Anti-angiogenic treatment with
tyrosine kinase inhibitors (TKI) has lead to an impressive increase in progression-free survival for patients with metastatic RCC (mRCC), but mRCC remains largely incurable. We combined
sunitinib, targeting the endothelial cells with
Girentuximab (
monoclonal antibody cG250, recognizing
carbonic anhydrase IX (CAIX) targeting the
tumor cells to study the effect of
sunitinib on the biodistribution of
Girentuximab because combination of modalities targeting
tumor vasculature and
tumor cells might result in improved effect. Nude mice with human RCC xenografts (NU12, SK-RC-52) were treated orally with 0.8 mg/day
sunitinib, or vehicle for 7 to 14 days. Three days before start or
cessation of treatment mice were injected i.v. with 0.4 MBq/5 μg (111)In-
Girentuximab followed by biodistribution studies. Immunohistochemical analyses were performed to study the
tumor vasculature and CAIX expression and to confirm
Girentuximab uptake. NU12 appeared to represent a
sunitinib sensitive
tumor:
sunitinib treatment resulted in extensive
necrosis and decreased microvessel density (MVD). Accumulation of
Girentuximab was significantly decreased when
sunitinib treatment preceded the antibody injection but remained unchanged when
sunitinib followed
Girentuximab injection. Cessation of
therapy led to a rapid neovascularization, reminiscent of a
tumor flare. SK-RC-52 appeared to represent a
sunitinib-resistant
tumor: (central)
tumor necrosis was minimal and MVD was not affected.
Sunitinib treatment resulted in increased
Girentuximab uptake, regardless of the sequence of treatment. These data indicate that
sunitinib can be combined with
Girentuximab. Since these two modalities have different modes of action, this combination might lead to enhanced therapeutic efficacy.