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Protein Toxins

Protein toxin is one type of conjugates that can be linked to an antibody. Various strategies in ADC approach are developed to increase the specificity of cell targeting and the principles include increasing the efficacy to toxicity window for the chosen therapy or lowering the dosage needed.

Protein toxins Figure: Schematic diagram of antibody-PE (Yvonne Andersson)

Small molecule (natural product) toxins are the major class of the ADCs therapeutically approved or in clinical trials, accounting for 70% market. Protein toxins conjugated to an anti-tumor antibody to produce fusion proteins are successful biopharmaceuticals. VB4-845(Vicinium™ and Proxinium™) and anti-CD22-PE (CAT-8015) are two promising immunotoxins currently in clinical trials, both of them are scFv-fused Pseudomonas exotoxin. Protein toxins are usually produced from bacteria and plants. Most bacterial toxins and plant toxins consist of two moieties, one target on the cell surface and the other enters the cytosol, inhibiting protein synthesis. Bacterial toxins widely studied mainly include Shiga toxin, Shiga-like toxin, Pseudomonas exotoxin, diphtheria toxin and cholera toxin.Plant toxins, such as ricin, modeccin, abrin, volkensin and viscumin are well identified and researched. In the strategy of protein toxin conjugates, Pseudomonas exotoxin (PE) and diphtheria toxin (DT) are the most intensively explored. Pseudomonas exotoxin (PE), also known as exotoxin A, is a major virulence factor of Pseudomonas aeruginosa. It is composed of three structural and functional domains (domains I, II, and III) and it can be cleaved by furin in vivo and in vitro to generate a C-terminal toxin fragment. The toxin fragment is retro-translocated to the cytosol and can block protein synthesis by ADP ribosylation of elongation factor 2, thereby triggering cell death. Diphtheria toxin (DT), produced by Corynebacterium diphtheria, is an alternative toxin that can be used to conjugate with antibodies. Diphtheria toxin (DT) is produced by Corynebacterium diphtheria that inhibits protein synthesis and kills susceptible cells. Moreover, diphtheria toxoid is an effective vaccine for immunization against diphtheria.

Based on ADC applications and client’s individual requirements, scientists from Creative Biolabs will provide the most appropriate strategy to assist the ADC development.

Categories of ADC payloads that Creative Biolabs provides:

References:
Juliette Morlon-Guyot, et al. Processing of Pseudomonas aeruginosa Exotoxin A is dispensable for cell intoxication. Infect Immun. 2009 Jul; 77(7): 3090–3099.
Holmes RK. Biology and molecular epidemiology of diphtheria toxin and the tox gene. J Infect Dis. 2000 Feb; 181 Suppl 1:S156-67.
Kirsten Sandvig, et al. Protein toxins from plants and bacteria: probes for intracellular transport and tools in medicine. FEBS Lett. 2010 Jun 18; 584(12):2626-34.

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