General considerations for clinical pharmacology of antitumor antibody-conjugated drugs: Implications from FDA review cases / 中国临床药理学与治疗学

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.

Antibody-drug conjugates: Recent advances in payloads

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.

Self-assembly of CXCR4 antagonist peptide-docetaxel conjugates for breast tumor multi-organ metastasis inhibition

As a representative chemotherapeutic drug, docetaxel (DTX) has been used for breast cancer treatment for decades. However, the poor solubility of DTX limits its efficacy, and the DTX based therapy increases the metastasis risk due to the upregulation of C-X-C chemokine receptor type 4 (CXCR4) expression during the treatment. Herein, we conjugated CXCR4 antagonist peptide (CTCE) with DTX (termed CTCE-DTX) as an anti-metastasis agent to treat breast cancer. CTCE-DTX could self-assemble to nanoparticles, targeting CXCR4-upregulated metastatic tumor cells and enhancing the DTX efficacy. Thus, the CTCE-DTX NPs achieved promising efficacy on inhibiting both bone-specific metastasis and lung metastasis of triple-negative breast cancer. Our work provided a rational strategy on designing peptide-drug conjugates with synergistic anti-tumor efficacy.

Research advances in peptide‒drug conjugates

Peptide‒drug conjugates (PDCs) are drug delivery systems consisting of a drug covalently coupled to a multifunctional peptide via a cleavable linker. As an emerging prodrug strategy, PDCs not only preserve the function and bioactivity of the peptides but also release the drugs responsively with the cleavable property of the linkers. Given the ability to significantly improve the circulation stability and targeting of drugs in vivo and reduce the toxic side effects of drugs, PDCs have already been extensively applied in drug delivery. Herein, we review the types and mechanisms of peptides, linkers and drugs used to construct PDCs, and summarize the clinical applications and challenges of PDC drugs.

Click chemistry and drug delivery: A bird's-eye view

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.

Research Progress of Antibody-drug Conjugates in Small-cell Lung Cancer / 肿瘤防治研究

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.

Efficacy and safety of antibody-drug conjugates in the treatment of breast cancer：a meta-analysis / 中国药房

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.

Research Progress of Antibody-drug Conjugates in Advanced Non-small Cell Lung Cancer / 中国肺癌杂志

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.
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Research Advances of Immunotherapy for Follicular Lymphoma --Review / 中国实验血液学杂志

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.

Current Progress and Future Developments of Antibody Drug Conjugates in Lung Cancer / 中国肺癌杂志

Antibody drug conjugates (ADCs) are a novel class of anti-cancer drugs, which combined the specificity of monoclonal antibodies with the cytotoxic palyload via the linkers. Many ADCs have not only verified impressive activity in a variety of cancers, including breast cancer and hematological system tumors, but also in lung cancer. The aim of this study was to provide informations for practice by summarizing the mechanism of action, clinical application and problems and challenges of ADCs.
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Enzyme-linked immunosorbent assays for quantification of MMMAE-conjugated ADCs and total antibodies in cynomolgus monkey sera / 药物分析学报

Antibody-drug conjugates(ADCs)are commonly heterogeneous and require extensive assessment of exposure-efficacy and exposure-safety relationships in preclinical and clinical studies.In this study,we report the generation of a monoclonal antibody against monomethyl auristatin E(MMAE)and the development,validation,and application of sensitive and high-throughput enzyme-linked immunosor-bent assays(ELISA)to measure the concentrations of MMAE-conjugated ADCs and total antibodies(tAb,antibodies in ADC plus unconjugated antibodies)in cynomolgus monkey sera.These assays were suc-cessfully applied to in vitro plasma stability and pharmacokinetic(PK)studies of SMADC001,an MMAE-conjugated ADC against trophoblast cell surface antigen 2(TROP-2).The plasma stability of SMADC001 was better than that of similar ADCs coupled with PEG4-Val-Cit,Lys(m-dPEG24)-Cit,and Val-Cit linkers.The developed ELISA methods for the calibration standards of ADC and tAb revealed a correlation be-tween serum concentrations and the OD450 values,with R2 at 1.000,and the dynamic range was 0.3-35.0 ng/mL and 0.2-22.0 ng/mL,respectively;the intra-and inter-assay accuracy bias％ranged from-12.2％to-5.2％,precision ranged from-12.4％to-1.4％,and the relative standard deviation(RSD)was less than 6.6％and 8.7％,respectively.The total error was less than 20.4％.The development and validation steps of these two assays met the acceptance criteria for all addressed validation parameters,which suggested that these can be applied to quantify MMAE-conjugated ADCs,as well as in PK studies.Furthermore,these assays can be easily adopted for development of other similar immunoassays.

Research Progress of Antibody-drug Conjugates in Advanced Non-small Cell Lung Cancer / 肿瘤防治研究

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.

