RESUMEN
BACKGROUND: The dominant allergen in cat dander, Felis domesticus allergen 1 (Fel d 1), is a persistent trigger for allergic rhinitis and asthma symptoms. OBJECTIVE: We evaluated the efficacy of Fel d 1 monoclonal antibodies (REGN1908/1909) in preventing cat allergen-induced early asthmatic responses (EARs) in cat-allergic patients with mild asthma. METHODS: Patients were randomized to single-dose REGN1908/1909 600 mg (n = 29) or placebo (n = 27). The FEV1 was measured for up to 4 hours in a cat allergen environmental exposure unit up to 85 days after dosing. Assessments included between-group differences in change from baseline in FEV1 area under the curve (AUC; 0-2 hours) and incidence of EAR (FEV1 reduction ≥20%). TRIAL REGISTRATION: NCT03838731. RESULTS: Single-dose REGN1908/1909 significantly prevented reductions in FEV1 on days 8, 29, 57, and 85. Most REGN1908/1909 patients did not have an EAR by 4 hours (the last time point tested). In contrast, placebo-treated patients experienced a ≥20% mean FEV1 reduction on days 8, 29, 57, and 85 after dosing, with most experiencing an EAR within 1 hour. REGN1908/1909-treated patients tolerated 3-fold higher allergen quantities (P < .05 at all time points) versus placebo. REGN1908/1909 substantially reduced skin test reactivity to cat allergen versus placebo at all time points tested (nominal P < .001). REGN1908/1909 was generally well tolerated; no serious adverse events or deaths were reported. CONCLUSION: Single-dose REGN1908/1909 significantly prevented reductions in FEV1 in cat-allergic patients with mild asthma on cat allergen environmental exposure unit exposure at 8 days and up to 85 days after dose.
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Alérgenos , Estado de Salud , Exposición a Riesgos Ambientales/efectos adversosRESUMEN
BACKGROUND: The efficacy of an allergen-specific IgG cocktail to treat cat allergy suggests that allergen-specific IgG may be a major protective mechanism elicited by allergen immunotherapy. OBJECTIVES: Extending these findings, we tested a Bet v 1-specific antibody cocktail in birch-allergic subjects. METHODS: This was a phase 1, randomized, double-blind, study with 2 parts. Part A administered ascending doses of the Bet v 1-specific antibody cocktail REGN5713/14/15 (150-900 mg) in 32 healthy adults. Part B administered a single subcutaneous 900-mg dose or placebo in 64 birch-allergic subjects. Total nasal symptom score response to titrated birch extract nasal allergen challenge and skin prick test (SPT) with birch and alder allergen were assessed at screening and days 8, 29, 57, and 113 (SPT only); basophil activation tests (n = 26) were conducted. RESULTS: Single-dose REGN5713/14/15 significantly reduced total nasal symptom score following birch nasal allergen challenge relative to baseline. Differences in total nasal symptom score areas under the curve (0-1 hour) for subjects treated with REGN5713/14/15 versus those given placebo (day 8: -1.17, P = .001; day 29: -1.18, P = .001; day 57: -0.85, P = .024) and titration SPT with birch difference in area under the curve of mean wheal diameters for subjects treated with REGN5713/14/15 versus placebo (all P < .001) were sustained for ≥2 months; similar results were observed with alder SPT. REGN5713/14/15 was well tolerated. Basophil responsiveness to birch-related allergens was significantly decreased in subjects treated with REGN5713/14/15 versus those given placebo on days 8, 57, and 113 (all P < .01). CONCLUSIONS: Single-dose REGN5713/14/15 was well tolerated and provided a rapid (1 week) and durable (2 months) reduction in allergic symptoms after birch allergen nasal allergen challenge, potentially offering a new paradigm for the treatment of birch allergy symptoms.
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Alérgenos/inmunología , Anticuerpos Monoclonales/uso terapéutico , Antígenos de Plantas/inmunología , Inmunoglobulina G/uso terapéutico , Rinitis Alérgica Estacional/terapia , Adulto , Basófilos/inmunología , Betula/inmunología , Desensibilización Inmunológica , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Rinitis Alérgica Estacional/inmunología , Adulto JovenRESUMEN
BACKGROUND: To determine the proportion and reproducibility of cat-allergic mild asthmatics with early asthmatic response (EAR) during cat allergen exposure in a naturalistic exposure chamber (NEC). METHODS: This was a prospective, observational study in 30 cat-allergic mild asthmatics who received two 180-min cat-allergen (Felis domesticus allergen 1 [Fel d 1]) challenges 27 days apart in an NEC. RESULTS: An EAR (≥20% reduction from baseline in forced expiratory volume in 1 s [FEV1]) was observed in 67% and 52% of subjects at first and second NEC exposure, respectively, with similar median time to EAR; 44% of subjects had an EAR on days 1 and 28. Late asthmatic response (≥15% reduction in FEV1 within 24 h of NEC exit) was observed in 33% of subjects following either exposure. Average FEV1 and total nasal symptom score during NEC exposure were highly correlated within subjects between NEC exposures (r = 0.91, p < 0.0001; r = 0.73, p < 0.001), but total ocular symptom score was not. Time to EAR, but not average FEV1, was significantly associated with NEC Fel d 1 concentration, which was variable. There were no serious adverse events; 12/30 subjects experienced 20 adverse events (including asthma, 10%; headache, 10%). CONCLUSIONS: The NEC model demonstrates that average FEV1 change is highly reproducible and has a low correlation with cat allergen levels. However, time to EAR and incidence of EAR are less reproducible and are highly correlated with NEC allergen levels. Average FEV1, rather than incidence of EAR or time to EAR, could be considered as an endpoint for interventional trials testing cat-specific anti-allergy therapies using an NEC.
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Asma , Hipersensibilidad , Alérgenos , Pruebas de Provocación Bronquial , Volumen Espiratorio Forzado , Humanos , Hipersensibilidad/complicaciones , Estudios Prospectivos , Reproducibilidad de los ResultadosRESUMEN
Rationale: Sensitization to Fel d 1 (Felis domesticus allergen 1) contributes to persistent allergic rhinitis and asthma. Existing treatment options for cat allergy, including allergen immunotherapy, are only moderately effective, and allergen immunotherapy has limited use because of safety concerns. Objectives: To explore the relationship among the pharmacokinetic, clinical, and immunological effects of anti-Fel d 1 monoclonal antibodies (REGN1908-1909) in patients after treatment. Methods: Patients received REGN1908-1909 (n = 36) or a placebo (n = 37) in a phase 1b study. Fel d 1-induced basophil and IgE-facilitated allergen binding responses were evaluated at baseline and Days 8, 29, and 85. Cytokine and chemokine concentrations in nasal fluids were measured, and REGN1908-1909 inhibition of allergen-IgE binding in patient serum was evaluated. Measurements and Main Results: Peak serum drug concentrations were concordant with maximal observed clinical response. The anti-Fel d 1 IgE/cat dander IgE ratio in pretreatment serum correlated with Total Nasal Symptom Score improvement. The allergen-neutralizing capacity of REGN1908-1909 was observed in serum and nasal fluid and was detected in an inhibition assay. Type 2 cytokines (IL-4, IL-5, and IL-13) and chemokines (CCL17/TARC, CCL5/RANTES [regulated upon activation, normal T-cell expressed and secreted]) in nasal fluid were inhibited in REGN1908-1909-treated patients compared with placebo (P < 0.05 for all); IL-13 and IL-5 concentrations correlated with Total Nasal Symptom Score improvement. Ex vivo assays demonstrated that REGN1908 and REGN1909 combined were more potent than each alone for inhibiting FcεRI- and FcεRII (CD23)-mediated allergic responses and subsequent T-cell activation. Conclusions: A single, passive-dose administration of Fel d 1-neutralizing IgG antibodies improved nasal symptoms in cat-allergic patients and was underscored by suppression of FcεRI-, FcεRII-, and T-helper cell type 2-mediated allergic responses. Clinical trial registered with www.clinicaltrials.gov (NCT02127801).
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Alérgenos/efectos adversos , Antialérgicos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Gatos , Glicoproteínas/efectos adversos , Factores Inmunológicos/uso terapéutico , Rinitis Alérgica/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Animales , Antialérgicos/administración & dosificación , Anticuerpos Monoclonales/inmunología , Método Doble Ciego , Femenino , Humanos , Factores Inmunológicos/administración & dosificación , Inmunoterapia , Masculino , Persona de Mediana Edad , Efecto Placebo , Rinitis Alérgica/etiología , Rinitis Alérgica/inmunologíaRESUMEN
BACKGROUND: Characterising the clinical and immunological impact of daily cat exposure in cat-allergic subjects with asthma who live with cats (WC) and those who do not (WoC) may provide understanding of the drivers of the allergic response. METHODS: Clinical and immunological characteristics (skin prick test, spirometry, symptom assessments, immunological markers) were compared between asthmatic subjects WC (n = 10) and WoC (n = 9). RESULTS: WC subjects had greater use of long-acting beta agonists (p < .05) and high-potency corticosteroids. No differences were observed in lung function, nasal and ocular symptoms, or asthma control between the groups. Cat dander- and Fel d 1-specific IgG4 concentrations were higher in WC than WoC subjects (both p < .05). Total IgE and cat dander-, Fel d 1- and Fel d 7-specific IgE concentrations were similar, but Fel d 4-sIgE was higher in WC subjects (p < .05) versus WoC. Basophil sensitivity to cat dander extract and Fel d 1 was lower in WC versus WoC subjects (p < .05) and correlated with higher IgG4 concentrations (r = 0.63; p = .009). Fel d 1-specific CD4+ T-cell responses polarised toward Th2A responses in WC versus WoC subjects; Fel d 1-specific IgE correlated with surface expression of CRTH2 and CD200R (both p ≤ .05). CONCLUSION: Immunological differences observed in WC versus WoC did not reflect clinical tolerance with natural cat exposure. The ability to live with a cat despite allergy could be driven by higher preventative medication use. This study may support design of novel therapeutics for allergy management.
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Asma , Hipersensibilidad , Alérgenos , Asma/diagnóstico , Glicoproteínas , Humanos , Inmunoglobulina ERESUMEN
BACKGROUND: Birch pollen is a prevalent aeroallergen during the springtime allergy season. In field studies, variable allergen exposure and environmental factors can affect data quality while environmental exposure units (EEUs) deliver controlled, standardized, and reproducible allergen exposures. OBJECTIVE: To inform study design for EEU trials evaluating antiallergic therapies. METHODS: In this prospective study, 76 participants with birch allergy experienced 3 exposures to birch pollen: (1) an out-of-season EEU challenge (two 3-hour sessions on consecutive days); (2) a natural seasonal exposure; and (3) an in-season EEU challenge (3-hour exposure for 2 weeks after birch pollen season initiation). RESULTS: The total nasal symptom score, total ocular symptom score, and total symptom score (TSS = total nasal symptom score plus total ocular symptom score) were assessed every 30 minutes and daily during EEU and natural exposures. A high association between TSSs and day 2 of the out-of-season and in-season EEU challenges was noted, with a good association between the maximum TSS during the natural and in-season EEU challenges, and natural season and day 2 of the out-of-season EEU challenge (P < .001 for all). Participants had higher maximum change from the baseline TSS during day 2 of the out-of-season EEU challenge (12.4) vs the following: (1) first day (9.8); (2) in-season EEU challenge (8.4); and (3) natural seasonal exposure (7.6) (P < .001 for all). CONCLUSION: A strong association was seen between the presence of allergy symptoms and exposure to birch pollen in the EEU (maximum change in symptom scores during day 2) and in the field. A hybrid trial design may be useful to demonstrate the clinical efficacy of novel antiallergic therapies requiring fewer participants and shorter timelines and expediting treatment availability.
