Effect of interleukin-2 on biodistribution of monoclonal antibody in tumor and normal tissues in mice bearing SL-2 thymoma.
BACKGROUND
Our laboratory demonstrated previously that treatment with a tumor-specific, radiolabeled anti-Thy 1 murine monoclonal antibody (MAb) in mice can eradicate a T-cell lymphoma mass, but the doses required were toxic to normal organs. Approaches to increase MAb concentration in tumor tissue versus normal tissue may overcome this problem. Interleukin-2 (IL-2) has been shown to increase capillary permeability, as indicated by extravasation of albumin.


OBJECTIVE
The purpose of this study was to determine whether increased extravasation of MAb at the tumor site might result in selective binding to tumor antigen, increasing localization of radiolabeled MAb at the tumor site.


METHODS
We studied the effect of IL-2 on biodistribution of 1A14 MAb (anti-Thy 1.1) in normal AKR/Cum (Thy 1.2+) mice and in AKR/Cum mice bearing SL-2, a spontaneous T-cell lymphoma (Thy 1.1+), compared with biodistribution of albumin in normal mice and biodistribution of the nonreactive G3G6 MAb in tumor-bearing mice. IL-2 was given intravenously in the tail vein in doses of 0, 25,000, 50,000, 100,000, or 200,000 U twice a day for a total of seven doses over 3.5 days. Mice received injections of a mixture of 1A14 MAb (250 muCi/100 micrograms) and albumin or G3G6 MAb (145 muCi/100 micrograms) in a total volume of 200 microL at 12 hours after the last IL-2 dose.


RESULTS
In normal mice, IL-2 caused a dose-dependent increase of both radiolabeled MAb and albumin in the spleen, liver, lung, and lymph node, but it spared the brain. In tumor-bearing mice, IL-2 resulted in higher levels of MAb in the tumors 72 hours after receiving injections, with 17.5% and 24.3% of the injected dose per gram of tumor present in the mice pretreated with 100,000 or 200,000 U of IL-2 twice a day for 3.5 days, compared with 13.4% in the controls. In IL-2-treated mice, levels of MAb were greater in the tumors than in critical normal organs; the differences were statistically significant for tumors versus lungs at 24 hours after injection and for tumors versus livers at 48 hours and 72 hours after injection.


CONCLUSIONS
These results suggest that pretreatment with IL-2 may lead to enhanced distribution of tumor-specific MAb to the tumor site, compared with normal tissues, thus increasing therapeutic efficacy of radiolabeled MAb.
Schultz
K R
KR
Department of Pediatrics, University of Washington, Seattle.
Badger
C C
CC
Dombi
G W
GW
Greenberg
P D
PD
Bernstein
I D
ID
D000418:Albumins / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D007376:Interleukin-2 / Q000008:administration & dosage / Q000494:pharmacology*; D007518:Isoantibodies / Q000378:metabolism*; D016399:Lymphoma, T-Cell / Q000628:therapy*; D051379:Mice; D008806:Mice, Inbred AKR; D013945:Thymoma / Q000378:metabolism* / Q000628:therapy; D014018:Tissue Distribution
D000418:Albumins; D000911:Antibodies, Monoclonal; D007376:Interleukin-2; D007518:Isoantibodies; C035678:anti-Thy antibody