Experimental Treatment of Human Hodgkin's Disease with Ricin A-Chain Immunotoxins

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Abstract
In the present paper we describe the evaluation of ricin A-chain immunotoxins for clinical application in Hodgkin's disease. The immunotoxins were constructed by chemically linking deglycosylated ricin-A to monoclonal antibodies (MoAb) recognising lymphocyte activation markers CD25, CD30, or IRac, which are expressed by Hodgkin's and Reed-Sternberg (H-RS) cells. The cytotoxic effects of the immunotoxins were investigated in vitro against L540Cy Hodgkin cells and in vivo against Hodgkin's tumors in nude mice and disseminated Hodgkin's tumors in SCID mice. MoAbs were evaluated for crossreactivity with normal human tissues and staining of sections from Hodgkin's disease tissue. Of 32 MoAbs, eight showed little crossreactivity with vital human organs and produced highly active immunotoxins. The most effective immunotoxin, RFT5γ1.dgA (CD25), inhibits the growth of H-RS cells at concentrations of 7 × 10−12 M. RFT5γ1.dgA destroys about 60% of solid Hodgkin's tumors of 0.5 cm diameter in nude mice and induces complete remissions in 95% of SCID mice with disseminated Hodgkin's tumors when administered one day after tumor challenge. This immunotoxin binds to all H-RS cells in more than 90% of patients with Hodgkin's disease. Patients with refractory Hodgkin's disease are currently being treated in a phase-I/II clinical trial.