FP33-6 Inhibition of the Insulin Receptor Function by a Human, Allosteric, Monoclonal Antibody: a Novel Approach for the Treatment of Hyperinsulinemic Hypoglycemia

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP33-Insulin Signaling & Inflammation
Monday, June 17, 2013: 10:45 AM-11:15 AM
Presentation Start Time: 11:10 AM
Room 303 (Moscone Center)

Poster Board MON-845
John Allen Corbin*1, Vinay Bhaskar2, Ira D Goldfine3, Daniel H Bedinger4, Paul Rubin5 and Mark L White6
1XOMA Corporation, Berkelely, CA, 2XOMA Corporation, Berkeley, CA, 3University of California San Francisco, San Francisco, CA, 4XOMA (US) LLC, Berkelely, CA, 5XOMA (US) LLC, Berkeley, CA, 6XOMA Corporation, Berkeley, CA
Novel therapies are needed for the treatment of hypoglycemia that results from both endogenous and exogenous hyperinsulinema.  To provide a potential new treatment option we identified XMetD, an allosteric monoclonal antibody to the insulin receptor (INSR).  XMetD was obtained from a human antibody phage display library by panning with the insulin-INSR complex as the antigen.  The effect of XMetD on INSR binding and signaling was then investigated in vitro with cultured cells expressing either the human INSR or mouse INSR, and in vivo with mice.  Mechanistic studies in vitro indicated that XMetD bound allosterically to the INSR with nanomolar affinity.  Although XMetD did not directly compete with insulin for binding to the INSR orthosteric binding site, it reduced the affinity of the receptor for insulin 5-fold via negative allosteric modulation.  In addition to inhibiting INSR binding by affinity modulation, XMetD also inhibited several insulin-induced INSR signaling functions 20 to 100-fold by efficacy modulation.  These signaling functions included INSR autophosphorylation, Akt activation, and glucose transport.  IP injection of XMetD at 10 mg/kg twice weekly into non-fasted normal mice induced hyperglycemia.  When sustained-release insulin implants were placed into normal mice, they developed fasting hypoglycemia in the range of 50 mg/dl or less.  This hypoglycemia was reversed by XMetD treatment.  These studies demonstrate that allosteric monoclonal antibodies, such as XMetD, can antagonize INSR signaling both in vitro and in vivo.  They also suggest that this class of allosteric monoclonal antibody could become a treatment for conditions of hyperinsulinemic hypoglycemia such as insulinoma, congenital hyperinsulinism and insulin overdose.

Disclosure: JAC: Employee, XOMA (US) LLC. VB: Employee, XOMA (US) LLC. IDG: Researcher, XOMA (US) LLC. PR: Employee, XOMA (US) LLC. MLW: Employee, XOMA (US) LLC. Nothing to Disclose: DHB

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

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