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1.
F1000Res ; 9: 72, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32117569

RESUMEN

A novel coronavirus (2019-nCoV) originating in Wuhan, China presents a potential respiratory viral pandemic to the world population. Current efforts are focused on containment and quarantine of infected individuals. Ultimately, the outbreak could be controlled with a protective vaccine to prevent 2019-nCoV infection. While vaccine research should be pursued intensely, there exists today no therapy to treat 2019-nCoV upon infection, despite an urgent need to find options to help these patients and preclude potential death. Herein, I review the potential options to treat 2019-nCoV in patients, with an emphasis on the necessity for speed and timeliness in developing new and effective therapies in this outbreak. I consider the options of drug repurposing, developing neutralizing monoclonal antibody therapy, and an oligonucleotide strategy targeting the viral RNA genome, emphasizing the promise and pitfalls of these approaches. Finally, I advocate for the fastest strategy to develop a treatment now, which could be resistant to any mutations the virus may have in the future. The proposal is a biologic that blocks 2019-nCoV entry using a soluble version of the viral receptor, angiotensin-converting enzyme 2 (ACE2), fused to an immunoglobulin Fc domain, providing a neutralizing antibody with maximal breath to avoid any viral escape, while also helping to recruit the immune system to build lasting immunity. The sequence of the ACE2-Fc protein is provided to investigators, allowing its possible use in recombinant protein expression systems to start producing drug today to treat patients under compassionate use, while formal clinical trials are later undertaken. Such a treatment could help infected patients before a protective vaccine is developed and widely available in the coming months to year(s).


Asunto(s)
Anticuerpos Monoclonales , Anticuerpos Neutralizantes/uso terapéutico , Betacoronavirus , Infecciones por Coronavirus/tratamiento farmacológico , Reposicionamiento de Medicamentos , Peptidil-Dipeptidasa A/efectos de los fármacos , Neumonía Viral/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéutico , Betacoronavirus/efectos de los fármacos , China/epidemiología , Ensayos de Uso Compasivo , Brotes de Enfermedades , Humanos , Oligonucleótidos/uso terapéutico
2.
Zhonghua Jie He He Hu Xi Za Zhi ; 43(3): 170-172, 2020 Mar 12.
Artículo en Chino | MEDLINE | ID: mdl-32164080

RESUMEN

The recent outbreak of respiratory illness in Wuhan, China is caused by a novel coronavirus, named 2019-nCoV, which is genetically close to a bat-derived coronavirus. 2019-nCoV is categorized as beta genus coronavirus, same as the two other strains-severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Antiviral drugs commonly used in clinical practice, including neuraminidase inhibitors (oseltamivir, paramivir, zanamivir, etc.), ganciclovir, acyclovir and ribavirin, are invalid for 2019-nCoV and not recommended. Drugs are possibly effective for 2019-nCoV include: remdesivir, lopinavir/ritonavir, lopinavir/ritonavir combined with interferon-ß, convalescent plasma, and monoclonal antibodies. But the efficacy and safety of these drugs for 2019-nCoV pneumonia patients need to be assessed by further clinical trials.


Asunto(s)
Antivirales/uso terapéutico , Betacoronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéutico , China , Inhibidores del Citocromo P-450 CYP3A/uso terapéutico , Humanos , Interferón beta , Lopinavir/uso terapéutico , Coronavirus del Síndrome Respiratorio de Oriente Medio , Ritonavir/uso terapéutico , Síndrome Respiratorio Agudo Grave/tratamiento farmacológico
3.
Lancet Haematol ; 7(3): e209-e217, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32027862

