title: Immunomodulation in type 1 diabetes by NBI-6024, an altered peptide ligand of the insulin B epitope.
abstract: NBI-6024 is an altered peptide ligand (APL) corresponding to the 9-23 amino acid region of the insulin B chain (B(9-23)), an epitope recognized by inflammatory interferon-gamma-producing T helper (Th)1 lymphocytes in type 1 diabetic patients. Immunomodulatory effects of NBI-6024 administration in recent-onset diabetic patients in a phase I clinical trial (NBI-6024-0003) were measured in peripheral blood mononuclear cells using the enzyme-linked immunosorbent spot assay. Analysis of the mean magnitude of cytokine responses to B(9-23) and NBI-6024 for each cohort showed significant increases in interleukin-5 responses (a Th2 regulatory phenotype) in cohorts that received APL relative to those receiving placebo. A responder analysis showed that Th1 responses to B(9-23) and NBI-6024 were observed almost exclusively in the placebo-treated diabetic population but not in nondiabetic control subjects and that APL administration (five biweekly subcutaneous injections) significantly and dose-dependently reduced the percentage of patients with these Th1 responses. The results of this phase I clinical study strongly suggest that NBI-6024 treatment shifted the Th1 pathogenic responses in recent-onset type 1 diabetic patients to a protective Th2 regulatory phenotype. The significance of these findings on the clinical outcome of disease is currently under investigation in a phase II multidose study.
authors.affiliation: Neurocrine Biosciences, Inc., San Diego, CA 92130, USA.
authors.forename: D G
authors.initials: DG
authors.lastname: Alleva
authors.forename: R A
authors.initials: RA
authors.lastname: Maki
authors.forename: A L
authors.initials: AL
authors.lastname: Putnam
authors.forename: J M
authors.initials: JM
authors.lastname: Robinson
authors.forename: M S
authors.initials: MS
authors.lastname: Kipnes
authors.forename: P
authors.initials: P
authors.lastname: Dandona
authors.forename: J B
authors.initials: JB
authors.lastname: Marks
authors.forename: D L
authors.initials: DL
authors.lastname: Simmons
authors.forename: C J
authors.initials: CJ
authors.lastname: Greenbaum
authors.forename: R G
authors.initials: RG
authors.lastname: Jimenez
authors.forename: P J
authors.initials: PJ
authors.lastname: Conlon
authors.forename: P A
authors.initials: PA
authors.lastname: Gottlieb
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D016207:Cytokines / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D006801:Humans; D016056:Immunodominant Epitopes / Q000008:administration & dosage; D007155:Immunologic Factors / Q000008:administration & dosage*; D007328:Insulin / Q000008:administration & dosage*; D007371:Interferon-gamma / Q000378:metabolism*; D008297:Male; D010446:Peptide Fragments / Q000008:administration & dosage*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: D016207:Cytokines; D016056:Immunodominant Epitopes; D007155:Immunologic Factors; D007328:Insulin; C460599:NBI6024; D010446:Peptide Fragments; C097877:insulin B (9-23); D007371:Interferon-gamma