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Antialérgicos/uso terapéutico , Betula/inmunología , Exposición a Riesgos Ambientales/efectos adversos , Polen/inmunología , Rinitis Alérgica Estacional/tratamiento farmacológico , Adulto , Alérgenos/administración & dosificación , Alérgenos/inmunología , Cetirizina/uso terapéutico , Femenino , Humanos , Masculino , Furoato de Mometasona/uso terapéutico , Clorhidrato de Olopatadina/uso terapéutico , Estudios Prospectivos , Rinitis Alérgica Estacional/inmunología , Estaciones del Año , Índice de Severidad de la EnfermedadRESUMEN
DNA double strand breaks (DSBs) are one of the most deleterious lesions and if left unrepaired, they lead to cell death, genomic instability and carcinogenesis. Cells combat DSBs by two pathways: homologous recombination (HR) and non-homologous end-joining (NHEJ), wherein the two DNA ends are re-joined. Recently a back-up NHEJ pathway has been reported and is referred to as alternative NHEJ (aNHEJ), which joins ends but results in deletions and insertions. NHEJ requires processing enzymes including nucleases and polymerases, although the roles of these enzymes are poorly understood. Emerging evidence indicates that X family DNA polymerases lambda (Pol λ) and mu (Pol µ) promote DNA end-joining. Here, we show that DNA polymerase beta (Pol ß), another member of the X family of DNA polymerases, plays a role in aNHEJ. In the absence of DNA Pol ß, fewer small deletions are observed. In addition, depletion of Pol ß results in cellular sensitivity to bleomycin and DNA protein kinase catalytic subunit inhibitors due to defective repair of DSBs. In summary, our results indicate that Pol ß in functions in aNHEJ and provide mechanistic insight into its role in this process.
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Roturas del ADN de Doble Cadena , Reparación del ADN por Unión de Extremidades , ADN Polimerasa beta/metabolismo , ADN/metabolismo , Línea Celular Tumoral , ADN/genética , Daño del ADN , Replicación del ADN/genética , Proteínas de Unión al ADN/metabolismo , Humanos , Células MCF-7RESUMEN
The impact of iron chelation therapy (ICT) on overall survival (OS) and progression to acute myeloid leukemia (AML) in patients with iron overload and International Prognostic Scoring System low- or intermediate-risk myelodysplastic syndromes (MDS) is not well understood. We conducted a systematic review and meta-analysis of published studies of ICT in patients with MDS to better elucidate these relationships. We searched PubMed, EMBASE, Cochrane databases, and the World Health Organization Clinical Trial Registry for studies reporting the impact of ICT on OS in patients with low- or intermediate-risk MDS. Studies were examined for demographics, effect measures, and potential bias risk. Fixed and random-effects models were used to calculate adjusted OS and adjusted hazards ratio (aHR) estimates, respectively, among the different studies. Nine observational studies (four prospective and five retrospective) were identified. For patients with MDS, ICT was associated with an overall lower risk of mortality compared with no ICT (aHR 0.42; 95% confidence interval (CI) 0.28-0.62; P < 0.01); however, there was significant heterogeneity across the studies. In studies reporting progression to AML, ICT was not associated with decreased risk of progression (odds ratio 0.68; 95% CI 0.31-1.43; P < 0.030). This systematic review and meta-analysis of nine nonrandomized trials demonstrated significant reduction in risk of mortality in patients with iron overload and low- or intermediate-risk MDS treated with ICT; however, a causal relationship cannot be established. Randomized, controlled trials are needed to more definitively evaluate the relationship between ICT and survival in patients with iron overload and low- or intermediate-risk MDS.
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Quelantes del Hierro/uso terapéutico , Modelos Biológicos , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/mortalidad , Ensayos Clínicos como Asunto , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
We propose a two-stage design for a single arm clinical trial with an early stopping rule for futility. This design employs different endpoints to assess early stopping and efficacy. The early stopping rule is based on a criteria determined more quickly than that for efficacy. These separate criteria are also nested in the sense that efficacy is a special case of, but usually not identical to, the early stopping endpoint. The design readily allows for planning in terms of statistical significance, power, expected sample size, and expected duration. This method is illustrated with a phase II design comparing rates of disease progression in elderly patients treated for lung cancer to rates found using a historical control. In this example, the early stopping rule is based on the number of patients who exhibit progression-free survival (PFS) at 2 months post treatment follow-up. Efficacy is judged by the number of patients who have PFS at 6 months. We demonstrate our design has expected sample size and power comparable with the Simon two-stage design but exhibits shorter expected duration under a range of useful parameter values.
