Killing of target cells by redirected granzyme B in the absence of perforin.
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.
Kurschus
Florian C
FC
Department of Neuroimmunology, Max-Planck-Institute of Neurobiology, Am Klopferspitz 18A, D-82152 Planegg-Martinsried, Germany. kurschus@neuro.mpg.de
Kleinschmidt
Martin
M
Fellows
Edward
E
Dornmair
Klaus
K
Rudolph
Rainer
R
Lilie
Hauke
H
Jenne
Dieter E
DE
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001427:Bacterial Toxins / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D053804:Granzymes; D006801:Humans; D007983:Lewis Blood Group Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D011956:Receptors, Cell Surface / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism
D001427:Bacterial Toxins; D007983:Lewis Blood Group Antigens; C094162:Lewis Y antigen; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D052899:Pore Forming Cytotoxic Proteins; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D054353:Perforin; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases