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首页> 外文期刊>Antibodies >Human Cytolytic Fusion Proteins: Modified Versions of Human Granzyme B and Angiogenin Have the Potential to Replace Bacterial Toxins in Targeted Therapies against CD64+ Diseases
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Human Cytolytic Fusion Proteins: Modified Versions of Human Granzyme B and Angiogenin Have the Potential to Replace Bacterial Toxins in Targeted Therapies against CD64+ Diseases

机译：人细胞溶解性融合蛋白：人粒酶B和血管生成素的修改后的版本有潜力在针对CD64 +疾病的靶向治疗中取代细菌毒素

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Targeted therapies for the treatment of cancer, but also inflammation and autoimmune diseases will reduce major side effects accompanied with conventional treatment modalities. The immunotoxin concept uses bacterial or plant toxins, coupled to antibodies or natural ligands targeting cancer cells. Initially, immunotoxins suffered from drawbacks like nonspecific cytotoxicity. Even the third generation of immunotoxins comprised of truncated antibodies and modified effector molecules experienced clinical set-backs due to immune responses. Long-term treatment of cancer and non-life-threatening chronic inflammatory diseases requires their complete ‘humanization’. This lead to evaluating human cytolytic fusion proteins (hCFPs), based on human apoptosis-inducing proteins. Lacking an endogenous translocation domain dramatically reduces the cell-death inducing capacity of such proteins. Here, we report on optimizing hCFPs, based on the anti-CD64 single chain variable fragment H22(scFv), specifically eliminating CD64+ macrophages and malignant progenitor cells. We replaced the bacterial toxin in H22(scFv)-ETA' with the pro-apoptotic human granzyme B or angiogenin. Translocation was promoted by a sophisticated adapter containing a membrane transfer peptide (MTD) flanked by endosomal and cytosolic cleavable peptides, thus achieving in vitro cytotoxic activity comparable to bacterial immunotoxins. We demonstrate for the first time that optimized hCFPs, based on granzyme B or angiogenin, can compete with classical ETA-based immunotoxins.
机译：用于治疗癌症以及炎症和自身免疫性疾病的靶向疗法将减少伴随常规治疗方式的主要副作用。免疫毒素概念使用细菌或植物毒素，并与靶向癌细胞的抗体或天然配体偶联。最初，免疫毒素具有诸如非特异性细胞毒性的缺点。甚至由截短的抗体和修饰的效应子分子组成的第三代免疫毒素也因免疫反应而遭受临床挫折。癌症和非威胁生命的慢性炎症性疾病的长期治疗需要其完全的“人性化”。这导致基于人类凋亡诱导蛋白评估人类溶细胞融合蛋白（hCFP）。缺乏内源性易位结构域极大地降低了此类蛋白质的细胞死亡诱导能力。在这里，我们报告基于抗CD64单链可变片段H22（scFv）优化hCFP，特别是消除了CD64 +巨噬细胞和恶性祖细胞。我们用促凋亡的人类颗粒酶B或血管生成素代替了H22（scFv）-ETA'中的细菌毒素。通过包含膜转移肽（MTD）的复杂衔接子促进了易位，该膜转移肽的侧面是内体和胞质可裂解的肽，从而获得了与细菌免疫毒素相当的体外细胞毒活性。我们首次证明基于颗粒酶B或血管生成素的优化hCFPs可以与经典的基于ETA的免疫毒素竞争。

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