Evidence for absence of toxicity of T101 immunotoxin on human hematopoietic progenitor cells prior to bone marrow transplantation.

T101-ricin A-chain immunotoxin is a hybrid molecule made up of the T101 monoclonal antibody bound to the A-chain of ricin. It specifically destroys cells expressing the cell surface T65 antigen. We have designed a preclinical study to evaluate its possible use for the in vitro treatment of T-cell hematological cancers prior to autologous bone marrow transplantation. The data presented here show that conditions previously defined to produce high tumor cell killing, i.e., a 20-hr incubation at 37 degrees in the presence of T101-ricin A-chain immunotoxin up to 10(-7) M in a 10 mM ammonium chloride solution, do not affect the in vitro proliferative capacity of human hematopoietic stem cells studied by means of semisolid medium cultures (granulocyte-macrophage progenitors, burst-forming units-erythrocyte) and continuous liquid cultures (pre-granulocyte-macrophage progenitors). Therefore, autologous bone marrow transplantation with T101-ricin A-chain immunotoxin-treated graft should be feasible.

Present potential of immunotoxins.

Immuno-a-toxins (I-a-T) are hybrid molecules designed for a more selective therapy of cancer, which combine an antibody preferentially directed against tumour cells and the A-chain of the toxin ricin. Although a majority of them are highly and selectively cytotoxic to their target cells in vitro, only some of them gave rise to a therapeutic effect in animal models. In vitro kinetics studies suggested the importance of a rapid mode of action for in vivo efficacy, which is not the property of all I-a-T. Ways of accelerating and potentiating such conjugates are proposed, such as the use of lysosomotropic amines like ammonium chloride. Whereas the in vivo use of these activators is still under research, their in vitro use gives rise to a 99.99% cytoreduction of leukemic cells and thus is directly applicable to clinical situations such as bone marrow transplantations.