HER2/neu oncogene encodes a 185 kDa trans-
membrane protein which is overexpressed in 20-30% of breast and
ovarian cancers and portends a poor prognosis. We have studied the targeting and
therapy of this
oncoprotein with 4D5, a murine
monoclonal antibody which recognizes a distinct
epitope on the extracelluar domain of HER2/neu. We conjugated the antibody with an active
ester of the macrocyclic
chelating agent DOTA, radiolabeled the conjugate with either (111)In or (90)Y, and studied the antibody distribution and
therapy, respectively, in athymic mice bearing xenografts of MCF7/HER2/neu, a human
breast cancer cell line transfected with the HER2/neu oncogene. For the biodistribution of (111)In-labeled
DOTA-4D5, a high specificity of
tumor localization (30% ID/g) was seen with a
tumor-to-blood ratio of greater than 2 at 48 h postinjection. Compared to a previously published study with (125)I-labeled 4D5 in beige nude mice bearing NIH3T3/HER2/neu xenografts [De Santes et al. (1992)
Cancer Res. 52, 1916-1923], (111)In-labeled 4D5 antibody gave superior antibody uptake in
tumor (30% ID/g vs 17% ID/g at 48h). In the
therapy study, treatment of the nude mice bearing MCF7/HER2/neu xenografts with 100 microCi (3 microg) of (90)Y-labeled
DOTA-4D5 caused a 3-fold reduction of
tumor growth compared to untreated controls (injected with
human serum albumin) in 40 days. Treatment of animals with 100 microCi of nonspecific antibody (90)Y-labeled DOTA-Leu16 (3 microg) had no
tumor growth inhibition. Treatment with unlabeled
DOTA-4D5 (3 microg) had a slight effect on
tumor growth compared to untreated controls. When analyzed at the level of single animals, no effect was seen in seven of nine animals; however, in two of the animals,
tumor growth inhibition was observed. Although a cold antibody
therapeutic effect was unexpected at this dose level (3 microg), it may be possible that in some animals that 3 microg of antibody of (90)Y-labeled
DOTA-4D5 augmented
tumor growth reduction. To further explore the effects of cold antibody treatment alone, animals were treated with 100 or 400 microg of unlabeled 4D5 administered in two doses. These animals showed a 1.7-1.8-fold reduction in
tumor growth over 28 days, a result less than that obtained with RIT only.