Human-derived antibody targeting pancreatic islet amyloid for the treatment of type 2 diabetes

[摘要] Type 2 diabetes (T2DM) is one of the most important public health challenges in humans. One of the hallmarks of T2DM is the deposition of islet amyloid derived from islet amyloid polypeptide (IAPP) in pancreatic islets. Amyloidogenesis involves the stepwise aggregation of IAPP monomers into oligomers, fibrils and, ultimately, matureamyloid deposits. The small toxic IAPP oligomers seem to cause β-cell failure and death. None of the available treatments against T2DM counteracts the aggregation of IAPP and the subsequent loss of pancreatic β-cells. A human-derived antibody NI-203.26C11, which targets human IAPP aggregates was identified, cloned and characterized in vitro and in vivo. Because rat IAPP is not amyloidogenic, transgenic rats with the human IAPP gene (hIAPP, RIPHAT rats) were used. NI-203.26C11 significantly improved glucose tolerance and β-cell function, increased insulin secretion and pancreatic insulin content, reduced fasting glucose and normalized body weight inNI-203.26C11-treated RIPHAT rats compared to controls. In a dose-response study, three different doses of NI-203.26C11 (1, 3, 10 mg/kg) were found to be safe and effective in slowing the progression of T2DM. Interestingly, 1 mg/kg and 10 mg/kg were generally more effective than 3 mg/kg in improving glucose tolerance and insulinsecretion. The lower dose even normalized body weight gain. As conclusion, passive immunization targeting IAPP aggregates is a very promising approach to treat T2DM.

[发布机构] University of Zurich

[效力级别] 570 Life sciences

[关键词] Institute of Veterinary Physiology;570 Life sciences;biology