RESUMEN
This paper outlines a novel drug delivery system for highly cytotoxic mertansine (DM1) by conjugating to an albumin-binding Evans blue (EB) moiety through a tuneable responsive disulfide linker, providing valuable insights for the development of effective drug delivery systems toward cancer therapy.
Asunto(s)
Antineoplásicos , Sistemas de Liberación de Medicamentos , Oxidación-Reducción , Humanos , Antineoplásicos/química , Antineoplásicos/farmacología , Animales , Albúminas/química , Maitansina/química , Maitansina/farmacología , Ratones , Neoplasias/tratamiento farmacológico , Portadores de Fármacos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos AntitumoralesRESUMEN
The notable characteristics of recently emerged Antibody-Drug Conjugates (ADCs) encompass the targeting of Human Epidermal growth factor Receptor 2 (HER2) through monoclonal antibodies (mAbs) and a high ratio of drug to antibody (DAR). The achievements of Kadcyla® (T-DM1) and Enhertu® (T-Dxd) have demonstrated that HER2-targeting antibodies, such as trastuzumab, have shown to be competitive in terms of efficacy and price for development. Furthermore, with the arrival of T-Dxd and Trodelvy®, high-DAR (7-8) ADCs, which differ from the moderate DAR (3-4) ADCs that were formerly regarded as conventional, are being acknowledged for their worth. Following this trend of drug development, we endeavored to develop a high-DAR ADC using a straightforward approach involving the utilization of DM1, a highly potent substance, in combination with the widely recognized trastuzumab. To achieve a high DAR, DM1 was conjugated to reduced cysteine through the simple design and synthesis of various dimaleimide linkers with differing lengths. Using LC and MS analysis, we have demonstrated that our synthesis methodology is uncomplicated and efficacious, yielding trastuzumab-based ADCs that exhibit a remarkable degree of uniformity. These ADCs have been experimentally substantiated to exert an inhibitory effect on cancer cells in vitro, thus affirming their value as noteworthy additions to the realm of ADCs.
Asunto(s)
Ado-Trastuzumab Emtansina , Inmunoconjugados , Receptor ErbB-2 , Trastuzumab , Humanos , Inmunoconjugados/química , Inmunoconjugados/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-2/metabolismo , Ado-Trastuzumab Emtansina/química , Trastuzumab/química , Trastuzumab/farmacología , Estructura Molecular , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Maleimidas/química , Maleimidas/síntesis química , Relación Dosis-Respuesta a Droga , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Relación Estructura-Actividad , Maitansina/química , Maitansina/farmacología , Maitansina/síntesis química , Maitansina/análogos & derivados , Línea Celular Tumoral , Antineoplásicos Inmunológicos/química , Antineoplásicos Inmunológicos/síntesis química , Antineoplásicos Inmunológicos/farmacologíaRESUMEN
Urothelial carcinoma (UC) is the most common malignancy of the urinary tract in dogs and has aggressive behaviour. Although human epidermal growth factor receptor 2 (HER2) is a known therapeutic target with evidence in canine UC, the efficacy of anti-HER2 antibody drugs remains unknown. This study aimed to investigate the effects of anti-HER2 antibody drugs including trastuzumab and trastuzumab emtansine (T-DM1) on canine UC cell lines in vitro and in vivo. Four canine UC cell lines (Nene, TCCUB, Love, and Sora) were used. In western blotting, HER2 protein expression was observed in all the cell lines. Although both trastuzumab and T-DM1 showed dose-dependent growth inhibitory activity in the cell lines, T-DM1 showed much stronger activity than that of trastuzumab. In flow cytometry analyses with the canine UC cell line (Sora), T-DM1 but not trastuzumab significantly increased the percentages of early and late apoptotic cells in annexin V apoptotic assays and the sub-G1 phase fraction in cell cycle analyses. For the in vivo experiment, the canine UC cells (Sora) were subcutaneously injected into nude mice. Four days after inoculation, trastuzumab, T-DM1, or vehicle was administered intraperitoneally once a week for three times. Tumour volumes were significantly smaller in the T-DM1 group compared to the trastuzumab and vehicle control groups. These findings indicate that T-DM1 exerts a stronger antitumour effect than that of trastuzumab on canine UC cells in vitro and in vivo, possibly by inducing apoptosis due to DM1.
