Immunotoxins are genetically engineered recombinant proteins consisting of a targeting moiety, such as an antibody, and a cytotoxic toxin moiety of microbial origin. Pseudomonas exotoxin A and diphtheria toxin (DT) have been abundantly used in immunotoxins, with the latter applied as the toxin moiety of the FDA-approved drug Denileukin diftitox (ONTAK®). However, the use of immunotoxins provokes an adverse immune response in the host body against the toxin moiety, limiting their efficacy. In silico approaches have received increasing attention in protein engineering. In this study, the epitopes responsible for immunogenicity were identified through multiple platforms. By subtracting conserved and ligand-binding residues, K33, T111, and E112 were identified as common epitopes across all platforms. Substitution analysis evaluated alternative residues regarding their impact on protein stability, considering 19 different amino acid substitutions. Among the mutants explored, the T111A-E112G mutant exhibited the most destabilizing substitution for DT, thereby reducing immunogenicity. Finally, a 3D model of the mutant was generated and verified. The model was then docked with its native ligand NADH, and the complex's molecular behavior was simulated using molecular dynamics.

01 Jan 2023·Immunotherapy Advances

A recombinant Der p 1-specific allergen-toxin demonstrates superior killing of allergen-reactive IgG+ hybridomas in comparison to its recombinant allergen-drug conjugate

Article

Author: Mthembu, N ; Brombacher, F ; Fadeyi, O E ; Hunter, R ; Naran, K ; Daramola, A K ; Huysamen, A M ; Fajemisin, E A ; Barth, S ; Akinrinmade, O A ; Hadebe, S

SummaryIntroductionCurrent treatments for asthma help to alleviate clinical symptoms but do not cure the disease. In this study, we explored a novel therapeutic approach for the treatment of house dust mite allergen Der p 1induced asthma by aiming to eliminate specific population of B-cells involved in memory IgE response to Der p 1.Materials and MethodsTo achieve this aim, we developed and evaluated two different proDer p 1-based fusion proteins; an allergen-toxin (proDer p 1-ETA) and an allergen-drug conjugate (ADC) (proDer p 1-SNAP-AURIF) against Der p 1 reactive hybridomas as an in vitro model for Der p 1 reactive human B-cells. The strategy involved the use of proDer p 1 allergen as a cell-specific ligand to selectively deliver the bacterial protein toxin Pseudomonas exotoxin A (ETA) or the synthetic small molecule toxin Auristatin F (AURIF) into the cytosol of Der p 1 reactive cells for highly efficient cell killing.ResultsAs such, we demonstrated recombinant proDer p 1 fusion proteins were selectively bound by Der p 1 reactive hybridomas as well as primary IgG1+ B-cells from HDM-sensitized mice. The therapeutic potential of proDer p 1-ETAʹ and proDer p 1-SNAP-AURIF was confirmed by their selective cytotoxic activities on Der p 1 reactive hybridoma cells. The allergen-toxin demonstrated superior cytotoxic activity, with IC50 values in the single digit nanomolar value, compared to the ADC.DiscussionsAltogether, the proof-of-concept experiments in this study provide a promising approach for the treatment of patients with house dust mite-driven allergic asthma.

01 Jan 2023·Therapeutic Delivery

New Insights on Pseudomonas Aeruginosa Exotoxin A-based Immunotoxins in Targeted Cancer Therapeutic Delivery

Review

Author: Farrag, Hala A. ; Morgan, Radwa N. ; Aboshanab, Khaled M. ; Saleh, Sarra E.

Pseudomonas aeruginosa exotoxin A-based immunotoxins (PE-ITs) are fusion proteins that harness targeting and toxin moieties. Structural optimizations in PE and targeting moieties were implemented to lower their immunogenicity and alleviate undesirable side effects. PE moiety was engineered to lack its cell-binding domain and T cell epitope regions, whereas single chain (scFv) and disulfide Fv portions (dsFv), nanobodies, and monobodies were utilized as targeting moieties. This review discusses applications of PE-ITs on different types of cancer, structural optimizations to reduce PE-ITs drawbacks, and recent modifications applied for efficient therapeutic delivery. Finally, we draw attention to the possibility of combining radiotherapy, radionuclides, and RGDs with PE-IT to improve overall response rates of IT-based treatments and reduce cancer cell resistance.

100 Deals associated with Pseudomonas exotoxin(John Wayne Cancer Institute)

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Indication	Highest Phase	Country/Location	Organization	Date
Brain Cancer	Phase 2	-	John Wayne Cancer Institute	-

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