Microdistribution of fluorescently-labeled monoclonal antibody in a peritoneal dissemination model of ovarian cancer

Abstract

The microdistribution of therapeutic monoclonal antibodies within a tumor is important for determining clinical response.Nonuniform microdistribution predicts therapy failure. Herein, we developed a semiquantitative method for measuring microdistribution of an antibody within a tumor using in situ fluorescence microscopy and sought to modulate the microdistribution by altering the route and timing of antibody dosing. The microdistribution of a fluorescently-labeled antibody, trastuzumab (50-µg and 150-µg intraperitoneal injection (i.p.), and 100-µg intravenous injection (i.v.)) was evaluated in a peritoneal dissemination mouse model of ovarian cancer. In addition, we evaluated the microdistribution of concurrently-injected (30-µg i.p. and 100-µg i.v.) or serial (two doses of 30-µg i.p.) trastuzumab using in situ multicolor fluorescence microscopy. After the administration of 50-µg i.p. and 100-µg i.v. trastuzumab fluorescence imaging showed no significant difference in the central to peripheral signal ratio (C/P ratio) and demonstrated a peripheral-dominant accumulation, whereas administration of 150-µg i.p. trastuzumab showed relatively uniform, central dominant accumulation. With concurrent-i.p.-i.v. injections trastuzumab showed slightly higher C/P ratio than concurrently-injected i.p. trastuzumab. Moreover, in the serial injection study, the second injection of trastuzumab distributed more centrally than the first injection, while no difference was observed in the control group. Our results suggest that injection routes do not affect the microdistribution pattern of antibody in small peritoneal disseminations.However, increasing the dose results in a more uniform antibody distribution within peritoneal nodules. Furthermore, the serial i.p. injection of antibody can modify the microdistribution within tumor nodules. This work has implications for the optimal delivery of antibody based cancer therapies.

Cancer cell–selective in vivo near infrared photoimmunotherapy targeting specific membrane molecules

“…Doses required for diagnosis (50 μg), however, were significantly lower than those required for therapy (300 μg) Improved intratumoral distribution of antibody occurred with the therapeutic dose ( Supplementary Fig. 6 ) 22 , 23 . Because both bound and unbound agent fluoresces, there is relatively high background signal at therapeutic doses ( Fig.…”

Molecular targeted photoimmunotherapy for HER2-positive human gastric cancer in combination with chemotherapy results in improved treatment outcomes through different cytotoxic mechanisms

“…However, some cancer cells survived after PIT, and recurrences eventually developed in our in vivo model [ 12 , 13 ]. Generally, mAb distribution is heterogeneous in most tumors, especially in peripheral locations where the tumors receive good blood supply [ 13 , 20 – 22 ]. In addition, tumor heterogeneity is relatively common in human epithelial carcinomas, including in gastric cancer [ 9 , 16 , 17 ].…”

Near-infrared Theranostic Photoimmunotherapy (PIT): Repeated Exposure of Light Enhances the Effect of Immunoconjugate

“…8, 10–12 Similar to unlabeled MAb, efficacy of MAb-IR700 mediated PIT is partly determined with MAb-IR700 micro-distribution in the targeted tumor.…”

“…Preferable distribution of therapeutic mAb in the tumor is required for the effective target-specific tumor cell killing; however, generally mAb distribution is inhomogeneous in most tumors, especially in peripheral localization where xenografted tumors receive good blood supply, leading to require multiple high-dose mAb administration. ,− Similar to unlabeled mAb, efficacy of mAb–IR700 mediated PIT is partly determined with mAb–IR700 microdistribution in the targeted tumor.…”