Development of Novel, Highly Cytotoxic Fusion Constructs Containing Granzyme B: Unique Mechanisms and Functions

M.   G.   Rosenblum; S.      Barth

Abstract

Recombinant fusion proteins are an expanding, important class of novel therapeutic agents. The designs of these constructs typically involve a cell-targeting motif genetically fused to a highly toxic class of enzymes capable of ruthlessly attacking critical cellular machinery once delivered successfully to the cytoplasm of the target cell. Initial development of this class of constructs typically contained recombinant growth factors or single-chain antibodies as the celltargeting motif fused to highly cytotoxic plant or bacterial toxins. This review describes second-generation molecules composed of cell-targeting molecules fused to highly cytotoxic human enzymes capable of generating intense apoptotic response once delivered to the cytoplasm. The human serine protease granzyme B has been shown to be extremely effective as a cytotoxic molecule when incorporated into numerous cell-targeting constructs. The biological activity of GrBcontaining constructs rivals that of plant or bacterial toxins and appears to represent a new generation and class of completely human proteins with unique biological activities.

Keywords: Fusion proteins, granzyme B, immunotoxins, serine protease, gp240, VEGF, serpins, H22