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Transforming Growth Factor-α and Epidermal Growth Factor
Published in Jason Kelley, Cytokines of the Lung, 2022
Another cytotoxic therapy directed toward EGF receptor-expressing tumor cells utilizes an immunotoxin consisting of the protein synthesis inhibitor, gelonin, conjugated to monoclonal antibody against the human EGF receptor (Hirota et al., 1989). This conjugate is toxic in vitro for tumor cells that overexpress the EGF receptor and dramatically suppresses the growth of such tumor cells in nude mice, without evidence of side effects. By a similar strategy, radioisotopes conjugated to antibodies against the EGF receptor or its ligands can be used for diagnostic imaging as well as target-specific radiotherapy. Unfortunately, antibody-mediated therapies have the potential for significant toxicity when administered to humans. The most obvious drawback to the use of heterologous antibodies is their antigenicity through repeated administration. In addition, since the EGF receptor and the precursors of TGF-α and EGF are expressed on the surface of some normal diploid cells, the cytotoxic actions of immunotoxins and monoclonal antibodies of the IgG2a isotype could result in vital organ damage in these patients.
Microalgae and Cyanobacteria as a Potential Source of Anticancer Compounds
Published in Gokare A. Ravishankar, Ranga Rao Ambati, Handbook of Algal Technologies and Phytochemicals, 2019
An exciting area of development is the use of algal chloroplast as a synthetic biology platform for production of therapeutics (Dyo and Purton 2018). Using this approach, transgenes can be inserted at precise and predetermined locations within the chloroplast genome to allow for stable synthesis of a desired recombinant protein. Among the microalgal species, Chlamydomonas reinhardtii is one of the most advanced microalgal platforms for chloroplast transformation. The chloroplast genetic system of this microalga is well suited for synthetic biology as its genome is small (205 kb) and of low complexity (99 genes) (Maul et al. 2002). Recombinant proteins including anticancer immunotoxins have been successfully produced using this microalgal platform. For instance, Tran et al. (2013) successfully developed Chlamyomonas reinhardtii as a platform to produce a series of chimeric proteins. The recombinant protein consists of a single chain antibody (scFV) targeting the B-cell surface antigen CD22, genetically fused to the eukaryotic ribosome inactivating protein, gelonin, from Gelonium multiform. The antibody-toxin chimeric protein is useful as an immunotoxin that acts as a cytotoxic agent against B-cell lymphomas.
Drug Targeting to the Lung: Chemical and Biochemical Considerations
Published in Anthony J. Hickey, Sandro R.P. da Rocha, Pharmaceutical Inhalation Aerosol Technology, 2019
Peter A. Crooks, Narsimha R. Penthala, Abeer M. Al-Ghananeem
Developments in the cancer area are worthy of mention. In earlier studies, an immunotoxin consisting of a murine monoclonal antibody (B4G7) that recognizes EGF receptor conjugated with gelonin, a ribose-inactivating protein, was specifically cytotoxic to EGF receptor-hyperproducing cells in mice and was non-toxic at 250 μm conjugate per mouse (Hirota et al. 1989). The results suggested that this conjugate may be useful for targeted therapy to epidermal growth factor receptor-hyperproducing squamous carcinoma. Also, a 125I-labeled monoclonal antibody directed against MW 48,000 human lung cancer-associated antigen may be useful in the diagnosis and treatment of lung cancer (Endo et al. 1987). Chan et al. (1986) reported that a set of mouse monoclonal antibodies directed against the c-myc oncogene product, a 62,000-d nuclear binding protein involved in cell cycle control, was constructed by immunization with synthetic peptide fragments. After intravenous administration, these monoclonal antibodies exhibited good tumor localization with primary bronchial carcinoma patients, thus indicating that monoclonal antibodies directed against oncogene products may provide novel selective tools for diagnosis and targeted therapy of cancer. Utilization of mAb to prevent cancer cell metastasis has been examined too. Studies have been done to utilize mAb, such as the inhibitor of lung endothelial cell adhesion molecule (anti-lu-ECAM-1) to inhibit colonization of the lung by lung metastatic murine B16 melanoma cells (Zhu et al. 1992). Lung endothelial cell adhesion molecule (Lu-ECAM-1) has been isolated and characterized (Elble et al. 1997); this molecule selectively binds lung-metastatic melanoma cells (Zhu and Pauli 1993). In a similar manner, mAb 6A3 selectively binds a membrane glycoprotein of rat lung capillary endothelia and has been shown to inhibit specific adhesion of lung endothelial vesicles to lung metastatic breast cancer cells.
