Ricin A-chain containing immunotoxins directed against different epitopes on the CD2 molecule differ in their ability to kill normal and malignant T cells.
Open Access
- 15 December 1988
- journal article
- research article
- Published by The American Association of Immunologists in The Journal of Immunology
- Vol. 141 (12), 4410-4417
- https://doi.org/10.4049/jimmunol.141.12.4410
Abstract
Immunoconjugates consisting of mAb covalently coupled to plant or bacterial toxins or to cytotoxic drugs have provided novel experimental reagents for the treatment of malignancies and autoimmune diseases. In this report, we analyzed the efficacy of three ricin A chain-containing immunotoxins (IT-A) which recognize different epitopes on the CD2 molecule (E rosette receptor) on human T cells. Although all IT-A had similar binding avidities and A-chain activities, one (RFT11-A) was 100-1000-fold more effective in killing normal and malignant T cells than the others (35.1-A, 9.6-A). Immunoprecipitation experiments confirmed that all IT-A bound to the CD2 molecule. However, cross-blocking experiments, differential proteolysis with trypsin, and T cell co-activation experiments showed that the less effective IT-A, 35.1-A and 9.6-A, bound to an epitope far from the cell membrane (region I), whereas the more effective IT-A, RFT11-A bound to an epitope closer to the membrane (region II). Using cellular RIA and immunoelectron microscopy, it was shown that both RFT11-A and 35.1-A were rapidly internalized by T cells, but that their intracellular fates differed. The more toxic IT-A, RFT11-A, was retained for longer periods of time inside the cells and was more slowly degraded than the less effective IT-A, 35.1-A, which was rapidly transported to lysosomes, digested, and expelled. These results demonstrate that different IT-A targeting the same surface molecule can differ markedly in potency, and that the epitope recognized by an IT-A may have a significant impact on the ability of the IT-A to insert into cell membranes, translocate to the cytosol, and kill cells.This publication has 23 references indexed in Scilit:
- OPTIMAL ELIMINATION OF LEUKEMIC T-CELLS FROM HUMAN-BONE MARROW WITH T101-RICIN A-CHAIN IMMUNOTOXIN1985
- ENDOCYTOSIS OF AN ANTIBODY RICIN A-CHAIN CONJUGATE (IMMUNO-A-TOXIN) ADSORBED ON COLLOIDAL GOLD - EFFECTS OF AMMONIUM-CHLORIDE AND MONENSIN1985
- Monensin inhibits recycling of macrophage mannose-glycoprotein receptors and ligand delivery to lysosomesBiochemical Journal, 1984
- Internalization and degradation of macrophage Fc receptors bound to polyvalent immune complexes.The Journal of cell biology, 1984
- EX-VIVO TREATMENT OF DONOR BONE MARROW WITH ANTI-T-CELL IMMUNOTOXINS FOR PREVENTION OF GRAFT-VERSUS-HOST DISEASEThe Lancet, 1984
- T cell nature and heterogeneity of recognition structures of human natural killer (NK) cells.The Journal of Immunology, 1983
- Identification and functional characterization of two distinct epitopes on the human T cell surface protein Tp50.The Journal of Immunology, 1983
- Posttranslational processing of the LDL receptor and its genetic disruption in familial hypercholesterolemiaCell, 1982
- Kinetics of protein synthesis inactivation by ricin-anti-Thy 1.1 monoclonal antibody hybrids. Role of the ricin B subunit demonstrated by reconstitution.Journal of Biological Chemistry, 1982
- Epidermal growth factor-toxin A chain conjugates: EGF-Ricin A is a potent toxin while EGF-diphtheria fragment A is nontoxicCell, 1980