Lym-1-induced apoptosis of non-Hodgkin's lymphomas produces regression of transplanted tumors.
Lym-1 was one of the first antibodies to be used successfully for the radioimmunotherapy of the human malignant lymphomas. This antibody, which recognizes the HLA-DR10 antigen preferentially expressed in B-cell lymphomas, was recently shown to induce apoptosis upon binding to lymphoma cells. In this study, Lym-1-induced apoptosis was studied to identify the potential molecular pathways of programmed cell death and to demonstrate the clinical potential of this antibody in the treatment of the human malignant lymphomas. Immunofluorescence microscopy revealed that Lym-1 stained focal areas of the cell surface, consistent with the fact that the HLA-DR10 antigen is associated with lipid rafts, a known prerequisite for apoptosis signaling. Likewise, Annexin V/propidium iodide staining and TUNEL assays demonstrated that both murine Lym-1 and chimeric Lym-1 induced both early and late apoptosis, respectively, unlike anti-CD20 rituximab. Furthermore, Lym-1 was found to produce a rapid loss of mitochondrial membrane potential and mitochondrial release of cytochrome C 14 hours post-Lym-1 treatment. Although it was found to activate caspase-3, inhibitors of caspase pathways showed that the Lym-1-induced apoptosis in lymphoma cell lines is independent of caspase induction. Finally, treatment studies in vivo demonstrated that, compared with murine anti-CD20 (2B8), Lym-1 was more effective in inducing the regression of human lymphoma xenografts. Based upon these results, chimeric Lym-1 should be especially effective in treating lymphoma patients, as, in addition to being able to elicit immune effector functions such as chimeric anti-CD20, it can also induce apoptosis directly upon cell binding.
Zhang
Nan
N
Department of Pathology, University of Southern California, Keck School of Medicine, Los Angeles, CA 90089, USA.
Khawli
Leslie A
LA
Hu
Peisheng
P
Epstein
Alan L
AL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000032:analysis; D004789:Enzyme Activation / Q000528:radiation effects; D006684:HLA-DR Antigens / Q000276:immunology; D059810:HLA-DR Serological Subtypes; D006801:Humans; D019169:Jurkat Cells; D008228:Lymphoma, Non-Hodgkin / Q000276:immunology* / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000528:radiation effects; D051379:Mice; D008819:Mice, Nude; D011480:Protease Inhibitors / Q000494:pharmacology; D000069283:Rituximab; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D006684:HLA-DR Antigens; D059810:HLA-DR Serological Subtypes; C421823:HLA-DR10 antigen; C410509:Lym-1 monoclonal antibody; D011480:Protease Inhibitors; D000069283:Rituximab; D045304:Cytochromes c; D053148:Caspase 3