RESUMEN

BACKGROUND: Siltuximab is recommended by international consensus as a first-line treatment for idiopathic multicentric Castleman disease on the basis of durable efficacy and safety data. This study was done to assess the long-term safety and activity of siltuximab over up to 6 years of treatment. METHODS: This study is a prespecified open-label extension analysis of a phase 1 trial (NCT00412321) and a phase 2 trial (NCT01024036), done at 26 hospitals worldwide. Patients in both studies were at least 18 years old with histologically confirmed, symptomatic Castleman disease. This extension study enrolled 60 patients who completed the previous trials without disease progression on siltuximab. Patients received siltuximab infusions of 11 mg/kg every 3 weeks (which could be extended to 6 weeks) for up to 6 years. Descriptive statistics were used to summarise the data. No formal hypothesis testing was performed. The primary endpoint was the safety of siltuximab, assessed at each dosing cycle. The study was registered with ClinicalTrials.gov, number NCT01400503 and with EudraCT, number 2010-022837-27. FINDINGS: Patient enrolment into the phase 1 trial was from June 20, 2005, to Sept 15, 2009, and enrolment into the phase 2 trial was from Feb 9, 2010, to Feb 3, 2012. Patients were enrolled in this long-term extension from April 1, 2011, to Jan 15, 2014. Median follow-up was 6 years (IQR 5·11-7·76). Median treatment duration, from the beginning of the previous trials to the end of the present study, was 5·5 years (IQR 4·26-7·14). Siltuximab was well tolerated; however, adverse events of grade 3 or worse were reported in 36 (60%) of 60 patients with the most common being hypertension (eight [13%]), fatigue (five [8%]), nausea (four [7%]), neutropenia (four [7%]), and vomiting (three [5%]). 25 (42%) patients reported at least one serious adverse event, which most commonly was an infection (eight [13%]). Only two serious adverse events, polycythaemia and urinary retention, were considered related to siltuximab treatment. 18 patients discontinued before study completion, either to receive siltuximab locally (eight) or because of progressive disease (two), adverse events (two), or other reasons (six). No deaths were reported. INTERPRETATION: These results show that siltuximab is well tolerated long term and provides important evidence for the feasibility of the life-long use required by patients with idiopathic multicentric Castleman disease. FUNDING: Janssen R&D and EUSA Pharma.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Enfermedad de Castleman/tratamiento farmacológico , Adulto , Enfermedad de Castleman/patología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Seguridad del Paciente , Pronóstico
4.
Cancer Radiother ; 24(1): 67-72, 2020 Feb.
Artículo en Francés | MEDLINE | ID: mdl-32037126

RESUMEN

Concomitant radiochemotherapy has been the standard of care for unresectable stage III non-small cell lung cancer (NSCLC), irrespective of histological sub-type or molecular characteristics. Currently, only 15-30 % of patients are alive five years after radiochemotherapy, and this figure remains largely unchanged despite multiple phase III randomised trials. In recent years, immune-checkpoint blockades with anti-PD-(L)1 have revolutionised the care of metastatic NSCLC, becoming the standard front- and second-line strategy. Several preclinical studies reported an increased tumour antigen release, improved antigen presentation, and T-cell infiltration in irradiated tumours. Immunotherapy has therefore recently been evaluated for patients with locally advanced stage III NSCLC. Following the PACIFIC trial, the anti-PD-L1 durvalumab antibody has emerged as a new standard consolidative treatment for patients with unresectable stage III NSCLC whose disease has not progressed following concomitant platinum-based chemoradiotherapy. Immunoradiotherapy therefore appears to be a promising association in patients with localised NSCLC. Many trials are currently evaluating the value of concomitant immunotherapy and chemoradiotherapy and/or consolidative chemotherapy with immunotherapy in patients with locally advanced unresectable NSCLC.


Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/terapia , Anticuerpos Monoclonales/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Quimioterapia Adyuvante , Ensayos Clínicos como Asunto , Humanos , Neoplasias Pulmonares/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Radioterapia Ayuvante
5.
Medicine (Baltimore) ; 99(7): e19059, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32049805

RESUMEN

Nivolumab, a monoclonal antibody targeting programmed cell death-1, significantly prolongs survival for patients with advanced non-small-cell lung cancer (NSCLC). However, little is known about the value of predictive biomarkers. Hence, we investigated the impact of skeletal muscle (SM) mass loss on clinical outcomes in NSCLC patients undergoing nivolumab treatment. Thirty patients with histologically confirmed NSCLC treated with nivolumab were included in this study. Computed tomography was used to determine SM loss based on the SM index (SMI). The SMI is the cross-sectional area of the bilateral psoas muscles at the third lumbar vertebra, divided by height squared. The cut-off values were defined as 6.36 cm/m for men and 3.92 cm/m for women. Among the 30 patients, 13 (43%) had SM loss. There was no significant association between SM loss and immune-related adverse events. The SM loss group had undergone significantly more prior chemotherapy cycles (P = .04). SM loss was significantly associated with fewer nivolumab cycles (P = .01). No patients in the SM loss group achieved a partial response. Patients with SM loss had a significantly shorter progression-free survival period (P = .008) and median overall survival than those with normal SM mass (10 vs 25 months, respectively, P = .03). SM loss was an independent prognostic factor of poor survival. In conclusion, SM loss may be a predictive factor of poor outcomes in NSCLS patients undergoing nivolumab therapy.


Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Nivolumab/administración & dosificación , Sarcopenia/epidemiología , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nivolumab/uso terapéutico , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Sarcopenia/diagnóstico por imagen , Análisis de Supervivencia , Tomografía Computarizada por Rayos X , Resultado del Tratamiento
6.
Internist (Berl) ; 61(3): 326-332, 2020 Mar.
Artículo en Alemán | MEDLINE | ID: mdl-32072189

RESUMEN

Migraine has a very high lifetime prevalence with a severe illness-related burden. As a result, extensive long-term and regular treatment is required, which cannot be covered solely by neurologists. This is particularly the case for the long-term monitoring of migraine, which often takes place over several decades. The diagnosis is made using the diagnostic criteria of the International Headache Society (ICHD-3) based on the clinical phenotype. Owing to often complex neurological symptoms, a detailed weighing up of the differential diagnoses is required, which calls for specialist neurological expertise. The same is true for follow-up appointments of more complex therapy issues. Acute therapy with antiemetics, analgesics, and triptans can, so long as it is effective and is administered not longer than 10 days per month, be carried out by the general practitioner or specialist in internal medicine. This is also true for medical prophylactic treatment with dietary supplements, antihypertensive drugs, and tricyclic antidepressants. If this therapy is unsuccessful, prophylactic substances must be used that require more specialized knowledge, which is also reflected in the formal prescription requirements. Neurologists and pain therapists should then be involved in the treatment. This is particularly true for the use of Onabotulinumtoxin A and monoclonal CGRP-(receptor)-antibodies.


Asunto(s)
Analgésicos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/uso terapéutico , Péptido Relacionado con Gen de Calcitonina/metabolismo , Cefalea/tratamiento farmacológico , Trastornos Migrañosos/tratamiento farmacológico , Analgésicos/administración & dosificación , Anticuerpos Monoclonales/administración & dosificación , Péptido Relacionado con Gen de Calcitonina/antagonistas & inhibidores , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/administración & dosificación , Cefalea/metabolismo , Humanos , Cuidados a Largo Plazo , Trastornos Migrañosos/diagnóstico , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Resultado del Tratamiento , Triptaminas/uso terapéutico
7.
Br J Anaesth ; 124(3): 251-260, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32007241

RESUMEN

Immunotherapy has revolutionised the treatment of oncologic malignancies. Immune checkpoint inhibitors represent a new class of immunotherapy drugs. Although these drugs show promise, they are associated with immune-related adverse reactions. An increasing number of patients who undergo surgery will have had treatment with immune checkpoint inhibitors. In this narrative review article, we discuss their mechanism of action, therapeutic effects, pertinent toxicities, and address specific perioperative considerations for patients treated with immune checkpoint inhibitors.


Asunto(s)
Anestesiólogos , Antineoplásicos Inmunológicos/efectos adversos , Inmunoterapia/efectos adversos , Neoplasias/tratamiento farmacológico , Atención Perioperativa/métodos , Rol del Médico , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Antígeno CTLA-4/antagonistas & inhibidores , Humanos , Inmunoterapia/métodos , Complicaciones Intraoperatorias/inducido químicamente , Complicaciones Intraoperatorias/prevención & control , Neoplasias/inmunología , Complicaciones Posoperatorias/inducido químicamente , Complicaciones Posoperatorias/prevención & control
8.
Medicine (Baltimore) ; 99(5): e19013, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32000444

RESUMEN

BACKGROUND: Cancer patients with hepatitis B or C virus (HBV/HCV) infection are commonly seen in clinical practice, however, the data of safety and efficacy of immune checkpoint inhibitors (ICIs) among them are sparse, because active HBV/HCV infected patients were generally excluded by clinical trials and the correlation between previous infection and treatment-related adverse events was rarely reported. This review is the first to summarize the results on the safety and efficacy of immune checkpoint inhibitors (ICIs) in HBV/HCV infected cancer patients. METHOD: We searched literature and conference abstracts in PubMed and Embase followed the PRISMA guideline, using the keywords hepatitis B, hepatitis C, immune checkpoint inhibitor, ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, tremelimumab. Studies described patients with HBV/HCV infection treated with ICIs for advanced stage cancer were included. FINDINGS: One hundred eighty six patients were identified from 14 articles (8 case reports, 4 case series, 2 trials). Eighty nine patients had HBV infection and 98 had HCV infection (1 both had HBV and HCV). The majority of patients were treated with PD-1 inhibitor monotherapy (140 of 186, 75.3%) and anti-CTLA-4 monotherapy (36 of 186, 19.4%). No treatment-related death was reported. The incidence of grade 3 or 4 hepatic transaminase elevating (HTE) in HBV and HCV infected patients were 3.4% (3/89) and 17.3% (17/98), respectively. 2.8% patients without antivirus therapy experienced virus load increasing, and 1.9% presented virus-related hepatitis. In terms of efficacy, 22 of 118 (18.6%) patients with liver cancer, 11 of 34 (32.4%) with melanoma, 1 of 6 (16.7%) with NSCLC showed objective responses (CR and PR) to ICIs in spite of lines of therapies. CONCLUSION: ICIs is considered to be safe and effective in advanced cancer patients with hepatitis B or C infection, but still has possibilities to reactive hepatitis virus due to uncertain mechanisms. We recommend that those with viral hepatitis be monitored closely and treated with antiviral therapy if indicated before or during ICIs treatment.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Hepatitis B/complicaciones , Hepatitis C/complicaciones , Neoplasias/tratamiento farmacológico , Humanos
9.
Medicine (Baltimore) ; 99(2): e18723, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31914087

