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    • 5. 发明申请
    • IMMUNOSUPPRESSIVE AGENTS AND THEIR USE IN THERAPY
    • 免疫抑制剂及其治疗用途
    • WO2016177898A1
    • 2016-11-10
    • PCT/EP2016/060231
    • 2016-05-06
    • NORWEGIAN UNIVERSITY OF SCIENCE AND TECHNOLOGY (NTNU)
    • OTTERLEI, Marit
    • A61K38/17C07K14/435A61P37/00
    • A61K38/1709C07K14/52Y02A50/385Y02A50/411Y02A50/423Y02A50/478Y02A50/481
    • The present invention provides an agent, or composition containing an agent, for use in treating or preventing hypercytokinemia in a subject resulting from cytokine release from non-proliferating immune cells in blood, wherein said agent comprises: (i) an oligopeptidic compound comprising a PCNA interacting motif and a domain that facilitates the cellular uptake of said compound, wherein the PCNA interacting motif is X 1 X 2 X 3 X 4 X 5 X 6 (SEQ ID NO: 1 ) and wherein: X 1 is a basic amino acid; X 2 is an aromatic amino acid; X 3 is an aromatic amino acid or a hydrophobic amino acid that has an R group comprising at least three carbon atoms; X 4 is an uncharged amino acid other than an aromatic amino acid, Glycine (G) and Proline (P); X 5 is any amino acid other than an acidic amino acid or an aromatic amino acid; and X 6 is any amino acid other than an acidic amino acid or an aromatic amino acid, preferably a basic amino acid or Proline (P), wherein when X 3 is not an aromatic amino acid, X 5 is not lysine (K) and X 6 is a basic amino acid or Proline (P); or (ii) a nucleic acid molecule comprising a sequence encoding the oligopeptidic compound of (i). In certain aspects the agent and composition of the invention may be used as single agents. In other aspects of the invention the agents and composition may be used in conjunction with one or more additional active agents, such as kinase inhibitors.
    • 本发明提供了一种用于治疗或预防由血液中的非增殖性免疫细胞释放细胞因子而产生的高细胞因子血症的试剂或组合物,其中所述试剂包含:(i)包含PCNA的寡肽化合物 促进所述化合物的细胞摄取的相互作用基序和结构域,其中所述PCNA相互作用基序是X1X2X3X4X5X6(SEQ ID NO:1),其中:X1是碱性氨基酸; X2是芳香族氨基酸; X3是具有至少三个碳原子的R基团的芳族氨基酸或疏水性氨基酸; X4是除芳香族氨基酸,甘氨酸(G)和脯氨酸(P)之外的不带电荷的氨基酸; X5是酸性氨基酸或芳香族氨基酸以外的氨基酸; X6是酸性氨基酸或芳香族氨基酸,优选碱性氨基酸或脯氨酸(P)以外的氨基酸,其中,当X3不是芳香族氨基酸时,X5不是赖氨酸(K),X6是 碱性氨基酸或脯氨酸(P); 或(ii)包含编码(i)的寡肽化合物的序列的核酸分子。 在某些方面,本发明的试剂和组合物可以用作单一试剂。 在本发明的其它方面,试剂和组合物可以与一种或多种另外的活性剂如激酶抑制剂结合使用。