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

Ronit 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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)8571-8576
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number23
DOIs
StatePublished - 10 Jun 2014

Keywords

  • Deimmunization
  • Protein engineering

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