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Ensayos Clínicos Fase II como Asunto/métodos , Interpretación Estadística de Datos , Terminación Anticipada de los Ensayos Clínicos/métodos , Proyectos de Investigación , Anciano , Progresión de la Enfermedad , Determinación de Punto Final , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Supervivencia sin Progresión , Tamaño de la Muestra , Factores de TiempoRESUMEN
Patients with primary refractory or relapsed acute myeloid leukemia (RR-AML) have very poor prognosis. Due to limited treatment options, some patients are treated with hypomethylating agents (HMAs) due to their tolerability. Little is known about the role of allogeneic hematopoietic stem cell transplantation (HSCT) following HMA therapy in this setting. We retrospectively analyzed an international cohort of 655 RR-AML patients who received HMA therapy to study patterns and outcomes with HSCT. Only 37 patients (5.6%) patients underwent HSCT after HMA therapy. The conditioning regimen was myeloablative in 57% and nonmyeloablative in 43%. Patients received matched unrelated donor, matched sibling, haploidentical and mismatched unrelated HSCT in 56%, 24%, 16% and 4% of cases, respectively. Acute GvHD and chronic GvHD were observed in 40% and 17% of patients. While the median OS for the entire cohort of patients was 15.3 months (95% CI 9.5 - 21.7 months), OS reached 29.7 months (95% CI 7.01 - not-reached) for patients who achieved a complete remission (CR) to HMA and no intervening therapies between HMA therapy and HSCT. Our study suggests that HMA therapy can effectively bridge some patients with RR-AML to HSCT.
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Antimetabolitos Antineoplásicos/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/terapia , Terapia Recuperativa/métodos , Acondicionamiento Pretrasplante/métodos , Adulto , Anciano , Femenino , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Terapia Recuperativa/mortalidad , Análisis de Supervivencia , Acondicionamiento Pretrasplante/mortalidad , Trasplante HomólogoRESUMEN
Red blood cell transfusions have become standard of care for the prevention of life-threatening anemia in patients with ß-thalassemia and sickle cell disease (SCD). However, frequent transfusions can lead to accumulation of iron that can result in liver cirrhosis, diabetes mellitus, arthritis, arrhythmias, cardiomyopathy, heart failure, and hypogonadotropic hypogonadism. Iron chelation therapy has been shown to reduce serum ferritin levels and liver iron content, but limitations of trial design have prevented any demonstration of improved survival. The objective of this systematic review was to investigate the impact of iron chelation therapy on overall and event-free survival in patients with ß-thalassemia and SCD. Eighteen articles discussing survival in ß-thalassemia and 3 in SCD were identified. Overall iron chelation therapy resulted in better overall survival, especially if it is instituted early and compliance is maintained. Comparative studies did not show any significant differences between available iron chelation agents, although there is evidence that deferiprone is better tolerated than deferoxamine and that compliance is more readily maintained with the newer oral drugs, deferiprone and deferasirox. Iron chelation therapy, particularly the second-generation oral agents, appears to be associated with improved overall and event-free survival in transfusion-dependent patients with ß-thalassemia and patients with SCD.
