An Allosteric Monoclonal Antibody that Increases the Affinity of the Insulin Receptor for Insulin, and Preferentially Improves Insulin Signaling for the B but not the A Isoform of the Receptor

Program: Late-Breaking Abstracts
Session: SUN-LB-Late-Breaking Poster Session 2
Bench to Bedside
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-LB-04
John Allen Corbin*1, Vinay Bhaskar2, Ira D Goldfine3, Daniel H Bedinger4, Angela Lau5, Kristen Michelson6, Lisa M Gross6, Betty A Maddux7, Hua F Kuan6, Catarina Tran6, Llewelyn Lao6 and Mark L White5
1XOMA Corporation, Berkelely, CA, 2XOMA Corporation, Berkeley, CA, 3UCSF-Mt Zion Med Ctr, San Francisco, CA, 4XOMA (US) LLC, Berkelely, CA, 5XOMA Corporation, Berkeley, CA, 6XOMA Corporation, 7UCSF-Mt Zion Med Ctr
XMetS is a novel, fully human, allosteric monoclonal antibody to the insulin receptor (INSR). XMetS binds with picomolar affinity to both isoforms of the INSR: the B isoform that is present in most adult tissues and primarily mediates metabolic effects and the A isoform that is present in most fetal tissues and primarily mediates mitogenic effects.  In contrast to the INSR, XMetS does not potentiate the closely related IGF-1 receptor.  The effects of this antibody were characterized with cultured CHO cells expressing either the A or B isoforms of the INSR.  XMetS was found to be a strong positive allosteric modulator of the INSR that increased insulin binding affinity to both isoforms by over 10-fold.  Next, the effect of XMetS on the potentiation of insulin-stimulated downstream INSR signaling was quantitated. XMetS alone had no agonist effect on either isoform.  In cells expressing the B isoform of the INSR, the sensitivity of the cells to insulin-stimulated phosphorylation of both Akt and Erk was increased 30-40 fold by XMetS.  In contrast, in cells expressing the A isoform of the INSR, the sensitivity of the cells to insulin-stimulated phosphorylation of both Akt and Erk was increased only 3-5 fold by XMetS. In cultured L6 muscle cells, which express the B isoform, XMetS enhanced insulin-stimulated glucose transport. However, in MCF-7 and SAOS-2 cancer cells, which express mainly the A isoform, XMetS had no effect either alone or on insulin-mediated cell growth. In two mouse models of insulin resistance and diabetes, the obese, insulin resistant, hyperinsulinemic DIO mouse and the diabetic multi-low dose streptozotocin/high-fat diet (MLDS/HFD) insulinopenic mouse, XMetS normalized fasting blood glucose levels and glucose tolerance.  In concert with its ability to potentiate insulin action at the INSR, XMetS reduced insulin and C-peptide levels in these mouse models.  In addition, XMetS improved the response to exogenous insulin without causing hypoglycemia.  These data indicate that an allosteric monoclonal antibody markedly and selectively enhances the binding affinity and signaling of insulin with the B isoform of the INSR  with only minor effects on signaling via the A isoform.  These data also suggest that an INSR monoclonal antibody with these characteristics may have the potential to both improve glucose metabolism in insulinopenic type 2 diabetes mellitus and correct compensatory hyperinsulinism in insulin resistant conditions.

Disclosure: JAC: Employee, XOMA (US) LLC. VB: Employee, XOMA (US) LLC. IDG: Researcher, XOMA (US) LLC. AL: Employee, XOMA. KM: Employee, XOMA. LMG: Employee, XOMA. HFK: Employee, XOMA. CT: Employee, XOMA. LL: Employee, XOMA. MLW: Employee, XOMA (US) LLC. Nothing to Disclose: DHB, BAM

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