Proceedings of the National Academy of Sciences - PNAS, 2011-04, Vol.108 (14), p.5742-5747
2011
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- Autor(en) / Beteiligte
- Titel
- Recombinant immunotoxin against B-cell malignancies with no immunogenicity in mice by removal of B-cell epitopes
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2011-04, Vol.108 (14), p.5742-5747
- Ort / Verlag
- United States: National Academy of Sciences
- Erscheinungsjahr
- 2011
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Many nonhuman proteins have useful pharmacological activities, but are infrequently effective in humans because of their high immunogenicity. A recombinant immunotoxin (HA22, CAT8015, moxetumomab pasudotox) composed of an anti-CD22 antibody variable fragment fused to PE38, a 38-kDa portion of Pseudomonas exotoxin A, has produced many complete remissions in drug-resistant hairy-cell leukemia when several cycles of the agent can be given, but has much less activity when antibodies develop. We have pursued a strategy to deimmunize recombinant immunotoxins by identifying and removing B-cell epitopes. We previously reported that we could eliminate most B-cell epitopes using a combination of point mutations and deletions. Here we show the location and amino acid composition of all of the B-cell epitopes in the remaining 25-kDa portion of Pseudomonas exotoxin. Using this information, we eliminated these epitopes to produce an immunotoxin (HA22-LR-8M) that is fully cytotoxic against malignant B-cell lines, has high cytotoxic activity against cells directly isolated from patients with chronic lymphocytic leukemia, and has excellent antitumor activity in mice. HA22-LR-8M does not induce antibody formation in mice when given repeatedly by intravenous injection and does not induce a secondary antibody response when given to mice previously exposed to HA22. HA22-LR-8M also has greatly reduced antigenicity when exposed to sera from patients who have produced antibodies to HA22. The properties of HA22-LR-8M make it an excellent candidate for further clinical development.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424eISSN: 1091-6490DOI: 10.1073/pnas.1102746108Titel-ID: cdi_crossref_primary_10_1073_pnas_1102746108
- Format
- –
- Schlagworte
- ADP Ribose Transferases - genetics, ADP Ribose Transferases - metabolism, Amino acid composition, Amino Acid Sequence, Amino acids, Animals, Antibodies, Antibodies, Monoclonal, antibody formation, Antibody response, Antigenicity, antineoplastic activity, Antitumor activity, B lymphocyte epitopes, B-lymphocytes, Bacteria, Bacterial Toxins - genetics, Bacterial Toxins - metabolism, Biological Sciences, Cell Line, Tumor, Cell lines, Cells, Chronic lymphatic leukemia, Cytotoxicity, Drug resistance, Enzyme-Linked Immunosorbent Assay, Epitopes, Epitopes, B-Lymphocyte - genetics, exotoxin A, Exotoxins, Exotoxins - genetics, Exotoxins - metabolism, humans, Immune response, Immunization, Passive - methods, Immunogenicity, Immunotoxins, Inhibitory concentration 50, Intravenous administration, intravenous injection, Leukemia, Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell - immunology, Lymphocytes, Lymphocytes B, lymphocytic leukemia, Malignancy, Mice, Mice, Inbred BALB C, Models, Molecular, Molecular Sequence Data, Mutagenesis, Mutation, patients, Point mutation, Protein Engineering - methods, Proteins, Pseudomonas, Pseudomonas aeruginosa Exotoxin A, Reactivity, Recombinant Fusion Proteins - biosynthesis, Recombinant Fusion Proteins - genetics, Recombinant Fusion Proteins - immunology, Recombinant Fusion Proteins - therapeutic use, Remission, Rodents, Statistics, Nonparametric, Toxins, Virulence Factors - genetics, Virulence Factors - metabolism