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Evaluation of anti insulin receptor antibodies as potential novel therapies for human insulin receptoropathy

Gemma. V. Brierley, Kenneth. Siddle, Robert. K. Semple
doi: https://doi.org/10.1101/223883
Gemma. V. Brierley
1The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, CB2 0QQ, UK
2The National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke’s Hospital, Cambridge, CB2 0QQ, UK.
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Kenneth. Siddle
1The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, CB2 0QQ, UK
2The National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke’s Hospital, Cambridge, CB2 0QQ, UK.
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Robert. K. Semple
1The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, CB2 0QQ, UK
2The National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke’s Hospital, Cambridge, CB2 0QQ, UK.
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Abstract

Biallelic loss-of-function mutations in the insulin receptor (INSR) commonly cause extreme insulin resistance and early mortality. Therapeutic options are limited, but anti-INSR antibodies have previously been shown to activate two mutant receptors. This study evaluated four murine anti-INSR monoclonal antibodies, each capable of stimulating wildtype INSR signaling, against ten known pathogenic INSR mutants and one novel mutation, F248C. All the mutant INSR bound antibody. Eight mutants showed antibody-induced autophosphorylation while co-treatment with antibody and insulin increased maximal phosphorylation. After simultaneous knockdown of mouse Insr and expression of mutant INSR in 3T3-L1 adipocytes two antibodies activated signaling via AKT preferentially over signaling via ERK1/2 for seven mutants. Two antibodies (83-7 and 83-14) stimulated glucose uptake via P193L, S323L, F382V, and D707A mutant INSR, with antibody response greater than insulin response for D707A. These findings suggest that selected monoclonal anti-INSR antibodies elicit sufficient signaling by some mutated INSR to be clinically significant.

One sentence summary Anti-insulin receptor monoclonal antibodies can activate selected naturally occurring mutated human insulin receptors, raising the prospect of novel therapy for lethal recessive insulin resistance.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted November 22, 2017.
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Evaluation of anti insulin receptor antibodies as potential novel therapies for human insulin receptoropathy
Gemma. V. Brierley, Kenneth. Siddle, Robert. K. Semple
bioRxiv 223883; doi: https://doi.org/10.1101/223883
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Evaluation of anti insulin receptor antibodies as potential novel therapies for human insulin receptoropathy
Gemma. V. Brierley, Kenneth. Siddle, Robert. K. Semple
bioRxiv 223883; doi: https://doi.org/10.1101/223883

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