Yan Hai, Gu Wei, Yang Jie, Bi Vivian, Shen Yuqing, Lee Eunkyung, Winters Katherine A, Komorowski Renée, Zhang Cheng, Patel Jennifer J, Caughey Dorothy, Elliott Gary S, Lau Yvonne Y, Wang Jin, Li Yue-Sheng, Boone Tom, Lindberg Richard A, Hu Sylvia, Véniant Murielle M
Department of Protein Sciences, Amgen Inc., Thousand Oaks, CA 91320, USA.
J Pharmacol Exp Ther. 2009 Apr;329(1):102-11. doi: 10.1124/jpet.108.147009. Epub 2009 Jan 7.
Antagonizing the glucagon signaling pathway represents an attractive therapeutic approach for reducing excess hepatic glucose production in patients with type 2 diabetes. Despite extensive efforts, there is currently no human therapeutic that directly inhibits the glucagon/glucagon receptor pathway. We undertook a novel approach by generating high-affinity human monoclonal antibodies (mAbs) to the human glucagon receptor (GCGR) that display potent antagonistic activity in vitro and in vivo. A single injection of a lead antibody, mAb B, at 3 mg/kg, normalized blood glucose levels in ob/ob mice for 8 days. In addition, a single injection of mAb B dose-dependently lowered fasting blood glucose levels without inducing hypoglycemia and improved glucose tolerance in normal C57BL/6 mice. In normal cynomolgus monkeys, a single injection improved glucose tolerance while increasing glucagon and active glucagon-like peptide-1 levels. Thus, the anti-GCGR mAb could represent an effective new therapeutic for the treatment of type 2 diabetes.
拮抗胰高血糖素信号通路是减少2型糖尿病患者肝脏葡萄糖过量生成的一种有吸引力的治疗方法。尽管付出了巨大努力，但目前尚无直接抑制胰高血糖素/胰高血糖素受体途径的人体治疗药物。我们采用了一种新方法，即生成针对人胰高血糖素受体（GCGR）的高亲和力人单克隆抗体（mAb），这些抗体在体外和体内均表现出强大的拮抗活性。单次注射3 mg/kg的先导抗体mAb B可使ob/ob小鼠的血糖水平在8天内恢复正常。此外，单次注射mAb B可剂量依赖性降低正常C57BL/6小鼠的空腹血糖水平，且不诱导低血糖，并改善葡萄糖耐量。在正常食蟹猴中，单次注射可改善葡萄糖耐量，同时增加胰高血糖素和活性胰高血糖素样肽-1水平。因此，抗GCGR单克隆抗体可能是治疗2型糖尿病的一种有效的新疗法。
