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.
Blumenthal
R D
RD
Garden State Cancer Center at the Center for Molecular Medicine and Immunology, Belleville, NJ 07109, USA. rblumenthal.gscancer@worldnet.att.net
Sharkey
R M
RM
Haywood
L
L
Behr
T
T
Goldenberg
D M
DM
D000818:Animals; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage*; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage; D007074:Immunoglobulin G / Q000008:administration & dosage*; D007375:Interleukin-1 / Q000008:administration & dosage*; D007457:Iodine Radioisotopes / Q000008:administration & dosage; D007958:Leukocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D009503:Neutropenia / Q000517:prevention & control; D016499:Radioimmunotherapy / Q000009:adverse effects / Q000379:methods*; D012211:Rhenium / Q000008:administration & dosage; D013921:Thrombocytopenia / Q000517:prevention & control; D015021:Yttrium Radioisotopes / Q000008:administration & dosage
D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D007375:Interleukin-1; D007457:Iodine Radioisotopes; D015021:Yttrium Radioisotopes; D012211:Rhenium; D016178:Granulocyte-Macrophage Colony-Stimulating Factor