RESUMEN
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disorder with minimally effective treatment options. An important hurdle in ALS drug development is the non-invasive therapeutic access to the motor cortex currently limited by the presence of the blood-brain barrier (BBB). Focused ultrasound and microbubble (FUS+ MB) treatment is an emerging technology that was successfully used in ALS patients to temporarily open the cortical BBB. However, FUS+ MB-mediated drug delivery across ALS patients' BBB has not yet been reported. Similarly, the effects of FUS+ MB on human ALS BBB cells remain unexplored. METHODS: Here we established the first FUS+ MB-compatible, fully-human ALS patient-cell-derived BBB model based on induced brain endothelial-like cells (iBECs) to study anti-TDP-43 antibody delivery and FUS+ MB bioeffects in vitro. RESULTS: Generated ALS iBECs recapitulated disease-specific hallmarks of BBB pathology, including reduced BBB integrity and permeability, and TDP-43 proteinopathy. The results also identified differences between sporadic ALS and familial (C9orf72 expansion carrying) ALS iBECs reflecting patient heterogeneity associated with disease subgroups. Studies in these models revealed successful ALS iBEC monolayer opening in vitro with no adverse cellular effects of FUS+ MB as reflected by lactate dehydrogenase (LDH) release viability assay and the lack of visible monolayer damage or morphology change in FUS+ MB treated cells. This was accompanied by the molecular bioeffects of FUS+ MB in ALS iBECs including changes in expression of tight and adherens junction markers, and drug transporter and inflammatory mediators, with sporadic and C9orf72 ALS iBECs generating transient specific responses. Additionally, we demonstrated an effective increase in the delivery of anti-TDP-43 antibody with FUS+ MB in C9orf72 (2.7-fold) and sporadic (1.9-fold) ALS iBECs providing the first proof-of-concept evidence that FUS+ MB can be used to enhance the permeability of large molecule therapeutics across the BBB in a human ALS in vitro model. CONCLUSIONS: Together, this study describes the first characterisation of cellular and molecular responses of ALS iBECs to FUS+ MB and provides a fully-human platform for FUS+ MB-mediated drug delivery screening on an ALS BBB in vitro model.
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Esclerosis Amiotrófica Lateral , Barrera Hematoencefálica , Proteínas de Unión al ADN , Microburbujas , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Humanos , Proteínas de Unión al ADN/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Células Endoteliales/metabolismo , Anticuerpos/administración & dosificación , Ondas Ultrasónicas , Células CultivadasRESUMEN
Status epilepticus (SE) is a medical emergency associated with high mortality and morbidity. Na+, K+-ATPase, is a promising therapeutic target for SE, given its critical role in regulation of neuron excitability and cellular homeostasis. We investigated the effects of a Na+, K+-ATPase-activating antibody (DRRSAb) on short-term electrophysiological and behavioral consequences of pilocarpine-induced SE. Rats were submitted to pilocarpine-induced SE, followed by intranasal administration (2 µg/nostril). The antibody increased EEG activity following SE, namely, EEG power in theta, beta, and gamma frequency bands, assessed by quantitative analysis of EEG power spectra. One week later, DRRSAb-treated animals displayed less behavioral hyperreactivity in pick-up tests and better performance in novel object recognition tests, indicating that the intranasal administration of this Na+, K+-ATPase activator immediately after SE improves behavioral outcomes at a later time point. These results suggest that Na+, K+-ATPase activation warrants further investigation as an adjunctive therapeutic strategy for SE.
