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Selective Induction of Cancer Cell Death by Targeted Granzyme B

机译：靶向颗粒酶B选择性诱导癌细胞死亡

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The potential utility of immunotoxins for cancer therapy has convincingly been demonstrated in clinical studies. Nevertheless, the high immunogenicity of their bacterial toxin domain represents a critical limitation, and has prompted the evaluation of cell-death inducing proteins of human origin as a basis for less immunogenic immunotoxin-like molecules. In this review, we focus on the current status and future prospects of targeted fusion proteins for cancer therapy that employ granzyme B (GrB) from cytotoxic lymphocytes as a cytotoxic moiety. Naturally, this serine protease plays a critical role in the immune defense by inducing apoptotic target cell death upon cleavage of intracellular substrates. Advances in understanding of the structure and function of GrB enabled the generation of chimeric fusion proteins that carry a heterologous cell binding domain for recognition of tumor-associated cell surface antigens. These hybrid molecules display high selectivity for cancer cells, with cell killing activities similar to that of corresponding recombinant toxins. Recent findings have helped to understand and circumvent intrinsic cell binding of GrB and susceptibility of the enzyme to inhibition by serpins. This now allows the rational design of optimized GrB derivatives that avoid sequestration by binding to non-target tissues, limit off-target effects, and overcome resistance mechanisms in tumor cells.
机译：临床研究已令人信服地证明了免疫毒素在癌症治疗中的潜在效用。然而，它们的细菌毒素结构域的高免疫原性代表了关键的局限性，并促使人们评估人类起源的细胞死亡诱导蛋白，将其作为免疫原性较低的免疫毒素样分子的基础。在这篇综述中，我们集中于针对癌症的靶向融合蛋白的现状和未来前景，该融合蛋白采用了来自细胞毒性淋巴细胞的粒酶B（GrB）作为细胞毒性部分。自然地，这种丝氨酸蛋白酶通过在裂解细胞内底物时诱导凋亡性靶细胞死亡而在免疫防御中起关键作用。在理解GrB的结构和功能方面的进展使得能够产生嵌合融合蛋白，该融合蛋白携带用于识别肿瘤相关细胞表面抗原的异源细胞结合域。这些杂合分子对癌细胞显示出高选择性，具有与相应重组毒素相似的细胞杀伤活性。最近的发现有助于理解和绕过GrB的内在细胞结合以及该酶对丝氨酸蛋白酶抑制剂抑制的敏感性。现在，这可以对优化的GrB衍生物进行合理设计，从而避免与非靶标组织结合而隔离螯合，限制脱靶效应并克服肿瘤细胞的耐药机制。

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