title: Immunogenicity of therapeutic recombinant immunotoxins.
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.
authors: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Ronit
authors: R
authors: Mazor
authors: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Masanori
authors: M
authors: Onda
authors: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Ira
authors: I
authors: Pastan
mesh_terms: D036002:ADP Ribose Transferases / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology / Q000627:therapeutic use; D057134:Antibodies, Neutralizing / Q000276:immunology; D000917:Antibody Formation; D000941:Antigens / Q000276:immunology; D001427:Bacterial Toxins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D002986:Clinical Trials as Topic; D004333:Drug Administration Routes; D004359:Drug Therapy, Combination; D018604:Epitope Mapping; D018985:Epitopes, B-Lymphocyte / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005098:Exotoxins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D005818:Genetic Engineering; D006801:Humans; D007128:Immunoglobulin Fragments / Q000276:immunology / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use; D007167:Immunotherapy; D000922:Immunotoxins / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use*; D000090204:Mesothelin; D051379:Mice; D009369:Neoplasms / Q000276:immunology / Q000628:therapy; D011092:Polyethylene Glycols; D011993:Recombinant Fusion Proteins; D017384:Sequence Deletion; D037521:Virulence Factors / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D000097668:Pseudomonas aeruginosa Exotoxin A
chemical_list: D036002:ADP Ribose Transferases; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D000941:Antigens; D001427:Bacterial Toxins; D018985:Epitopes, B-Lymphocyte; D018984:Epitopes, T-Lymphocyte; D005098:Exotoxins; D007128:Immunoglobulin Fragments; D007166:Immunosuppressive Agents; D000922:Immunotoxins; D000090204:Mesothelin; D011092:Polyethylene Glycols; D011993:Recombinant Fusion Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C000715528:Msln protein, mouse
keywords: anti-drug antibodies; immunotherapy; mesothelin; mesothelioma; neutralizing antibodies