The role of caveolin-1 in the biofate and efficacy of anti-tumor drugs and their nano-drug delivery systems

As one of the most important components of caveolae, caveolin-1 is involved in caveolae-mediated endocytosis and transcytosis pathways, and also plays a role in regulating the cell membrane cholesterol homeostasis and mediating signal transduction. In recent years, the relationship between the expression level of caveolin-1 in the tumor microenvironment and the prognostic effect of tumor treatment and drug treatment resistance has also been widely explored. In addition, the interplay between caveolin-1 and nano-drugs is bidirectional. Caveolin-1 could determine the intracellular biofate of specific nano-drugs, preventing from lysosomal degradation, and facilitate them penetrate into deeper site of tumors by transcytosis; while some nanocarriers could also affect caveolin-1 levels in tumor cells, thereby changing certain biophysical function of cells. This article reviews the role of caveolin-1 in tumor prognosis, chemotherapeutic drug resistance, antibody drug sensitivity, and nano-drug delivery, providing a reference for the further application of caveolin-1 in nano-drug delivery systems.

Anticuerpos conjugados a fármaco: la nueva generación de terapias biotecnológicas contra el cáncer / Antibody-drug conjugates: the new generation of biotechnological therapies against cancer

Resumen Los anticuerpos terapéuticos son proteínas recombinantes empleadas en el tratamiento del cáncer. Existe una nueva generación de anticuerpos monoclonales con actividad contra las células cancerosas, conocidos como anticuerpos conjugados a fármacos. Estas moléculas están integradas por tres elementos: un anticuerpo monoclonal, un fármaco citotóxico con alta potencia y un enlazador químico que los une. El anticuerpo reconoce antígenos tumorales, por lo que permite la entrega dirigida del agente citotóxico hacia las células cancerosas. Tras el reconocimiento de su antígeno, el anticuerpo conjugado a fármaco es endocitado por las células blanco, donde se induce la degradación lisosomal de la fracción proteica y se libera el fármaco citotóxico. En el presente artículo se revisan las características generales de los anticuerpos conjugados a fármacos y se describe la evidencia clínica de la eficacia y seguridad de los primeros cuatro aprobados por las agencias reguladoras de Estados Unidos y Europa.

Abstract Therapeutic antibodies are recombinant proteins used in the treatment of cancer. There is a new generation of monoclonal antibodies with activity against cancer cells, known as antibody-drug conjugates. These molecules are made up of three elements: a monoclonal antibody, a highly potent cytotoxic drug, and a chemical linker that binds them together. The antibody recognizes tumor antigens, thereby allowing targeted delivery of the cytotoxic agent to cancer cells. After recognizing its antigen, the antibody-drug conjugate is endocytosed by the target cells, where the protein fraction is degradated into lysosomes, releasing the cytotoxic drug. This article reviews antibody-drug conjugates general characteristics and describes the clinical evidence of efficacy and safety of the first four approved by regulatory agencies in the United States and Europe.

Biophysical interactions between silver nanoparticle-albumin interface and curcumin / 药物分析学报

Active targeted drug delivery methods facilitate effective uptake of functionalized nanoparticles through receptor-mediated transcytosis. In recent years, albumin-nanoparticle interaction has been critically examined so that this functionalized nanoparticle can be efficiently loaded with drugs. The present investigation aims at understanding the adsorption of Bovine Serum Albumin (BSA) on Silver Nano-particle (SNP) surface, preparation of soft conjugates (SC) and hard conjugates (HC) of BSA-functionalized SNP (SNP-BSA), and their interaction with curcumin (CUR). HC contains tightly bound BSA whereas SC involves tightly and loosely bound BSA. Increase in the hydrodynamic radii of conjugates was observed upon SNP incubation with increased concentration of BSA. Three different SNP-BSA conjugate ratios were selected to study their interaction with CUR. Fluorescence spectroscopy showed a strong association between CUR and SNP:BSA conjugates. However, binding varied with a change in the conjugate ratio. Circular Dichroism (CD)/Fourier Transform Infrared (FTIR) spectroscopy revealed the alterations in the secondary structure of BSA upon CUR binding to the conjugates. Zeta potential data indicated stable conjugate formation. CUR in SNP:BSA conjugate was found to have a higher half-life as compared to the control. We believe that this is the first biophysical characterization report of conjugates that can be effectively extrapolated for targeted drug delivery.

Research Progress on Stimuli-responsive Polymer-drug Conjugates for Anti-tumor Drugs Delivery / 中国药学杂志

Polymer-drug conjugates (PDCs) have been extensively studied as nanocarriers for anti-tumor drugs delivery due to excellent stability in circulation and high drug loading ability. Stimuli-responsive PDCs(SRPDCs) could release the loading drug in response to various intra-or extracellular biological stimulis (eg, acidic pH, altered redox potential, and upregulated enzyme), as well as external artificial stimulis (eg, magnetic feld, light, temperature, and ultrasound), which are considered as "smart" nanocarriers for delivery of anti-tumor drugs. In this article, recent progresses in the development of SRPDCs for cancer therapy are reviewed, covering the design, smart linkages as well as responsive drug release property, so as to provide reference for the development of related drug delivery systems. In order to improve the successful translation of stimuli-responsive PDCs, drawbacks and limitations of current researches are discussed, besides, future perspectives and research strategies are also provided.

