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

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Abstract
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.