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Anemia de Células Falciformes/tratamiento farmacológico , Quelantes del Hierro/uso terapéutico , Talasemia beta/tratamiento farmacológico , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/mortalidad , Transfusión Sanguínea , Deferiprona/efectos adversos , Deferiprona/uso terapéutico , Deferoxamina/efectos adversos , Deferoxamina/uso terapéutico , Humanos , Quelantes del Hierro/efectos adversos , Cumplimiento de la Medicación , Análisis de Supervivencia , Talasemia beta/mortalidadAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Enfermedad Injerto contra Huésped/prevención & control , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas , Donante no Emparentado , Adulto , Anciano , Aloinjertos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/mortalidad , Neoplasias Hematológicas/mortalidad , Humanos , Masculino , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Persona de Mediana Edad , Proyectos Piloto , Sirolimus/administración & dosificación , Sirolimus/efectos adversos , Tasa de Supervivencia , Tacrolimus/administración & dosificación , Tacrolimus/efectos adversosRESUMEN
PURPOSE: We present a phase I/II first-in-human trial evaluating the safety and efficacy of 50 mg and 200 mg doses of linvoseltamab, a B-cell maturation antigen × CD3 bispecific antibody in relapsed/refractory multiple myeloma (RRMM). METHODS: Phase II eligible patients had RRMM that either progressed on/after ≥three lines of therapy including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody or was triple-class (PI/IMiD/anti-CD38) refractory. Phase II treatment was once a week through week 14 and then once every 2 weeks. Phase II 200 mg patients who achieved a ≥very good partial response by week 24 received linvoseltamab once every 4 weeks. The primary end point in phase II was overall response rate (ORR). RESULTS: Among the 117 patients treated with 200 mg, the median age was 70 years, 39% had high-risk cytogenetics, and 28% had penta-refractory disease. At a median follow-up of 14.3 months, the ORR was 71%, with 50% achieving ≥complete response (CR). In 104 patients treated with 50 mg at a median follow-up of 7.4 months, the ORR was 48%, with 21% achieving ≥CR. The median duration of response (DOR) for 200 mg patients (n = 83) was 29.4 months (95% CI, 19.2 to not evaluable). Among 200 mg patients, the most common adverse events included cytokine release syndrome (35.0% Gr1, 10.3% Gr2, 0.9% Gr3), neutropenia (0.9% Gr2, 18.8% Gr3, 23.1% Gr4), and anemia (3.4% Gr1, 4.3% Gr2, 30.8% Gr3). Immune effector cell-associated neurotoxicity syndrome occurred in 7.7% of patients (2.6% each Gr1, Gr2, Gr3). Infections were reported in 74.4% of patients (33.3% Gr3, 2.6% Gr4); infection frequency and severity declined over time. CONCLUSION: Linvoseltamab 200 mg induced deep and durable responses, with a median DOR of 29.4 months, in patients with RRMM with an acceptable safety profile.
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Anticuerpos Biespecíficos , Mieloma Múltiple , Humanos , Mieloma Múltiple/tratamiento farmacológico , Anciano , Masculino , Femenino , Persona de Mediana Edad , Anciano de 80 o más Años , Anticuerpos Biespecíficos/uso terapéutico , Anticuerpos Biespecíficos/efectos adversos , Anticuerpos Biespecíficos/administración & dosificación , Antígeno de Maduración de Linfocitos B/antagonistas & inhibidores , Antígeno de Maduración de Linfocitos B/inmunología , Adulto , Recurrencia Local de Neoplasia/tratamiento farmacológicoRESUMEN
Immunoglobulin E (IgE) is a key driver of type 1 hypersensitivity reactions and allergic disorders, which are globally increasing in number and severity. Although eliminating pathogenic IgE may be a powerful way to treat allergy, no therapeutic strategy reported to date can fully ablate IgE production. Interleukin-4 receptor α (IL-4Rα) signaling is required for IgE class switching, and IL-4Rα blockade gradually reduces, but does not eliminate, IgE. The persistence of IgE after IL-4Rα blockade may be due to long-lived IgE+ plasma cells that maintain serological memory to allergens and thus may be susceptible to plasma cell-targeted therapeutics. We demonstrate that transient administration of a B cell maturation antigen x CD3 (BCMAxCD3) bispecific antibody markedly depletes IgE, as well as other immunoglobulins, by ablating long-lived plasma cells, although IgE and other immunoglobulins rapidly rebound after treatment. Concomitant IL-4Rα blockade specifically and durably prevents the reemergence of IgE by blocking IgE class switching while allowing the restoration of other immunoglobulins. Moreover, this combination treatment prevented anaphylaxis in mice. Together with additional cynomolgus monkey and human data, our studies demonstrate that allergic memory is primarily maintained by both non-IgE+ memory B cells that require class switching and long-lived IgE+ plasma cells. Our combination approach to durably eliminate pathogenic IgE has potential to benefit allergy in humans while preserving antibody-mediated immunity.
