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    • 99. 发明公开
    • Soluble non-depot insulin conjugates and uses thereof
    • LÖSLICHENICHTDEPOT-INSULINKONJUGATE和IHRE VERWENDUNG
    • EP2408470A4
    • 2012-08-29
    • EP10753833
    • 2010-01-27
    • SMARTCELLS INC
    • ZION TODD CLANCASTER THOMAS M
    • A61K38/28A61K38/17A61K38/30C07K14/47C07K14/62C07K14/65
    • C07K14/62A61K38/28A61K47/549A61K47/6415C07K14/4713C07K14/4743C07K14/65
    • In one aspect, the disclosure provides a conjugate comprising an insulin molecule having an A-chain and a B-chain; an affinity ligand covalently bound to the A-chain; and a monovalent glucose binding agent covalently bound to the B-chain, wherein the affinity ligand competes with glucose for non-covalent binding with the monovalent glucose binding agent. In the absence of glucose, the monovalent glucose binding agent binds the affinity ligand to produce a "closed" inactive form of the insulin molecule. When free glucose is added, it competes with the affinity ligand for binding with the monovalent glucose binding agent to produce an "open" active form of the insulin molecule. The monovalent glucose binding agent and affinity ligand are covalently bound to the insulin molecule. The disclosure also provides methods of using these conjugates and methods of making these conjugates. In another aspect, the disclosure provides exemplary conjugates. The disclosure also provides alternative conjugates that are not necessarily activated by glucose.
    • 在一个方面,本公开提供了包含具有A-链和B-链的胰岛素分子的缀合物; 与A链共价结合的亲和配体; 和与B链共价结合的单价葡萄糖结合剂,其中亲和配体与葡萄糖竞争与单价葡萄糖结合剂非共价结合。 在不存在葡萄糖的情况下,单价葡萄糖结合剂结合亲和配体以产生胰岛素分子的“封闭”失活形式。 当添加游离葡萄糖时,其与亲和配体竞争与单价葡萄糖结合剂结合以产生胰岛素分子的“开放”活性形式。 单价葡萄糖结合剂和亲和配体与胰岛素分子共价结合。 本公开还提供了使用这些缀合物的方法和制备这些缀合物的方法。 另一方面,本公开提供了示例性的缀合物。 本公开还提供了不一定被葡萄糖激活的替代缀合物。