Despite major advances in the treatment of Hodgkin's disease by combination chemotherapy, about 30% of patients still die from their disease. The long term goal of the present study is to develop highly potent 2nd generation immunotoxins which will destroy those tumor cells that elude conventional therapy. This proposal concerns the development of a CD25 immunotoxin directed against the IL-2 receptor alpha-chain which is consistently expressed on Hodgkin/Reed-Sternberg cells (the putative malignant cells). Two types of CD25 immunotoxin will be used: the first consists of intact IgG antibodies linked by a stable disulfide crosslinker, SMPT, to ricin A- chain which has been deglycosylated to prevent hepatic entrapment; the second consists of the smaller Fab' fragment of antibody linked through a cystine bridge to deglycosylated ricin A-chain. The project has three specific aims. The first is to screen a panel of CD25 monoclonal antibodies a) for their ability as immunotoxins to kill L540 Hodgkin tumor cells in vitro and b) for their lack of crossreactivity with life- sustaining normal human tissues.
The second aim i s to determine how to administer the immunotoxins to achieve the maximal antitumor effect in immunodeficient mice bearing solid or disseminated human Hodgkin tumors. Parameters to be explored include: a) multiple versus single treatments; b) IgG versus Fab' immunotoxins; c) immunotoxins given alone versus in combination with chemotherapeutic or vasoactive drugs; d) CD25 immunotoxins given alone versus in combination with immunotoxins directed against other Hodgkin's tumor-associated antigens including the CD30 and IRac antigens. In preliminary studies, a single i.v. injection of a cocktail of a CD25 and an IRac immunotoxin induced permanent complete remissions in virtually 100% of mice bearing established (0.75 cm diameter) solid Hodgkin tumors, whereas administration of the individual immunotoxins was significantly less effective. The third specific aim is to determine the pharmacokinetics and immunogenicity of the best CD25 immunotoxin construct in Rhesus monkeys (CD25 positive) and to validate the safety of the intended starting dose for patients. This information will be used to support an IND application to enable CD25 immunotoxins to be tested in patients with advanced refractory Hodgkin's disease (Phase I) and, later, as a cocktail with CD30 or IRac immunotoxins in patients with minimal residual disease (Phase II).
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