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


Hugentobler, Leoni. Human-derived antibody targeting pancreatic islet amyloid for the treatment of type 2 diabetes. 2017, University of Zurich, Vetsuisse Faculty.

Abstract

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, mature
amyloid 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 in
NI-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 insulin
secretion. The lower dose even normalized body weight gain. As conclusion, passive immunization targeting IAPP aggregates is a very promising approach to treat T2DM.

Abstract

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, mature
amyloid 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 in
NI-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 insulin
secretion. The lower dose even normalized body weight gain. As conclusion, passive immunization targeting IAPP aggregates is a very promising approach to treat T2DM.

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Additional indexing

Item Type:Dissertation
Referees:Lutz Thomas A, Zini Eric
Communities & Collections:05 Vetsuisse Faculty > Institute of Veterinary Physiology
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:2017
Deposited On:18 Oct 2017 16:25
Last Modified:19 Mar 2018 08:49
Number of Pages:66
OA Status:Green
Related URLs:https://www.recherche-portal.ch/ZAD:default_scope:ebi01_prod010911738 (Library Catalogue)

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