Application of cytokine intervention for improved radio-antibody dose delivery

The goal of our studies was to determine whether administration of IL-1/GM-CSF to mice could reduce radio-antibody-induced myelosuppression and allow either dose escalation of radio-antibody using 131I, 90Y or 188Re conjugated to either intact antibody or bivalent fragments or more frequent dosing with 131I-IgG. Survival, peripheral blood counts, hematopoietic tissue weight and number of marrow CFCs were used to determine the ability to dose-intensify with a single dose or to reduce the spacing between doses. In this report, we show that in the absence of cytokines, 2 cycles of 131I-IgG spaced at 28, 35, 42 and 49 days resulted in 100%, 100%, 40% and 0% lethality, respectively. In contrast, cytokine intervention reduced lethality to 45%, 20%, 0% and 0% at the same time intervals between doses. Thus, the use of cytokines permits at least a 1 week earlier redosing of 131I-IgG. Cytokine intervention also has reduced the magnitude of myelosuppression, as measured by neutropenia and thrombocytopenia, thus permitting intensification of single doses of radio-iodinated intact antibodies, bivalent fragments and 90Y-IgG by at least 30%, 50% and 25%, respectively. However, cytokines were not effective at permitting dose escalation of either 90Y-F(ab')2 or 188Re-IgG. Further optimization of the dose schedule of cytokine administration needs to be explored for these 2 nuclide-antibody forms.