title: Inhibition of insulin receptor function by a human, allosteric monoclonal antibody: a potential new approach for the treatment of hyperinsulinemic hypoglycemia.
abstract: Novel therapies are needed for the treatment of hypoglycemia resulting 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) that was isolated from a human antibody phage display library. To selectively obtain antibodies directed at allosteric sites, panning of the phage display library was conducted using the insulin-INSR complex. Studies indicated that XMetD bound to the INSR with nanomolar affinity. Addition of insulin reduced the affinity of XMetD to the INSR by 3-fold, and XMetD reduced the affinity of the INSR for insulin 3-fold. In addition to inhibiting INSR binding, XMetD also inhibited insulin-induced INSR signaling by 20- to 100-fold. These signaling functions included INSR autophosphorylation, Akt activation and glucose transport. These data indicated that XMetD was an allosteric antagonist of the INSR because, in addition to inhibiting the INSR via modulation of binding affinity, it also inhibited the INSR via modulation of signaling efficacy. Intraperitoneal injection of XMetD at 10 mg/kg twice weekly into normal mice induced insulin resistance. When sustained-release insulin implants were placed into normal mice, they developed fasting hypoglycemia in the range of 50 mg/dl. 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 antibodies has the potential to treat hyperinsulinemic hypoglycemia resulting from conditions such as insulinoma, congenital hyperinsulinism and insulin overdose.
authors.affiliation: Preclinical Research; XOMA Corporation; Berkeley, CA USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Corbin
authors.affiliation: Preclinical Research; XOMA Corporation; Berkeley, CA USA.
authors.forename: Vinay
authors.initials: V
authors.lastname: Bhaskar
authors.affiliation: Department of Medicine; University of California; San Francisco, CA USA.
authors.forename: Ira D
authors.initials: ID
authors.lastname: Goldfine
authors.affiliation: Preclinical Research; XOMA Corporation; Berkeley, CA USA.
authors.forename: Hassan
authors.initials: H
authors.lastname: Issafras
authors.affiliation: Preclinical Research; XOMA Corporation; Berkeley, CA USA.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Bedinger
authors.affiliation: Preclinical Research; XOMA Corporation; Berkeley, CA USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Lau
authors.affiliation: Preclinical Research; XOMA Corporation; Berkeley, CA USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Michelson
authors.affiliation: Preclinical Research; XOMA Corporation; Berkeley, CA USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Gross
authors.affiliation: Department of Medicine; University of California; San Francisco, CA USA.
authors.forename: Betty A
authors.initials: BA
authors.lastname: Maddux
authors.affiliation: Preclinical Research; XOMA Corporation; Berkeley, CA USA.
authors.forename: Hua F
authors.initials: HF
authors.lastname: Kuan
authors.affiliation: Preclinical Research; XOMA Corporation; Berkeley, CA USA.
authors.forename: Catarina
authors.initials: C
authors.lastname: Tran
authors.affiliation: Preclinical Research; XOMA Corporation; Berkeley, CA USA.
authors.forename: Llewelyn
authors.initials: L
authors.lastname: Lao
authors.affiliation: Preclinical Research; XOMA Corporation; Berkeley, CA USA.
authors.forename: Masahisa
authors.initials: M
authors.lastname: Handa
authors.affiliation: Preclinical Research; XOMA Corporation; Berkeley, CA USA.
authors.forename: Susan R
authors.initials: SR
authors.lastname: Watson
authors.affiliation: Preclinical Research; XOMA Corporation; Berkeley, CA USA.
authors.forename: Ajay J
authors.initials: AJ
authors.lastname: Narasimha
authors.affiliation: Preclinical Research; XOMA Corporation; Berkeley, CA USA.
authors.forename: Shirley
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Preclinical Research; XOMA Corporation; Berkeley, CA USA.
authors.forename: Raphael
authors.initials: R
authors.lastname: Levy
authors.affiliation: Preclinical Research; XOMA Corporation; Berkeley, CA USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Webster
authors.affiliation: Preclinical Research; XOMA Corporation; Berkeley, CA USA.
authors.forename: Sujeewa D
authors.initials: SD
authors.lastname: Wijesuriya
authors.affiliation: Preclinical Research; XOMA Corporation; Berkeley, CA USA.
authors.forename: Naichi
authors.initials: N
authors.lastname: Liu
authors.affiliation: Preclinical Research; XOMA Corporation; Berkeley, CA USA.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Wu
authors.affiliation: Preclinical Research; XOMA Corporation; Berkeley, CA USA.
authors.forename: David
authors.initials: D
authors.lastname: Chemla-Vogel
authors.affiliation: Preclinical Research; XOMA Corporation; Berkeley, CA USA.
authors.forename: Steve R
authors.initials: SR
authors.lastname: Lee
authors.affiliation: Preclinical Research; XOMA Corporation; Berkeley, CA USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Wong
authors.affiliation: Preclinical Research; XOMA Corporation; Berkeley, CA USA.
authors.forename: Diane
authors.initials: D
authors.lastname: Wilcock
authors.affiliation: Preclinical Research; XOMA Corporation; Berkeley, CA USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Rubin
authors.affiliation: Preclinical Research; XOMA Corporation; Berkeley, CA USA.
authors.forename: Mark L
authors.initials: ML
authors.lastname: White
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology; D001693:Biological Transport, Active / Q000187:drug effects / Q000276:immunology; D016466:CHO Cells; D044903:Congenital Hyperinsulinism / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D006224:Cricetinae; D003412:Cricetulus; D005947:Glucose / Q000276:immunology; D007333:Insulin Resistance / Q000276:immunology; D051379:Mice; D051381:Rats; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors* / Q000276:immunology; D057127:Single-Chain Antibodies / Q000276:immunology* / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D057127:Single-Chain Antibodies; D011972:Receptor, Insulin; D005947:Glucose
keywords: antagonist; hypoglycemia; insulin; insulin receptor; monoclonal antibody; negative allosteric modulation