RESUMEN

Effectiveness, efficacy and safety of biosimilar infliximab (CT-P13) in inflammatory bowel disease (IBD) patients has been shown in previous studies. Limited data exist on health-related quality of life (HRQoL) of switching originator to biosimilar infliximab (IFX) in IBD patients. The objective of this study was to evaluate impact of switching originator to biosimilar IFX on HRQoL, disease activity, and health care costs in IBD maintenance treatment.In this single-center prospective observational study, all IBD patients receiving maintenance IFX therapy were switched to biosimilar IFX. HRQoL was measured using the generic 15D health-related quality of life instrument (15D) utility measurement and the disease-specific Inflammatory Bowel Disease Questionnaire (IBDQ). Crohn Disease Activity Index (CDAI) or Partial Mayo Score (pMayo), and fecal calprotectin (FC) served for evaluation of disease activity. Data were collected at time of switching and 3 and 12 months after switching. Patients' characteristics, clinical background information and costs were collected from patient records and the hospital's electronic database.Fifty-four patients were included in the analysis. No statistically significant changes were observed in 15D, CDAI, pMayo, and FC during 1-year follow-up. IBDQ scores were higher (P = .018) in Crohn disease 3 months after switching than at time of switching. Costs of biosimilar IFX were one-third of costs of originator one. Total costs related to secondary health care (excluding costs of IFX), were similar before and after the onset of biosimilar IFX.HRQoL and disease activity were after switching from originator to biosimilar IFX comparable, but the costs of biosimilar IFX were only one-third of those of the originator one.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Biosimilares Farmacéuticos/uso terapéutico , Fármacos Gastrointestinales/uso terapéutico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Infliximab/uso terapéutico , Calidad de Vida , Adulto , Anticuerpos Monoclonales/economía , Biosimilares Farmacéuticos/economía , Sustitución de Medicamentos/economía , Femenino , Fármacos Gastrointestinales/economía , Recursos en Salud/economía , Servicios de Salud/economía , Servicios de Salud/estadística & datos numéricos , Humanos , Infliximab/economía , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Inducción de Remisión
10.
Immunity ; 52(1): 36-54, 2020 01 14.
Artículo en Inglés | MEDLINE | ID: mdl-31940272

RESUMEN

Therapeutics that target the T cell inhibitory checkpoint proteins CTLA-4 and PD(L)1 are efficacious across a broad range of cancers, resulting in reductions in tumor burden and increased long-term survival in subsets of patients. The significant and wide-ranging effects of these immunotherapies have prompted the clinical investigation of additional therapies that modulate anti-tumor immunity through effects on T cells, myeloid cells, and other cell types within the tumor microenvironment. The clinical activity of these newer investigational therapies has been mixed, with some therapeutics showing promise but others not exhibiting appreciable efficacy. In this review, we summarize the results of select recent clinical studies of cancer immunotherapies beyond anti-CTLA-4 and anti-PD(L)1 and discuss how these results are providing new insights into the regulation of human anti-tumor immunity.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Inmunoterapia/métodos , Neoplasias/terapia , Linfocitos T/inmunología , Antígeno B7-H1/antagonistas & inhibidores , Antígeno CTLA-4/antagonistas & inhibidores , Humanos , Activación de Linfocitos/inmunología , Neoplasias/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Microambiente Tumoral/inmunología
11.
Nursing ; 50(2): 31-38, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31895198
12.
Emerg Microbes Infect ; 9(1): 78-87, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31894728

RESUMEN

The H7N9 influenza virus has been circulating in China for more than six years. The neuraminidase (NA) has gained great concern for the development of antiviral drugs, therapeutic antibodies, and new vaccines. In this study, we screened seven mouse monoclonal antibodies (mAbs) and compared their protective effects against H7N9 influenza virus. The epitope mapping from escape mutants showed that all the seven mAbs could bind to the head region of the N9 NA close to the enzyme activity sites, and four key sites of N9 NA were reported for the first time. The mAbs D3 and 7H2 could simultaneously inhibit the cleavage of the sialic acid of fetuin protein with large molecular weight and NA-XTD with small molecule weight in the NA inhibition experiment, prevent the formation of virus plaque at a low concentration, and effectively protect the mice from the challenge of the lethal dose of H7N9 virus.


