RESUMEN
Type 2 diabetes (T2D) is a complex and progressive disease requiring polypharmacy to manage hyperglycaemia and cardiovascular risk factors. However, most patients do not achieve combined treatment goals. To address this therapeutic gap, we have developed MEDI4166, a novel glucagon-like peptide-1 (GLP-1) receptor agonist peptide fused to a proprotein convertase subtilisin/kexin type 9 (PCSK9) neutralising antibody that allows for glycaemic control and low-density lipoprotein cholesterol (LDL-C) lowering in a single molecule. The fusion has been engineered to deliver sustained peptide activity in vivo in combination with reduced potency, to manage GLP-1 driven adverse effects at high dose, and a favourable manufacturability profile. MEDI4166 showed robust and sustained LDL-C lowering in cynomolgus monkeys and exhibited the anticipated GLP-1 effects in T2D mouse models. We believe MEDI4166 is a novel molecule combining long acting agonist peptide and neutralising antibody activities to deliver a unique pharmacology profile for the management of T2D.
Asunto(s)
Anticuerpos Monoclonales , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Péptido 1 Similar al Glucagón , Hipoglucemiantes , Inhibidores de PCSK9 , Proteínas Recombinantes de Fusión , Animales , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales/farmacología , Células CHO , Cricetulus , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Células Hep G2 , Humanos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Macaca fascicularis , Masculino , Ratones , Proteínas Recombinantes de Fusión/farmacocinética , Proteínas Recombinantes de Fusión/farmacologíaRESUMEN
Bone morphogenetic proteins (BMPs) and growth differentiation factors (GDFs) control the development and homeostasis of multiple tissue types in many organisms, from humans to invertebrates. These morphogens are expressed in a tissue-specific manner and they signal by binding to serine-threonine kinase receptors, resulting in coordinated changes in gene expression that regulate the differentiation and development of multiple tissue types. In addition, these proteins are regulated post-transcriptionally through binding to several soluble proteins. In this review we focus on a subset of BMPs and GDFs that have been implicated in the pathophysiology of type 2 diabetes and cardiovascular disease.
Asunto(s)
Receptores de Proteínas Morfogenéticas Óseas/metabolismo , Proteínas Morfogenéticas Óseas/metabolismo , Enfermedades Cardiovasculares/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Enfermedades Metabólicas/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Animales , Aterosclerosis/metabolismo , Proteína Morfogenética Ósea 7 , Receptores de Proteínas Morfogenéticas Óseas/efectos de los fármacos , Receptores de Proteínas Morfogenéticas Óseas/genética , Proteínas Morfogenéticas Óseas/antagonistas & inhibidores , Fármacos Cardiovasculares/farmacología , Enfermedades Cardiovasculares/genética , Diabetes Mellitus Tipo 2/metabolismo , Factor 3 de Diferenciación de Crecimiento , Humanos , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/metabolismo , Hipoglucemiantes/farmacología , Enfermedades Renales/metabolismo , Transducción de Señal/efectos de los fármacos , Factor de Crecimiento Transformador beta/antagonistas & inhibidoresRESUMEN
Myostatin is a secreted protein that negatively regulates skeletal muscle mass determining both muscle fiber number and size. The myostatin pathway is conserved and regulates muscle mass in a number of animal species ranging from fish to humans. Inhibition of myostatin using a variety of therapeutic approaches can increase muscle mass in a number of animal models of human disease, including muscular dystrophy.