Immunogenicity of therapeutic recombinant immunotoxins

Immunol Rev. 2016 Mar;270(1):152-64. doi: 10.1111/imr.12390.

Abstract

Recombinant immunotoxins (RITs) are chimeric proteins designed to treat cancer. They are made up of an Fv or Fab that targets an antigen on a cancer cell fused to a 38-kDa portion of Pseudomonas exotoxin A (PE38). Because PE38 is a bacterial protein, it is highly immunogenic in patients with solid tumors that have normal immune systems, but much less immunogenic in patients with hematologic malignancies where the immune system is suppressed. RITs have shown efficacy in refractory hairy cell leukemia and in some children with acute lymphoblastic leukemia, but have been much less effective in solid tumors, because neutralizing antibodies develop and prevent additional treatment cycles. In this paper we will (i) review data from clinical trials describing the immunogenicity of PE38 in different patient populations; (ii) review results from clinical trials using different immunosuppressive drugs; and (iii) describe our efforts to make new less-immunogenic RITs by identifying and removing T- and B-cell epitopes to hide the RIT from the immune system.

Keywords: anti-drug antibodies; immunotherapy; mesothelin; mesothelioma; neutralizing antibodies.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • ADP Ribose Transferases / chemistry
  • ADP Ribose Transferases / genetics
  • ADP Ribose Transferases / immunology
  • Animals
  • Antibodies, Monoclonal, Humanized / immunology
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Antibodies, Neutralizing / immunology
  • Antibody Formation
  • Antigens / immunology
  • Bacterial Toxins / chemistry
  • Bacterial Toxins / genetics
  • Bacterial Toxins / immunology
  • Clinical Trials as Topic
  • Drug Administration Routes
  • Drug Therapy, Combination
  • Epitope Mapping
  • Epitopes, B-Lymphocyte / immunology
  • Epitopes, T-Lymphocyte / immunology
  • Exotoxins / chemistry
  • Exotoxins / genetics
  • Exotoxins / immunology
  • Genetic Engineering
  • Humans
  • Immunoglobulin Fragments / immunology
  • Immunoglobulin Fragments / therapeutic use
  • Immunosuppressive Agents / administration & dosage
  • Immunosuppressive Agents / therapeutic use
  • Immunotherapy
  • Immunotoxins / administration & dosage
  • Immunotoxins / adverse effects
  • Immunotoxins / chemistry
  • Immunotoxins / genetics
  • Immunotoxins / immunology*
  • Immunotoxins / therapeutic use*
  • Mesothelin
  • Mice
  • Neoplasms / immunology
  • Neoplasms / therapy
  • Polyethylene Glycols
  • Recombinant Fusion Proteins*
  • Sequence Deletion
  • Virulence Factors / chemistry
  • Virulence Factors / genetics
  • Virulence Factors / immunology

Substances

  • Antibodies, Monoclonal, Humanized
  • Antibodies, Neutralizing
  • Antigens
  • Bacterial Toxins
  • Epitopes, B-Lymphocyte
  • Epitopes, T-Lymphocyte
  • Exotoxins
  • Immunoglobulin Fragments
  • Immunosuppressive Agents
  • Immunotoxins
  • Msln protein, mouse
  • Recombinant Fusion Proteins
  • Virulence Factors
  • Polyethylene Glycols
  • ADP Ribose Transferases
  • toxA protein, Pseudomonas aeruginosa
  • Mesothelin