Asunto(s)
Anticuerpos Monoclonales/química , Subtipo H7N9 del Virus de la Influenza A/inmunología , Neuraminidasa/antagonistas & inhibidores , Neuraminidasa/química , Infecciones por Orthomyxoviridae/prevención & control , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Antígenos Virales , Dominio Catalítico , Línea Celular , Perros , Mapeo Epitopo , Humanos , Gripe Humana/tratamiento farmacológico , Gripe Humana/prevención & control , Ratones , Ratones Endogámicos BALB C , Infecciones por Orthomyxoviridae/tratamiento farmacológico
13.
N Engl J Med ; 382(5): 416-426, 2020 01 30.
Artículo en Inglés | MEDLINE | ID: mdl-31995687

RESUMEN

BACKGROUND: Acute kidney injury is common, with a major effect on morbidity and health care utilization. Soluble urokinase plasminogen activator receptor (suPAR) is a signaling glycoprotein thought to be involved in the pathogenesis of kidney disease. We investigated whether a high level of suPAR predisposed patients to acute kidney injury in multiple clinical contexts, and we used experimental models to identify mechanisms by which suPAR acts and to assess it as a therapeutic target. METHODS: We measured plasma levels of suPAR preprocedurally in patients who underwent coronary angiography and patients who underwent cardiac surgery and at the time of admission to the intensive care unit in critically ill patients. We assessed the risk of acute kidney injury at 7 days as the primary outcome and acute kidney injury or death at 90 days as a secondary outcome, according to quartile of suPAR level. In experimental studies, we used a monoclonal antibody to urokinase plasminogen activator receptor (uPAR) as a therapeutic strategy to attenuate acute kidney injury in transgenic mice receiving contrast material. We also assessed cellular bioenergetics and generation of reactive oxygen species in human kidney proximal tubular (HK-2) cells that were exposed to recombinant suPAR. RESULTS: The suPAR level was assessed in 3827 patients who were undergoing coronary angiography, 250 who were undergoing cardiac surgery, and 692 who were critically ill. Acute kidney injury developed in 318 patients (8%) who had undergone coronary angiography. The highest suPAR quartile (vs. the lowest) had an adjusted odds ratio of 2.66 (95% confidence interval [CI], 1.77 to 3.99) for acute kidney injury and 2.29 (95% CI, 1.71 to 3.06) for acute kidney injury or death at 90 days. Findings were similar in the surgical and critically ill cohorts. The suPAR-overexpressing mice that were given contrast material had greater functional and histologic evidence of acute kidney injury than wild-type mice. The suPAR-treated HK-2 cells showed heightened energetic demand and mitochondrial superoxide generation. Pretreatment with a uPAR monoclonal antibody attenuated kidney injury in suPAR-overexpressing mice and normalized bioenergetic changes in HK-2 cells. CONCLUSIONS: High suPAR levels were associated with acute kidney injury in various clinical and experimental contexts. (Funded by the National Institutes of Health and others.).


Asunto(s)
Lesión Renal Aguda/sangre , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Angiografía Coronaria/efectos adversos , Receptores del Activador de Plasminógeno Tipo Uroquinasa/sangre , Activador de Plasminógeno de Tipo Uroquinasa/antagonistas & inhibidores , Lesión Renal Aguda/etiología , Lesión Renal Aguda/prevención & control , Anciano , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Biomarcadores/sangre , Enfermedad Crítica , Modelos Animales de Enfermedad , Femenino , Humanos , Unidades de Cuidados Intensivos , Túbulos Renales/citología , Túbulos Renales/efectos de los fármacos , Túbulos Renales/patología , Masculino , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Oportunidad Relativa , Podocitos/efectos de los fármacos , Podocitos/metabolismo , Complicaciones Posoperatorias/sangre , Complicaciones Posoperatorias/etiología , Medición de Riesgo/métodos , Activador de Plasminógeno de Tipo Uroquinasa/farmacología
14.
Clin Biochem ; 75: 40-47, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31669513

