Alleva D G, Maki R A, Putnam A L, Robinson J M, Kipnes M S, Dandona P, Marks J B, Simmons D L, Greenbaum C J, Jimenez R G, Conlon P J, Gottlieb P A
Neurocrine Biosciences, Inc., San Diego, CA 92130, USA.
Scand J Immunol. 2006 Jan;63(1):59-69. doi: 10.1111/j.1365-3083.2005.01705.x.
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.
NBI-6024是一种修饰肽配体（APL），对应于胰岛素B链的9-23氨基酸区域（B(9-23)），这是1型糖尿病患者中产生炎性干扰素-γ的辅助性T（Th）1淋巴细胞识别的一个表位。在一项I期临床试验（NBI-6024-0003）中，使用酶联免疫斑点试验在外周血单核细胞中测定了NBI-6024给药对近期发病糖尿病患者的免疫调节作用。对每个队列中细胞因子对B(9-23)和NBI-6024反应的平均强度分析显示，相对于接受安慰剂的队列，接受APL的队列中白细胞介素-5反应（一种Th2调节表型）显著增加。反应者分析表明，几乎仅在接受安慰剂治疗的糖尿病患者群体中观察到对B(9-23)和NBI-6024的Th1反应，而在非糖尿病对照受试者中未观察到，并且APL给药（每两周皮下注射5次）显著且剂量依赖性地降低了出现这些Th1反应的患者百分比。这项I期临床研究的结果强烈表明，NBI-6024治疗使近期发病的1型糖尿病患者的Th1致病反应转变为保护性的Th2调节表型。目前正在一项II期多剂量研究中调查这些发现对疾病临床结局的意义。
