Patient-specific targeted
therapy represents the holy grail of anti-
cancer therapeutics, allowing potent
tumor depletion without detrimental off-target toxicities. Disease-specific
monoclonal antibodies have been employed to bind to oncogenic
cell-surface receptors, representing the earliest form of
immunotherapy. Targeted drug delivery was first achieved by means of
antibody-drug conjugates, which exploit the differential expression of
tumor-associated
antigens as a guiding mechanism for the specific delivery of chemically-conjugated chemotherapeutic agents to diseased target cells. Biotechnological advances have expanded the repertoire of immunology-based
tumor-targeting strategies, also paving the way for the next intuitive step in targeted drug delivery: the construction of
recombinant protein drugs consisting of an antibody-based targeting domain genetically fused with a cytotoxic
peptide, known as an
immunotoxin. However, the most potent
protein toxins have typically been derived from bacterial or plant
virulence factors and commonly feature both off-target toxicity and immunogenicity in human patients. Further refinement of
immunotoxin technology thus led to the replacement of
monoclonal antibodies with humanized antibody derivatives, including the substitution of non-human toxic
peptides with human cytolytic
proteins. Preclinically tested human cytolytic fusion
proteins (hCFPs) have proven promising as non-immunogenic combinatory anti-
cancer agents, however they still require further enhancement to achieve convincing candidacy as a single-mode therapeutic. To date, a portfolio of highly potent human toxins has been established; ranging from
microtubule-associated protein tau (MAP tau), RNases,
granzyme B (GrB) and
death-associated protein kinase (DAPk). In this review, we discuss the most recent findings on the use of these apoptosis-inducing hCFPs for the treatment of various
cancers.