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Administración Intranasal , Electroencefalografía , Pilocarpina , ATPasa Intercambiadora de Sodio-Potasio , Estado Epiléptico , Animales , Estado Epiléptico/inducido químicamente , Estado Epiléptico/tratamiento farmacológico , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Masculino , Pilocarpina/farmacología , Electroencefalografía/métodos , Electroencefalografía/efectos de los fármacos , Ratas , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Ratas Wistar , Anticuerpos/farmacología , Anticuerpos/administración & dosificaciónRESUMEN
Subcutaneous (SC) administration of therapeutic proteins is perceived to pose higher risk of immunogenicity when compared with intravenous (IV) route of administration (RoA). However, systematic evaluations of clinical data to support this claim are lacking. This meta-analysis was conducted to compare the immunogenicity of the same therapeutic protein by IV and SC RoA. Anti-drug antibody (ADA) data and controlling variables for 7 therapeutic proteins administered by both IV and SC routes across 48 treatment groups were analyzed. RoA was the primary independent variable of interest while therapeutic protein, patient population, adjusted dose, and number of ADA samples were controlling variables. Analysis of variance was used to compare the ADA incidence between IV and SC RoA, while accounting for controlling variables and potential interactions. Subsequently, 10 additional therapeutic proteins with ADA data published for both IV and SC administration were added to the above 7 therapeutic proteins and were evaluated for ADA incidence. RoA had no statistically significant effect on ADA incidence for the initial dataset of 7 therapeutic proteins (p = 0.55). The only variable with a significant effect on ADA incidence was the therapeutic protein. None of the other controlling variables, including their interactions with RoA, was significant. When all data from the 17 therapeutic proteins were pooled, there was no statistically significant effect of RoA on ADA incidence (p = 0.81). In conclusion, there is no significant difference in ADA incidence between the IV and SC RoA, based on analysis of clinical ADA data from 17 therapeutic proteins.
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Administración Intravenosa , Humanos , Inyecciones Subcutáneas , Anticuerpos/administración & dosificación , Anticuerpos/inmunología , Proteínas/administración & dosificación , Proteínas/inmunologíaRESUMEN
Because of their high specificity, high affinity, and targeting, antibody drugs have been widely used in the treatment of many diseases and have become the most favored new drugs for research in the world. However, some antibody drugs (such as small-molecule antibody fragments) have a short half-life and need to be administered frequently, and are often associated with injection-site reactions and local toxicities during use. Increasing attention has been paid to the development of antibody drugs that are long-acting and have fewer side effects. This paper reviews existing strategies to achieve long-acting antibody drugs, including modification of the drug structure, the application of drug delivery systems, and changing their administration route. Among these, microspheres have been studied extensively regarding their excellent tolerance at the injection site, controllable loading and release of drugs, and good material safety. Subcutaneous injection is favored by most patients because it can be quickly self-administered. Subcutaneous injection of microspheres is expected to become the focus of developing long-lasting antibody drug strategies in the near future.
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Preparaciones de Acción Retardada , Sistemas de Liberación de Medicamentos , Microesferas , Humanos , Sistemas de Liberación de Medicamentos/métodos , Animales , Inyecciones Subcutáneas , Anticuerpos/administración & dosificación , Semivida , Vías de Administración de Medicamentos , Liberación de FármacosRESUMEN
The use of antibody-conjugated nanoparticles for brain tumor treatment has gained significant attention in recent years. Nanoparticles functionalized with anti-transferrin receptor antibodies have shown promising results in facilitating nanoparticle uptake by endothelial cells of brain capillaries and post-capillary venules. This approach offers a potential alternative to the direct conjugation of biologics to antibodies. Furthermore, studies have demonstrated the potential of antibody-conjugated nanoparticles in targeting brain tumors, as evidenced by the specific binding of these nanoparticles to brain cancer cells. Additionally, the development of targeted nanoparticles designed to transcytoses the blood-brain barrier (BBB) to deliver small molecule drugs and therapeutic antibodies to brain metastases holds promise for brain tumor treatment. While the use of nanoparticles as a delivery method for brain cancer treatment has faced challenges, including the successful delivery of nanoparticles to malignant brain tumors due to the presence of the BBB and infiltrating cancer cells in the normal brain, recent advancements in nanoparticle-mediated drug delivery systems have shown potential for enhancing the efficacy of brain cancer therapy. Moreover, the development of brain-penetrating nanoparticles capable of distributing over clinically relevant volumes when administered via convection-enhanced delivery presents a promising strategy for improving drug delivery to brain tumors. In conclusion, the use of antibody-conjugated nanoparticles for brain tumor treatment shows great promise in overcoming the challenges associated with drug delivery to the brain. By leveraging the specific targeting capabilities of these nanoparticles, researchers are making significant strides in developing effective and targeted therapies for brain tumors.
