PRECLINICAL STUDIES ON THE USE OF SELECTIVE ANTIBODY-RICIN CONJUGATES IN AUTOLOGOUS BONE-MARROW TRANSPLANTATION

  • 1 January 1985
    • journal article
    • research article
    • Vol. 65  (5) , 1149-1157
Abstract
Whole-ricin immunoconjugates were synthesized with the pan-T cell antibodies T101 and 3A1 and assayed in the presence of 0.1/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) < E rosette-positive lymphocytes < bone marrow progenitors < 8402 (human T ALL [acute lymphocytic leukemia]) < 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 > 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 10-fold 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. Normal blood cells and malignant cell lines exhibit varying degrees of ricin sensitivity in the presence of lactose; T101-ricin is at least 10-fold more toxic to T lymphocytes than to bone marrow progenitor cells and is effective in mixtures of normal and malignant cells; and 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.

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