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Ado-Trastuzumab Emtansina , Enfermedades de los Perros , Trastuzumab , Animales , Perros , Enfermedades de los Perros/tratamiento farmacológico , Trastuzumab/farmacología , Trastuzumab/uso terapéutico , Línea Celular Tumoral , Ado-Trastuzumab Emtansina/farmacología , Ado-Trastuzumab Emtansina/uso terapéutico , Ratones , Antineoplásicos Inmunológicos/farmacología , Antineoplásicos Inmunológicos/uso terapéutico , Maitansina/farmacología , Maitansina/análogos & derivados , Maitansina/uso terapéutico , Receptor ErbB-2/metabolismo , Ratones Desnudos , Femenino , Apoptosis/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoAsunto(s)
Ado-Trastuzumab Emtansina , Neoplasias de la Mama Triple Negativas , Femenino , Humanos , Ado-Trastuzumab Emtansina/uso terapéutico , Ado-Trastuzumab Emtansina/farmacología , Inmunoconjugados/uso terapéutico , Inmunoconjugados/farmacología , Maitansina/análogos & derivados , Maitansina/uso terapéutico , Maitansina/farmacología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Anexina A5/farmacología , Anexina A5/uso terapéuticoRESUMEN
Macrolides are widely used for the long-term treatment of infections and chronic inflammatory diseases. The pharmacokinetic features of macrolides include extensive tissue distribution because of favorable membrane permeability and accumulation within lysosomes. Trastuzumab emtansine (T-DM1), a HER2-targeting antibody-drug conjugate (ADC), is catabolized in the lysosomes, where Lys-SMCC-DM1, a potent cytotoxic agent, is processed by proteinase degradation and subsequently released from the lysosomes to the cytoplasm through the lysosomal membrane transporter SLC46A3, resulting in an antitumor effect. We recently demonstrated that erythromycin and clarithromycin inhibit SLC46A3 and attenuate the cytotoxicity of T-DM1; however, the effect of other macrolides and ketolides has not been determined. In this study, we evaluated the effect of macrolide and ketolide antibiotics on T-DM1 cytotoxicity in a human breast cancer cell line, KPL-4. Macrolides used in the clinic, such as roxithromycin, azithromycin, and josamycin, as well as solithromycin, a ketolide under clinical development, significantly attenuated T-DM1 cytotoxicity in addition to erythromycin and clarithromycin. Of these, azithromycin was the most potent inhibitor of T-DM1 efficacy. These antibiotics significantly inhibited the transport function of SLC46A3 in a concentration-dependent manner. Moreover, these compounds extensively accumulated in the lysosomes at the levels estimated to be 0.41-13.6 mM when cells were incubated with them at a 2 µM concentration. The immunofluorescence staining of trastuzumab revealed that azithromycin and solithromycin inhibit the degradation of T-DM1 in the lysosomes. These results suggest that the attenuation of T-DM1 cytotoxicity by macrolide and ketolide antibiotics involves their lysosomal accumulation and results in their greater lysosomal concentrations to inhibit the SLC46A3 function and T-DM1 degradation. This suggests a potential drug-ADC interaction during cancer chemotherapy.
