title: A fully human, allosteric monoclonal antibody that activates the insulin receptor and improves glycemic control.
abstract: Many patients with diabetes mellitus (both type 1 and type 2) require therapy to maintain normal fasting glucose levels. To develop a novel treatment for these individuals, we used phage display technology to target the insulin receptor (INSR) complexed with insulin and identified a high affinity, allosteric, human monoclonal antibody, XMetA, which mimicked the glucoregulatory, but not the mitogenic, actions of insulin. Biophysical studies with cultured cells expressing human INSR demonstrated that XMetA acted allosterically and did not compete with insulin for binding to its receptor. XMetA was found to function as a specific partial agonist of INSR, eliciting tyrosine phosphorylation of INSR but not the IGF-IR. Although this antibody activated metabolic signaling, leading to enhanced glucose uptake, it neither activated Erk nor induced proliferation of cancer cells. In an insulin resistant, insulinopenic model of diabetes, XMetA markedly reduced elevated fasting blood glucose and normalized glucose tolerance. After 6 weeks, significant improvements in HbA(1c), dyslipidemia, and other manifestations of diabetes were observed. It is noteworthy that hypoglycemia and weight gain were not observed during these studies. These studies indicate, therefore, that allosteric monoclonal antibodies have the potential to be novel, ultra-long acting, agents for the regulation of hyperglycemia in diabetes.
authors.affiliation: Preclinical Research Department, XOMA (US) LLC, Berkeley, California, USA. bhaskar@xoma.com
authors.forename: Vinay
authors.initials: V
authors.lastname: Bhaskar
authors.forename: Ira D
authors.initials: ID
authors.lastname: Goldfine
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Bedinger
authors.forename: Angela
authors.initials: A
authors.lastname: Lau
authors.forename: Hua F
authors.initials: HF
authors.lastname: Kuan
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Gross
authors.forename: Masahisa
authors.initials: M
authors.lastname: Handa
authors.forename: Betty A
authors.initials: BA
authors.lastname: Maddux
authors.forename: Susan R
authors.initials: SR
authors.lastname: Watson
authors.forename: Shirley
authors.initials: S
authors.lastname: Zhu
authors.forename: Ajay J
authors.initials: AJ
authors.lastname: Narasimha
authors.forename: Raphael
authors.initials: R
authors.lastname: Levy
authors.forename: Lynn
authors.initials: L
authors.lastname: Webster
authors.forename: Sujeewa D
authors.initials: SD
authors.lastname: Wijesuriya
authors.forename: Naichi
authors.initials: N
authors.lastname: Liu
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Wu
authors.forename: David
authors.initials: D
authors.lastname: Chemla-Vogel
authors.forename: Catarina
authors.initials: C
authors.lastname: Tran
authors.forename: Steve R
authors.initials: SR
authors.lastname: Lee
authors.forename: Steve
authors.initials: S
authors.lastname: Wong
authors.forename: Diane
authors.initials: D
authors.lastname: Wilcock
authors.forename: Mark L
authors.initials: ML
authors.lastname: White
authors.forename: John A
authors.initials: JA
authors.lastname: Corbin
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D000918:Antibody Specificity; D015415:Biomarkers; D001786:Blood Glucose / Q000502:physiology*; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003921:Diabetes Mellitus, Experimental / Q000628:therapy*; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011972:Receptor, Insulin / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction; D013047:Specific Pathogen-Free Organisms
chemical_list: D000911:Antibodies, Monoclonal; D015415:Biomarkers; D001786:Blood Glucose; D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt