Immunotoxins are a novel class of cancer therapeutics that contains a cytotoxic agent fused to a targeting moiety. Various toxic agents from different sources are used in immunotoxin development, including bacterial, plant and human origin cytotoxic elements. Although bacterial and plant-derived toxins are highly toxic and commonly used in immunotoxins, their immunogenicity for human restricted their application in cancer therapy. Here, we discuss the advantages and limitations of bacterial toxins such as Pseudomonas and Diphtheria toxins, plant toxins such as ricin and gelonin, and some endogenous protein of human origin such as RNases and Granzymes. This article will also review different generations of immunotoxins with special focus on immunotoxins which are under clinical trials or approved for clinical use. Finally, current deimmunization strategies for development of new less-immunogenic recombinant immunotoxins will be discussed.
mAbs: Monoclonal antibodies; EF2: elongation factor 2; ITs: Immunotoxins; DT: Diphtheria toxin; PE: Pseudomonas exotoxin; dgA: de-glycosylated A-chain of ricin; rGel: recombinant de-glycosylated form of gelonin; NKC: natural killer cells; HTR: human transferrin receptor; EGF: epidermal growth factor; GM-CSF: granulocyte-macrophage colony-stimulating factor; DAB389: truncated Diphtheria toxin; B-CCL: B-cell chronic lymphocytic leukemia; RCC: renal cell carcinoma; GVHD: Graft-versus-host disease; EGFR: epidermal growth factor receptor; AML: acute myeloid leukemia; Fab: fragment antigen-binding; dsFv: disulfide-stabilized fragment variable; scFv: single-chain fragment variable; B-ALL: B-lineage Acute Lymphoblastic Leukemia; Fv: fragment variable; HCL: hairy cell leukemia; IL-2R: Interleukin-2 receptor; CR: complete response; CLL: chronic lymphocytic leukemia; ATL: adult T-cell leukemia; DARPins: designed Ankyrin repeat proteins; pmol: picomolar; HAMA: human-anti mouse antibody.

Fungi establish a complex network of biological interactions with other organisms in nature. In many cases, these involve the production of toxins for survival or colonization purposes. Among these toxins, ribotoxins stand out as promising candidates for their use in biotechnological applications. They constitute a group of highly specific extracellular ribonucleases that target a universally conserved sequence of RNA in the ribosome, the sarcin-ricin loop. The detailed molecular study of this family of toxic proteins over the past decades has highlighted their potential in applied research. Remarkable examples would be the recent studies in the field of cancer research with promising results involving ribotoxin-based immunotoxins. On the other hand, some ribotoxin-producer fungi have already been studied in the control of insect pests. The recent role of ribotoxins as insecticides could allow their employment in formulas and even as baculovirus-based biopesticides. Moreover, considering the important role of their target in the ribosome, they can be used as tools to study how ribosome biogenesis is regulated and, eventually, may contribute to a better understanding of some ribosomopathies.

There are no reference guidelines for health care providers regarding appropriate use and interpretation of urine eosinophil protein X (u-EPX) in clinical practice. Currently, there are no clear-cut clinical or laboratory parameters to diagnose asthma in young children.
In this study, we (1) systematically reviewed and qualitatively appraised the epidemiological evidence to determine diagnostic u-EPX cut points for pediatric asthma, and (2) performed a meta-analysis to provide u-EPX estimates for diagnosing pediatric asthma.
Research articles in literature were identified from PubMed/Medline and Web of Science databases from 1966 to August 2015. Children <18 years of age were included. Both serum and urine EPX were included. Twenty-seven studies met the inclusion criteria for the systematic review and nine studies for the meta-analysis. Details regarding EPX analyses, treatment efficacy, and outcomes were assessed. For meta-analyses, effect estimates were abstracted using standardized means.
Over 70% of studies found a significant relationship between u-EPX and childhood asthma. There was 1.94 times higher standardized means of u-EPX among acute asthmatics compared to healthy controls (confidence interval [CI]: 1.67-2.22). Similarly, the difference in standardized means between asymptomatic asthmatics and healthy controls was 1.58 times higher (CI: 1.27-1.88).
Despite differences in sample sizes, EPX processing and measurement, and ages of children, a consistent trend of higher EPX levels with childhood asthma was revealed.

The Ribonuclease A Superfamily is composed of a group of structurally similar peptides that are secreted by immune cells and epithelial tissues. Several members of the Ribonuclease A Superfamily demonstrate antimicrobial activity, and it has been suggested that some of these ribonucleases play an essential role in host defense. Ribonuclease 7 (RNase 7) is an epithelial-derived secreted peptide with potent broad-spectrum antimicrobial activity. This review summarizes the published literature on RNase 7\'s antimicrobial properties, structure, regulation, and contributions to host defense. In doing so, we conclude by highlighting key knowledge gaps that must be investigated to completely understand the potential of developing RNase 7 as a novel therapeutic for human infectious diseases.

Cancer is the leading cause of death in economically developed countries and the second leading cause of death in developing countries. This global burden of cancer continues to increase largely because of the aging and growth of the world population. Although very much progress has been attained in the development of new therapies, there is a clear need of more efficient and selective antitumor drugs for the effective treatment of many types of cancer. Among the different strategies developed to create new antitumor drugs, pleiotropic non-genotoxic effectors have gained interest since this approach is less susceptible to known resistance mechanisms. The cell nucleus is the subcellular compartment where the genetic information and the transcription machinery reside and accordingly where numerous therapeutic agents efficiently work. Hence, nuclear-targeted drugs are expected to kill cancer cells more directly and efficiently. In this review, we discuss the potential of nuclear-targeted drugs as antineoplastic therapeutics and reason the benefits of the strategy to endow ribonucleases with cytotoxic properties based on its targeting into the nucleus.

Cytotoxic ribonucleases (RNases), such as ranpiranase, represent a novel mechanism-based approach to anticancer therapy. These relatively small proteins selectively attack malignant cells, triggering apoptotic response and inhibiting protein synthesis. Ranpirnase, originally isolated from oocytes of Rana pipiens, is a member of a family of endoribonucleases. The anticancer effects of ranpiranase have been documented in both in vitro and in vivo experimental tumor models. The effects of ranpiranase appear to be selective for cancer cells. Based on Phase I study data, the maximum tolerated dose (MTD) was 960 microg/m2, with the dose-limiting toxicity (DLT) characterized by proteinuria with or without azotemia, peripheral edema, and fatigue. Ranpirnase did not induce myelosuppression, mucositis, alopecia, cardiotoxicity, coagulopathy, hepatotoxicity, or adverse metabolic effects. Phase II tumor-specific trials investigated the activity of ranpirnase in malignant mesothelioma, breast cancer, non-small cell lung cancer, and renal cell cancer. A Phase III randomized study in malignant mesothelioma patients compares the combination of ranpirnase plus doxorubicin to doxorubicin monotherapy.

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Results of studies of certain fungal extracellular ribonucleases mainly isolated from representatives of the genera Aspergillus and Penicillium are summarized. The isolation of these enzymes in highly purified states in the 1970-1980s strongly stimulated further studies of their structure, functions, and mechanisms of action. This also promoted the use of ribonucleases as catalysts in oligoribonucleotide syntheses and as objects of comparative and evolutionary biochemistry and other research works. Results of studies of the primary, secondary, and spatial structures of guanyl-specific fungal ribonucleases are reviewed. These studies revealed a high homology within the subfamilies of fungal, bacterial, and actinomycete RNases. Characteristics of the nonspecific Pb2 RNase are considered.

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