Kurschus Florian C, Kleinschmidt Martin, Fellows Edward, Dornmair Klaus, Rudolph Rainer, Lilie Hauke, Jenne Dieter E
Department of Neuroimmunology, Max-Planck-Institute of Neurobiology, Am Klopferspitz 18A, D-82152 Planegg-Martinsried, Germany.
FEBS Lett. 2004 Mar 26;562(1-3):87-92. doi: 10.1016/S0014-5793(04)00187-5.
Granzyme B (GzmB) is a potent apoptosis-inducing serine protease of cytotoxic lymphocytes. Following receptor-mediated endocytosis, GzmB is supposed to enter the cytosol through perforin-mediated membrane disruption. We investigated whether retargeting of GzmB to Lewis Y positive surface receptors could lead to perforin-independent target cell death. We coupled recombinant GzmB to the Lewis Y-binding antibody dsFv-B3. Targeting of GzmB to Lewis Y positive cells triggered cell death with similar efficacy as dsFv-B3 targeted Pseudomonas exotoxin fragment 38 (PE38). Since GzmB was only weakly inhibited by plasma proteins, GzmB-based immunoconjugates should be useful as a new class of immunotoxins with low immunogenicity utilizing programmed cell death for therapeutic purposes.
颗粒酶B（GzmB）是一种细胞毒性淋巴细胞中具有强大凋亡诱导作用的丝氨酸蛋白酶。在受体介导的内吞作用后，GzmB被认为通过穿孔素介导的膜破坏进入细胞质。我们研究了将GzmB重新靶向Lewis Y阳性表面受体是否会导致不依赖穿孔素的靶细胞死亡。我们将重组GzmB与Lewis Y结合抗体dsFv-B3偶联。将GzmB靶向Lewis Y阳性细胞引发细胞死亡，其效果与dsFv-B3靶向铜绿假单胞菌外毒素片段38（PE38）相似。由于GzmB仅受到血浆蛋白的微弱抑制，基于GzmB的免疫偶联物应可作为一类新型免疫毒素，利用程序性细胞死亡用于治疗目的，且免疫原性较低。