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Anafilaxia , Inmunoglobulina E , Ratones , Humanos , Animales , Macaca fascicularis , Células Plasmáticas , AlérgenosRESUMEN
The artemin-GFRα3 signaling pathway has been implicated in various painful conditions including migraine, cold allodynia, hyperalgesia, inflammatory bone pain, and mouse knees contain GFRα3-immunoreactive nerve endings. We developed high affinity mouse (REGN1967) and human (REGN5069) GFRα3-blocking monoclonal antibodies and, following in vivo evaluations in mouse models of chronic joint pain (osteoarthritic-like and inflammatory), conducted a first-in-human phase 1 pharmacokinetics (PK) and safety trial of REGN5069 (NCT03645746) in healthy volunteers, and a phase 2 randomized placebo-controlled efficacy and safety trial of REGN5069 (NCT03956550) in patients with knee osteoarthritis (OA) pain. In three commonly used mouse models of chronic joint pain (destabilization of the medial meniscus, intra-articular monoiodoacetate, or Complete Freund's Adjuvant), REGN1967 and REGN5069 attenuated evoked behaviors including tactile allodynia and thermal hyperalgesia without discernably impacting joint pathology or inflammation, prompting us to further evaluate REGN5069 in humans. In the phase 1 study in healthy subjects, the safety profiles of single doses of REGN5069 up to 3000 mg (intravenous) or 600 mg (subcutaneous) were comparable to placebo; PK were consistent with a monoclonal antibody exhibiting target-mediated disposition. In the phase 2 study in patients with OA knee pain, two doses of REGN5069 (100 mg or 1000 mg intravenous every 4 weeks) for 8 weeks failed to achieve the 12-week primary and secondary efficacy endpoints relative to placebo. In addition to possible differences in GFRα3 biology between mice and humans, we highlight here differences in experimental parameters that could have contributed to a different profile of efficacy in mouse models versus human OA pain. Additional research is required to more fully evaluate any potential role of GFRα3 in human pain.
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REGN1908-1909, a 1:1 cocktail of two fully human IgG4 monoclonal antibodies (mAbs), REGN1908 and REGN1909, is being evaluated for treatment of cat allergy. Both REGN1908 and REGN1909 bind to the dominant cat allergen, Fel d 1. Adults with cat allergy confirmed by skin prick test (SPT) were randomized to single subcutaneous administration of placebo (n = 6) or REGN1908-1909 at doses of 150 (n = 6), 300 (n = 6), or 600 mg (n = 6). Blood samples were taken at prespecified time points for pharmacokinetic (PK) analysis and exploratory evaluation of biomarkers (IgE and SPT). Safety was assessed. Drug concentration-time profiles in serum for ascending doses of REGN1908-1909 were consistent with linear PKs. Noncompartmental analysis showed that maximum concentration (Cmax ) and exposure increased proportionately with dose, with similar time to maximum concentration (Tmax ) for REGN1908 and REGN1909 (6.2 to 8.2 days across doses), and a longer terminal half-life for REGN1908 (~ 30 days) relative to REGN1909 (~ 21 days). Adverse events were not dose dependent; there were no dose-limiting toxicities. REGN1908-1909 is characterized by linear and dose-proportional kinetics of the two individual mAb components. A single 600 mg dose maintains total mAb mean concentrations in serum above the target (mean of ~ 10 mg/L) for 8-12 weeks. Maintaining this mean target concentration resulted in translational pharmacodynamic effects: maximal mast cell degranulation in a passive cutaneous anaphylaxis mouse model, and maintenance of clinical efficacy measured by Total Nasal Symptom Score in a previous proof-of-mechanism study.
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Alérgenos/efectos de los fármacos , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/farmacocinética , Hipersensibilidad/tratamiento farmacológico , Adolescente , Adulto , Alérgenos/inmunología , Animales , Antialérgicos/farmacología , Antialérgicos/uso terapéutico , Anticuerpos Monoclonales/inmunología , Gatos , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Although combination BRAF and MEK inhibitors are highly effective for the 40-50% of cutaneous metastatic melanomas harboring BRAFV600 mutations, targeted agents have been ineffective for BRAFV600wild-type (wt) metastatic melanomas. The SU2C Genomics-Enabled Medicine for Melanoma Trial utilized a Simon two-stage optimal design to assess whether comprehensive genomic profiling improves selection of molecular-based therapies for BRAFV600wt metastatic melanoma patients who had progressed on standard-of-care therapy, which may include immunotherapy. Of the response-evaluable patients, binimetinib was selected for 20 patients randomized to the genomics-enabled arm, and nine were treated on the alternate treatment arm. Response rates for 27 patients treated with targeted recommendations included one (4%) partial response, 18 (67%) with stable disease, and eight (30%) with progressive disease. Post-trial genomic and protein pathway activation mapping identified additional drug classes that may be considered for future studies. Our results highlight the complexity and heterogeneity of metastatic melanomas, as well as how the lack of response in this trial may be associated with limitations including monotherapy drug selection and the dearth of available single and combination molecularly-driven therapies to treat BRAFV600wt metastatic melanomas.
