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1.
MAbs ; 13(1): 1860476, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33459118

RESUMEN

In this 12th annual installment of the Antibodies to Watch article series, we discuss key events in antibody therapeutics development that occurred in 2020 and forecast events that might occur in 2021. The coronavirus disease 2019 (COVID-19) pandemic posed an array of challenges and opportunities to the healthcare system in 2020, and it will continue to do so in 2021. Remarkably, by late November 2020, two anti-SARS-CoV antibody products, bamlanivimab and the casirivimab and imdevimab cocktail, were authorized for emergency use by the US Food and Drug Administration (FDA) and the repurposed antibodies levilimab and itolizumab had been registered for emergency use as treatments for COVID-19 in Russia and India, respectively. Despite the pandemic, 10 antibody therapeutics had been granted the first approval in the US or EU in 2020, as of November, and 2 more (tanezumab and margetuximab) may be granted approvals in December 2020.* In addition, prolgolimab and olokizumab had been granted first approvals in Russia and cetuximab saratolacan sodium was first approved in Japan. The number of approvals in 2021 may set a record, as marketing applications for 16 investigational antibody therapeutics are already undergoing regulatory review by either the FDA or the European Medicines Agency. Of these 16 mAbs, 11 are possible treatments for non-cancer indications and 5 are potential treatments for cancer. Based on the information publicly available as of November 2020, 44 antibody therapeutics are in late-stage clinical studies for non-cancer indications, including 6 for COVID-19, and marketing applications for at least 6 (leronlimab, tezepelumab, faricimab, ligelizumab, garetosmab, and fasinumab) are planned in 2021. In addition, 44 antibody therapeutics are in late-stage clinical studies for cancer indications. Of these 44, marketing application submissions for 13 may be submitted by the end of 2021. *Note added in proof on key events announced during December 1-21, 2020: margetuximab-cmkb and ansuvimab-zykl were approved by FDA on December 16 and 21, 2020, respectively; biologics license applications were submitted for ublituximab and amivantamab.


Asunto(s)
Anticuerpos/uso terapéutico , Antivirales/uso terapéutico , Desarrollo de Medicamentos/tendencias , Descubrimiento de Drogas/tendencias , Reposicionamiento de Medicamentos/tendencias , /efectos de los fármacos , Animales , Anticuerpos/efectos adversos , Antivirales/efectos adversos , /virología , Difusión de Innovaciones , Aprobación de Drogas , Predicción , Interacciones Huésped-Patógeno , Humanos , /inmunología
2.
Nature ; 589(7843): 630-632, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33500572

Asunto(s)
Anticuerpos/uso terapéutico , Biología Celular , Biología Evolutiva , Nariz Electrónica , Espectrometría de Masas/instrumentación , Neurociencias , Animales , Anticuerpos/química , Anticuerpos/genética , Anticuerpos/inmunología , Proteínas Bacterianas/efectos de los fármacos , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/efectos de la radiación , Bioimpresión/tendencias , /inmunología , /química , /provisión & distribución , Biología Celular/instrumentación , Biología Celular/tendencias , Biología Evolutiva/métodos , Biología Evolutiva/tendencias , Embrión de Mamíferos/citología , Embrión de Mamíferos/embriología , Embrión de Mamíferos/metabolismo , Desarrollo Embrionario/genética , Holografía/tendencias , Humanos , Inmunoglobulina E/química , Inmunoglobulina E/genética , Inmunoglobulina E/inmunología , Inmunoglobulina E/uso terapéutico , Canales Iónicos/metabolismo , Espectrometría de Masas/métodos , Proteínas de la Membrana/efectos de los fármacos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/efectos de la radiación , Ratones , Microscopía/instrumentación , Microscopía/tendencias , Sondas Moleculares/análisis , Neoplasias/tratamiento farmacológico , Neurociencias/métodos , Neurociencias/tendencias , Optogenética/tendencias , Análisis de la Célula Individual , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción
3.
Cells ; 9(12)2020 12 10.
Artículo en Inglés | MEDLINE | ID: mdl-33322031

