GLP-1类似物融合蛋白质

摘要

本发明提供与特定IgG4-Fc衍生物融合的特定GLP-1类似物。这些融合蛋白质具有增加的半寿期、降低的免疫原性，并降低了效应子活性。这些融合蛋白质可用于治疗糖尿病、肥胖、肠易激综合征以及将通过降低血浆葡萄糖、抑制胃和/或肠运动和抑制胃和/或肠排空、或抑制食物摄入而受益的其他疾病。

主权项

异源融合蛋白质，其包含GLP 1类似物，其中GLP 1类似物由选自如下的序列组成：a)(SEQ ID NO：1)His Xaa8 Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly其中Xaa8选自Gly和Val；b)(SEQ ID NO：2)His Xaa8 Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Lys Asn Gly Gly Gly其中Xaa8选自Gly和Val；c)(SEQ ID NO：3)His Xaa8 Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Pro其中Xaa8选自Gly和Val；d)(SEQ ID NO：4)His Xaa8 Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Lys Asn Gly Gly Pro其中Xaa8选自Gly和Val；e)(SEQ ID NO：5)His Xaa8 Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly其中Xaa8选自Gly和Val；f)(SEQ ID NO：6)His Xaa8 Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Lys Asn Gly Gly其中Xaa8选自Gly和Val；GLP 1类似物与由SEQ ID NO：7序列组成的免疫球蛋白Fc部分通过肽接头融合Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Xaa16 Xaa17 Xaa18 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Xaa80 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Xaaa230(SEQ ID NO：7)其中：第16位的Xaa为Pro或Glu；第17位的Xaa为Phe、Val或Ala；第18位的Xaa为Leu、Glu或Ala；第80位的Xaa为Asn或Ala；以及第230位的Xaa为Lys或缺乏。