancer patients with different molecular subtypes and discuss the clinical application value of ADCs in breast cancer.
الملخص
Antibody-drug conjugates (ADCs) are a class of targeted biological agents that link cytotoxic drugs to monoclonal antibodies through linkers. The monoclonal antibody targets tumor cells and transports small-molecule cytotoxic drugs for specific delivery and minimal off-target side effects. September 30, 2022, 14 anti-tumor ADC drugs have been approved for marketing in the world, and four ADCs have been approved in China. With the improvement of the clinical accessibility of ADC drugs, clinicians urgently need to understand the molecular characteristics and mechanisms of ADCs, and clarify the indications for rational use of drugs. Patients' survival mainly depends on the appropriate dose and course of treatment and also on proper management of adverse reactions. In view of this, on the basis of the "Expert Consensus on the Clinical Application of Antibody-drug Conjugates for the Treatment of Malignant Tumors (2020 edition)" , Professional Committee on Clinical Research of Oncology Drugs, Chinese Anti-Cancer Association fully combines the existing clinical research evidence and the feasibility of current ADC drugs in China to update the consensus content. This consensus aims to provide a systematic overview of ADC drugs, so as to provide practical and effective suggestions and references for clinicians to apply and manage ADC drugs more accurately.
الموضوعات
Humans , Immunoconjugates/therapeutic use , Consensus , Neoplasms/drug therapy , Antineoplastic Agents/adverse effects , Antibodies, Monoclonal/therapeutic useالملخص
Currently, breast cancer is the most commonly diagnosed cancer of all malignant tumor worldwide. Notably, the poor survival outcome of patients with metastatic breast cancer remains to be solved. With the exploration of molecular targeted therapy, the application of antibody drug conjugate (ADC) in cancer has attracted extensive attentions. ADC represents a class of therapeutics with combination of an antibody targeting a specific antigen and a toxic payload conjugated with the antibody via a linker. The monoclonal antibody of an ADC enables it to specifically bind to the targeted tumor cell surface. Upon binding, the ADC is internalized and trafficked to lysosomes, from where the cytotoxic drug is released within the cell, thus resulting in the cell death. Here, we presented the results of clinical trials evaluating trastuzumab duocarmazine, trastuzumab deruxtecan and sacituzumab govitecan in different treatment settings for breast cancer patients. It is necessary for clinicians to deeply understand the mechanism and clinical efficacy or safety of different ADCs when formulating treatment plans for breast cancer patients.
الملخص
At present, antibody-drug conjugate is the focus of the research and development of new anticancer drugs. Three antibody-drug conjugates have been approved for the treatment of urothelial carcinoma, including Enfortumab Vedotin (Nectin-4 antibody-MMAE conjugate), Sacitumab Govitecan (Trop-2 antibody-SN-38 conjugate), and Disitamab Vedotin (HER2 antibody-MMAE conjugate) significantly improved the prognosis in patients with advanced disease, revolutionizing the treatment landscape of urothelial carcinoma. In addition, a number of studies that focus on combination of antibody-drug conjugate with targeted therapy, immunocheckpoint inhibitors is also under way. This article reviews the recent clinical development of antibody-drug conjugate in the treatment of urothelial carcinoma in recent years.
الملخص
OBJECTIVE To evaluate the efficacy and safety of antibody-drug conjugates （ADC） in the treatment of breast cancer， so as to provide an evidence-based reference for clinical medication. METHODS Retrieved from CNKI， Wanfang database， VIP， PubMed， the Cochrane Library， Embase， and Web of Science， randomized controlled trials （RCTs） about trastuzumab emtansine， trastuzumab deruxtecan and sacituzumab govitecan （trial group） versus chemotherapy or other anti-tumor drugs （control group）， were collected during the inception to April 2023. After screening the literature， extracting data， and evaluating the quality of the literature， a meta-analysis was conducted by using RevMan 5.4.1 software. RESULTS A total of 8 RCTs were included， with a total of 5 577 patients. The results of the meta-analysis showed that the progression-free survival （PFS） [HR＝0.76， 95%CI （0.69， 0.83）， P＜0.000 01]， overall survival （OS） [HR＝0.87， 95%CI （0.81， 0.93）， P＜0.000 1]， and clinical benefit rate （CBR） [OR＝2.70， 95%CI （1.15， 6.33）， P＝0.02] of the trial group were significantly higher than control group. There was no statistically significant difference in objective response rate （ORR） between the two groups [OR＝2.34， 95%CI （0.59， 9.33）， P＝0.23]. The results of subgroup analysis showed that the PFS of HER2-positive patients and HER2-negative patients， and the OS of HER2-positive patients in the trial group were significantly higher than control group （P＜0.05）. The incidence of anemia and increase of aspartic acid transaminase （AST） in the trial group was significantly higher than control group （P＜0.05）. The results of sensitivity analysis showed that the results obtained with PFS， OS， and ORR as indicators were relatively robust， while the results obtained with CBR as indicators lacked robustness. CONCLUSIONS ADC drugs have significant effects on breast cancer， but will increase the risk of anemia and elevated AST.
