Killing of target cells by redirected granzyme B in the absence of perforin

FEBS Letters

Jenne, Dieter E.²  Kurschus, Florian C.²  Lilie, Hauke¹  Kleinschmidt, Martin¹  Dornmair, Klaus²  Fellows, Edward²  Rudolph, Rainer¹ 

[1] Institut für Biotechnologie, Martin-Luther-Universität Halle, Kurt-Mothes Strasse 3, D-06120 Halle, Germany;Department of Neuroimmunology, Max-Planck-Institute of Neurobiology, Am Klopferspitz 18A, D-82152 Planegg-Martinsried, Germany

关键词: Granzyme B;    Apoptosis;    Immunotoxin;    Lewis Y;    Tumor;    α1-AT;    α1-antitrypsin;    BSA;    bovine serum albumin;    CI-MPR;    cation-independent mannose-6-phosphate/insulin-like growth factor receptor;    CrmA;    cytokine response modifier A;    CTL;    cytotoxic T lymphocytes;    FACS;    fluorescence-activated cell sorter;    GzmB;    granzyme B;    NK;    natural killer;    PBS;    phosphate-buffered saline;    PE38;    Pseudomonas exotoxin fragment 38;    PI;    propidium iodide;    PR3;    proteinase 3;    RT;    room temperature;    SLO;    streptolysin O;   

DOI  :  10.1016/S0014-5793(04)00187-5

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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.

【 授权许可】

Unknown