| Title: |
Evaluation of anti-insulin receptor antibodies as potential novel therapies for human insulin receptoropathy using cell culture models. |
| Authors: |
Brierley, Gemma V; Siddle, Kenneth; Semple, Robert K |
| Publisher Information: |
Springer Nature; //doi.org/10.1007/s00125-018-4606-2 |
| Publication Year: |
2018 |
| Collection: |
Apollo - University of Cambridge Repository |
| Subject Terms: |
Diabetes; Donohue syndrome; Insulin receptor; Insulin resistance; Insulin signalling; Monoclonal antibodies; Rabson–Mendenhall syndrome; 3T3-L1 Cells; Adipocytes; Animals; Antibodies; Antigens; CD; CHO Cells; Cricetulus; Glucose; Humans; Hypoglycemic Agents; Insulin; Mice; Mutation; Phosphorylation; Receptor; Signal Transduction |
| Description: |
AIMS/HYPOTHESIS: Bi-allelic loss-of-function mutations in the INSR gene (encoding the insulin receptor [INSR]) commonly cause extreme insulin resistance and early mortality. Therapeutic options are limited, but anti-INSR antibodies have been shown to activate two mutant receptors, S323L and F382V. This study evaluates four well-characterised murine anti-INSR monoclonal antibodies recognising distinct epitopes (83-7, 83-14, 18-44, 18-146) as surrogate agonists for potential targeted treatment of severe insulin resistance arising from insulin receptoropathies. METHODS: Ten naturally occurring mutant human INSRs with defects affecting different aspects of receptor function were modelled and assessed for response to insulin and anti-INSR antibodies. A novel 3T3-L1 adipocyte model of insulin receptoropathy was generated, permitting conditional knockdown of endogenous mouse Insr by lentiviral expression of species-specific short hairpin (sh)RNAs with simultaneous expression of human mutant INSR transgenes. RESULTS: All expressed mutant INSR bound to all antibodies tested. Eight mutants showed antibody-induced autophosphorylation, while co-treatment with antibody and insulin increased maximal phosphorylation compared with insulin alone. After knockdown of mouse Insr and expression of mutant INSR in 3T3-L1 adipocytes, two antibodies (83-7 and 83-14) activated signalling via protein kinase B (Akt) preferentially over signalling via extracellular signal-regulated kinase 1/2 (ERK1/2) for seven mutants. These antibodies stimulated glucose uptake via P193L, S323L, F382V and D707A mutant INSRs, with antibody response greater than insulin response for D707A. CONCLUSIONS/INTERPRETATION: Anti-INSR monoclonal antibodies can activate selected naturally occurring mutant human insulin receptors, bringing closer the prospect of novel therapy for severe insulin resistance caused by recessive mutations. |
| Document Type: |
article in journal/newspaper |
| File Description: |
Print-Electronic; application/pdf |
| Language: |
English |
| Relation: |
https://www.repository.cam.ac.uk/handle/1810/276693 |
| DOI: |
10.17863/CAM.23988 |
| Availability: |
https://www.repository.cam.ac.uk/handle/1810/276693; https://doi.org/10.17863/CAM.23988 |
| Rights: |
Attribution 4.0 International ; https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.CB687F41 |
| Database: |
BASE |