RESUMEN

Myostatin inhibition therapy has held much promise for the treatment of muscle wasting disorders. This is particularly true for the fatal myopathy, Duchenne Muscular Dystrophy (DMD). Following on from promising pre-clinical data in dystrophin-deficient mice and dogs, several clinical trials were initiated in DMD patients using different modality myostatin inhibition therapies. All failed to show modification of disease course as dictated by the primary and secondary outcome measures selected: the myostatin inhibition story, thus far, is a failed clinical story. These trials have recently been extensively reviewed and reasons why pre-clinical data collected in animal models have failed to translate into clinical benefit to patients have been purported. However, the biological mechanisms underlying translational failure need to be examined to ensure future myostatin inhibitor development endeavors do not meet with the same fate. Here, we explore the biology which could explain the failed translation of myostatin inhibitors in the treatment of DMD.


Asunto(s)
Anticuerpos/uso terapéutico , Distrofia Muscular de Duchenne/tratamiento farmacológico , Miostatina/antagonistas & inhibidores , Animales , Anticuerpos/farmacología , Ensayos Clínicos como Asunto , Humanos , Ratones , Músculo Esquelético/efectos de los fármacos , Distrofia Muscular de Duchenne/genética , Insuficiencia del Tratamiento
4.
Eur Cytokine Netw ; 31(3): 81-93, 2020 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-33361013

RESUMEN

Coronavirus disease (COVID-19) reached pandemic proportions at the beginning of 2020 and continues to be a worldwide concern. End organ damage and acute respiratory distress syndrome are the leading causes of death in severely or critically ill patients. The elevated cytokine levels in severe patients in comparison with mildly affected patients suggest that cytokine release syndrome (CRS) occurs in the severe form of the disease. In this paper, the significant role of pro-inflammatory cytokines, including IL-1, IL-6, and TNF-alpha, and their mechanism of action in the CRS cascade is explained. Potential therapeutic approaches involving anti-IL-6 and anti-TNF-alpha antibodies to fight COVID-19 and reduce mortality rate in severe cases are also discussed.


Asunto(s)
Anticuerpos/uso terapéutico , Síndrome de Liberación de Citoquinas , Interleucina-6/antagonistas & inhibidores , Pandemias , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , /sangre , /tratamiento farmacológico , Síndrome de Liberación de Citoquinas/sangre , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/mortalidad , Humanos , Interleucina-6/sangre , Factor de Necrosis Tumoral alfa/sangre
5.
Nat Commun ; 11(1): 5667, 2020 11 09.
Artículo en Inglés | MEDLINE | ID: mdl-33168818

RESUMEN

Poor tissue penetration remains a major challenge for antibody-based therapeutics of solid tumors, but proper dosing can improve the tissue penetration and thus therapeutic efficacy of these biologics. Due to dose-limiting toxicity of the small molecule payload, antibody-drug conjugates (ADCs) are administered at a much lower dose than their parent antibodies, which further reduces tissue penetration. We conducted an early-phase clinical trial (NCT02415881) and previously reported the safety of an antibody-dye conjugate (panitumumab-IRDye800CW) as primary outcome. Here, we report a retrospective exploratory analysis of the trial to evaluate whether co-administration of an unconjugated antibody could improve the intratumoral distribution of the antibody-dye conjugate in patients. By measuring the multiscale distribution of the antibody-dye conjugate, this study demonstrates improved microscopic antibody distribution without increasing uptake (toxicity) in healthy tissue when co-administered with the parent antibody, supporting further clinical investigation of the co-administration dosing strategy to improve the tumor penetration of ADCs.


Asunto(s)
Anticuerpos/administración & dosificación , Anticuerpos/uso terapéutico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Inmunoconjugados/administración & dosificación , Inmunoconjugados/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Femenino , Neoplasias de Cabeza y Cuello/patología , Humanos , Indoles/administración & dosificación , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados no Aleatorios como Asunto , Panitumumab/administración & dosificación , Estudios Prospectivos , Estudios Retrospectivos
6.
Nat Commun ; 11(1): 4981, 2020 10 05.
Artículo en Inglés | MEDLINE | ID: mdl-33020469

