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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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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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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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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.
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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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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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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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The treatment of breast cancer with low expression of human epidermal growth factor receptor 2 (HER-2) has become a focused area in recent years. With the proved therapeutic effect of antibody-drug conjugate on breast cancer patients with HER-2 low expression, HER-2-low expression may become a new subtype for targeted therapies of breast cancer. Standardized diagnosis and treatment are the foundation to guarantee efficacy. In order to improve the standardization of clinical diagnosis and treatment of HER-2-low breast cancer, the Consensus Expert Committee has summarized the latest domestic and global clinical data and the key relevant publications in recent years. We have combined them with clinical experience of pathologists and oncologists, had a deep discussion within the committee, and developed the consensus. We believe this consensus could help clinicians improve the understanding about HER-2-low breast cancer, promote the accuracy of decision-making and achieve the ultimate goal of prolonging the overall survival and improving the quality of life of patients.
Subject(s)
Humans , Female , Breast Neoplasms/drug therapy , Consensus , Quality of Life , Receptor, ErbB-2/metabolismABSTRACT
Antibody-drug conjugates (ADCs) are widely used in cancer treatment. Human epidermal growth factor receptor-2 (HER2) is overexpressed in various types of solid tumors and is a validated therapeutic target for cancers. To develop a more effective therapy, we generated a novel anti-HER2 humanized monoclonal antibody MIL40 and MIL40 drug conjugates as novel cancer therapies. The MIL40 was conjugated with small molecule cytotoxic agents DM1 [emtansine, N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-maytansine] or monomethylauristatin E (MMAE) to generate ADCs, which were evaluated for their in vitro and in vivo anti-cancer activities. Experimental results show that MIL40-DM1 and MIL40-MMAE can effectively identify and bind to HER2-positive tumor cells. The binding capabilities of MIL40-DM1 and MIL40-MMAE with HER2 extracellular domain (ECD) antigens were not different after conjugation with DM1 or MMAE. The ADCs showed potent cytotoxicity in HER2-positive ovarian cancer cells SKOV3, breast cancer cells SKBR3 and stomach cancer cells N87 in vitro. MIL40-DM1 can effectively inhibit the volume and weight growth of SKOV3 transplant tumors in mice. The mice in this study were used and treated by following the international guidelines for the care and use of laboratory animals, and approved by Animal Ethics Committee of Institute of Military Cognitive and Brain Sciences.
ABSTRACT
Antibody-drug conjugate (ADC) is a type of targeted biological agent which connect cytotoxic drug to monoclonal antibody by a connector head, which enables monoclonal antibody acted as a carrier to efficiently transport small molecular cytotoxic drugs to target tumor cells. It is very important for clinicians to have an in-depth understanding of the molecular characteristics and mechanism of ADC drugs, rationally choose the appropriate dose, course of treatment and manage adverse reactions according to the indications during the clinical application of ADC drugs, which may even affect the survival of patients. Therefore, the consensus aims to conduct a systematic overview of commercially available ADC drugs, provide effective recommendations and references for clinicians to better apply and manage ADC drugs.
Subject(s)
Humans , Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Consensus , Immunoconjugates/therapeutic use , Neoplasms/drug therapyABSTRACT
Antibody-drug conjugates (ADCs) are one of the most important classes of anticancer therapeutics. Human epidermal growth factor receptor-2 (HER2), which is highly expressed in many types of aggressive cancers including breast and ovarian cancer, has been approved as an ideal target for ADCs. Lidamycin (LDM), developed by Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, is an enediyne-containing antibiotic with potent anti-tumor activity. LDM is a promising payload for ADCs. In the present research, using a special site-directed conjugating technology, we made a novel ADC (607-LDM) with a drug-to-antibody ratio (DAR) of 2 and composed of the anti-HER2 antibody 607 and LDM. The new ADC exhibited potent antitumor activity against human ovarian cancer SKOV3 and breast cancer BT-474 cells. It also induced apoptosis and G2/M arrest. In nude mice with SKOV3 xenografts and a tumor volume of 150-200 mm3, a single intravenous injection 607-LDM at 1 mg·kg-1 induced tumor growth inhibition of 72.4%, which was significant compared to either LDM (50.6%) or antibody (30.2%) treatment alone, or both in combination (50.1%, P < 0.05). All animal experiments were performed in accord with National Regulations and approved by the Animal Experiments Ethical Committee of College of Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences. The novel ADC designed in this study, 607-LDM, is a promising candidate for the treatment of HER2-positive cancers.
