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A Boy with Diphtheria
Published in Norman Begg, The Remarkable Story of Vaccines, 2023
“He needs antitoxin,” muttered Ed. The boy had advanced diphtheria. His symptoms were being caused by the powerful toxin that is released by the bacterium that causes diphtheria. Diphtheria toxin is extraordinarily potent. It destroys heart and liver tissue and paralyses the nervous system. Seven - millionths of a gram is enough to kill an adult. The only way to reverse this is by giving a specific diphtheria antitoxin, which can neutralise its effects. Ed asked me to call the pharmacist.
Bacteria
Published in Julius P. Kreier, Infection, Resistance, and Immunity, 2022
The clinical signs of diphtheria are a result of toxin production by lysogenic strains of Cornyebacterium diphtheriae. A lysogenic strain is one which has been infected with a temperate bacteriophage mu, that carries the genetic code for production of diphtheria toxin. Mu integrates with the host bacterium DNA. Only phage-infected lysogenic strains of the bacterium produce toxin and cause diphtheria. The organism is not very invasive and usually only causes a localized infection of the mucosal membranes of the upper respiratory tract; it is from this site that the toxin diffuses and causes damage. The toxin produced is capable of killing most eukaryotic cells. Antibodies to the toxin neutralize it and prevent the disease even though infection may be present and the host becomes a carrier of the organisms. Immunization with inactivated diphtheria toxin effectively prevents the disease.
Diseases of the Nervous System
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
There are certain toxins which block protein synthesis, such as diphtheria and polio virus infection-produced toxins. The neuronal perikaryon is the principal site of macromolecular synthesis. Proteins and glycoproteins are produced on perikaryal ribosomes attached to the Nissl bodies which represent the endoplasmic reticulum in the nervous cell. Polio virus infection blocks protein synthesis in the neuronal cell body, resulting in complete stoppage, death of the motor neuron, and paralysis. Diphtheria toxin, a highly neurotoxic protein occurs in some strains of Corynebacterium diphtheriae.449 The diphtheria toxin impairs protein synthesis and its action is localized to the Schwann cells responsible for the maintenance of myelin. The result of diphtheria toxemia is demyelination, failure of conduction, and paralysis.277,449,466 These effects result in neuropathy by demyelinating peripheral nerves. Palatal weakness and blurring of vision occur at early stages, followed by involvement of other cranial nerves and generalized motor sensory neuropathy.
New nonchemotherapy treatment options for cutaneous T-cell lymphomas
Published in Expert Review of Anticancer Therapy, 2021
E7777 is a recombinant cytotoxic fusion protein composed of diphtheria toxin fragments A and B and the receptor-binding domain of IL-2. IL-2 is involved in the differentiation of effector T-cell subsets and the survival of T-regs[85]. Components of IL-2 include the common gamma chain (CD132), the beta chain (CD122), and the alpha chain (CD25)[85]. The fusion protein shares the same amino acid sequence with denileukin diftitox (DD), which was previously approved by the FDA for use in persistent/recurrent CD25+ CTCL but discontinued due to production issues[7,86]. Both E7777 and DD enter cells by binding to IL-2 receptors and undergoing receptor-mediated endocytosis[87]. The diphtheria toxin domain is then cleaved and translocated to the cytoplasm, where it inhibits protein synthesis and causes cell death. In addition to targeting CD25+ malignant cells, DD is also theorized to eliminate CD25+ T-regs and enhance the antitumor immune response[87,88]. In a phase III trial of DD in patients with stage IA to III CTCL positive for CD25 by immunohistochemistry of skin biopsies, DD achieved a higher ORR compared to placebo (44% vs 15.9%)[89]. Two doses of DD were tested (18 μg/kg/d and 9 μg/kg/d) and the larger dose had a higher ORR (49.1% vs 37.8%).
Inhibition of neovascularisation in human endothelial cells using anti NRP-1 nanobody fused to truncated form of diphtheria toxin as a novel immunotoxin
Published in Immunopharmacology and Immunotoxicology, 2021
Shamsi Naderi, Reyhaneh Roshan, Mahdi Behdani, Fatemeh Kazemi-Lomedasht
Recombinant immunotoxins are encoded by the ligand-toxin sequences on plasmids and expressed in bacteria as fusion proteins [3]. Diphtheria toxin (DT) is a bacterial toxin of 535 amino acids comprising two major domains. Domain A (amino acids 1–186) is the catalytic domain and inhibits protein synthesis in eukaryotic cells by ADP-ribosylation of elongation factor 2 (eEF-2), thereby inducing cell apoptosis. Domain B (amino acids 389–535) is responsible for cell binding. The translocation or transmembrane (T) domain (amino acids 187–388) separates domain A from domain B. The translocation domain is responsible for internalizing the toxin into the cytosolic compartment [4]. Denileukin diftitox (Ontak) was the first targeted toxin therapy approved by the Food and Drug Administration (FDA). Ontak consists of human IL-2 genetically fused to truncated DT [5] and has been applied for the treatment of cutaneous T-cell lymphoma.
Tagraxofusp as treatment for patients with blastic plasmacytoid dendritic cell neoplasm
Published in Expert Review of Anticancer Therapy, 2020
Sophia S. Lee, Deborah McCue, Naveen Pemmaraju
In a study done by Pemmaraju and his colleagues, the most common adverse events observed were increased alanine aminotransferase (64%) and aspartate aminotransferase levels (60%), hypoalbuminemia (55%), peripheral edema (51%), and thrombocytopenia (49%) [1, Table 1]. Hepatotoxicity was further noted in many studies to be about 88%. Grade 3 or higher adverse events occurred in 78% of the treatment-naive patients and 87% of previously treated (relapsed or refractory) patients [1,10]. Other adverse effects seen include nausea, fatigue, pyrexia, weight increase, anemia, a decrease in calcium and sodium, and an increase in glucose. Patients 75 years and older were noted to have a greater likelihood of grade 3 altered mental status (including confusion, delirium, dementia, and encephalopathy) compared to younger patients [10]. Moreover, infusion reactions/hypersensitivity can also be expected based on the nature of diphtheria toxin with a reported rate of 46% [10].