RESUMEN

Antagonism or agonism of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) prevents weight gain and leads to dramatic weight loss in combination with glucagon-like peptide-1 receptor agonists in preclinical models. Based on the genetic evidence supporting GIPR antagonism, we previously developed a mouse anti-murine GIPR antibody (muGIPR-Ab) that protected diet-induced obese (DIO) mice against body weight gain and improved multiple metabolic parameters. This work reconciles the similar preclinical body weight effects of GIPR antagonists and agonists in vivo, and here we show that chronic GIPR agonism desensitizes GIPR activity in primary adipocytes, both differentiated in vitro and adipose tissue in vivo, and functions like a GIPR antagonist. Additionally, GIPR activity in adipocytes is partially responsible for muGIPR-Ab to prevent weight gain in DIO mice, demonstrating a role of adipocyte GIPR in the regulation of adiposity in vivo.


Asunto(s)
Adipocitos/efectos de los fármacos , Fármacos Antiobesidad/farmacología , Receptores de la Hormona Gastrointestinal/agonistas , Receptores de la Hormona Gastrointestinal/antagonistas & inhibidores , Adipocitos/metabolismo , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Fármacos Antiobesidad/química , Fármacos Antiobesidad/uso terapéutico , Anticuerpos/farmacología , Anticuerpos/uso terapéutico , Peso Corporal/efectos de los fármacos , Membrana Celular/metabolismo , Células Cultivadas , AMP Cíclico/metabolismo , Dieta Alta en Grasa/efectos adversos , Ácidos Grasos/metabolismo , Polipéptido Inhibidor Gástrico/farmacología , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Obesidad/patología , Receptores de la Hormona Gastrointestinal/deficiencia , Receptores de la Hormona Gastrointestinal/metabolismo
7.
Intern Med ; 59(19): 2343-2351, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32999263

RESUMEN

Objective Anti-tumor necrosis factor (TNF)-α antibody-based regimens are effective in Behçet's disease (BD) with intestinal lesions. We therefore evaluated the efficacy of medium- to long-term anti-TNF-α antibody-based maintenance therapy of BD intestinal and non-intestinal lesions. Methods In this retrospective study, the response to the treatment was assessed endoscopically and clinically. Treatment responders were transferred to maintenance therapy. We evaluated the sustain rate of maintenance therapy, reductions in the dose of prednisolone (PSL), and the presence of non-intestinal BD involvement before and after the start of anti-TNF-α antibody-based the maintenance therapy. Patients We assessed 20 BD patients with intestinal lesions who underwent anti-TNF-α antibody-based therapy. Results Treatment was discontinued in 3 patients (18%). Loss of response was noted in 1 (5.9%) patient. Maintenance therapy was continued in 13 (76%) patients. The cumulative sustain rates to maintenance therapy after 2, 4, and 6 years were 94%, 87%, and 72%, respectively. In the 13 patients with remission of intestinal lesions, the mean PSL dose decreased from 13.4±2.16 mg/day before treatment to 0.92±0.47 after treatment (p<0.0001). PSL was discontinued in 9 (69%) patients. Five of the 13 (38%) patients developed clinical features of non-intestinal BD during the remission-maintenance treatment. Conclusion Our results demonstrated the efficacy of medium- to long-term anti-TNF-α antibody-based maintenance treatment against BD intestinal lesions. Nevertheless, some cases with well-controlled intestinal lesions developed active non-intestinal BD symptoms. The results highlight the importance of a carefully planned treatment strategy for BD patients with intestinal involvement.


Asunto(s)
Síndrome de Behçet/terapia , Factor de Necrosis Tumoral alfa/uso terapéutico , Adulto , Anticuerpos/uso terapéutico , Femenino , Humanos , Inmunoterapia , Intestinos/patología , Masculino , Persona de Mediana Edad , Prednisolona/uso terapéutico , Estudios Retrospectivos
8.
Nat Commun ; 11(1): 5066, 2020 10 08.
Artículo en Inglés | MEDLINE | ID: mdl-33033255