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Antibody-drug conjugates (ADCs) are gradually revolutionizing clinical cancer therapy. The antibody-drug conjugate linker molecule determines both the efficacy and the adverse effects, and so has a major influence on the fate of ADCs. An ideal linker should be stable in the circulatory system and release the cytotoxic payload specifically in the tumor. However, existing linkers often release payloads nonspecifically and inevitably lead to off-target toxicity. This defect is becoming an increasingly important factor that restricts the development of ADCs. The pursuit of ADCs with optimal therapeutic windows has resulted in remarkable progress in the discovery and development of novel linkers. The 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 ADCs. This work also helps clarify future developmental directions for the linkers.
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Antibody drug conjugates (ADCs), as they combine the targetability of monoclonal antibody and cytotoxicity of small molecules, are a growing class of therapeutics for cancer. The key factor of ADCs development is the accurate selection of parameters including tumor target, monoclonal antibody, cytotoxic payload, and linkage strategy of antibody to payload. Here, we summarize the main elements in the structural design and the development of ADCs, as well as the regulatory consideration of product manufacturing and control, which would be helpful for the research and development of ADCs.
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Pharmacological activity and drug likeness depend in principle upon the microscopic structure and macroscopic properties of drugs, which reside in their molecular structures. By means of medicinal chemistry the evolution of an active compound to a novel drug (NME) essentially makes the two pillars coexistence in one chemical structure, which either could merge as an intrinsic structure or connect from external fragments to each other with covalent bonds. Since the new millennium the advance in biology provides several knowledge and technologies, for example humanized monoclonal antibody, proteasome-ubiquitin system, allosteric modulation, natural macromolecules, structural biology, etc., for innovation of novel medicines. Taking several examples on marketed drugs or drug candidates in clinical trials, this article tries to concisely illustrate R & D conception of biology-driven drug design.
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The past few years have witnessed enormous progresses in the development of antibody-drug conju-gates (ADCs). Consequently, comprehensive analysis of ADCs in biological systems is critical in sup-porting discovery, development and evaluation of these agents. Liquid chromatography-mass spectrometry (LC-MS) has emerged as a promising and versatile tool for ADC analysis across a wide range of scenarios, owing to its multiplexing ability, rapid method development, as well as the capability of analyzing a variety of targets ranging from small-molecule payloads to the intact protein with a high, molecular resolution. However, despite this tremendous potential, challenges persist due to the high complexity in both the ADC molecules and the related biological systems. This review summarizes the up-to-date LC-MS-based strategies in ADC analysis and discusses the challenges and opportunities in this rapidly-evolving field.
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Lung cancer is the most common malignancy tumor. Non-small cell lung cancer (NSCLC) accounts for about 85% of lung cancer. Human epidermal growth factor receptor-2 (HER2) is a tyrosine kinase receptor in ERBB/HER family, which activates downstream signal transduction with other family members such as epidermal growth factor receptor (EGFR). HER2 gene mutation is closely related to the progression of many epithelial cell cancers. Tumors with high expression of HER2 show strong metastasis and invasion ability, poor sensitivity to chemotherapy, and are prone to relapse. At present, lung cancer driven gene targeted therapy has made rapid progress. Although the frequency of HER2 gene mutation in NSCLC is lower than that of EGFR, its driving mechanism in lung cancer is clear and partial targeted therapy is effective, which may become a new standard treatment in the future. This review focuses on the research progress of HER2 gene mutation in the treatment of NSCLC. .
