RESUMEN
Current treatments for advanced stage, hormone-resistant prostate cancer are largely ineffective, leading to high patient mortality and morbidity. To fulfill this unmet medical need, we used global gene expression profiling to identify new potential antibody-drug conjugate (ADC) targets that showed maximal prostate cancer-specific expression. TMEFF2, a gene encoding a plasma membrane protein with two follistatin-like domains and one epidermal growth factor-like domain, had limited normal tissue distribution and was highly overexpressed in prostate cancer. Immunohistochemistry analysis using a specific monoclonal antibody (mAb) to human TMEFF2 showed significant protein expression in 74% of primary prostate cancers and 42% of metastatic lesions from lymph nodes and bone that represented both hormone-naïve and hormone-resistant disease. To evaluate anti-TMEFF2 mAbs as potential ADCs, one mAb was conjugated to the cytotoxic agent auristatin E via a cathepsin B-sensitive valine-citrulline linker. This ADC, Pr1-vcMMAE, was used to treat male severe combined immunodeficient mice bearing xenografted LNCaP and CWR22 prostate cancers expressing TMEFF2. Doses of 3 to 10 mg/kg of this specific ADC resulted in significant and sustained tumor growth inhibition, whereas an isotype control ADC had no significant effect. Similar efficacy and specificity was shown with huPr1-vcMMAE, a humanized anti-TMEFF2 ADC. No overt in vivo toxicity was observed with either murine or human ADC, despite significant cross-reactivity of anti-TMEFF2 mAb with the murine TMEFF2 protein, implying minimal toxicity to other body tissues. These data support the further evaluation and clinical testing of huPr1-vcMMAE as a novel therapeutic for the treatment of metastatic and hormone-resistant prostate cancer.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Proteínas de la Membrana/química , Proteínas de la Membrana/inmunología , Proteínas de Neoplasias/química , Proteínas de Neoplasias/inmunología , Oligopéptidos/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Secuencia de Aminoácidos , Animales , Anticuerpos Monoclonales/química , Antineoplásicos/química , Encéfalo/metabolismo , Membrana Celular/metabolismo , Proliferación Celular , Clonación Molecular , ADN Complementario/metabolismo , Citometría de Flujo , Folistatina/química , Humanos , Hibridomas/química , Inmunohistoquímica , Cinética , Metástasis Linfática , Masculino , Ratones , Microscopía Fluorescente , Datos de Secuencia Molecular , Metástasis de la Neoplasia , Análisis de Secuencia por Matrices de Oligonucleótidos , Oligopéptidos/química , Próstata/metabolismo , Neoplasias de la Próstata/metabolismo , Estructura Terciaria de Proteína , ARN Mensajero/metabolismo , Proteínas Recombinantes de Fusión/metabolismo , Homología de Secuencia de Aminoácido , Resonancia por Plasmón de Superficie , Factores de Tiempo , TransfecciónRESUMEN
Agents used to control end-of-life suffering are associated with troublesome side effects. The use of dexmedetomidine for sedation during withdrawal of support in pediatrics is not yet described. An adolescent female with progressive and irreversible pulmonary deterioration was admitted. Despite weeks of therapy, she did not tolerate weaning of supplemental oxygen or continuous bilevel positive airway pressure. Given her condition and the perception that she was suffering, the family requested withdrawal of support. Despite opioids and benzodiazepines, she appeared to be uncomfortable after support was withdrawn. Ketamine was initiated. Relief from ketamine was brief, and its use was associated with a "wide-eyed" look that was distressing to the family. Ketamine was discontinued and a dexmedetomidine infusion was initiated. The patient's level of comfort improved greatly. The child died peacefully 24 hours after initiating dexmedetomidine from her underlying disease rather than the effects of the sedative.