RESUMEN

The inducible co-stimulator (ICOS) is a member of the CD28/B7 superfamily, and delivers a positive co-stimulatory signal to activated T cells upon binding to its ligand (ICOS-L). Dysregulation of this pathway has been implicated in autoimmune diseases and cancer, and is currently under clinical investigation as an immune checkpoint blockade. Here, we describe the molecular interactions of the ICOS/ICOS-L immune complex at 3.3 Å resolution. A central FDPPPF motif and residues within the CC' loop of ICOS are responsible for the specificity of the interaction with ICOS-L, with a distinct receptor binding orientation in comparison to other family members. Furthermore, our structure and binding data reveal that the ICOS N110 N-linked glycan participates in ICOS-L binding. In addition, we report crystal structures of ICOS and ICOS-L in complex with monoclonal antibodies under clinical evaluation in immunotherapy. Strikingly, antibody paratopes closely mimic receptor-ligand binding core interactions, in addition to contacting peripheral residues to confer high binding affinities. Our results uncover key molecular interactions of an immune complex central to human adaptive immunity and have direct implications for the ongoing development of therapeutic interventions targeting immune checkpoint receptors.


Asunto(s)
Anticuerpos/uso terapéutico , Complejo Antígeno-Anticuerpo/química , Ligando Coestimulador de Linfocitos T Inducibles/química , Proteína Coestimuladora de Linfocitos T Inducibles/química , Imitación Molecular/inmunología , Secuencia de Aminoácidos , Complejo Antígeno-Anticuerpo/metabolismo , Antígenos CD28/metabolismo , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Ligando Coestimulador de Linfocitos T Inducibles/metabolismo , Proteína Coestimuladora de Linfocitos T Inducibles/metabolismo , Cinética , Ligandos , Modelos Moleculares , Unión Proteica , Multimerización de Proteína
10.
Rinsho Ketsueki ; 61(8): 912-921, 2020.
Artículo en Japonés | MEDLINE | ID: mdl-32908055

RESUMEN

Although multiple myeloma has been defined as incurable, and the treatment outcome has recently improved rapidly. Antibodies against multiple myeloma, elotuzumab, and daratumumab can safely enhance their effects even when added to the combination therapy of proteasome inhibitors and immunomodulators that have been used till date. Initially, triplet therapy combining antibody therapy with doublet therapy was approved in Japan for relapsed or refractory multiple myeloma. In 2019, daratumumab combination therapies were approved for newly diagnosed multiple myeloma patients, and these therapies are the new standard of care. Recently, the results of clinical trials that added daratumumab to the triplet therapies of proteasome inhibitors, immunomodulators, and dexamethasone have been reported. These trials report greater therapeutic effects, with a significant improvement in the MRD negative rate. We hope that quadruplet therapy including these antibodies will be available in clinical practice, leading to further improvements in the treatment outcomes.


Asunto(s)
Anticuerpos/uso terapéutico , Mieloma Múltiple , Humanos , Factores Inmunológicos , Japón , Mieloma Múltiple/tratamiento farmacológico , Inhibidores de Proteasoma , Radioinmunoterapia
11.
Rinsho Ketsueki ; 61(8): 922-928, 2020.
Artículo en Japonés | MEDLINE | ID: mdl-32908056

RESUMEN

In 2018, two novel antibody therapies, inotuzumab ozogamicin (InO) and blinatumomab, against relapsed or refractory acute lymphoblastic leukemia were approved in Japan. In InO, the antitumor drug ozogamicin is conjugated to the anti-CD22 antibody. Blinatumomab is a bispecific T cell engager antibody comprising the variable regions of the anti-CD19 and the anti-CD3 antibodies. The remission rate of InO is about 75%; however, the frequency of sinusoidal obstruction syndrome is increased when allogeneic hematopoietic cell transplantation is performed after InO treatment. Blinatumomab has a remission rate of 45-70%. The management of cytokine release syndrome during blinatumomab treatment is required in certain cases. Although both the treatments have higher remission and negativity of minimal residual disease rates compared to those in conventional chemotherapy, it is difficult to maintain remission in the long term. Allogeneic hematopoietic stem cell transplantation should be performed as commonly as possible.