الملخص
Antibody-drug conjugates (ADCs) are novel drugs consisting of monoclonal antibodies targeting tumor-specific or tumor-associated antigens coupled with different numbers of payloads via linkers. ADCs have shown promising clinical benefits in the treatment of a variety of malignancies. Small-cell lung cancer (SCLC) is a hypo-differentiated neuroendocrine tumor with an extremely high degree of malignancy. Although SCLC is sensitive to radiotherapy and chemotherapy, it has a poor prognosis due to characteristics such as early susceptibility to metastasis and recurrence. Progress in the treatment of SCLC is very limited, and more durable and effective therapies should be developed to improve prognosis. However, the progress of SCLC-related therapeutic agents has been limited by the lack of specific molecular targets. This article reviews the basic principles and mechanisms of ADCs, highlights the research progress of relevant drugs against some targets in SCLC, and summarizes new targets that may be developed as targeted drugs.
الملخص
The morbidity and mortality of gastrointestinal malignancies are the highest in the world. For patients with poor response to conventional chemotherapy, new treatment methods are urgently needed. In recent years, under the background of precision medicine, antibody-drug conjugates (ADCs) with high tumor specificity and potent toxicity have become a hot research spot in the field of biomedicine. However, due to the complex structure and mechanism of ADCs, its pharmacokinetic research is facing great challenges which are the biggest resistance to the development of ADCs at present. In this case, it is of great significance to understand the pharmacokinetic properties of ADCs and make use of it to improve the efficacy of ADCs in the treatment of gastrointestinal malignancies. Based on the basic composition and mechanism of ADCs, this review summarizes the pharmacokinetic properties of ADCs, discusses its recent advances in the treatment of gastrointestinal malignancies, in order to provide more references for follow-up research on ADCs.
الملخص
Bladder cancer (BC) is one of the most common malignancies of the urinary tract. Surgery combined with chemoradiotherapy is the mainstay of treatment, but BC is markedly heterogeneous, leading to unsatisfactory outcomes. Antibody-drug conjugate (ADC), a new type of targeted drug, has achieved remarkable results in the treatment of tumors by coupling a chemical junction with a highly cytotoxic small molecule, which can exert anti-tumor effects while avoiding the impacts on normal cells. To date, several ADCs have been used in the treatment of BC at home and abroad, and play an increasingly important role in the field of BC therapy. This article briefly introduces the mechanism of ADC, the current application of ADC in BC treatment, and the problems and challenges faced, hoping to provide reference for clinical work.
الملخص
Antibody‒drug conjugates (ADCs), which combine the advantages of monoclonal antibodies with precise targeting and payloads with efficient killing, show great clinical therapeutic value. The ADCs' payloads play a key role in determining the efficacy of ADC drugs and thus have attracted great attention in the field. An ideal ADC payload should possess sufficient toxicity, low immunogenicity, high stability, and modifiable functional groups. Common ADC payloads include tubulin inhibitors and DNA damaging agents, with tubulin inhibitors accounting for more than half of the ADC drugs in clinical development. However, due to clinical limitations of traditional ADC payloads, such as inadequate efficacy and the development of acquired drug resistance, novel highly efficient payloads with diverse targets and reduced side effects are being developed. This perspective summarizes the recent research advances of traditional and novel ADC payloads with main focuses on the structure-activity relationship studies, co-crystal structures, and designing strategies, and further discusses the future research directions of ADC payloads. This review also aims to provide valuable references and future directions for the development of novel ADC payloads that will have high efficacy, low toxicity, adequate stability, and abilities to overcome drug resistance.
الملخص
Antibody drug conjugations (ADCs) are a new class of drugs with both targeted specificity and high activity of chemotherapy drugs, which has gradually become a novel generation of therapeutic models with great clinical application prospects. In recent years, ADCs composed of monoclonal antibodies against different tumor cell surface antigens and small molecule potent cytotoxic drugs have shown superior therapeutic effects on recurrent / metastatic breast cancer. This article reviews the clinical application and research progress of ADCs with different molecular targets in the field of breast cancer.