Targeted human cytolytic fusion proteins at the cutting edge: harnessing the apoptosis-inducing properties of human enzymes for the selective elimination of tumor cells
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Neelakshi Mungra1, Sandra Jordaan1, Precious Hlongwane1, Krupa Naran1,*, Shivan Chetty1,* and Stefan Barth1,2,*
1Medical Biotechnology and Immunotherapy Unit, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town 7700, South Africa
2South African Research Chair in Cancer Biotechnology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town 7700, South Africa
*These authors contributed equally to this work
Neelakshi Mungra, email: [email protected]
Stefan Barth, email: [email protected]
Keywords: death-associated protein kinase (DAPk); granzyme B (GrB); targeted human cytolytic fusion proteins (hCFPs); microtubule-associated protein tau (MAPT tau); RNase-based hCFPs
Received: October 19, 2018 Accepted: January 10, 2019 Published: January 25, 2019
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.
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