Asunto(s)
Anticuerpos/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras , Antineoplásicos , Humanos , Inotuzumab Ozogamicina , Japón , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Inducción de Remisión
12.
Rinsho Ketsueki ; 61(8): 929-936, 2020.
Artículo en Japonés | MEDLINE | ID: mdl-32908057

RESUMEN

Treatment with eculizumab (Soliris®), a humanized anti-C5 monoclonal antibody improves the quality of life of patients with paroxysmal nocturnal hemoglobinuria (PNH), remarkably reduces hemolysis, improves symptoms associated with hemolysis, and prevents thrombosis. Because eculizumab therapy is not a curative treatment, it is necessary to continue infusion every two weeks, which has been an issue from the viewpoint of convenience. In recent years, an improved version of eculizumab, ravulizumab (Ultomiris®), which relies on the technology of recycling antibodies has been developed and can be administered every 8 weeks. Crovalimab (SKY59), which can be administered subcutaneously every four weeks, is also under development, and therefore, the convenience for patients with PNH is improving. However, many issues still persist, and several new anti-complement drugs are currently under development. Hopefully, a better drug will be developed by thorough examination of what drug is best for the patient by considering not only its efficacy and safety but also its convenience.


Asunto(s)
Anticuerpos/uso terapéutico , Hemoglobinuria Paroxística , Proteínas del Sistema Complemento , Hemoglobinuria Paroxística/tratamiento farmacológico , Hemólisis , Humanos , Calidad de Vida , Radioinmunoterapia
13.
PLoS One ; 15(8): e0237267, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32785291

RESUMEN

BACKGROUND: Knowledge regarding differences in care for psoriatic patients is limited. The aim of this study was to investigate factors influencing prescription of systemic treatments for patients with psoriasis with a special focus on socioeconomic factors. METHODS AND FINDINGS: This was a non-interventional, cross-sectional study, conducted in 18 Italian University and/or hospital centers with psoriasis-specialized units. Questionnaires evaluating demographic and socioeconomic characteristics were administered to participants. Overall, 1880 consecutive patients affected by mild-to-severe psoriasis were recruited. Univariate and multivariable logistic regression analyses of systemic therapy prescription, with a special focus on biologics, accounting for the above mentioned characteristics were performed. Our analysis showed that all analyzed patients' characteristics were significantly associated with biological therapy compared to non-biological systemic one. Particularly, women were less likely to receive biologics than men (OR = 0.66; 95% CI, 0.57-0.77). Elderly patients (≥65 years) and subjects with a BMI ≥30 had lower odds to receive biologics respect to adults (≥35-64 years) (OR = 0.33; 95% CI, 0.25-0.40), and subjects with BMI≥25<30 (OR = 0.64; 95% CI, 0.53-0.77), respectively. Northern and Southern patients were both less likely to receive biologics than Central patients (OR = 0.75; 95% CI, 0.63-0.89, and OR = 0.56; 95% CI,0.47-0.68, respectively). Lower economic profile and never reading books were both associated with decreased odds of receiving biological therapy. CONCLUSIONS: This study shows that sex, age, comorbidities, and socioeconomic characteristics influence the prescription of systemic treatments in psoriasis, highlighting that there are still unmet needs influencing the therapeutic decision-making process that have to be addressed.


Asunto(s)
Anticuerpos/uso terapéutico , Psoriasis/tratamiento farmacológico , Psoriasis/epidemiología , Adolescente , Adulto , Anciano , Estudios Transversales , Femenino , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Factores Socioeconómicos , Adulto Joven
14.
Science ; 369(6510): 1481-1489, 2020 09 18.
Artículo en Inglés | MEDLINE | ID: mdl-32792462

RESUMEN

Several species of intestinal bacteria have been associated with enhanced efficacy of checkpoint blockade immunotherapy, but the underlying mechanisms by which the microbiome enhances antitumor immunity are unclear. In this study, we isolated three bacterial species-Bifidobacterium pseudolongum, Lactobacillus johnsonii, and Olsenella species-that significantly enhanced efficacy of immune checkpoint inhibitors in four mouse models of cancer. We found that intestinal B. pseudolongum modulated enhanced immunotherapy response through production of the metabolite inosine. Decreased gut barrier function induced by immunotherapy increased systemic translocation of inosine and activated antitumor T cells. The effect of inosine was dependent on T cell expression of the adenosine A2A receptor and required costimulation. Collectively, our study identifies a previously unknown microbial metabolite immune pathway activated by immunotherapy that may be exploited to develop microbial-based adjuvant therapies.


