Preclinical studies on the use of selective antibody-ricin conjugates in autologous bone marrow transplantation.
Whole-ricin immunoconjugates were synthesized with the pan-T cell antibodies T101 and 3A1 and assayed in the presence of 0.1 mol/L lactose. Their toxicity for cell lines, peripheral blood T lymphocytes, and normal bone marrow progenitors was compared with that of whole ricin. In the presence of 0.1 mol/L lactose, normal cells and cell lines exhibited the following sensitivities to ricin: 8392 (human malignant B cell line) less than E rosette-positive lymphocytes less than bone marrow progenitors less than 8402 (human T ALL) less than CEM (human T ALL). Ricin sensitivities correlated with ricin binding as determined by immunofluorescence. In the presence of lactose, peripheral blood T cells were resistant to 0.1 nmol/L ricin, but a similar concentration of T101-ricin inhibited normal and malignant T colony formation by greater than 98%. 3A1-ricin was slightly less effective. At a conjugate concentration of 0.1 nmol/L, bone marrow progenitor colony formation was inhibited by 30% or less; T101-positive cells were at least tenfold more sensitive than normal progenitors. When mixtures of 10% CEM cells and marrow cells were incubated with T101-ricin, 95% of CEM colonies were killed, and 96% of marrow granulocyte/ macrophage progenitors survived. Some free ricin was released from immunotoxin-treated cells, producing minimal inhibition of protein synthesis or cell growth. We conclude that (a) normal blood cells and malignant cell lines exhibit varying degrees of ricin sensitivity in the presence of lactose; (b) T101-ricin is at least tenfold more toxic to T lymphocytes than to bone marrow progenitor cells and is effective in mixtures of normal and malignant cells; and (c) treatment of infiltrated marrow with anti-T cell immunotoxins should safely remove target T cells without excessively damaging normal progenitors or producing excessive free ricin. Anti-T cell, whole-ricin immunotoxins merit trials for autologous transplantation.
D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D000920:Antibody-Dependent Cell Cytotoxicity; D000936:Antigen-Antibody Complex / Q000276:immunology*; D016026:Bone Marrow Transplantation; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007785:Lactose / Q000494:pharmacology; D008212:Lymphocyte Depletion; D008214:Lymphocytes / Q000187:drug effects; D012276:Ricin / Q000494:pharmacology / Q000633:toxicity; D014182:Transplantation, Autologous; D014410:Tumor Stem Cell Assay
D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D012276:Ricin; D007785:Lactose