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    • 3. 发明授权
    • Bcr-Abl directed compositions and uses for inhibiting Philadelphia
chromosome stimulated cell growth
    • Bcr-Abl定向组合物和用于抑制费城染色体刺激的细胞生长的用途
    • US6107457A
    • 2000-08-22
    • US390353
    • 1995-02-16
    • Ralph B. ArlinghausJiaxin LiuDai LuGabriel Lopez-Berestein
    • Ralph B. ArlinghausJiaxin LiuDai LuGabriel Lopez-Berestein
    • C12N15/09A61K35/76A61K38/00A61P31/12C07K14/82C12N5/08C12N15/12C12P21/02C07K7/00C07K14/00
    • C07K14/82A61K38/00
    • Compositions comprising a mixture of peptides that bind to molecules involved in Bcr-Abl oncoprotein function are disclosed. In addition, expression of functional BCR protein (p160 BCR) or amino terminal fragments thereof (159, 221 and 413 amino terminal residues) by way of retrovirus vectors will oppose the biological function of Bcr-Abl (p160 BCR) or inactivate Bcr-Abl tyrosine kinase function or its signal transduction function. Bcr and Abl peptides, either tyrosine phosphorylated or unphosphorylated, that bind to a region near the amino terminus of Bcr to prevent formation of tetramer Bcr-Abl molecules, that bind to the SH2 domain of Grb2, to sites on tyrosine phosphorylated Shc protein, to sites of Crkl, and to an SH2 domain of Ras Gap comprise particular peptide preparations of the invention. The peptides and polypeptides inhibit Bcr-Abl oncoprotein activation, or block the oncogenic signal generated by the Bcr-Abl oncoprotein and, thereby, inhibit growth and induce cell death of leukemia cells expressing the oncoprotein. Methods for processing bone marrow using the peptide and polypeptide compositions of the invention are also provided. Stem cells present in bone marrow may thus be enriched for Philadelphia chromosome-negative cells prior to transplantation, particularly as part of autologous bone marrow transplant therapy of leukemia, including CML, ALL and AML.
    • 公开了包含与参与Bcr-Abl癌蛋白功能的分子结合的肽的混合物的组合物。 此外,通过逆转录病毒载体的功能性BCR蛋白(p160BCR)或其氨基末端片段(159,221和413氨基末端残基)的表达将反对Bcr-Abl(p160BCR)的生物学功能或者使Bcr-Abl失活 酪氨酸激酶功能或其信号转导功能。 Bcr和Abl肽,酪氨酸磷酸化或未磷酸化,其结合到Bcr的氨基末端附近的区域,以防止结合到Grb2的SH2结构域的四聚体Bcr-Abl分子到酪氨酸磷酸化的Shc蛋白上的位点到 Crk1的位点和Ras Gap的SH2结构域包含本发明的特定的肽制剂。 肽和多肽抑制Bcr-Abl癌蛋白激活,或阻断由Bcr-Abl癌蛋白产生的致癌信号,从而抑制表达癌蛋白的白血病细胞的生长并诱导细胞死亡。 还提供了使用本发明的肽和多肽组合物处理骨髓的方法。 因此,存在于骨髓中的干细胞可以在移植之前被富集成为费城染色体阴性细胞,特别是作为白血病(包括CML,ALL和AML)的自体骨髓移植治疗的一部分。