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OBJECTIVE: To conduct a single dose toxicology study of humanized anti-HER2 antibody drug conjugate for injection (HS630) and small molecular maytansine (DM1) in Sprague-Dawley rats. METHODS: Rats were divided randomly into nine groups including HS630 blank control group (0 mg•kg-1), DM1 vehicle control group (0 mg•kg-1), positive control group (Kadcyla®, 60 mg•kg-1), HS630 low-, middle-, high-dose groups (6, 20, 60 mg•kg-1) and DM1 low-, middle-, high-dose groups (0.10, 0.20, 0.40 mg•kg-1). Each group had twenty rats with female and male in half. Each rat was administered intravenously once. Animals were observed clinical symptoms consisting of behavior, fur and feces daily as well as body weight and food consumption twice or three times per week. Dissection was executed at D2 and D21 to examine gross anatomy with histopathological changes and weight main tissues. RESULTS: Rats given 60 mg•kg-1 HS630 appeared some adverse effects that 1/20 animal was dead. It was found that maximal tolerance dose of HS630 was 20 mg•kg-1 equivalent to 0.34 mg•kg-1 DM1. High dose could lead body weight and food consumption reduced and organ weights changed including liver, kidney, spleen and lung increased and testicle and epididymis decreased. Histopathological changes were observed in liver, spleen, lung, thymus, pancreas, kidney, mesenteric glands, intestinum, seminal vesicle, prostate, testicle, epididymis, adrenal gland, thyroid gland, pituitary body, eye, tongue, sternum (marrow), bone, skin, injection site. Rats given Kadcyla® showed the similar side effects with HS630. Rats given 20 mg•kg-1 HS630, abnormality weren′t observed in clinical symptom, body weight and food consumption. It could lead kidney and lung weighted. Histopathological changes were found in liver, spleen, thymus, pancreas, lung, kidney, mesenteric glands, duodenum, adrenal gland, pituitary body, skin. Rats given DM1 exhibited worse adverse effects that 2/20 animals were dead at 0.40 mg•kg-1 level. The maximal tolerance dose of DM1 was 0.20 mg•kg-1. High dose could lead body weight and food consumption reduced and organ weights changed including liver, spleen and adrenal gland increased and thymus decreased. Histopathological changes were found in liver, spleen, thymus, kidney, mesenteric glands, duodenum, intestinum, seminal vesicle, adrenal gland, pituitary body, eye, tongue, sternum (marrow), bone, skin. CONCLUSION: Rats given single dose of humanized anti-HER2 antibody-drug conjugate for injection (HS630) and chemical maytansine (DM1) respectively, the RESULTS: show that HS630, a kind of ADC products, have similar toxicological profile with Kadcyla® and exhibit better tolerability and wider safety margin when given the comparable dosage with DM1 based on the RESULTS: of tolerance, clinical symptoms, organ weight and histopathological findings.
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Although numbers of naked antibodies showing clinical efficacy as single agents, their therapeutic effect is limited. Chemotherapy is very effective but with relatively large side effects, so conjugation of small chemotherapeutic drugs to antibodies is one of the important methods to enhance therapeutic potential of antibodies. Antibody-drug conjugates (ADCs) represent a promising therapeutic approach for cancer patients by combining the antigen-targeting specificity of monoclonal antibodies (mAbs) with the cytotoxic potency of chemotherapeutic drugs. These modified antibodies are expected to selectively deliver chemotherapeutic drugs to tumor cells and provide sustained clinical benefit to cancer patients, at the same time, minimizing systemic toxicity. ADCs are expected to bring together the benefits of highly potent drugs on the one hand and selective binders of specific tumor antigens on the other hand. However, designing an ADC is very complex, requiring thoughtful combination of antibody, linker, and payload drugs in the context of a target and a defined cancer indication. Although many challenges remain, recent clinical success has generated intense interest in this therapeutic class.