RESUMEN

OBJECTIVES: Multiple myeloma (MM) is characterized by malignant growth of plasma cells, usually producing a monoclonal antibody (mAb). New treatments for MM include therapeutic monoclonal antibodies (tmAbs), but patients treated with tmAb demonstrate interference on serum electrophoresis (SPE) and immunoprecipitation electrophoresis (IEP). Evaluation of treatment efficacy and determination of MM remission include SPE and IEP which identifies mAb, but cannot differentiate between disease associated mAb and tmAb. We hypothesized that tmAb could be removed from patient sera before testing by SPE and IEP to provide accurate diagnoses for clinicians. DESIGN AND METHODS: We developed the Antigen Specific therapeutic monoclonal Antibody Depletion Assay (ASADA), that utilizes magnetic beads coated with the cognate antigen of the tmAbs, to deplete two different tmAb (daratumumab, elotuzumab) from saline and patient sera and assessed for complete removal of tmAb by SPE and IEP. RESULTS: We found that tmAb could be efficiently removed from saline and patient sera. ASADA demonstrated acceptable analytical specificity and sensitivity in IEP. Recovery of appropriate quantitative values by SPE was demonstrated with clinically acceptable precision. A single bead cocktail could be used to treat both daratumumab and elotuzumab. CONCLUSIONS: This demonstrates proof of principle that ASADA can be used to remove current and future tmAb from patient sera, regardless of platform. This research provides for accurate diagnosis, disease monitoring, and remission status in MM patients being treated with tmAb.


Asunto(s)
Métodos Analíticos de la Preparación de la Muestra , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales/efectos adversos , Antineoplásicos/efectos adversos , Monitoreo de Drogas , Mieloma Múltiple/inmunología , Mieloma Múltiple/terapia , Anticuerpos Monoclonales/sangre , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/sangre , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/sangre , Antineoplásicos/uso terapéutico , Biomarcadores/sangre , Electroforesis de las Proteínas Sanguíneas , Humanos , Inmunoprecipitación , Mieloma Múltiple/sangre , Recurrencia , Resultado del Tratamiento
15.
Scand J Immunol ; 91(1): e12839, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31630416

RESUMEN

The humanized IgG1κ monoclonal antibody siplizumab and its rat parent monoclonal IgG2b antibody BTI-322 are directed against the CD2 antigen. Siplizumab is species-specific, reacting with human and chimpanzee cells but not with cells from any other species, including other non-human primates. Because siplizumab treatment has recently shown great potential in clinical transplantation, we now present the results of our previous pharmacokinetic, pharmacodynamic and safety studies of both antibodies. Fourteen chimpanzees received 1-3 doses of 0.143 to 5.0 mg/kg iv The effects were followed with flow cytometry on peripheral lymphocytes and staining of lymph nodes. Side effects were recorded. Serum antibody concentrations were followed. Across the doses, a rapid, transient depletion of CD2, CD3, CD4 and CD8 lymphocytes and NK cells was observed for both antibodies. Immune reconstitution was more rapid for BTI-322 compared to siplizumab. Paracortical lymph node T cell depletion was moderate, estimated at 45% with doses of >0.6 mg/kg. Restoration of lymph node architecture was seen after two weeks to two months for all animals. All four subjects receiving BTI-322 experienced AEs on the first dosing day, while the eight subjects dosed with siplizumab experienced few mild, transient AEs. Infusion with siplizumab and BTI-322 resulted in rapid depletion of CD2+ cells in circulation and tissue. Siplizumab had a longer t1/2 and fewer AEs compared to BTI-322.


Asunto(s)
Anticuerpos Monoclonales/farmacocinética , Antígenos CD2/antagonistas & inhibidores , Animales , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos Monoclonales Humanizados/uso terapéutico , Biomarcadores , Biopsia , Citocinas/sangre , Femenino , Inmunoglobulina G/administración & dosificación , Inmunoglobulina G/farmacología , Inmunofenotipificación , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Depleción Linfocítica , Linfocitos/inmunología , Linfocitos/metabolismo , Masculino , Pan troglodytes , Ratas
16.
Infect Immun ; 88(2)2020 01 22.
Artículo en Inglés | MEDLINE | ID: mdl-31818965