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Barrera Hematoencefálica , Neoplasias Encefálicas , Sistemas de Liberación de Medicamentos , Nanopartículas , Humanos , Neoplasias Encefálicas/tratamiento farmacológico , Animales , Barrera Hematoencefálica/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Nanopartículas/química , Inmunoconjugados/administración & dosificación , Inmunoconjugados/farmacocinética , Inmunoconjugados/química , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Anticuerpos/administración & dosificación , Anticuerpos/químicaRESUMEN
BACKGROUND: Transthyretin amyloid (ATTR) cardiomyopathy is a progressive and fatal disease caused by misfolded transthyretin. Despite advances in slowing disease progression, there is no available treatment that depletes ATTR from the heart for the amelioration of cardiac dysfunction. NI006 is a recombinant human anti-ATTR antibody that was developed for the removal of ATTR by phagocytic immune cells. METHODS: In this phase 1, double-blind trial, we randomly assigned (in a 2:1 ratio) 40 patients with wild-type or variant ATTR cardiomyopathy and chronic heart failure to receive intravenous infusions of either NI006 or placebo every 4 weeks for 4 months. Patients were sequentially enrolled in six cohorts that received ascending doses (ranging from 0.3 to 60 mg per kilogram of body weight). After four infusions, patients were enrolled in an open-label extension phase in which they received eight infusions of NI006 with stepwise increases in the dose. The safety and pharmacokinetic profiles of NI006 were assessed, and cardiac imaging studies were performed. RESULTS: The use of NI006 was associated with no apparent drug-related serious adverse events. The pharmacokinetic profile of NI006 was consistent with that of an IgG antibody, and no antidrug antibodies were detected. At doses of at least 10 mg per kilogram, cardiac tracer uptake on scintigraphy and extracellular volume on cardiac magnetic resonance imaging, both of which are imaging-based surrogate markers of cardiac amyloid load, appeared to be reduced over a period of 12 months. The median N-terminal pro-B-type natriuretic peptide and troponin T levels also seemed to be reduced. CONCLUSIONS: In this phase 1 trial of the recombinant human antibody NI006 for the treatment of patients with ATTR cardiomyopathy and heart failure, the use of NI006 was associated with no apparent drug-related serious adverse events. (Funded by Neurimmune; NI006-101 ClinicalTrials.gov number, NCT04360434.).
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Neuropatías Amiloides Familiares , Anticuerpos , Cardiomiopatías , Insuficiencia Cardíaca , Proteínas Recombinantes , Humanos , Neuropatías Amiloides Familiares/diagnóstico por imagen , Neuropatías Amiloides Familiares/tratamiento farmacológico , Neuropatías Amiloides Familiares/complicaciones , Anticuerpos/administración & dosificación , Anticuerpos/efectos adversos , Anticuerpos/farmacología , Anticuerpos/uso terapéutico , Cardiomiopatías/diagnóstico por imagen , Cardiomiopatías/tratamiento farmacológico , Cardiomiopatías/etiología , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/etiología , Imagen por Resonancia Magnética , Prealbúmina , Método Doble Ciego , Enfermedad Crónica , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/uso terapéutico , Infusiones IntravenosasRESUMEN
The signal transducer and activator of transcription 3 (STAT3) signaling pathway is a key mediator of cancer cell proliferation, survival, and invasion. We discovered YHO-1701 as a small molecule inhibitor of STAT3 dimerization and demonstrated its potent anti-tumor activity using xenograft mouse models as monotherapy and combination therapy with molecular targeted drugs. STAT3 is also associated with cancer immune tolerance; therefore, we used the female CT26 syngeneic mouse model to examine the effect of combining YHO-1701 administration with PD-1/PD-L1 blockade. Pretreatment of the mice with YHO-1701 before starting anti-PD-1 antibody administration resulted in a significant therapeutic effect. In addition, the effect of monotherapy and combination treatment with YHO-1701 was significantly abolished by depleting natural killer (NK) cell activity. YHO-1701 was also found to restore the activity of mouse NK cells under inhibitory conditions in vitro. Furthermore, this combination therapy significantly inhibited tumor growth in an immunotherapy-resistant model of murine CMS5a fibrosarcoma. These results suggest that the combination of YHO-1701 with PD-1/PD-L1 blockade might be a new candidate for cancer immunotherapy involving the enhancement of NK cell activity in the tumor microenvironment.
