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Molecular cancer therapeutics
Dec, 2015;14 (12): 2789-96.

Recombinant Immunotoxin with T-cell Epitope Mutations That Greatly Reduce Immunogenicity for Treatment of Mesothelin-Expressing Tumors.

Ronit Mazor, Jingli Zhang, Laiman Xiang, Selamawit Addissie, Prince Awuah, Richard Beers, Raffit Hassan, Ira Pastan
Author Information
  1. Ronit Mazor: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
  2. Jingli Zhang: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
  3. Laiman Xiang: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
  4. Selamawit Addissie: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
  5. Prince Awuah: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
  6. Richard Beers: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
  7. Raffit Hassan: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
  8. Ira Pastan: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland. pastani@mail.nih.gov.
PMID: 26443804 DOI: 10.1158/1535-7163.MCT-15-0532

Abstract

SS1P is a recombinant immunotoxin (RIT) that targets mesothelin. It consists of an antimesothelin Fv fused to a portion of Pseudomonas exotoxin A. In clinical studies, it has produced dramatic responses in patients with advanced mesothelioma, when combined with immunosuppressive therapy so that several treatment cycles could be given. Otherwise its activity is limited by its immunogenicity. In this work, we describe the development and characterization of LMB-T20, a highly potent RIT targeted at mesothelin-expressing cancers with low immunogenicity due to removal of its eight T-cell epitopes. LMB-T20 was more active than SS1P when tested on four different mesothelin-expressing cell lines as well as on cells obtained from patients with mesothelioma. It also has potent antitumor activity in mice, and has reduced immunogenicity as measured by cytokine secretion assays. In conclusion, LMB-T20 is a favorable candidate for evaluation in clinical trials due to its reduced immunogenicity and excellent activity.

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Grants

  1. Z01 BC008753-25/Intramural NIH HHS

MeSH Term

ADP Ribose Transferases
Animals
Antibodies, Monoclonal
Bacterial Toxins
Cell Line, Tumor
Epitopes, T-Lymphocyte
Exotoxins
GPI-Linked Proteins
Humans
Immunogenetic Phenomena
Mesothelin
Mesothelioma
Mice
Mutation
Recombinant Proteins
Virulence Factors
Xenograft Model Antitumor Assays
Pseudomonas aeruginosa Exotoxin A

Chemicals

Antibodies, Monoclonal
Bacterial Toxins
Epitopes, T-Lymphocyte
Exotoxins
GPI-Linked Proteins
Msln protein, mouse
Recombinant Proteins
SS1(dsFv)PE38
Virulence Factors
ADP Ribose Transferases
Mesothelin
Journal Article Research Support, N.I.H., Intramural
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