RESUMEN
Adrenocorticotropic hormone (ACTH) is the primary regulator of adrenal glucocorticoid production. Elevated levels of ACTH play a critical role in disease progression in several indications, including congenital adrenal hyperplasia and Cushing disease. We have generated a specific, high-affinity, neutralizing monoclonal antibody (ALD1613) to ACTH. In vitro, ALD1613 neutralizes ACTH-induced signaling via all 5 melanocortin receptors and inhibited ACTH-induced cyclic adenosine monophosphate accumulation in a mouse adrenal cell line (Y1). ALD1613 administration to wild-type rats significantly reduced plasma corticosterone levels in a dose-dependent manner. In rodent models with either chronic infusion of ACTH or acute restraint stress-induced ACTH, corticosterone levels were significantly reduced by ALD1613. Administration of ALD1613 to nonhuman primates on days 1 and 7 stably reduced plasma cortisol levels >50% for 57 days. ALD1613 demonstrates the potential of a monoclonal antibody to be an effective therapeutic for conditions with elevated ACTH levels.
Asunto(s)
Hormona Adrenocorticotrópica/antagonistas & inhibidores , Anticuerpos Monoclonales/farmacología , Hidrocortisona/sangre , Hiperplasia Suprarrenal Congénita/tratamiento farmacológico , Hormona Adrenocorticotrópica/metabolismo , Animales , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Células CHO , Corticosterona/sangre , Cricetinae , Cricetulus , Evaluación Preclínica de Medicamentos , Humanos , Macaca fascicularis , Masculino , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/tratamiento farmacológico , Conejos , Ratas , Ratas Endogámicas Lew , Receptor de Melanocortina Tipo 2/metabolismo , Estrés Psicológico/sangreRESUMEN
Enteropneust hemichordates share several characteristics with chordates, such as a Hox-specified anterior-posterior axis, pharyngeal gill slits, a dorsal central nervous system (CNS), and a juvenile postanal tail. Ptychoderid hemichordates, such as the indirect-developer Ptychodera flava, have feeding larvae and a remarkable capacity to regenerate their CNS. We compared neurulation of ptychoderid hemichordates and chordates using histological analyses, and found many similarities in CNS development. In ptychoderid hemichordates, which lack a notochord, the proboscis skeleton develops from endoderm after neurulation. The position of the proboscis skeleton directly under the nerve cord suggests that it serves a structural role similar to the notochord of chordates. These results suggest that either the CNS preceded evolution of the notochord or that the notochord has been lost in hemichordates. The evolution of the notochord remains ambiguous, but it may have evolved from endoderm, not mesoderm.