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Anticuerpos , Fibrosarcoma , Células Asesinas Naturales , Receptor de Muerte Celular Programada 1 , Quinolinas , Animales , Ratones , Ratones Endogámicos BALB C , Fibrosarcoma/tratamiento farmacológico , Células Asesinas Naturales/efectos de los fármacos , Factor de Transcripción STAT3/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Quinolinas/administración & dosificación , Anticuerpos/administración & dosificación , Trasplante IsogénicoRESUMEN
Dysregulated activation of the complement system is implicated in the onset or progression of several diseases. Most clinical-stage complement inhibitors target the inactive complement proteins present at high concentrations in plasma, which increases target-mediated drug disposition and necessitates high drug levels to sustain therapeutic inhibition. Furthermore, many efforts are aimed at inhibiting only terminal pathway activity, which leaves opsonin-mediated effector functions intact. We describe the discovery of SAR443809, a specific inhibitor of the alternative pathway C3/C5 convertase (C3bBb). SAR443809 selectively binds to the activated form of factor B (factor Bb) and inhibits alternative pathway activity by blocking the cleavage of C3, leaving the initiation of classical and lectin complement pathways unaffected. Ex vivo experiments with patient-derived paroxysmal nocturnal hemoglobinuria erythrocytes show that, although terminal pathway inhibition via C5 blockade can effectively inhibit hemolysis, proximal complement inhibition with SAR443809 inhibits both hemolysis and C3b deposition, abrogating the propensity for extravascular hemolysis. Finally, intravenous and subcutaneous administration of the antibody in nonhuman primates demonstrated sustained inhibition of complement activity for several weeks after injection. Overall, SAR443809 shows strong potential for treatment of alternative pathway-mediated disorders.
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Factor B del Complemento , Vía Alternativa del Complemento , Animales , Factor B del Complemento/antagonistas & inhibidores , Eritrocitos/efectos de los fármacos , Hemólisis/efectos de los fármacos , Convertasas de Complemento C3-C5/antagonistas & inhibidores , Vía Alternativa del Complemento/efectos de los fármacos , Enfermedades del Sistema Inmune/tratamiento farmacológico , Enfermedades del Sistema Inmune/enzimología , Humanos , Macaca fascicularis , Anticuerpos/administración & dosificación , Proteolisis/efectos de los fármacosRESUMEN
An imbalance between bone resorption and bone formation underlies the devastating osteolytic lesions and subsequent fractures seen in more than 90% of multiple myeloma (MM) patients. Currently, Wnt-targeted therapeutic agents that prevent soluble antagonists of the Wnt signaling pathway, sclerostin (SOST) and dickkopf-1 (DKK1), have been shown to prevent bone loss and improve bone strength in preclinical models of MM. In this study, we show increasing Wnt signaling via a novel anti-low-density lipoprotein receptor-related protein 6 (LRP6) antibody, which potentiates Wnt1-class ligand signaling through binding the Wnt receptor LRP6, prevented the development of myeloma-induced bone loss primarily through preventing bone resorption. When combined with an agent targeting the soluble Wnt antagonist DKK1, we showed more robust improvements in bone structure than anti-LRP6 treatment alone. Micro-computed tomography (µCT) analysis demonstrated substantial increases in trabecular bone volume in naïve mice given the anti-LRP6/DKK1 combination treatment strategy compared to control agents. Mice injected with 5TGM1eGFP murine myeloma cells had significant reductions in trabecular bone volume compared to naïve controls. The anti-LRP6/DKK1 combination strategy significantly improved bone volume in 5TGM1-bearing mice by 111%, which was also superior to anti-LRP6 single treatment; with similar bone structural changes observed within L4 lumbar vertebrae. Consequently, this combination strategy significantly improved resistance to fracture in lumbar vertebrae in 5TGM1-bearing mice compared to their controls, providing greater protection against fracture compared to anti-LRP6 antibody alone. Interestingly, these improvements in bone volume were primarily due to reduced bone resorption, with significant reductions in osteoclast numbers and osteoclast surface per bone surface demonstrated in 5TGM1-bearing mice treated with the anti-LRP6/DKK1 combination strategy. Importantly, Wnt stimulation with either single or combined Wnt-targeted agents did not exacerbate tumor activity. This work provides a novel approach of targeting both membrane-bound and soluble Wnt pathway components to provide superior skeletal outcomes in patients with multiple myeloma and other bone destructive cancers. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Péptidos y Proteínas de Señalización Intercelular , Proteína-6 Relacionada a Receptor de Lipoproteína de Baja Densidad , Mieloma Múltiple , Osteólisis , Animales , Ratones , Ratones Endogámicos C57BL , Anticuerpos/administración & dosificación , Proteína-6 Relacionada a Receptor de Lipoproteína de Baja Densidad/antagonistas & inhibidores , Huesos/efectos de los fármacos , Mieloma Múltiple/complicaciones , Mieloma Múltiple/tratamiento farmacológico , Vía de Señalización Wnt/efectos de los fármacos , Osteólisis/tratamiento farmacológico , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Femenino , Línea Celular TumoralRESUMEN
We studied the effects of chronic intranasal administration of amyloidogenic fibrils of the proinflammatory protein S100A9 alone or in combination with glutamate antibodies on the expression of the neuregulin-1 gene (NRG1), a regulator of various physiological processes, in particular, regulation of neurogenesis and apoptosis, in the hippocampus, prefrontal cortex, and cerebellum of aging C57BL/6 mice under conditions of long-term memory disturbances. Under conditions of amnesia induced by S100A9 fibrils, pronounced (>90%) blockade of the expression of the NRG1 gene was found in all cerebral structures. Glutamate antibodies prevented/corrected disturbances in the cerebral expression of the NRG1 gene, thereby maintaining the activity of the NRG1/ErbB molecular signaling system, probably associated with the formation of spatial memory.
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Cerebro , Trastornos de la Memoria , Neurregulina-1 , Memoria Espacial , Animales , Ratones , Ácido Glutámico/inmunología , Ácido Glutámico/metabolismo , Ratones Endogámicos C57BL , Neurregulina-1/genética , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/metabolismo , Envejecimiento , Proteínas Amiloidogénicas/farmacología , Calgranulina B/farmacología , Anticuerpos/administración & dosificación , Receptores ErbB/metabolismoRESUMEN
Decreased platelet count represents a feature of acute liver failure (ALF) pathogenesis. Platelets are the reservoir of transforming growth factor 1 (TGF-ß1), a multipotent cytokine involved in the maintenance of, i.a., central nervous system homeostasis. Here, we analyzed the effect of a decrease in TGF-ß1 active form on synaptic proteins levels, and brain electrophysiology, in mice after intraperitoneal (ip) administration of TGF-ß1 antibody (anti-TGF-ß1; 1 mg/mL). Next, we correlated it with a thrombocytopenia-induced TGF-ß1 decrease, documented in an azoxymethane-induced (AOM; 100 mM ip) model of ALF, and clarified the impact of TGF-ß1 decrease on blood-brain barrier functionality. The increase of both synaptophysin and synaptotagmin in the cytosolic fraction, and its reduction in a membrane fraction, were confirmed in the AOM mice brains. Both proteins' decrease in analyzed fractions occurred in anti-TGF-ß1 mice. In turn, an increase in postsynaptic (NR1 subunit of N-methyl-D-aspartate receptor, postsynaptic density protein 95, gephyrin) proteins in the AOM brain cortex, but a selective compensatory increase of NR1 subunit in anti-TGF-ß mice, was observed. The alterations of synaptic proteins levels were not translated on electrophysiological parameters in the anti-TGF-ß1 model. The results suggest the impairment of synaptic vesicles docking to the postsynaptic membrane in the AOM model. Nevertheless, changes in synaptic protein level in the anti-TGF-ß1 mice do not affect neurotransmission and may not contribute to neurologic deficits in AOM mice.
