Asunto(s)
Miositis/complicaciones , Trastornos de la Motilidad Ocular/etiología , Músculos Oculomotores , Niño , Relación Dosis-Respuesta a Droga , Desensibilización y Reprocesamiento del Movimiento Ocular , Femenino , Glucocorticoides/administración & dosificación , Humanos , Miositis/diagnóstico , Miositis/tratamiento farmacológico , Trastornos de la Motilidad Ocular/diagnóstico , Trastornos de la Motilidad Ocular/tratamiento farmacológico , Prednisolona/administración & dosificación , Síndrome , Tomografía Computarizada por Rayos XRESUMEN
Mammalian cell culture systems are used predominantly for the production of therapeutic monoclonal antibody (mAb) products. A number of alternative platforms, such as Pichia engineered with a humanized N-linked glycosylation pathway, have recently been developed for the production of mAbs. The glycosylation profiles of mAbs produced in glycoengineered Pichia are similar to those of mAbs produced in mammalian systems. This report presents for the first time the comprehensive characterization of an anti-human epidermal growth factor receptor 2 (HER2) mAb produced in a glycoengineered Pichia, and a study comparing the anti-HER2 from Pichia, which had an amino acid sequence identical to trastuzumab, with trastuzumab. The comparative study covered a full spectrum of preclinical evaluation, including bioanalytical characterization, in vitro biological functions, in vivo anti-tumor efficacy and pharmacokinetics in both mice and non-human primates. Cell signaling and proliferation assays showed that anti-HER2 from Pichia had antagonist activities comparable to trastuzumab. However, Pichia-produced material showed a 5-fold increase in binding affinity to FcγIIIA and significantly enhanced antibody dependant cell-mediated cytotoxicity (ADCC) activity, presumably due to the lack of fucose on N-glycans. In a breast cancer xenograft mouse model, anti-HER2 was comparable to trastuzumab in tumor growth inhibition. Furthermore, comparable pharmacokinetic profiles were observed for anti-HER2 and trastuzumab in both mice and cynomolgus monkeys. We conclude that glycoengineered Pichia provides an alternative production platform for therapeutic mAbs and may be of particular interest for production of antibodies for which ADCC is part of the clinical mechanism of action.
Asunto(s)
Anticuerpos Monoclonales Humanizados/inmunología , Anticuerpos Monoclonales/inmunología , Pichia/genética , Receptor ErbB-2/inmunología , Proteínas Recombinantes/inmunología , Animales , Anticuerpos Monoclonales/genética , Anticuerpos Monoclonales/metabolismo , Afinidad de Anticuerpos/inmunología , Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacos , Citotoxicidad Celular Dependiente de Anticuerpos/inmunología , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Área Bajo la Curva , Unión Competitiva/inmunología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Evaluación Preclínica de Medicamentos , Fucosa/metabolismo , Ingeniería Genética , Humanos , Macaca fascicularis , Ratones , Ratones Endogámicos C57BL , Pichia/metabolismo , Polisacáridos/metabolismo , Unión Proteica/inmunología , Receptores de IgG/inmunología , Receptores de IgG/metabolismo , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/farmacología , Trastuzumab , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Strabismus is a well recognized complication of retrobulbar anesthesia for cataract surgery. This may manifest as either paresis or sometimes contracture (overaction) in the late stage. Management of the patient is tailored to the individual case. Herein, we report a patient with inferior rectus paresis and medial rectus overaction after retrobulbar anesthesia. The presenting symptom was diplopia increasing on downgaze, which improved with medial rectus recession and plication of the inferior rectus.