Asunto(s)
Bifidobacterium/metabolismo , Microbioma Gastrointestinal , Inmunoterapia , Inosina/metabolismo , Neoplasias Intestinales/terapia , Lactobacillus johnsonii/metabolismo , Melanoma/terapia , Neoplasias Cutáneas/terapia , Neoplasias de la Vejiga Urinaria/terapia , Animales , Anticuerpos/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/inmunología , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Neoplasias Experimentales/terapia , Receptor de Adenosina A2A/metabolismo , Linfocitos T/inmunología
15.
Int J Mol Sci ; 21(13)2020 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-32630064

RESUMEN

Vimentin is an intermediate filament protein that plays key roles in integration of cytoskeletal functions, and therefore in basic cellular processes such as cell division and migration. Consequently, vimentin has complex implications in pathophysiology. Vimentin is required for a proper immune response, but it can also act as an autoantigen in autoimmune diseases or as a damage signal. Although vimentin is a predominantly cytoplasmic protein, it can also appear at extracellular locations, either in a secreted form or at the surface of numerous cell types, often in relation to cell activation, inflammation, injury or senescence. Cell surface targeting of vimentin appears to associate with the occurrence of certain posttranslational modifications, such as phosphorylation and/or oxidative damage. At the cell surface, vimentin can act as a receptor for bacterial and viral pathogens. Indeed, vimentin has been shown to play important roles in virus attachment and entry of severe acute respiratory syndrome-related coronavirus (SARS-CoV), dengue and encephalitis viruses, among others. Moreover, the presence of vimentin in specific virus-targeted cells and its induction by proinflammatory cytokines and tissue damage contribute to its implication in viral infection. Here, we recapitulate some of the pathophysiological implications of vimentin, including the involvement of cell surface vimentin in interaction with pathogens, with a special focus on its role as a cellular receptor or co-receptor for viruses. In addition, we provide a perspective on approaches to target vimentin, including antibodies or chemical agents that could modulate these interactions to potentially interfere with viral pathogenesis, which could be useful when multi-target antiviral strategies are needed.


Asunto(s)
Virus del SRAS/fisiología , Vimentina/metabolismo , Virosis/patología , Anticuerpos/inmunología , Anticuerpos/metabolismo , Anticuerpos/uso terapéutico , Betacoronavirus/aislamiento & purificación , Infecciones por Coronavirus/tratamiento farmacológico , Interacciones Huésped-Patógeno , Humanos , Pandemias , Neumonía Viral/tratamiento farmacológico , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Vimentina/química , Vimentina/inmunología , Virosis/tratamiento farmacológico , Virosis/metabolismo , Replicación Viral/efectos de los fármacos
16.
J Vis Exp ; (159)2020 05 22.
Artículo en Inglés | MEDLINE | ID: mdl-32510494

RESUMEN

One mechanism of action for clinical efficacy by therapeutic antibodies is the promotion of immune-related functions, such as cytokine secretion and cytotoxicity, driven by FcγRIIIa (CD16) expressed on natural killer (NK) cells. These observations have led to research focusing on methods to increase Fc receptor-mediated events, which include removal of a fucose moiety found on the Fc portion of the antibody. Further studies have elucidated the mechanistic changes in signaling, cellular processes, and cytotoxic characteristics that increase ADCC activity with afucosylated antibodies. Additionally, other studies have shown the potential benefits of these antibodies in combination with small molecule inhibitors. These experiments demonstrated the molecular and cellular mechanisms underlying the benefits of using afucosylated antibodies in combination settings. Many of these observations were based on an artificial in vitro activation assay in which the FcγRIIIa on human NK cells was activated by therapeutic antibodies. This assay provided the flexibility to study downstream effector NK cell functions, such as cytokine production and degranulation. In addition, this assay has been used to interrogate signaling pathways and identify molecules that can be modulated or used as biomarkers. Finally, other therapeutic molecules (i.e., small molecule inhibitors) have been added to the system to provide insights into the combination of these therapeutics with therapeutic antibodies, which is essential in the current clinical space. This manuscript aims to provide a technical foundation for performing this artificial human NK cell activation assay. The protocol demonstrates key steps for cell activation as well as potential downstream applications that range from functional readouts to more mechanistic observations.


