Abstract
Conventional cancer treatments lack specificity and often cause severe side effects. Targeted therapeutic approaches are therefore preferred, including the use of immunotoxins (ITs) that comprise cell-binding and cell death-inducing components to allow the direct and specific delivery of pro-apoptotic agents into malignant cells. The first generation of ITs consisted of toxins derived from bacteria or plants, making them immunogenic in humans. The recent development of human cytolytic fusion proteins (hCFP) consisting of human effector enzymes offers the prospect of highly-effective targeted therapies with minimal side effects. One of the most promising candidates is granzyme B (GrB) and this enzyme has already demonstrated its potential for targeted cancer therapy. However, the clinical application of GrB may be limited because it is inactivated by the overexpression in tumors of its specific inhibitor serpin B9 (PI-9). It is also highly charged, which means it can bind non-specifically to the surface of non-target cells. Furthermore, human enzymes generally lack an endogenous translocation domain, thus the endosomal release of GrB following receptor-mediated endocytosis can be inefficient. In this review we provide a detailed overview of these challenges and introduce promising solutions to increase the cytotoxic potency of GrB for clinical applications.
Highlights
Typical treatment strategies for cancer include surgery, chemotherapy and radiotherapy, but success is limited by the concurrent killing of nonmalignant cells, which can result in serious and often lifethreatening side effects
In this review we focus on granzyme B (GrB), a human immunoprotease involved in the granulemediated apoptosis of virus-infected or transformed tumor cells
Our group and others have developed a number of innovative strategies to optimize human cytolytic fusion proteins (hCFP) based on GrB, including the production of engineered variants that are insensitive to PI-9, having lower surface charge to reduce off-target effects, and to promote endosomal release by the insertion of functional elements
Summary
Typical treatment strategies for cancer include surgery, chemotherapy and radiotherapy, but success is limited by the concurrent killing of nonmalignant cells, which can result in serious and often lifethreatening side effects. Several strategies have been developed to enhance the anti-tumor activity of mAbs, including the humanization of antibodies [9], the optimization of antibody effector functions [10] and the fusion of antibodies to a potent cytotoxic drug. The complete humanization of ITs is an important criterion for the development of fourthgeneration molecules [29,32], named human cytolytic fusion proteins (hCFPs) This concept is supported by the use of endogenous human enzymes that induce cell death, fused to humanized or even fully human antibody fragments. In this review we focus on granzyme B (GrB), a human immunoprotease involved in the granulemediated apoptosis of virus-infected or transformed tumor cells This enzyme has several inherent advantages as an IT component such as its high cytotoxic efficacy reflecting its status as an effector molecule in the cellular immune system, its broad portfolio of apoptosis inducing mechanisms, and its low immunogenicity. Our group and others have developed a number of innovative strategies to optimize hCFPs based on GrB, including the production of engineered variants that are insensitive to PI-9, having lower surface charge to reduce off-target effects, and to promote endosomal release by the insertion of functional elements
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