Antibodies and other macromolecular
therapeutics can gain access to
tumor cells via leaky
tumor vessels. Inhibition of
vascular endothelial growth factor (
VEGF) signaling can reduce the vascularity of
tumors and leakiness of surviving vessels, but little is known about how these changes affect the distribution of
antibodies within
tumors. We addressed this issue by examining the distribution of extravasated
antibodies in
islet cell tumors of RIP-Tag2 transgenic mice and implanted Lewis lung
carcinomas using fluorescence and confocal microscopic imaging. Extravasated nonspecific
immunoglobulin G (
IgG) and
antibodies to
fibrin or
E-cadherin accumulated in irregular patchy regions of stroma.
Fibrin also accumulated in these regions. Anti-
E-cadherin antibody, which targets
epitopes on
tumor cells of RIP-Tag2
adenomas, was the only antibody to achieve detectable levels within
tumor cell clusters at 6 hours after i.v. injection. Treatment for 7 days with
AG-013736, a potent inhibitor of
VEGF signaling, reduced the
tumor vascularity by 86%. The overall area density of extravasated
IgG/
antibodies decreased
after treatment but the change was less than the reduction in vascularity and actually increased when expressed per surviving
tumor vessel. Accumulation of anti-
E-cadherin antibody in
tumor cell clusters was similarly affected. The patchy pattern of
antibodies in stroma
after treatment qualitatively resembled untreated
tumors and surprisingly coincided with sleeves of basement membrane left behind after pruning of
tumor vessels. Together, the findings suggest that antibody transport increases from surviving
tumor vessels after normalization by inhibition of
VEGF signaling. Basement membrane sleeves may facilitate this transport.
Antibodies preferentially distribute to
tumor stroma but also accumulate on
tumor cells if binding sites are accessible.