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首页> 外文期刊>Molecular cancer therapeutics >Neutralization of KIT Oncogenic Signaling in Leukemia with Antibodies Targeting KIT Membrane Proximal Domain 5
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Neutralization of KIT Oncogenic Signaling in Leukemia with Antibodies Targeting KIT Membrane Proximal Domain 5

机译：用抗体靶向试剂盒近端结构域的白血病套件致癌信号传导的中和

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KIT is a cell surface tyrosine kinase receptor whose ligand stem cell factor (SCF) triggers homodimerization and activation of downstream effector pathways involved in cell survival, proliferation, homing, or differentiation. KIT-activating mutations are major oncogenic drivers in subsets of acute myeloid leukemia (AML), in mast cell leukemia, and in gastrointestinal stromal tumors (GIST). The overexpression of SCF and/or wild-type (WT) KIT is also observed in a number of cancers, including 50% of AML and small cell lung cancer. The use of tyrosine kinase inhibitors (TKI) in these pathologies is, however, hampered by initial or acquired resistance following treatment. Using antibody phage display, we obtained two antibodies (2D1 and 3G1) specific for the most membrane proximal extracellular immunoglobulin domain (D5) of KIT, which is implicated in KIT homodimerization. Produced as single chain variable antibody fragments fused to the Fc fragment of a human IgG1, bivalent 2D1-Fc and 3G1-Fc inhibited KIT-dependent growth of leukemic cell lines expressing WT KIT (UT7/Epo) or constitutively active KIT mutants, including the TKI imatinib-resistant KIT D816V mutant (HMC1.2 cell line). In all models, either expressing WT KIT or mutated KIT, 2D1 and 3G1-Fc induced KIT internalization and sustained surface downregulation. However, interestingly, KIT degradation was only observed in leukemic cell lines with oncogenic KIT, a property likely to limit the toxicity of these antibodies in patients. These fully human antibody formats may represent therapeutic tools to target KIT signaling in leukemia or GIST, and to bypass TKI resistance of certain KIT mutants. (C) 2015 AACR.
机译：试剂盒是一种细胞表面酪氨酸激酶受体，其配体干细胞因子（SCF）触发均二聚体和激活细胞存活，增殖，归巢或分化中的下游效应途径。试剂盒激活突变是急性髓性白血病（AML），肥大细胞白血病和胃肠基质肿瘤（GIST）中的主要致癌司机。在许多癌症中也观察到SCF和/或野生型（WT）试剂盒的过表达，其中包括50％的AML和小细胞肺癌。然而，在这些病理中使用酪氨酸激酶抑制剂（TKI）是通过初始或获得的耐药后的抗性阻碍。使用抗体噬菌体展示，我们获得了用于套件的最多膜近端细胞外免疫球蛋白结构域（D5）的两种抗体（2D1和3G1），其涉及试剂盒同源化。作为单链可变抗体片段融合到人IgG1的Fc片段，二价2d1-Fc和3G1-Fc抑制表达WT试剂盒（UT7 / EPO）或组成型活性套件突变体的白血病细胞系的试剂依赖性生长，包括TKI imatinib抗性试剂盒D816V突变体（HMC1.2细胞系）。在所有型号中，表达WT套件或突变的套件，2D1和3G1-FC诱导的套件内化和持续的表面下调。然而，有趣的是，仅在白血病细胞系中观察到具有致癌套件的胰岛降解，可能限制这些抗体对患者的毒性的性质。这些完全人体抗体形式可以代表治疗工具以在白血病或GIST中靶向试剂盒信号传导，并绕过某些试剂夹突变体的TKI抗性。 （c）2015年AACR。

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