ABSTRACT
Antibody-drug conjugates (ADCs) are conjugated by a linker between an antibody drug targeting a specific antigen and a payload, such as a small cytotoxic drug. ADCs combine the potent killing effect of traditional small cytotoxic drugs with the tumor targeting property of antibody drugs. As of February 2022, the U.S. Food and Drug Administration (FDA) had approved 12 ADC antitumor agents. Based on the analysis of clinical pharmacology review reports of approved ADC drugs combined with relevant guidelines, it is found that in the development of ADC, in addition to the general research in clinical pharmacology, there are special considerations in dose selection and dose modification for special population due to the special anti-tumor mechanism of ADC. It is hoped that this paper will be enlightening to domestic researchers when developing ADC.
ABSTRACT
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.
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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.
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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.
Subject(s)
Humans , Immunoconjugates/therapeutic use , Consensus , Neoplasms/drug therapy , Antineoplastic Agents/adverse effects , Antibodies, Monoclonal/therapeutic useABSTRACT
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.
ABSTRACT
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.
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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.
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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.
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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.
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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.
Subject(s)
Humans , Leukemia, Myeloid, Acute/drug therapy , Immunotherapy , Immunotherapy, Adoptive , Antineoplastic Combined Chemotherapy Protocols/therapeutic useABSTRACT
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.
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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.
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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.
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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.
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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.
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Although targeted, immune and other therapeutic strategies have become the first-line standard therapy for patients with advanced lung cancer, acquired drug resistance is still inevitable in most cases. The advent of antibody-drug conjugates (ADC) provides a new choice. ADC is a new anticancer drug formed by the coupling of targeted anti-tumor monoclonal antibodies and cytotoxic drugs. Compared with chemotherapeutic drugs, ADC has the advantages of high tolerance, accurate target recognition and little effect on non-cancer cells, and has shown good clinical benefits in the treatment of a variety of malignant tumors. This article reviews the application of ADC in advanced non-small cell lung cancer.
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Novel antibody-drug conjugates (ADCs) are a hot spot in the research and development of new drugs for advanced solid tumors. ADCs have achieved significant efficacy in the treatment of advanced breast cancer, urothelial carcinoma, gastric cancer and other solid tumors, but their adverse reactions such as ocular toxicity, pulmonary toxicity, hematological toxicity, and liver toxicity cannot be ignored, and it is crucial to effectively deal with the adverse reactions of ADCs.
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As a member of the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases, HER3 is an aberrantly activator of the PI3K/AKT pathway. Studies have indicated that HER3 is related to the progression of a variety of tumor types such as breast cancer, non-small cell lung cancer (NSCLC), ovary cancer and colon cancer, and in acquired resistance to EGFR and HER2 therapies. However, the attempts to target HER3 with neutralizing antibodies are not ideal previously. This is most likely due to the fact that the antibodies targeting HER3 fail to completely block the heterodimerization of HER3 and other receptors. Antibody-drug conjugates (ADCs) can specifically bind to target cells and exert the highly cytotoxicity effect on cancer cells through chemical drugs. ADCs have been widely used in clinical cancer therapies. We analyzed and optimized the structure of the antigen-antibody complex between HER3 and antibody LmAb3 by computer-aided molecular simulation technology, and the key sites involved in antigen binding in LmAb3 were predicted by distance geometry and computer graphics technology. Then a novel anti-HER3 antibody FD001 was obtained by point mutation technology. The affinity measurement by ForteBio results showed that the affinity of FD001 is much higher than LmAb3, the KD values of FD001 and LmAb3 with HER3 were 1.48E-11 and 2.46E-10, respectively. Antibody drug conjugate FD001-DM1 is obtained by coupling FD001 to DM1 [emtansine, N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-maytansine] by lysine coupling technology. The results of cell cytotoxicity experiments showed that FD001-DM1 could effectively inhibit the proliferation of HER3-positive HT-29 colon cancer cells, with EC50 value of 33.62 nmol·L-1. The in vivo xenografts therapy results showed that the tumor volume of the FD001-DM1 treatment group was about 25% of that of the control group, and there was no significant weight reduction of the mice. These results reveal that FD001-DM1 had good in vivo and in vitro anti-tumor activity with high safety, which may provide effective help for further exploration of HER3-targeted ADCs drugs. The mice in this study were used and treated in accordance with international laboratory animal care and use guidelines and approved by the Animal Ethics Committee of the Military Cognitive and Brain Science Institute of the Military Medical Research Institute.
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Lung cancer is one of the malignant tumors with the highest morbidity and mortality in the world. Non-small cell lung cancer (NSCLC) is one of the most important pathological types of lung cancer. The prognosis of advanced NSCLC is poor and medical treatment is still the main treatment option. Antibody-drug conjugates (ADCs) are the kind of potentially new anti-tumor drugs, consisting of monoclonal antibodies conjugated to the cytotoxic payloads via the synthetic linkers. They have a broad application prospect in solid tumors such as lung cancer. This article focuses on the mechanism of action and research progress of ADCs in advanced NSCLC. .
Subject(s)
Humans , Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Immunoconjugates/therapeutic use , Lung Neoplasms/drug therapyABSTRACT
Follicular lymphoma is an indolent malignant tumor originating from lymph nodes and lymphoid tissues, which may affect the patients' quality of survival due to the recurrence and progression. In recent years, with the deepening understand of the molecular biology and signaling pathways, many new targeted drugs for follicular lymphoma have been discovered, such as monoclonal antibodies, checkpoint inhibitors, epigenetic regulation related targeted therapies and signaling pathway inhibitors. In this review, the new progress of immunotherapy for follicular lymphoma is summarized briefly.