RESUMEN

Antibody-based immunotherapy represents a promising strategy to eliminate chemorefractory leukemic cells in acute myeloid leukemia (AML). In this study, we evaluated a novel Fc-engineered antibody against CD157 (MEN1112) for its suitability as immunotherapy in AML. CD157 was expressed in 97% of primary AML patient samples. A significant, albeit lower expression level of CD157 was observed within the compartment of leukemia-initiating cells, which are supposed to be the major source of relapse. In healthy donor bone marrow, CD157 was expressed on CD34+ cells. In ex vivo assays, MEN1112 triggered natural killer (NK) cell-mediated cytotoxicity against AML cell lines and primary AML cells. Compared to its parental analogue, the Fc-engineered antibody exhibited higher antibody dependent cellular cytotoxicity responses. Using NK cells from AML patients, we observed heterogeneous MEN1112-mediated cytotoxicity against AML cells, most likely due to well-documented defects in AML-NK cells and corresponding inter-patient variations in NK cell function. Cytotoxicity could not be correlated to the time after completion of chemotherapy. In summary, we could demonstrate that CD157 is strongly expressed in AML. MEN1112 is a promising antibody construct that showed high cytotoxicity against AML cells and warrants further clinical testing. Due to variability in NK-cell function of AML patients, the time of application during the course of the disease as well as combinatorial strategies might influence treatment results.

Asunto(s)

ADP-Ribosil Ciclasa/antagonistas & inhibidores , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Terapia Molecular Dirigida , Proteínas Recombinantes de Fusión/uso terapéutico , ADP-Ribosil Ciclasa/genética , ADP-Ribosil Ciclasa/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Citotoxicidad Celular Dependiente de Anticuerpos , Antígenos CD/genética , Antígenos CD/metabolismo , Biomarcadores de Tumor , Línea Celular Tumoral , Femenino , Citometría de Flujo , Proteínas Ligadas a GPI/antagonistas & inhibidores , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Expresión Génica , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Humanos , Células Asesinas Naturales/inmunología , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/inmunología , Masculino , Persona de Mediana Edad , Adulto Joven

RESUMEN

A simple technique for the diastereoselective alkylation of a metal stabilised enolate is demonstrated within a pressure-driven micro reactor whereby enhanced diastereoselectivities were obtained compared to batch.

RESUMEN

We have demonstrated that peptides may be electrophoretically separated from unreacted reagents within an integrated micro reactor.

Asunto(s)

Electroforesis/métodos , Microquímica/instrumentación , Microquímica/métodos , Péptidos/aislamiento & purificación , Cromatografía Líquida de Alta Presión , Electroforesis/instrumentación , Estructura Molecular , Péptidos/química

RESUMEN

We demonstrate a simple method for the regioselective preparation of 1,3-diketones within a micro reactor from silyl enol ethers where the products are free from both competing O-acylation and diacylation products.

RESUMEN

We demonstrate that peptides derived from alpha-amino acids may be prepared in a micro reactor. The peptides were prepared in 20 min with quantitative conversion, compared to batch reactions which require prolonged reaction times. We illustrate that by using dilute reagent concentrations and short reaction times, less racemisation is observed in micro reactions than in bulk reactions.

Asunto(s)

Péptidos/síntesis química , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Estereoisomerismo

RESUMEN

We demonstrate the formation of a series of diketone enolates and their subsequent reaction with alpha,beta-unsaturated carbonyl compounds in order to prepare a variety of Michael adducts. In all cases, the conversions observed within a micro reactor were greater than those obtained in batch.