RESUMEN

The sialylatable lacto-N-neotetraose (LNnT; Gal-GlcNAc-Gal-Glc) moiety from heptose I (HepI) of the lipooligosaccharide (LOS) of Neisseria gonorrhoeae undergoes positive selection during human infection. Lactose (Gal-Glc) from HepII, although phase variable, is commonly expressed in humans; loss of HepII lactose compromises gonococcal fitness in mice. Anti-LOS monoclonal antibody (MAb) 2C7, a promising antigonococcal immunotherapeutic that elicits complement-dependent bactericidal activity and attenuates gonococcal colonization in mice, recognizes an epitope comprised of lactoses expressed simultaneously from HepI and HepII. Glycan extensions beyond lactose on HepI modulate binding and function of MAb 2C7 in vitro Here, four gonococcal LOS mutants, each with lactose from HepII but fixed (unable to phase-vary) LOS HepI glycans extended beyond the lactose substitution of HepI (lactose alone, Gal-lactose, LNnT, or GalNAc-LNnT), were used to define how HepI glycan extensions affect (i) mouse vaginal colonization and (ii) efficacy in vitro and in vivo of a human IgG1 chimeric derivative of MAb 2C7 (2C7-Ximab) with a complement-enhancing E-to-G Fc mutation at position 430 (2C7-Ximab-E430G). About 10-fold lower 2C7-Ximab-E430G concentrations achieved similar complement-dependent killing of three gonococcal mutants with glycan extensions beyond lactose-substituted HepI (lactose alone, LNnT, or GalNAc-LNnT) as 2C7-Ximab (unmodified Fc). The fourth mutant (Gal-lactose) resisted direct complement-dependent killing but was killed approximately 70% by 2C7-Ximab-E430G in the presence of polymorphonuclear leukocytes and complement. Only mutants with (sialylatable) LNnT from HepI colonized mice for >3 days, reiterating the importance of LNnT sialylation for infection. 2C7-Ximab-E430G significantly attenuated colonization caused by the virulent mutants.


Asunto(s)
Anticuerpos Antibacterianos/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Gonorrea/terapia , Lipopolisacáridos/inmunología , Neisseria gonorrhoeae/inmunología , Animales , Modelos Animales de Enfermedad , Femenino , Ratones Endogámicos BALB C , Resultado del Tratamiento , Vagina/microbiología
17.
Cancer Sci ; 111(3): 907-923, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31883418

RESUMEN

The phase 3 JAVELIN Renal 101 trial of avelumab + axitinib vs sunitinib in patients with treatment-naive advanced renal cell carcinoma (RCC) demonstrated significantly improved progression-free survival (PFS) and higher objective response rate (ORR) with the combination vs sunitinib. Japanese patients enrolled in the study (N = 67) were randomized to receive avelumab + axitinib (N = 33) or sunitinib (N = 34); 67% vs 59% had PD-L1+ tumors (≥1% of immune cells) and 6%/64%/27% vs 6%/82%/12% had International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) favorable/intermediate/poor risk status. In patients who received avelumab + axitinib vs sunitinib, median PFS (95% confidence interval [CI]) was not estimable (8.1 months, not estimable) vs 11.2 months (1.6 months, not estimable) (hazard ratio [HR], 0.49; 95% CI, 0.152, 1.563) in patients with PD-L1+ tumors and 16.6 months (8.1 months, not estimable) vs 11.2 months (4.2 months, not estimable) (HR, 0.66; 95% CI, 0.296, 1.464) in patients irrespective of PD-L1 expression. Median overall survival (OS) has not been reached in either arm in patients with PD-L1+ tumors and irrespective of PD-L1 expression. ORR (95% CI) was 60.6% (42.1%, 77.1%) vs 17.6% (6.8%, 34.5%) in patients irrespective of PD-L1 expression. Common treatment-emergent adverse events (all grade; grade ≥3) in each arm were hand-foot syndrome (64%; 9% vs 71%; 9%), hypertension (55%; 30% vs 44%; 18%), hypothyroidism (55%; 0% vs 24%; 0%), dysgeusia (21%; 0% vs 56%; 0%) and platelet count decreased (3%; 0% vs 65%; 32%). Avelumab + axitinib was efficacious and tolerable in treatment-naive Japanese patients with advanced RCC, which is consistent with results in the overall population.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Axitinib/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Sunitinib/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Grupo de Ascendencia Continental Asiática , Antígeno B7-H1/metabolismo , Carcinoma de Células Renales/metabolismo , Femenino , Humanos , Riñón/efectos de los fármacos , Riñón/metabolismo , Neoplasias Renales/metabolismo , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión
18.
Int J Cancer ; 146(2): 424-438, 2020 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-31241171

