title: Selective allosteric antibodies to the insulin receptor for the treatment of hyperglycemic and hypoglycemic disorders.
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.
authors.affiliation: Preclinical Research, XOMA Corporation, Berkeley, CA, USA issafras@xoma.com.
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: John A
authors.initials: JA
authors.lastname: Corbin
authors.affiliation: Preclinical Research, XOMA Corporation, Berkeley, CA, USA Department of Medicine, University of California, San Francisco, USA.
authors.forename: Ira D
authors.initials: ID
authors.lastname: Goldfine
authors.affiliation: Preclinical Research, XOMA Corporation, Berkeley, CA, USA.
authors.forename: Vinay
authors.initials: V
authors.lastname: Bhaskar
authors.affiliation: Preclinical Research, XOMA Corporation, Berkeley, CA, USA.
authors.forename: Mark L
authors.initials: ML
authors.lastname: White
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: Patrick J
authors.initials: PJ
authors.lastname: Scannon
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy*; D007003:Hypoglycemia / Q000188:drug therapy*; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D007004:Hypoglycemic Agents; D007328:Insulin; D011972:Receptor, Insulin; D051058:Oncogene Protein v-akt
keywords: allosteric; blood glucose; diabetes; glycemic disorders; hyperinsulinemia; monoclonal antibody