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Antineoplásicos , Neoplasias de la Mama , Inmunoconjugados , Cetólidos , Maitansina , Humanos , Femenino , Ado-Trastuzumab Emtansina , Neoplasias de la Mama/patología , Cetólidos/metabolismo , Cetólidos/uso terapéutico , Inmunoconjugados/uso terapéutico , Azitromicina , Claritromicina/farmacología , Maitansina/farmacología , Maitansina/uso terapéutico , Receptor ErbB-2/metabolismo , Anticuerpos Monoclonales Humanizados/uso terapéutico , Trastuzumab/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/metabolismo , Lisosomas/metabolismo , Antibacterianos/uso terapéuticoRESUMEN
Microbial bioactive natural products mediate ecologically beneficial functions to the producing strains, and have been widely used in clinic and agriculture with clearly defined targets and underlying mechanisms. However, the physiological effects of their biosynthesis on the producing strains remain largely unknown. The antitumor ansamitocin P-3 (AP-3), produced by Actinosynnema pretiosum ATCC 31280, was found to repress the growth of the producing strain at high concentration and target the FtsZ protein involved in cell division. Previous work suggested the presence of additional cryptic targets of AP-3 in ATCC 31280. Herein we use chemoproteomic approach with an AP-3-derived photoaffinity probe to profile the proteome-wide interactions of AP-3. AP-3 exhibits specific bindings to the seemingly unrelated deoxythymidine diphosphate glucose-4,6-dehydratase, aldehyde dehydrogenase, and flavin-dependent thymidylate synthase, which are involved in cell wall assembly, central carbon metabolism and nucleotide biosynthesis, respectively. AP-3 functions as a non-competitive inhibitor of all three above target proteins, generating physiological stress on the producing strain through interfering diverse metabolic pathways. Overexpression of these target proteins increases strain biomass and markedly boosts AP-3 titers. This finding demonstrates that identification and engineering of cryptic targets of bioactive natural products can lead to in-depth understanding of microbial physiology and improved product titers.
Asunto(s)
Actinobacteria , Productos Biológicos , Maitansina , Maitansina/farmacologíaRESUMEN
Systemic exposure to released cytotoxic payload contributes to the dose-limiting off-target toxicities of anticancer antibody-drug conjugates (ADC). In this work, we present an "inverse targeting" strategy to optimize the therapeutic selectivity of maytansinoid-conjugated ADCs. Several anti-maytansinoid sdAbs were generated via phage-display technology with binding IC50 values between 10 and 60 nmol/L. Co-incubation of DM4 with the anti-maytansinoid sdAbs shifted the IC50 value of DM4 up to 250-fold. Tolerability and efficacy of 7E7-DM4 ADC, an anti-CD123 DM4-conjugated ADC, were assessed in healthy and in tumor-bearing mice, with and without co-administration of an anti-DM4 sdAb. Co-administration with anti-DM4 sdAb reduced 7E7-DM4-induced weight loss, where the mean values of percentage weight loss at nadir for mice receiving ADC+saline and ADC+sdAb were 7.9% ± 3% and 3.8% ± 1.3% (P < 0.05). In tumor-bearing mice, co-administration of the anti-maytansinoid sdAb did not negatively affect the efficacy of 7E7-DM4 on tumor growth or survival following dosing of the ADC at 1 mg/kg (P = 0.49) or at 10 mg/kg (P = 0.9). Administration of 7E7-DM4 at 100 mg/kg led to dramatic weight loss, with 80% of treated mice succumbing to toxicity before the appearance of mortality relating to tumor growth in control mice. However, all mice receiving co-dosing of 100 mg/kg 7E7-DM4 with anti-DM4 sdAb were able to tolerate the treatment, which enabled reduction in tumor volume to undetectable levels and to dramatic improvements in survival. In summary, we have demonstrated the utility and feasibility of the application of anti-payload antibody fragments for inverse targeting to improve the selectivity and efficacy of anticancer ADC therapy.