Asunto(s)
Anticuerpos/uso terapéutico , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Receptores de IgG/metabolismo , Anticuerpos/inmunología , Genotipo , Humanos , Células Asesinas Naturales/citología , Activación de Linfocitos , Transducción de Señal
17.
Rev. cuba. hematol. inmunol. hemoter ; 36(2): e1115, abr.-jun. 2020. graf
Artículo en Español | LILACS, CUMED | ID: biblio-1149898

RESUMEN

Introducción: En la supervivencia del corazón trasplantado son de importancia el empleo de los anticuerpos contra el sistema principal de histocompatibilidad (anticuerpos anti-HLA). Hace seis años se introdujo en Cuba el porcentaje de anticuerpos anti-HLA frente a panel (PRA) por método de ensayo de inmunoabsorción ligado a enzima (ELISA) como parte de las pruebas de compatibilidad pretrasplante de los receptores de trasplante cardiaco. Objetivo: Caracterizar los anticuerpos anti-HLA en pacientes receptores cubanos de trasplante cardiaco. Métodos: Entre septiembre de 2013 y abril de 2017 se les realizó el PRA por ELISA a 38 muestras de pacientes recibidas en el laboratorio de histocompatibilidad del Instituto de Hematología e Inmunología. Se utilizó la comparación de proporciones para el análisis estadístico. Resultados: El 47,4 por ciento de los pacientes estudiados presentó anticuerpos anti-HLA, fueron los más frecuentes los de clase I. La proporción de pacientes con PRA del 0 por ciento fue mayor en PRA clase II que en I (p: 0,0027). Mientras que fue mayor la proporción de pacientes con PRA clase I entre el 20 y el 75 por ciento (p: 0,0046). El 77,8 por ciento de los pacientes tuvo un PRA clase I mayor al 10 por ciento y en el PRA clase II alcanzó el 80 por ciento. Conclusiones: El porcentaje de anticuerpos anti-HLA frente a panel por método de ensayo de inmunoabsorción ligado a enzima permitió una mejor caracterización de los anticuerpos anti-HLA, lo que contribuyó a mejorar la compatibilidad en este tipo de paciente(AU)


Introduction: In survival after heart transplantation, the use of antibodies against the main histocompatibility system (anti-HLA antibodies) is important. Six years ago, the percentage of anti-HLA antibodies against panel (PRA) by enzyme-linked immunosorbent assay (ELISA) method was introduced in Cuba as part of the pre-transplant compatibility tests of heart transplant recipients. Objective: To characterize anti-HLA antibodies in Cuban heart transplant recipients. Methods: Between September 2013 and April 2017, PRA by ELISA was performed on 38 patient samples received in the histocompatibility laboratory of the Institute of Hematology and Immunology. Comparison of proportions was used for statistical analysis. Results: 47.4 percent of the study patients presented anti-HLA antibodies; those in class were the most frequent. The proportion of patients with PRA of 0 percent was higher in PRA class II than in class I (p=0.0027). The proportion of patients with PRA class I was greater, accounting for 20-75 percent (p=0.0046). 77.8 percent of the patients had a class I PRA greater than 10 percent, while in class II PRA it reached 80 percent. Conclusions: The percentage of anti-HLA antibodies versus a panel of enzyme linked immunosorbent assay method allowed better characterization of anti-HLA antibodies, which contributed to improving compatibility in this type of patient(AU)


Asunto(s)
Humanos , Trasplante de Corazón/métodos , Receptores de Trasplantes , Anticuerpos/uso terapéutico , Ensayo de Inmunoadsorción Enzimática/métodos , Análisis de Supervivencia , Cuba
18.
Presse Med ; 49(2): 104025, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32437841

RESUMEN

Idiopathic pulmonary fibrosis (IPF) is a chronic and devastating disease of unknown etiology, characterized by irreversible morphological changes, ultimately leading to lung fibrosis and death. In recent years, significant progress has been achieved in understanding the pathogenesis of IPF. Moreover, we assisted to the conceptual change of the pathogenic hypothesis that currently considers IPF as a primarily fibrotic driven disease. However, despite the undeniable progress, the diagnosis of IPF remains still very complex requiring the presence of a team of experts to achieve the highest level of diagnostic confidence. The advent of antifibrotics has radically changed the treatment landscape of IPF and new promising drugs are currently under evaluation. Furthermore, a more extensive use of non-pharmacological treatments has also to be encouraged in all patients both to reduce symptoms and improve quality of life.