Immunotoxins and nanobody-based immunotoxins: review and update
Published in Journal of Drug Targeting, 2021
Mohammad Reza Khirehgesh, Jafar Sharifi, Fatemeh Safari, Bahman Akbari
Gelonin is a plant single-chain hemitoxin in the seeds of the Gelonium multiflorum that was described first by Stirpe et al [103]. Gelonin (∼30 kDa) belongs to the type I ribosome-inactivating proteins (RIP I) family that consists of a single-chain protein (258 residues) with enzymatic activity similar to RTA [104,105]. Gelonin is not very toxic for mammalian cells due to the lack of a cell-binding domain. Therefore, it seems that the toxin enters the cell through pinocytosis [106]. In gelonin-based ITs, gelonin fused to the targeted moiety.
Genetic engineering and characterisation of chlorotoxin-fused gelonin for enhanced glioblastoma therapy
Published in Journal of Drug Targeting, 2019
Taehoon Park, Kyoung Ah Min, Heesun Cheong, Cheol Moon, Meong Cheol Shin
Brain and central nervous system (CNS)-related cancers are the 16th leading cause of death and are responsible for 2.8% of all cancer deaths in the US [1]. Despite significant advancements in the medical diagnostics and therapy of these cancers, the survival rate remains poor (average 5-year survival: 33.2%) [2,3]. Among brain and CNS-related cancers, glioblastoma multiforme (GBM), the last stage of glioma, is the most aggressive form of brain cancer, which only allows a less than 10% survival rate. Surgery is generally the first-choice treatment for GBM, and either radiotherapy or chemotherapy is often used as adjuvant or alternative therapy [4]. However, the severity of GBM and the lack of significant improvement of the survival rate strongly require further exploration of new therapeutic approaches. To date, only a few small-molecule anticancer agents, such as nitrosoureas or temozolomide, have been clinically available. However, these agents only offer modest therapeutic benefits [5–7]. The major drawbacks of these conventional small molecule-based anticancer drugs include an insufficient therapeutic efficacy and nonselective cytotoxicity [8]. Although a relatively large dose is required for the treatment, any amount of the administered drug distributed in normal tissues can eventually cause severe toxicity due to the cytotoxic nature of these small molecule-based anticancer drugs. Regarding the potency issue, therapeutically active macromolecules may provide an effective way to solve the problem. In particular, ribosome-inactivating proteins (RIPs) such as gelonin, have attracted much interest as potential anticancer drug candidates [9]. Gelonin is a 30-kDa glycoprotein originating from the seeds of Gelonium multiflorum. As a typical type 1 RIP, gelonin inhibits the synthesis of eukaryotic proteins by cleavage of a unique adenine residue (A4324) located in 28S ribosomal RNA [10]. Because of its high substrate specificity and repetitive mode of action, gelonin exhibits an extraordinary potency (at the picomolar level) for inhibiting protein translation [11]. Therefore, once gelonin successfully reaches its target substrate, ribosomes, it can effectively kill tumour cells. Although highly potent, gelonin lacks any cell-binding domain and, therefore, is poorly internalised into tumour cells. To address this issue, in a previous study, we have explored a fusion strategy to develop gelonin fusion proteins with various types of peptide ligands, including cell-penetrating peptides, the membrane-active peptide melittin, the tumour-homing peptide F3 and an anti-insulin-like growth factor 1 receptor antibody mimetic [12–15]. Compared with unmodified gelonin, these gelonin fusion proteins showed a higher cellular uptake, which eventually led to an enhanced anticancer efficacy.