Rationale for the selection of ricin A-chain anti-T immunotoxins for mature T cell depletion.
A series of 25 different ricin A-chain immunotoxins (IT) were prepared with monoclonal antibodies reacting with several T cell antigens belonging to different clusters of differentiation (CD) to select the most appropriate immunotoxins (IT) for mature T cell depletion. Our screening procedure was performed in 2 steps. First, IT were evaluated using protein synthesis inhibition assay on clonogenic malignant cells in order to determine the most active IT for a given CD. Second, IT thus selected were evaluated for both mature T cell killing efficacy and tolerance on hematopoietic progenitor cells (HPC). This study showed that (1) different IT directed against the same CD antigen displayed a wide range of activity, suggesting the need for a large screening of IT to determine the most appropriate antibody for a given target antigen; (2) anti-CD3 and anti-CD5 ricin A-chain IT are the most active, displaying a cytoreduction of more than 2 logs on mature T cells; (3) the 3 different anti-CD2 ricin A-chain IT evaluated in this study induced poor mature T cell cytoreduction despite their relative efficacy on leukemic cells; (4) anti-CD8 ricin A-chain IT showed almost no efficacy on relevant target cells; (5) no toxicity on HPC was found for concentrations up to 10(-8) of A-chain whatever the IT used.
D000911:Antibodies, Monoclonal / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D003864:Depression, Chemical; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000276:immunology; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology*; D007938:Leukemia / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D008212:Lymphocyte Depletion; D009363:Neoplasm Proteins / Q000096:biosynthesis; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000276:immunology; D010835:Phytohemagglutinins / Q000494:pharmacology; D012276:Ricin / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000276:immunology
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D000922:Immunotoxins; D009363:Neoplasm Proteins; D010835:Phytohemagglutinins; D012276:Ricin