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Azoximetano/efectos adversos , Encéfalo/fisiopatología , Encefalopatía Hepática/fisiopatología , Fallo Hepático Agudo/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Animales , Anticuerpos/administración & dosificación , Anticuerpos/farmacología , Barrera Hematoencefálica/metabolismo , Línea Celular , Modelos Animales de Enfermedad , Regulación hacia Abajo , Fenómenos Electrofisiológicos , Encefalopatía Hepática/inducido químicamente , Encefalopatía Hepática/metabolismo , Inyecciones Intraperitoneales , Fallo Hepático Agudo/inducido químicamente , Fallo Hepático Agudo/fisiopatología , Masculino , Ratones , Ratas , Sinaptofisina/metabolismo , Sinaptotagminas/metabolismoRESUMEN
Traumatic brain injury (TBI) is an important cause of death in young adults and children. Till now, the treatment of TBI in the short- and long-term complications is still a challenge. Our previous evidence implied aquaporin 4 (AQP4) and hypoxia inducible factor-1α (HIF-1α) might be potential targets for TBI. In this study, we explored the roles of AQP4 and HIF-1α on brain edema formation, neuronal damage and neurological functional deficits after TBI using the controlled cortical injury (CCI) model. The adult male Sprague Dawley rats were randomly divided into sham and TBI group, the latter group was further divided into neutralized-AQP4 antibody group, 2-methoxyestradiol (2-ME2) group, and their corresponding control, IgG and isotonic saline groups, respectively. Brain edema was examined by water content. Hippocampal neuronal injury was assessed by neuron loss and neuronal skeleton related protein expressions. Spatial learning and memory deficits were evaluated by Morris water maze test and memory-related proteins were detected by western blot. Our data showed that increased AQP4 protein level was closely correlated with severity of brain edema after TBI. Compared with that in the control group, both blockage of AQP4 with neutralized-AQP4 antibody and inhibition of HIF-1α with 2-ME2 for one-time treatment within 30-60 min post TBI significantly ameliorated brain edema on the 1st day post-TBI, and markedly alleviated hippocampal neuron loss and spatial learning and memory deficits on the 21st day post-TBI. In summary, our preliminary study revealed the short-term and long-term benefits of targeting HIF-1α-AQP4 axis after TBI, which may provide new clues for the selection of potential therapeutic targets for TBI in clinical practice.
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Acuaporina 4/antagonistas & inhibidores , Edema Encefálico/tratamiento farmacológico , Edema Encefálico/metabolismo , Corteza Cerebral/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Neuronas/metabolismo , 2-Metoxiestradiol/administración & dosificación , Animales , Anticuerpos/administración & dosificación , Acuaporina 4/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Edema Encefálico/etiología , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/metabolismo , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/lesiones , Trastornos de Conversión/tratamiento farmacológico , Trastornos de Conversión/etiología , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Inyecciones Intravenosas , Aprendizaje/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/etiología , Neuronas/efectos de los fármacos , Ratas Sprague-DawleyRESUMEN
We previously demonstrated that lifelong antibiotic (ABX) perturbations of the gut microbiome in male APPPS1-21 mice lead to reductions in amyloid ß (Aß) plaque pathology and altered phenotypes of plaque-associated microglia. Here, we show that a short, 7-d treatment of preweaned male mice with high-dose ABX is associated with reductions of Aß amyloidosis, plaque-localized microglia morphologies, and Aß-associated degenerative changes at 9 wk of age in male mice only. More importantly, fecal microbiota transplantation (FMT) from transgenic (Tg) or WT male donors into ABX-treated male mice completely restored Aß amyloidosis, plaque-localized microglia morphologies, and Aß-associated degenerative changes. Transcriptomic studies revealed significant differences between vehicle versus ABX-treated male mice and FMT from Tg mice into ABX-treated mice largely restored the transcriptome profiles to that of the Tg donor animals. Finally, colony-stimulating factor 1 receptor (CSF1R) inhibitor-mediated depletion of microglia in ABX-treated male mice failed to reduce cerebral Aß amyloidosis. Thus, microglia play a critical role in driving gut microbiome-mediated alterations of cerebral Aß deposition.