RESUMEN

Stem cell chemoresistance remains challenging the efficacy of the front-line temozolomide against glioblastoma. Novel therapies are urgently needed to fight those cells in order to control tumor relapse. Here, we report that anti-O-acetyl-GD2 adjuvant immunotherapy controls glioma stem-like cell-driven chemoresistance. Using patient-derived glioblastoma cells, we found that glioma stem-like cells overexpressed O-acetyl-GD2. As a result, monoclonal antibody 8B6 immunotherapy significantly increased temozolomide genotoxicity and tumor cell death in vitro by enhancing temozolomide tumor uptake. Furthermore, the combination therapy decreased the expression of the glioma stem-like cell markers CD133 and Nestin and compromised glioma stem-like cell self-renewal capabilities. When tested in vivo, adjuvant 8B6 immunotherapy prevented the extension of the temozolomide-resistant glioma stem-like cell pool within the tumor bulk in vivo and was more effective than the single agent therapies. This is the first report demonstrating that anti-O-acetyl-GD2 monoclonal antibody 8B6 targets glioblastoma in a manner that control temozolomide-resistance driven by glioma stem-like cells. Together our results offer a proof of concept for using anti-O-acetyl GD2 reagents in glioblastoma to develop more efficient combination therapies for malignant gliomas.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Gangliósidos/antagonistas & inhibidores , Glioblastoma/tratamiento farmacológico , Células Madre Neoplásicas/efectos de los fármacos , Adyuvantes Inmunológicos/farmacología , Adyuvantes Inmunológicos/uso terapéutico , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Línea Celular Tumoral , Autorrenovación de las Células/efectos de los fármacos , Autorrenovación de las Células/inmunología , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/inmunología , Sinergismo Farmacológico , Gangliósidos/inmunología , Glioblastoma/inmunología , Glioblastoma/patología , Humanos , Ratones , Células Madre Neoplásicas/inmunología , Temozolomida/farmacología , Temozolomida/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto
19.
Biosci Biotechnol Biochem ; 84(1): 1-16, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31538538

RESUMEN

Recent investigations suggest that soluble oligomeric amyloid ß (Aß) species may be involved in early onset of Alzheimer's disease (AD). Using systematic proline replacement, solid-state NMR, and ESR, we identified a toxic turn at position 22 and 23 of Aß42, the most potent neurotoxic Aß species. Through radicalization, the toxic turn can induce formation of the C-terminal hydrophobic core to obtain putative Aß42 dimers and trimers. Synthesized dimer and trimer models showed that the C-terminal hydrophobic core plays a critical role in the formation of high molecular weight oligomers with neurotoxicity. Accordingly, an anti-toxic turn antibody (24B3) that selectively recognizes a toxic dimer model of E22P-Aß42 was developed. Sandwich enzyme-linked immunosorbent assay with 24B3 and 82E1 detected a significantly higher ratio of Aß42 with a toxic turn to total Aß42 in cerebrospinal fluid of AD patients compared with controls, suggesting that 24B3 could be useful for early onset of AD diagnosis.


Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/líquido cefalorraquídeo , Péptidos beta-Amiloides/inmunología , Anticuerpos Monoclonales/uso terapéutico , Fragmentos de Péptidos/líquido cefalorraquídeo , Fragmentos de Péptidos/inmunología , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/química , Animales , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Humanos , Ratones , Modelos Moleculares , Ovillos Neurofibrilares/química , Fragmentos de Péptidos/química , Placa Amiloide/química , Prolina/química , Agregado de Proteínas , Agregación Patológica de Proteínas , Estructura Terciaria de Proteína
20.
Ann Lab Med ; 40(2): 101-113, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31650726

RESUMEN

Biological drugs, such as proteins and immunogens, are increasingly used to treat various diseases, including tumors and autoimmune diseases, and biological molecules have almost completely replaced synthetic drugs in rheumatology. Although biological treatments such as anti-tumor necrosis factor (TNF) drugs seem to be quite safe, they cause some undesirable effects, such as the onset of infections due to weakening of the immune system. Given the biological nature of these drugs, they might be recognized as extraneous; this would induce an immune reaction that neutralizes their effectiveness or lead to more serious consequences. Laboratories play a pivotal role in appropriate therapeutic management. The aim of this review was to underline the production of anti-drug antibodies during treatment with biological drugs and highlight the role of laboratories in ensuring appropriate use of these drugs.


Asunto(s)
Factores Biológicos/sangre , Monitoreo de Drogas , Adalimumab/sangre , Adalimumab/inmunología , Adalimumab/uso terapéutico , Anticuerpos Monoclonales/sangre , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Factores Biológicos/inmunología , Factores Biológicos/uso terapéutico , Biosimilares Farmacéuticos/sangre , Biosimilares Farmacéuticos/uso terapéutico , Humanos
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