Abstract
BackgroundImmunotherapy is fast emerging as one of the leading modes of treatment of cancer, in combination with chemotherapy and radiation. Use of immunotoxins, proteins bearing a cell-surface receptor-specific antibody conjugated to a toxin, enhances the efficacy of cancer treatment. The toxin Abrin, isolated from the Abrus precatorius plant, is a type II ribosome inactivating protein, has a catalytic efficiency higher than any other toxin belonging to this class of proteins but has not been exploited much for use in targeted therapy.MethodsProtein synthesis assay using 3[H] L-leucine incorporation; construction and purification of immunotoxin; study of cell death using flow cytometry; confocal scanning microscopy and sub-cellular fractionation with immunoblot analysis of localization of proteins.ResultsWe used the recombinant A chain of abrin to conjugate to antibodies raised against the human gonadotropin releasing hormone receptor. The conjugate inhibited protein synthesis and also induced cell death specifically in cells expressing the receptor. The conjugate exhibited differences in the kinetics of inhibition of protein synthesis, in comparison to abrin, and this was attributed to differences in internalization and trafficking of the conjugate within the cells. Moreover, observations of sequestration of the A chain into the nucleus of cells treated with abrin but not in cells treated with the conjugate reveal a novel pathway for the movement of the conjugate in the cells.ConclusionsThis is one of the first reports on nuclear localization of abrin, a type II RIP. The immunotoxin mAb F1G4-rABRa-A, generated in our laboratory, inhibits protein synthesis specifically on cells expressing the gonadotropin releasing hormone receptor and the pathway of internalization of the protein is distinct from that seen for abrin.
Highlights
Chemotherapy is the most common modes of treatment of cancer
MAb VU1D9, an epithelial cell adhesion molecule (EpCAM) specific antibody, bound to MCF-7, HepG2 and KB cells whereas the binding to MCF-10A cells was low as the level of EpCAM in these cells has been reported to be low as compared to its cancerous counterpart, MCF-7 cells [49]
Though monoclonal antibodies (mAbs) A9E4 was raised to the same GnRH-R peptide, it does not bind to the receptor [38], served as an isotype control
Summary
Chemotherapy is the most common modes of treatment of cancer. its success and efficacy are challenged because of the side effects associated with the treatment, majorly caused due to the inhibition of fast proliferating normal cells of the body. Use of other modalities of treatment to combat cancer is the need of the hour and of late monoclonal antibodies (mAbs) are one of the front runners as potential drugs for treating cancer Apart from their use in antibody mediated cell and complement-mediated cytotoxicity, mAbs can be linked to various anti-cancer drugs, radionuclides and toxins [1,2,3]. This ensures site-specific delivery of the therapeutic molecules and maximizes the effect of the drug and minimizes side effects [1,3,4]. Proteins bearing a cell-surface receptor-specific antibody conjugated to a toxin, enhances the efficacy of cancer treatment. The toxin Abrin, isolated from the Abrus precatorius plant, is a type II ribosome inactivating protein, has a catalytic efficiency higher than any other toxin belonging to this class of proteins but has not been exploited much for use in targeted therapy
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