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Issafras H, Bedinger DH, Corbin JA, et al. Selective allosteric antibodies to the insulin receptor for the treatment of hyperglycemic and hypoglycemic disorders. J Diabetes Sci Technol. 2014;8(4):865-73doi: 10.1177/1932296814529886.
Issafras, H., Bedinger, D. H., Corbin, J. A., Goldfine, I. D., Bhaskar, V., White, M. L., Rubin, P., & Scannon, P. J. (2014). Selective allosteric antibodies to the insulin receptor for the treatment of hyperglycemic and hypoglycemic disorders. Journal of diabetes science and technology, 8(4), 865-73. https://doi.org/10.1177/1932296814529886
Issafras, Hassan, et al. "Selective allosteric antibodies to the insulin receptor for the treatment of hyperglycemic and hypoglycemic disorders." Journal of diabetes science and technology vol. 8,4 (2014): 865-73. doi: https://doi.org/10.1177/1932296814529886
Issafras H, Bedinger DH, Corbin JA, Goldfine ID, Bhaskar V, White ML, Rubin P, Scannon PJ. Selective allosteric antibodies to the insulin receptor for the treatment of hyperglycemic and hypoglycemic disorders. J Diabetes Sci Technol. 2014 Jul;8(4):865-73. doi: 10.1177/1932296814529886. Epub 2014 Apr 07. PMID: 24876415; PMCID: PMC4764207.
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J Diabetes Sci Technol. 2014 Jul;8(4):865-73. doi: 10.1177/1932296814529886. Epub 2014 Apr 07.

Selective allosteric antibodies to the insulin receptor for the treatment of hyperglycemic and hypoglycemic disorders.

Journal of diabetes science and technology

Hassan Issafras, Daniel H Bedinger, John A Corbin, Ira D Goldfine, Vinay Bhaskar, Mark L White, Paul Rubin, Patrick J Scannon

Affiliations

  1. Preclinical Research, XOMA Corporation, Berkeley, CA, USA [email protected].
  2. Preclinical Research, XOMA Corporation, Berkeley, CA, USA.
  3. Preclinical Research, XOMA Corporation, Berkeley, CA, USA Department of Medicine, University of California, San Francisco, USA.

PMID: 24876415 PMCID: PMC4764207 DOI: 10.1177/1932296814529886

Abstract

Many therapeutic monoclonal antibodies act as antagonists to receptors by targeting and blocking the natural ligand binding site (orthosteric site). In contrast, the use of antibodies to target receptors at allosteric sites (distinct from the orthosteric site) has not been extensively studied. This approach is especially important in metabolic diseases in which endogenous ligand levels are dysregulated. Herein, we review our investigations of 3 categories of human monoclonal antibodies that bind allosterically to the insulin receptor (INSR) and affect its activity: XMetA, XMetS and XMetD. XMetA directly activates the INSR either alone or in combination with insulin. XMetS, in contrast, does not directly activate the INSR but markedly enhances the receptor's ability to bind insulin and potentiate insulin signaling. Both XMetA and XMetS are effective in controlling hyperglycemia in mouse models of diabetes. A third allosteric antibody, XMetD, is an inhibitor of INSR signaling. This antibody reverses insulin-induced hypoglycemia in a mouse model of hyperinsulinemia. These studies indicate, therefore, that allosteric antibodies to INSR can modulate its signaling and correct conditions of glucose dysregulation. These studies also raise the possibility that the use of allosteric antibodies can be expanded to other receptors for the treatment of metabolic disorders.

© 2014 Diabetes Technology Society.

Keywords: allosteric; blood glucose; diabetes; glycemic disorders; hyperinsulinemia; monoclonal antibody

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