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首页> 外文期刊>Journal of Molecular Biology >Selection of tumor-specific internalizing human antibodies from phage libraries.
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Selection of tumor-specific internalizing human antibodies from phage libraries.

机译：从噬菌体文库中选择肿瘤特异性内在化人类抗体。

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Antibody internalization into the cell is required for many targeted therapeutics, such as immunotoxins, immunoliposomes, antibody-drug conjugates and for targeted delivery of genes or viral DNA into cells. To generate directly tumor-specific internalizing antibodies, a non-immune single chain Fv (scFv) phage antibody library was selected on the breast tumor cell line SKBR3. Internalized phage were recovered from within the cell and used for the next round of selection. After three rounds of selection, 40 % of clones analyzed bound SKBR3 and other tumor cells but did not bind normal human cells. Of the internalizing scFv identified, two (F5 and C1) were identified as binding to ErbB2, and one (H7) to the transferrin receptor. Both F5 and H7 scFv were efficiently endocytosed into SKBR3 cells, both as phage antibodies and as native monomeric scFv. Both antibodies were able to induce additional functional effects besides triggering endocytosis: F5 scFv induces downstream signaling through the ErbB2 receptor and H7 prevents transferrin binding to the transferrin receptor and inhibits cell growth. The results demonstrate the feasibility of selecting internalizing receptor-specific antibodies directly from phage libraries by panning on cells. Such antibodies can be used to target a variety of molecules into the cell to achieve a therapeutic effect. Furthermore, in some instances endocytosis serves as a surrogate marker for other therapeutic biologic effects, such as growth inhibition. Thus, a subset of selected antibodies will have a direct therapeutic effect. Copyright 2000 Academic Press.
机译：许多靶向治疗剂，例如免疫毒素，免疫脂质体，抗体-药物结合物，以及基因或病毒DNA靶向递送到细胞中，都需要抗体内化到细胞中。为了直接生成肿瘤特异性内在化抗体，在乳腺癌细胞系SKBR3上选择了非免疫单链Fv（scFv）噬菌体抗体库。从细胞内回收内化的噬菌体，并将其用于下一轮选择。经过三轮选择，分析出40％的克隆结合了SKBR3和其他肿瘤细胞，但不结合正常的人类细胞。在确定的内在化scFv中，有两个（F5和C1）与ErbB2结合，一个（H7）与运铁蛋白受体结合。 F5和H7 scFv均以噬菌体抗体和天然单体scFv的形式被高效内吞到SKBR3细胞中。除触发内吞作用外，这两种抗体均能够诱导其他功能作用：F5 scFv通过ErbB2受体诱导下游信号传导，而H7阻止运铁蛋白与运铁蛋白受体结合并抑制细胞生长。结果证明了通过淘选细胞直接从噬菌体文库选择内在化受体特异性抗体的可行性。此类抗体可用于将多种分子靶向细胞以达到治疗效果。此外，在某些情况下，内吞作用充当其他治疗生物学作用（例如生长抑制）的替代标志物。因此，选择的抗体的子集将具有直接的治疗作用。版权所有2000学术出版社。

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