Asunto(s)
Inmunoconjugados , Maitansina , Neoplasias , Animales , Ratones , Maitansina/farmacología , Neoplasias/tratamiento farmacológico , Índice Terapéutico , Pérdida de Peso , Línea Celular TumoralRESUMEN
Maytansine is a pharmacologically active 19-membered ansamacrolide derived from various medicinal plants and microorganisms. Among the most studied pharmacological activities of maytansine over the past few decades are anticancer and anti-bacterial effects. The anticancer mechanism of action is primarily mediated through interaction with the tubulin thereby inhibiting the assembly of microtubules. This ultimately leads to decreased stability of microtubule dynamics and cause cell cycle arrest, resulting in apoptosis. Despite its potent pharmacological effects, the therapeutic applications of maytansine in clinical medicine are quite limited due to its non-selective cytotoxicity. To overcome these limitations, several derivatives have been designed and developed mostly by modifying the parent structural skeleton of maytansine. These structural derivatives exhibit improved pharmacological activities as compared to maytansine. The present review provides a valuable insight into maytansine and its synthetic derivatives as anticancer agents.
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Antineoplásicos , Maitansina , Maitansina/farmacología , Maitansina/uso terapéutico , Microtúbulos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/metabolismo , Tubulina (Proteína)/metabolismoRESUMEN
The therapeutic modalities that involve the endocytosis pathway, including antibody-drug conjugates (ADCs), have recently been developed. Since the drug escape from endosomes/lysosomes is a determinant of their efficacy, it is important to optimize the escape, and the cellular evaluation system is needed. SLC46A3, a lysosomal membrane protein, has been implicated in the pharmacological efficacy of trastuzumab emtansine (T-DM1), a noncleavable ADC used for the treatment of breast cancer, and the cellular uptake efficacy of lipid-based nanoparticles. Recently, we identified the SLC46A3 function as a proton-coupled steroid conjugate and bile acid transporter, which can directly transport active catabolites of T-DM1. Thus, the rapid and convenient assay systems for evaluating the SLC46A3 function may help to facilitate ADC development and to clarify the physiological roles in endocytosis. Here, we show that SLC46A3 dC, which localizes to the plasma membrane owing to lacking a lysosomal-sorting motif, has a great ability to transport 5-carboxyfluorescein (5-CF), a fluorescent probe, in a pH-dependent manner. 5-CF uptake mediated by SLC46A3 was significantly inhibited by compounds reported to be SLC46A3 substrates/inhibitors and competitively inhibited by estrone 3-sulfate, a typical SLC46A3 substrate. The inhibition assays followed by uptake studies revealed that SG3199, a pyrrolobenzodiazepine dimer, which has been used as an ADC payload, is a substrate of SLC46A3. Accordingly, the fluorescence-based assay system for the SLC46A3 function using 5-CF can provide a valuable tool to evaluate the interaction of drugs/drug candidates with SLC46A3.
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Neoplasias de la Mama , Inmunoconjugados , Maitansina , Humanos , Femenino , Trastuzumab/farmacología , Maitansina/farmacología , Maitansina/química , Fluorescencia , Ado-Trastuzumab Emtansina , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Inmunoconjugados/uso terapéutico , Receptor ErbB-2/metabolismoRESUMEN
Here, we report a CD138 receptor targeting liposomal formulation (TNP[Prodrug-4]) that achieved efficacious tumor growth inhibition in treating multiple myeloma by overcoming the dose limiting severe toxicity issues of a highly potent drug, Mertansine (DM1). Despite the promising potential to treat various cancers, due to poor solubility and pharmacokinetic profile, DM1's translation to the clinic has been unsatisfactory. We hypothesized that the optimal prodrug chemistry would promote efficient loading of the prodrug into targeted nanoparticles and achieve controlled release following endocytosis by the cancer cells, consequently, accomplish the most potent tumor growth inhibition. We evaluated four functional linker chemistries for synthesizing DM1-Prodrug molecules and evaluated their stability and cancer cell toxicity in vitro. It was determined that the phosphodiester moiety, as part of nanoparticle formulations, demonstrated most favorable characteristics with an IC50 of â¼16 nM. Nanoparticle formulations of Prodrug-4 enabled its administration at 8-fold higher dosage of equivalent free drug while remaining below maximum tolerated dose. Importantly, TNP[Prodrug-4] achieved near complete inhibition of tumor growth (â¼99% by day 10) compared to control, without displaying noticeable systemic toxicity. TNP[Prodrug-4] promises a formulation that could potentially make DM1 treatment available for wider clinical applications with a long-term goal for better patient outcomes.
