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Recombinant immunotoxin for cancer treatment with low immunogenicity by identification and silencing of human T-cell epitopes.

Abstract
Nonhuman proteins have valuable therapeutic properties, but their efficacy is limited by neutralizing antibodies. Recombinant immunotoxins (RITs) are potent anticancer agents that have produced many complete remissions in leukemia, but immunogenicity limits the number of doses that can be given to patients with normal immune systems. Using human cells, we identified eight helper T-cell epitopes in PE38, a portion of the bacterial protein Pseudomonas exotoxin A which consists of the toxin moiety of the RIT, and used this information to make LMB-T18 in which three epitopes were deleted and five others diminished by point mutations in key residues. LMB-T18 has high cytotoxic and antitumor activity and is very resistant to thermal denaturation. The new immunotoxin has a 93% decrease in T-cell epitopes and should have improved efficacy in patients because more treatment cycles can be given. Furthermore, the deimmunized toxin can be used to make RITs targeting other antigens, and the approach we describe can be used to deimmunize other therapeutically useful nonhuman proteins.
AuthorsRonit Mazor, Jaime A Eberle, Xiaobo Hu, Aaron N Vassall, Masanori Onda, Richard Beers, Elizabeth C Lee, Robert J Kreitman, Byungkook Lee, David Baker, Chris King, Raffit Hassan, Itai Benhar, Ira Pastan
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 23 Pg. 8571-6 (Jun 10 2014) ISSN: 1091-6490 [Electronic] United States
PMID24799704 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
Chemical References
  • Amino Acids
  • Bacterial Toxins
  • Epitopes, T-Lymphocyte
  • Exotoxins
  • Immunotoxins
  • Peptides
  • Recombinant Fusion Proteins
  • Virulence Factors
  • ADP Ribose Transferases
  • Pseudomonas aeruginosa exotoxin A
Topics
  • ADP Ribose Transferases (genetics, immunology)
  • Amino Acids (genetics, immunology)
  • Animals
  • Antibody Formation (immunology)
  • Bacterial Toxins (genetics, immunology)
  • Cell Line, Tumor
  • Cell Survival (drug effects, immunology)
  • Electrophoresis, Polyacrylamide Gel
  • Epitope Mapping
  • Epitopes, T-Lymphocyte (immunology)
  • Exotoxins (genetics, immunology)
  • Female
  • Humans
  • Immunotherapy (methods)
  • Immunotoxins (genetics, immunology, therapeutic use)
  • Lymphocyte Activation (drug effects, immunology)
  • Mice
  • Mice, SCID
  • Models, Molecular
  • Neoplasms (immunology, pathology, therapy)
  • Peptides (genetics, immunology)
  • Point Mutation
  • Protein Structure, Tertiary
  • Recombinant Fusion Proteins (chemistry, immunology, therapeutic use)
  • T-Lymphocytes (drug effects, immunology, metabolism)
  • Virulence Factors (genetics, immunology)
  • Xenograft Model Antitumor Assays

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