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Péptidos beta-Amiloides/metabolismo , Amiloidosis/metabolismo , Encéfalo/metabolismo , Microbioma Gastrointestinal/fisiología , Microglía/metabolismo , Amiloidosis/genética , Animales , Anticuerpos/administración & dosificación , Encéfalo/efectos de los fármacos , Quimiocinas/sangre , Quimiocinas/genética , Quimiocinas/metabolismo , Citocinas/sangre , Citocinas/genética , Citocinas/metabolismo , Trasplante de Microbiota Fecal , Heces/microbiología , Femenino , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/genética , Perfilación de la Expresión Génica/métodos , Ontología de Genes , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , RNA-Seq/métodos , Factores SexualesAsunto(s)
Enzima Convertidora de Angiotensina 2/inmunología , Anticuerpos/uso terapéutico , COVID-19/terapia , Inmunoterapia/métodos , Células Madre Mesenquimatosas , Animales , Anticuerpos/administración & dosificación , COVID-19/inmunología , COVID-19/prevención & control , COVID-19/virología , Citocinas/metabolismo , Humanos , Células Madre Mesenquimatosas/inmunología , SARS-CoV-2RESUMEN
Cholangiocarcinoma (CC), the most lethal type of liver cancer, remains very difficult to treat due to an incomplete understanding of the cancer initiation and progression mechanisms and no effective therapeutic drugs. Thus, identification of genomic drivers and delineation of the underlying mechanisms are urgently needed. Here, we conducted a genome-wide CRISPR-Cas9 screening in liver-specific Smad4/Pten knockout mice (Smad4co/co;Ptenco/co;Alb-Cre, abbreviated as SPC), and identified 15 putative tumor suppressor genes, including Cullin3 (Cul3), whose deficiency increases protein levels of Nrf2 and Cyclin D1 that accelerate cholangiocytes expansion leading to the initiation of CC. Meanwhile, Cul3 deficiency also increases the secretion of Cxcl9 in stromal cells to attract T cells infiltration, and increases the production of Amphiregulin (Areg) mediated by Nrf2, which paracrinely induces inflammation in the liver, and promotes accumulation of exhausted PD1high CD8 T cells at the expenses of their cytotoxic activity, allowing CC progression. We demonstrate that the anti-PD1/PD-L1 blockade inhibits CC growth, and the effect is enhanced by combining with sorafenib selected from organoid mediated drug sensitive test. This model makes it possible to further identify more liver cancer suppressors, study molecular mechanisms, and develop effective therapeutic strategies.
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Anticuerpos/uso terapéutico , Colangiocarcinoma/patología , Proteínas Cullin/metabolismo , Neoplasias Hepáticas/patología , Sorafenib/uso terapéutico , Microambiente Tumoral , Animales , Anticuerpos/administración & dosificación , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Linfocitos T CD8-positivos , Sistemas CRISPR-Cas , Proteínas Cullin/genética , Regulación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Hígado/metabolismo , Ratones , Mutación , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/metabolismo , Proteína Smad4/genética , Proteína Smad4/metabolismo , Sorafenib/administración & dosificaciónRESUMEN
Immune checkpoint blockade antibodies have promising clinical applications but suffer from disadvantages such as severe toxicities and moderate patient-response rates. None of the current delivery strategies, including local administration aiming to avoid systemic toxicities, can sustainably supply drugs over the course of weeks; adjustment of drug dose, either to lower systemic toxicities or to augment therapeutic response, is not possible. Herein, we develop an implantable miniaturized device using electrode-embedded optical fibers with both local delivery and measurement capabilities over the course of a few weeks. The combination of local immune checkpoint blockade antibodies delivery via this device with photodynamic therapy elicits a sustained anti-tumor immunity in multiple tumor models. Our device uses tumor impedance measurement for timely presentation of treatment outcomes, and allows modifications to the delivered drugs and their concentrations, rendering this device potentially useful for on-demand delivery of potent immunotherapeutics without exacerbating toxicities.
Asunto(s)
Anticuerpos/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Inmunoterapia/métodos , Neoplasias/química , Neoplasias/tratamiento farmacológico , Animales , Terapia Combinada , Sistemas de Liberación de Medicamentos/instrumentación , Impedancia Eléctrica , Femenino , Humanos , Inmunoterapia/instrumentación , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Fibras Ópticas , Fotoquimioterapia , Prótesis e ImplantesRESUMEN
The dogma of engineering oncolytic viral vectors has shifted from emphasizing the viral lysis of individual cancer cells to the recruitment and coordination of the adaptive immune system to clear the tumor. To accomplish this, researchers have been adding several classes of transgenes to their preferred viral platforms. The most prevalent of these include antibodies and targeting moieties, interleukins and cytokines, and genes which rely on small molecule co-administration for tumor killing. Most current vectors rely exclusively on one of these types of transgenes to elicit the desired immune response to clear tumors, but are not mutually exclusive, with several larger OVs armed with several of these factors. The common theme of emerging armed vectors is to simply initiate or enhance infiltration of effector CD8+ T cells to clear the tumor locally at OV infection sites, and systemically throughout the body where the OV has not infected tumor cells. The precision of oncolytic vectors to target a cell type or tissue remains its key advantage over small-molecule drugs. Unlike chemo- and other drug therapies, viral vectors can be made to specifically infect and grow within tumor cells. This ensures localized expression of the therapeutic transgene to the diseased tissue, thereby limiting systemic toxicity. This review will examine the immunomodulating transgenes of current OVs, describe their general effect on the immune system, and provide the rationale for each vector's use in clearing its targeted tumor.