Asunto(s)
Fibrosis Pulmonar Idiopática/etiología , Fibrosis Pulmonar Idiopática/terapia , Anciano , Antiinflamatorios no Esteroideos/uso terapéutico , Anticuerpos/uso terapéutico , Factor de Crecimiento del Tejido Conjuntivo/inmunología , Quimioterapia Combinada , Humanos , Fibrosis Pulmonar Idiopática/diagnóstico , Fibrosis Pulmonar Idiopática/rehabilitación , Indoles/uso terapéutico , Integrinas/inmunología , Antagonistas de Leucotrieno/uso terapéutico , Trasplante de Pulmón , Microbiota/efectos de los fármacos , Persona de Mediana Edad , Multimorbilidad , Inhibidores de Fosfodiesterasa/uso terapéutico , Hidrolasas Diéster Fosfóricas , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridonas/uso terapéutico , Componente Amiloide P Sérico/antagonistas & inhibidores
19.
Cancer Imaging ; 20(1): 35, 2020 May 12.
Artículo en Inglés | MEDLINE | ID: mdl-32398076

RESUMEN

BACKGROUND: Anti-angiogenic treatment of glioblastoma (GBM) complicates radiologic monitoring. We evaluated magnetic resonance elastography (MRE) as an imaging tool for monitoring the efficacy of anti-VEGF treatment of GBM. METHODS: Longitudinal studies were performed in an orthotopic GBM xenograft mouse model. Animals treated with B20 anti-VEGF antibody were compared to untreated controls regarding survival (n = 13), classical MRI-contrasts and biomechanics as quantified via MRE (n = 15). Imaging was performed on a 7 T small animal horizontal bore MRI scanner. MRI and MRE parameters were compared to histopathology. RESULTS: Anti-VEGF-treated animals survived longer than untreated controls (p = 0.0011) with progressively increased tumor volume in controls (p = 0.0001). MRE parameters viscoelasticity |G*| and phase angle Y significantly decreased in controls (p = 0.02 for |G*| and p = 0.0071 for Y). This indicates that untreated tumors became softer and more elastic than viscous with progression. Tumor volume in treated animals increased more slowly than in controls, indicating efficacy of the therapy, reaching significance only at the last time point (p = 0.02). Viscoelasticity and phase angle Y tended to decrease throughout therapy, similar as for control animals. However, in treated animals, the decrease in phase angle Y was significantly attenuated and reached statistical significance at the last time point (p = 0.04). Histopathologically, control tumors were larger and more heterogeneous than treated tumors. Vasculature was normalized in treated tumors compared with controls, which showed abnormal vasculature and necrosis. In treated tumors, a higher amount of myelin was observed within the tumor area (p = 0.03), likely due to increased tumor invasion. Stiffness of the contralateral hemisphere was influenced by tumor mass effect and edema. CONCLUSIONS: Anti-angiogenic GBM treatment prolonged animal survival, slowed tumor growth and softening, but did not prevent progression. MRE detected treatment effects on tumor stiffness; the decrease of viscoelasticity and phase angle in GBM was attenuated in treated animals, which might be explained by normalized vasculature and greater myelin preservation within treated tumors. Thus, further investigation of MRE is warranted to understand the potential for MRE in monitoring treatment in GBM patients by complementing existing MRI techniques.


Asunto(s)
Inhibidores de la Angiogénesis/efectos adversos , Neoplasias Encefálicas/diagnóstico por imagen , Diagnóstico por Imagen de Elasticidad/métodos , Glioblastoma/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Anticuerpos/efectos adversos , Anticuerpos/inmunología , Anticuerpos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Femenino , Glioblastoma/tratamiento farmacológico , Ratones , Ratones Desnudos , Factor A de Crecimiento Endotelial Vascular/inmunología
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