FITC labeling of human insulin and transport of FITC-insulin conjugates through MDCK cell monolayer / 药物分析学报

Fluorescein isothiocyanate-labeled insulin (FITC-insulin) has been widely used for bioanalytical appli-cations. Due to the high cost of commercial FITC-insulin and tedious labeling procedures described in the literature, there is still a need to develop a cost effective, reliable and quick labeling method for insulin. The purpose of the present work was to develop a quick and affordable method for FITC labeling of human insulin and to determine the effect of different conjugations of FITC to human insulin on its permeability through the MDCK cell monolayer. FITC labeling of insulin gives mono-, di-or tri-conjugates depending on the reaction time and the molar ratio of FITC:insulin. Mono-conjugate with unlabeled insulin, mixture of di-and tri-conjugate, and tri-conjugate with very little amount of di-conjugate were synthesized in less than 4 h. Degree of conjugation had an effect on the permeability of insulin through the MDCK cell monolayer. Mono-conjugate had higher permeability than the unlabeled insulin due to increase in partition coefficient. However, tri-conjugate showed lower permeability than the unlabeled insulin due to the increase in molecular weight.

Preparation of monoclonal antibodies against pneumococcal polysaccharide and hepatitis B virus sur-face protein / 中华微生物学和免疫学杂志

Objective To prepare monoclonal antibodies against pneumonia serotype 33F polysac-charides (Pn33Fps) and hepatitis B virus ( HBV) surface proteins ( HBs) by using the conjugate of Pn33Fps and HBs as antigen. Methods The conjugate of Pn33Fps and HBs was used as antigen to immu-nize mice with different immune doses, different immune procedures and different immune sites. Mouse spleen cells with higher antibody level after immunization were isolated and fused with SP2/0 myeloma cells. The hybridoma cells were screened specifically with Pn33Fps or HBs to prepare corresponding monoclonal antibodies. Results Serum antibodies against Pn33Fps and HBs were induced by immunizing mice with the conjugate. Monoclonal cell lines capable of continuously expressing antibodies against Pn33Fps or HBs were obtained. It has been proved that the recovery rates of samples of Pn33Fps and HBs prepared in three bat-ches tested with ascites monoclonal antibodies prepared by these two monoclonal cell lines were between 95％ and 105％. Conclusions Monoclonal antibodies against Pn33Fps and HBs could be prepared simul-taneously by immunizing mice with the conjugate of Pn33Fps and HBs and used for the quantitative detection of Pn33Fps and HBs.

Preparation of monoclonal antibodies against pneumococcal polysaccharide and hepatitis B virus surface protein / 中华微生物学和免疫学杂志

Objective@#To prepare monoclonal antibodies against pneumonia serotype 33F polysaccharides (Pn33Fps) and hepatitis B virus (HBV) surface proteins (HBs) by using the conjugate of Pn33Fps and HBs as antigen.@*Methods@#The conjugate of Pn33Fps and HBs was used as antigen to immunize mice with different immune doses, different immune procedures and different immune sites. Mouse spleen cells with higher antibody level after immunization were isolated and fused with SP2/0 myeloma cells. The hybridoma cells were screened specifically with Pn33Fps or HBs to prepare corresponding monoclonal antibodies.@*Results@#Serum antibodies against Pn33Fps and HBs were induced by immunizing mice with the conjugate. Monoclonal cell lines capable of continuously expressing antibodies against Pn33Fps or HBs were obtained. It has been proved that the recovery rates of samples of Pn33Fps and HBs prepared in three batches tested with ascites monoclonal antibodies prepared by these two monoclonal cell lines were between 95% and 105%.@*Conclusions@#Monoclonal antibodies against Pn33Fps and HBs could be prepared simultaneously by immunizing mice with the conjugate of Pn33Fps and HBs and used for the quantitative detection of Pn33Fps and HBs.

Marine drugs for cancer: surfacing biotechnological innovations from the oceans

This review will discuss the contributions of marine natural molecules, a source only recently found to have pharmaceutical prospects, to the development of anticancer drugs. Of the seven clinically utilized compounds with a marine origin, four are used for the treatment of cancer. The development of these drugs has afforded valuable knowledge and crucial insights to meet the most common challenges in this endeavor, such as toxicity and supply. In this context, the development of these compounds will be discussed herein to illustrate, with successful examples provided by cytarabine, trabectedin, eribulin and brentuximab vedotin, the steps involved in this process as well as the scientific advances and technological innovation potential associated with developing a new drug from marine resources.