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Maitansina , Mieloma Múltiple , Nanopartículas , Profármacos , Humanos , Profármacos/química , Mieloma Múltiple/tratamiento farmacológico , Maitansina/uso terapéutico , Maitansina/farmacología , Nanopartículas/química , Liposomas , Péptidos , Línea Celular TumoralRESUMEN
PURPOSE: Ado-trastuzumab emtansine (T-DM1) treatment results in grade 3-4 thrombocytopenia in 8%-13% of patients. Prior in vitro studies reported T-DM1 inhibition of megakaryocyte maturation as the cause of decreased platelet production. The current observational study was initiated to evaluate causes of thrombocytopenia in patients with metastatic breast cancer. MATERIALS AND METHODS: Patients with human epidermal growth factor receptor 2-positive metastatic breast cancer (N = 11) were enrolled in this postmarket safety study. 111-Indium- radiolabeled autologous platelet recoveries and survivals as well as serial platelet counts, bleeding time assays, and platelet aggregation responses to a wide range of agonists were performed at baseline (BL) and during two consecutive cycles of the drug (3.6 mg/kg IV once every 3 weeks). RESULTS: Platelet nadirs occurred earlier in cycle 2 than in cycle 1. Average nadir counts (% BL) in cycles 1 and 2 were 116,000/µL (53% ± 6%) and 115,000/µL (51% ± 9%), respectively, with return to BL by D15 in both cycles. BL platelet survival averaged 8.8 (± 0.3) days but progressively shortened to 5.5 (± 0.5) days during cycle 1 and to 4.6 (± 0.3) days during cycle 2 (P < .001 compared with BL for both cycles). Aggregation responses to all agonists decreased during the study, both in cycle 1 and cycle 2. CONCLUSION: Following T-DM1 administration, we observed statistically significant progressive decreases in platelet survivals and decreased platelet function from BL values. In distinction to published in vitro studies, these unexpected results indicate a direct toxic effect of T-DM1 on patients' autologous circulating platelets.
Asunto(s)
Neoplasias de la Mama , Maitansina , Trombocitopenia , Ado-Trastuzumab Emtansina , Anticuerpos Monoclonales Humanizados/farmacología , Plaquetas/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Humanos , Indio/uso terapéutico , Cinética , Maitansina/farmacología , Receptor ErbB-2 , Trombocitopenia/tratamiento farmacológico , Trastuzumab/farmacologíaRESUMEN
BACKGROUND: Trastuzumab-emtansine (T-DM1, commercial name: Kadcyla) is well-known antibody-drug conjugate (ADC) and was first approved for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. This molecular format consisting of trastuzumab and maytansinoid payload (emtansine) is very simple, however, T-DM1 has wide heterogeneity due to non-specific conjugation, lowering its therapeutic index (TI). METHODS: To overcome this issue during the chemical modification of the random conjugation approach to generate T-DM1, we developed a novel chemical conjugation technology termed "AJICAP®" for modification of antibodies in site-specific manner by IgG Fc-affinity peptide based reagents. RESULTS: In this study, we compared site-specific maytansinoid-based ADCs synthesized by AJICAP and T-DM1 in rat safety studies. The results indicated an increase in the maximum tolerated dose, demonstrating an expansion of the AJICAP-ADC therapeutic index compared with that of commercially available T-DM1. Gram scale preparation of this AJICAP-ADC and the initial stability study are also described. CONCLUSIONS: Trastuzumab-AJICAP-maytansinoid produced by this unique chemical conjugation methodology showed higher stability and tolerability than commercially available T-DM1.
Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Inmunoconjugados , Maitansina , Ado-Trastuzumab Emtansina , Animales , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Femenino , Humanos , Inmunoconjugados/química , Inmunoconjugados/farmacología , Inmunoconjugados/uso terapéutico , Maitansina/química , Maitansina/farmacología , Maitansina/uso terapéutico , Ratas , Receptor ErbB-2/metabolismo , Trastuzumab/química , Trastuzumab/farmacología , Trastuzumab/uso terapéuticoRESUMEN
By harnessing the payload DM1 and a monoclonal antibody LR004 through a noncleavable linker succinimidyl-4-(N-maleimidomethyl)-cyclohexane-1-carboxylate, we designed and evaluated an antibody-drug conjugate LR-DM1 with an appropriate drug-antibody ratio of 3.6. LR-DM1, which was targeted toward the epidermal growth factor receptor for pancreatic cancer, exhibited potent antiproliferation activity in vitro with a half-maximal inhibitory concentration value of 7.03 nM for Capan-2 cells. Particularly, it displayed prominent tumor growth inhibition in vivo under 20 mg/kg LR-DM1 dosage in a single administration or multiple administrations without apparent abnormality of pathological observation. Moreover, LR-DM1 possessed a relatively broad therapeutic index with a half-lethal dose above 300 mg/kg, which was over 15-fold higher than the highest administration dosage of 20 mg/kg. This initial study on LR-DM1 holds promise for further development of a new antibody drug conjugate that is transformative for treatment of patients concerned.
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Neoplasias de la Mama , Inmunoconjugados , Maitansina , Neoplasias Pancreáticas , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Receptores ErbB/metabolismo , Femenino , Humanos , Inmunoconjugados/farmacología , Inmunoconjugados/uso terapéutico , Maitansina/farmacología , Maitansina/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Receptor ErbB-2 , Trastuzumab , Neoplasias PancreáticasRESUMEN
A two-dimensional (2D) glycomaterial for targeted delivery of maytansine to liver cancer cells was developed. Host-guest interaction between a galactosyl dye and human serum albumin (HSA) produces supramolecular galactoside-HSA conjugates, which are then used to coat 2D MoS2. The 2D glycomaterial was shown to be capable of the targeted delivery of maytansine to a liver cancer cell line that highly expresses a galactose receptor, resulting in greater cytotoxicity than maytansine alone.
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Neoplasias Hepáticas , Maitansina , Línea Celular , Línea Celular Tumoral , Galactosa , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Maitansina/farmacología , Albúmina Sérica HumanaRESUMEN
Asamitocins are maytansinoids produced by Actinosynnema pretiosum ssp. auranticum ATCC 31565 (A. pretiosum ATCC 31565), which have a structure similar to that of maytansine, therefore serving as a precursor of maytansine in the development of antibody-drug conjugates (ADCs). Currently, there are more than 20 known derivatives of ansamitocins, among which ansamitocin P-3 (AP-3) exhibits the highest antitumor activity. Despite its importance, the application of AP-3 is restricted by low yield, likely due to a substrate competition mechanism underlying the synthesis pathways of AP-3 and its byproducts. Given that N-demethylansamitocin P-3, the precursor of AP-3, is regulated by asm25 and asm10 to synthesize AGP-3 and AP-3, respectively, asm25 is predicted to be an inhibitory gene for AP-3 production. In this study, we inactivated asm25 in A. pretiosum ATCC 31565 by CRISPR-Cas9-guided gene editing. asm25 depletion resulted in a more than 2-fold increase in AP-3 yield. Surprisingly, the addition of isobutanol further improved AP-3 yield in the asm25 knockout strain by more than 6 times; in contrast, only a 1.53-fold increase was found in the WT strain under the parallel condition. Thus, we uncovered an unknown function of asm25 in AP-3 yield and identified asm25 as a promising target to enhance the large-scale industrial production of AP-3.
