Abstract #670: Anti-angiogenic and antitumor activity of XMT-1107, a fumagillin-derived polymer conjugate, and its in vivo release product XMT-1191

XMT-1107, a fumagillin-derived polymer conjugate, and XMT-1191, the in vivo release product of XMT-1107, were evaluated for (1) biochemical activity in a metAP2 inhibition assay, (2) anti-angiogenic activity in a matrigel plug study in mice, and (3) anti-tumor activity in a Caki-1 renal cell carcinoma human tumor xenograft (HTX) model in mice, and their activities were compared with known anti-angiogenic and anti-tumor agents. XMT-1191 displayed potent inhibition against human metAP2 in vitro, in contrast to XMT-1107 which was >50 fold less active. In addition, XMT-1107 caused a decrease in angiogenesis when administered intravenously (iv) to mice in a matrigel plug assay. Lastly, in a Caki-1 HTX study, XMT-1107 exhibited superior activity compared to XMT-1191, as well as compared to known efficacious doses of TNP-470 or sunitinib. Methods: To evaluate the ability of XMT-1107 and XMT-1191 to inhibit human metAP2 enzyme, compounds were incubated with human metAP2 (6 nM) in a buffered medium after which Met-Gly-Pro-AMC was added and release of AMC measured with a Decan Plate reader at 30 sec intervals over 30 min. To evaluate the anti-angiogenic properties of XMT-1107 and XMT-1191, C57BL/6 female mice were implanted with 500 \#956;L matrigel, subcutaneous (sc), containing FGFb and heparin and treated with XMT-1107 or XMT-1191 for 11 days. Plugs were harvested and their microvessel and hemoglobin content quantified. To evaluate the anti-tumor activity of XMT-1107 and XMT-1191, HRLN female mice with sc tumors were treated with XMT-1107, XMT-1191, TNP-470, and sunitinib. Tumor sizes and body weights were monitored for 60 days and tumor growth delays were evaluated. Conclusions: XMT-1107 has enhanced anti-angiogenic and anti-tumor activity compared to its in vivo release product XMT-1191. We hypothesize that conjugation of XMT-1191 to poly(1-hydroxymethylethylene hydroxymethyl formal) (PHF) provides superior tissue distribution and pharmacokinetics resulting in enhanced biologic activity compared to administration of XMT-1191 alone. Additionally, the activity of XMT-1191 against human metAP2 in vitro was significantly greater than the activity of XMT-1107, which does not release significant amounts of XMT-1191 under the assay conditions. The enhanced anti-angiogenic, and in vivo anti-tumor activity of XMT-1107 compared to XMT-1191 demonstrates the utility of conjugating XMT-1191 to PHF. In addition, XMT-1107 has enhanced anti-cancer activity compared to known anti-angiogenic agents TNP-470 and clinically effective sunitinib in a Caki-1 HTX model. In conclusion, the anti-tumor and anti-angiogenic properties of XMT-1107 and the biochemical activity of XMT-1191 support the potential clinical utility of XMT-1107 as an anti-cancer agent.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 670.