title: Novel Monoclonal Antibody Is an Allosteric Insulin Receptor Antagonist That Induces Insulin Resistance.
abstract: A hallmark of type 2 diabetes is impaired insulin receptor (IR) signaling that results in dysregulation of glucose homeostasis. Understanding the molecular origins and progression of diabetes and developing therapeutics depend on experimental models of hyperglycemia, hyperinsulinemia, and insulin resistance. We present a novel monoclonal antibody, IRAB-B, that is a specific, potent IR antagonist that creates rapid and long-lasting insulin resistance. IRAB-B binds to the IR with nanomolar affinity and in the presence of insulin efficiently blocks receptor phosphorylation within minutes and is sustained for at least 3 days in vitro. We further confirm that IRAB-B antagonizes downstream signaling and metabolic function. In mice, a single dose of IRAB-B induces rapid onset of hyperglycemia within 6 h, and severe hyperglycemia persists for 2 weeks. IRAB-B hyperglycemia is normalized in mice treated with exendin-4, suggesting that this model can be effectively treated with a GLP-1 receptor agonist. Finally, a comparison of IRAB-B with the IR antagonist S961 shows distinct antagonism in vitro and in vivo. IRAB-B appears to be a powerful tool to generate both acute and chronic insulin resistance in mammalian models to elucidate diabetic pathogenesis and evaluate therapeutics.
authors: Biologics Research, Janssen BioTherapeutics, Janssen Pharmaceutical Research & Development, Spring House, PA.
authors: Anne M
authors: AM
authors: Cieniewicz
authors: Cardiovascular & Metabolism Therapeutic Area, Janssen Pharmaceutical Research & Development, Spring House, PA.
authors: Thomas
authors: T
authors: Kirchner
authors: Cardiovascular & Metabolism Therapeutic Area, Janssen Pharmaceutical Research & Development, Spring House, PA.
authors: Simon A
authors: SA
authors: Hinke
authors: Biologics Research, Janssen BioTherapeutics, Janssen Pharmaceutical Research & Development, Spring House, PA.
authors: Rupesh
authors: R
authors: Nanjunda
authors: Cardiovascular & Metabolism Therapeutic Area, Janssen Pharmaceutical Research & Development, Spring House, PA.
authors: Katharine
authors: K
authors: D'Aquino
authors: Biologics Research, Janssen BioTherapeutics, Janssen Pharmaceutical Research & Development, Spring House, PA.
authors: Ken
authors: K
authors: Boayke
authors: Biologics Research, Janssen BioTherapeutics, Janssen Pharmaceutical Research & Development, Spring House, PA.
authors: Philip R
authors: PR
authors: Cooper
authors: Biologics Research, Janssen BioTherapeutics, Janssen Pharmaceutical Research & Development, Spring House, PA.
authors: Robert
authors: R
authors: Perkinson
authors: Biologics Research, Janssen BioTherapeutics, Janssen Pharmaceutical Research & Development, Spring House, PA.
authors: Mark L
authors: ML
authors: Chiu
authors: Biologics Research, Janssen BioTherapeutics, Janssen Pharmaceutical Research & Development, Spring House, PA.
authors: Stephen
authors: S
authors: Jarantow
authors: Cardiovascular & Metabolism Therapeutic Area, Janssen Pharmaceutical Research & Development, Spring House, PA.
authors: Dana L
authors: DL
authors: Johnson
authors: Cardiovascular & Metabolism Therapeutic Area, Janssen Pharmaceutical Research & Development, Spring House, PA.
authors: Jean M
authors: JM
authors: Whaley
authors: Biologics Research, Janssen BioTherapeutics, Janssen Pharmaceutical Research & Development, Spring House, PA.
authors: Eilyn R
authors: ER
authors: Lacy
authors: Biologics Research, Janssen BioTherapeutics, Janssen Pharmaceutical Research & Development, Spring House, PA.
authors: Russell B
authors: RB
authors: Lingham
authors: Cardiovascular & Metabolism Therapeutic Area, Janssen Pharmaceutical Research & Development, Spring House, PA.
authors: Yin
authors: Y
authors: Liang
authors: Biologics Research, Janssen BioTherapeutics, Janssen Pharmaceutical Research & Development, Spring House, PA akihm3@its.jnj.com.
authors: Anthony J
authors: http://orcid.org/0000-0002-7925-8308
authors: AJ
authors: Kihm
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015153:Blotting, Western; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2; D000067757:Glucagon-Like Peptide-1 Receptor / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation; D011485:Protein Binding; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D000911:Antibodies, Monoclonal; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; C532752:S961 peptide; D011972:Receptor, Insulin; D000097789:Glucagon-Like Peptide-1 Receptor Agonists