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Actinobacteria , Maitansina , Actinobacteria/metabolismo , Vías Biosintéticas/genética , Maitansina/análogos & derivados , Maitansina/farmacologíaRESUMEN
Lung cancer is the leading cause of cancer-related deaths. Small cell lung cancer (SCLC) accounts for 15-25% of all lung cancers. It exhibits a rapid doubling time and a high degree of invasiveness. Additionally, overexpression of c-Kit occurs in 70% of SCLC patients. In this study, we evaluated an antibody-drug conjugate (ADC) that targets c-Kit, which is a potential therapeutic agent for SCLC. First, we generated and characterized 4C9, a fully human antibody that targets c-Kit and specifically binds to SCLC cells expressing c-Kit with a binding affinity of KD = 5.5 × 10-9 M. Then, we developed an ADC using DM1, a microtubule inhibitor, as a payload. 4C9-DM1 efficiently induced apoptosis in SCLC with an IC50 ranging from 158 pM to 4 nM. An in vivo assay using a xenograft mouse model revealed a tumor growth inhibition (TGI) rate of 45% (3 mg/kg) and 59% (5 mg/kg) for 4C9-DM1 alone. Combination treatment with 4C9-DM1 plus carboplatin/etoposide or lurbinectedin resulted in a TGI rate greater than 90% compared with the vehicle control. Taken together, these results indicate that 4C9-DM1 is a potential therapeutic agent for SCLC treatment.
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Anticuerpos Monoclonales Humanizados/farmacología , Inmunoconjugados/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Animales , Carboplatino/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Etopósido/farmacología , Femenino , Humanos , Neoplasias Pulmonares/metabolismo , Maitansina/farmacología , Ratones , Proteínas Proto-Oncogénicas c-kit/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Receptor ErbB-2/metabolismo , Carcinoma Pulmonar de Células Pequeñas/metabolismo , Trastuzumab/farmacología , Moduladores de Tubulina/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
DNA materials have emerged as potential nanocarriers for targeted cancer therapy to precisely deliver cargos with specific purposes. The short half-life and low bioavailability of DNA materials due to their interception by the reticuloendothelial system and blood clearance further limit their clinical translation. This study employs an HER2-targeted DNA-aptamer-modified DNA tetrahedron (HApt-tFNA) as a drug delivery system, and combines maytansine (DM1) to develop the HApt-DNA tetrahedron/DM1 conjugate (HApt-tFNA@DM1, HTD, HApDC) for targeted therapy of HER2-positive cancer. To optimize the pharmacokinetics and tumor-aggregation of HTD, a biomimetic camouflage is applied to embed HTD. The biomimetic camouflage is constructed by merging the erythrocyte membrane with pH-responsive functionalized synthetic liposomes, thus with excellent performance of drug delivery and tumor-stimulated drug release. The hybrid erythrosome-based nanoparticles show better inhibition of HER2-positive cancer than other drug formulations and exhibit superior biosafety. With the strengths of precise delivery, increased drug loading, sensitive tumor probing, and prolonged circulation time, the HApDC represents a promising nanomedicine to treat HER2-positive tumors. Notably, this study developsa dual-targeting nanoparticle by combining pH-sensitive camouflage and HApDC, initiating an important step toward the development and application of DNA-based medicine and biomimetic cell membrane materials in cancer treatment and other potential biological applications.
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Neoplasias de la Mama , Maitansina , Humanos , Femenino , Maitansina/farmacología , Maitansina/uso terapéutico , Neoplasias de la Mama/patología , Biomimética , Línea Celular Tumoral , ADN , Concentración de Iones de Hidrógeno , Receptor ErbB-2/metabolismoRESUMEN
Myofibroblasts, or activated fibroblasts, play a critical role in the process of renal fibrosis. Targeting myofibroblasts to inhibit their activation or induce specific cell death has been considered to be an effective strategy to attenuate renal fibrosis. However, specific biomarkers for myofibroblasts are needed to ensure the efficacy of these strategies. Here, we verified that CD248 was mainly expressed in myofibroblasts in patients with chronic kidney disease, which was inversely correlated with renal function. The same result was also confirmed in renal fibrotic mice induced by unilateral ureteral obstruction and aristolochic acid nephropathy. By using an antibody-drug conjugate (ADC) named IgG78-DM1, in which maytansinoid (DM1) was linked to a fully human antibody IgG78 through an uncleavable SMCC linker, we demonstrated that it could effectively bind with and kill CD248+ fibroblasts in vitro and alleviate renal fibrosis in mice models. Besides, we confirmed that IgG78-DM1 had qualified biosafety in vivo. Our results confirmed that CD248 can be used as a specific marker for myofibroblasts, and specific killing of CD248+ myofibroblasts by IgG78-DM1 has excellent anti-fibrotic effect in renal fibrotic mice. Our study expanded the application of ADC and provided a novel strategy for the treatment of renal fibrosis.
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Antígenos CD/metabolismo , Antígenos de Neoplasias/metabolismo , Sistemas de Liberación de Medicamentos , Inmunoconjugados/farmacología , Maitansina/farmacología , Miofibroblastos/metabolismo , Insuficiencia Renal Crónica , Animales , Fibrosis , Masculino , Ratones , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/metabolismoRESUMEN
Targeted nanomedicines particularly armed with monoclonal antibodies are considered to be the most promising advanced chemotherapy for malignant cancers; however, their development is hindered by their instability and drug leakage problems. Herein, we constructed a robust cetuximab-polymersome-mertansine nanodrug (C-P-DM1) for highly potent and targeted therapy of epidermal growth factor receptor (EGFR)-positive solid tumors. C-P-DM1 with a tailored cetuximab surface density of 2 per P-DM1 exhibited a size of ca. 60 nm, high stability with minimum DM1 leakage, glutathione-triggered release of native DM1, and 6.0-11.3-fold stronger cytotoxicity in EGFR-positive human breast (MDA-MB-231), lung (A549), and liver (SMMC-7721) cancer cells (IC50 = 27.1-135.5 nM) than P-DM1 control. Notably, intravenous injection of C-P-DM1 effectively repressed subcutaneous MDA-MB-231 breast cancer and orthotopic A549-Luc lung carcinoma in mice without inducing toxic effects. Strikingly, intratumoral injection of C-P-DM1 completely cured 60% of mice bearing breast tumor without recurrence. This robust cetuximab-polymersome-mertansine nanodrug provides a promising new strategy for targeted treatment of EGFR-positive solid malignancies.
Asunto(s)
Neoplasias de la Mama , Cetuximab , Maitansina , Nanopartículas , Animales , Anticuerpos Monoclonales , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Cetuximab/farmacología , Receptores ErbB/metabolismo , Femenino , Humanos , Maitansina/farmacología , Ratones , Nanopartículas/metabolismo , Nanopartículas/uso terapéuticoRESUMEN
BACKGROUND: Thymic epithelial tumours (TETs) are rare tumours comprised of thymomas and thymic carcinoma. Novel therapies are needed, especially in thymic carcinoma where the 5-year survival rate hovers at 30%. Mesothelin (MSLN), a surface glycoprotein that is cleaved to produce mature MSLN (mMSLN) and megakaryocyte potentiating factor (MPF), is expressed in limited tissues. However, its expression is present in various cancers, including thymic carcinoma, where it is expressed in 79% of cases. METHODS: We utilised flow cytometry, in vitro cytotoxicity assays, and an in vivo xenograft model in order to demonstrate the ability of the MSLN targeting antibody-drug conjugate (ADC) anetumab ravtansine (ARav) in inhibiting the growth of thymic carcinoma. RESULTS: Thymoma and thymic carcinoma cell lines express MSLN, and anetumab, the antibody moiety of ARav, was capable of binding MSLN expressing thymic carcinoma cells and internalising. ARav was effective at inhibiting the growth of thymic carcinoma cells stably transfected with mMSLN in vitro. In vivo, 15 mg/kg ARav inhibited T1889 xenograft tumour growth, while combining 7.5 mg/kg ARav with 4 mg/kg cisplatin yielded an additive effect on inhibiting tumour growth. CONCLUSIONS: These data demonstrate that anetumab ravtansine inhibits the growth of MSLN positive thymic carcinoma cells in vitro and in vivo.