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Bencimidazoles/administración & dosificación , Genómica , Melanoma , Proteínas Proto-Oncogénicas B-raf , Neoplasias Cutáneas , Adulto , Anciano , Femenino , Humanos , Masculino , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/metabolismo , Persona de Mediana Edad , Metástasis de la Neoplasia , Proyectos Piloto , Estudios Prospectivos , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismo , Melanoma Cutáneo MalignoRESUMEN
Introduction: Previous studies have shown that cannabis use is common in adults with sickle cell disease (SCD), and that many patients report using cannabis to treat pain. Methods: We performed a cross-sectional study of adults with SCD and compared daily users of cannabis with others using validated patient-reported measures of pain and quality of life as well as opioid and health care utilization. Results: Daily cannabis users with SCD had worse pain episode severity scores than others (56.7 vs. 48.8, p=0.02) yet had 1.8 fewer annual admissions (p=0.01) and 1.2 fewer annual emergency room (ER) visits (p=0.01), and similar amounts of opioids dispensed to others after matching for age, gender, SCD genotype, hydroxyurea use, and pain impact scores. Conclusions: We show that people with SCD with more severe pain crisis are more likely to use daily cannabis, yet have lower rates of hospital admission and ER use as compared with others with similar disease severity and pain impact. Randomized controlled trials should be performed.
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PURPOSE: EGFR exon 19 deletion (Ex19Del) mutations account for approximately 60% of lung cancer-associated EGFR mutations and include a heterogeneous group of mutations. Although they are associated with benefit from tyrosine kinase inhibitors (TKI), the relative inhibitor sensitivity of individual Ex19Del mutations is unknown.Experimental Design: We studied the TKI sensitivity and structural features of common Ex19Del mutations and the consequences for patient outcomes on TKI treatment. RESULTS: We found that the L747-A750>P mutation, which represents about 4% of all Ex19Del mutations, displays unique inhibitor selectivity. L747-A750>P differs from other Ex19Del mutations in not being suppressed completely by erlotinib or osimertinib, yet is completely inhibited by low doses of afatinib. The HCC4006 cell line (with the L747-A750>P mutation) exhibited increased sensitivity to afatinib over erlotinib and osimertinib, and computational modeling suggests explanations for this sensitivity pattern. Clinically, patients with EGFR L747-A750>P mutant tumors showed inferior outcomes when treated with erlotinib than patients with E746-A750 mutant tumors. CONCLUSIONS: These results highlight important differences between specific Ex19Del mutations that may be relevant for optimizing TKI choice for patients.
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Adenocarcinoma del Pulmón/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/química , Acrilamidas/química , Acrilamidas/farmacología , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Afatinib/química , Afatinib/farmacología , Compuestos de Anilina/química , Compuestos de Anilina/farmacología , Animales , Células CHO , Cricetulus , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/química , Receptores ErbB/genética , Clorhidrato de Erlotinib/química , Clorhidrato de Erlotinib/farmacología , Exones/genética , Eliminación de Gen , Humanos , Modelos Químicos , Simulación de Dinámica Molecular , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Resultado del TratamientoRESUMEN
We introduce a discrete distribution suggested by curtailed sampling rules common in early-stage clinical trials. We derive the distribution of the smallest number of independent and identically distributed Bernoulli trials needed to observe either s successes or t failures. This report provides a closed-form expression for the mass function, moment generating function, and provides connections to other, standard distributions.