Asunto(s)
Vectores Genéticos , Inmunomodulación , Neoplasias/terapia , Viroterapia Oncolítica , Animales , Anticuerpos/administración & dosificación , Citocinas/metabolismo , Humanos , TransgenesRESUMEN
The economic burden of tumors is increasing, so there is an urgent need to develop new therapies for their treatment. Killing tumors by activating complement is an effective strategy for the treatment. We used the ABO blood group system and the corresponding antibodies to activate the killer cell capacity of the complement system. After the construction of a mouse model containing blood group A antibodies and inoculating colorectal cancer and breast cancer cells into the axillae of the mice, intratumoural injection using a lentivirus carrying a blood group antigen as a drug significantly reduced the tumor volume of the mice. Compared with the control group, the content of the C5b-9 complement membrane attack complex in the tumors of mice treated with the blood group A antigen was significantly increased, and the proportion of NK cells was also significantly increased. In vitro cell-based experiments proved that tumor cells expressing blood group A antigens showed significantly inhibited cell proliferation when added to serum containing blood group A antibodies. These results all prove that the ABO blood group antigen may become a powerful tool for the treatment of tumors in patients.
Asunto(s)
Sistema del Grupo Sanguíneo ABO/inmunología , Anticuerpos/administración & dosificación , Neoplasias de la Mama/terapia , Neoplasias Colorrectales/terapia , Activación de Complemento/inmunología , Proteínas del Sistema Complemento/inmunología , Células Asesinas Naturales/inmunología , Animales , Apoptosis , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Proliferación Celular , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Pleural sepsis stems from an infection within the pleural space typically from an underlying bacterial pneumonia leading to development of a parapneumonic effusion. This effusion is traditionally divided into uncomplicated, complicated, and empyema. Poor clinical outcomes and increased mortality can be associated with the development of parapneumonic effusions, reinforcing the importance of early recognition and diagnosis. Management necessitates a multimodal therapeutic strategy consisting of antimicrobials, catheter/tube thoracostomy, and at times, video-assisted thoracoscopic surgery.
Asunto(s)
Diagnóstico Precoz , Pleura , Enfermedades Pleurales/diagnóstico , Enfermedades Pleurales/terapia , Sepsis/diagnóstico , Sepsis/terapia , Anticuerpos/administración & dosificación , Terapia Combinada , Empiema Pleural/diagnóstico , Empiema Pleural/etiología , Empiema Pleural/terapia , Humanos , Enfermedades Pleurales/etiología , Derrame Pleural/diagnóstico , Derrame Pleural/etiología , Derrame Pleural/terapia , Neumonía Bacteriana/complicaciones , Neumonía Bacteriana/diagnóstico , Neumonía Bacteriana/terapia , Sepsis/etiología , Cirugía Torácica Asistida por Video , Toracostomía/métodosRESUMEN
Due to their high specificity, monoclonal antibodies have been widely investigated for their application in drug delivery to the central nervous system (CNS) for the treatment of neurological diseases such as stroke, Alzheimer's, and Parkinson's disease. Research in the past few decades has revealed that one of the biggest challenges in the development of antibodies for drug delivery to the CNS is the presence of blood-brain barrier (BBB), which acts to restrict drug delivery and contributes to the limited uptake (0.1-0.2% of injected dose) of circulating antibodies into the brain. This article reviews the various methods currently used for antibody delivery to the CNS at the preclinical stage of development and the underlying mechanisms of BBB penetration. It also describes efforts to improve or modulate the physicochemical and biochemical properties of antibodies (e.g., charge, Fc receptor binding affinity, and target affinity), to adapt their pharmacokinetics (PK), and to influence their distribution and disposition into the brain. Finally, a distinction is made between approaches that seek to modify BBB permeability and those that use a physiological approach or antibody engineering to increase uptake in the CNS. Although there are currently inherent difficulties in developing safe and efficacious antibodies that will cross the BBB, the future prospects of brain-targeted delivery of antibody-based agents are believed to be excellent.