Abstract A147: MI130004, a new ADC with a payload of marine origin shows outstanding activity against HER2-expressing tumors

Abstract

Abstract PM050489 is a tubulin-binding agent originally isolated from the marine sponge Lithoplocamia lithistoides. This compound binds with very high affinity to β-tubulin at a new site, disrupting the microtubule network and impairing its function during divison, which leads to mitotic aberrations. MI130004 (a novel antibody-drug conjugate formed by PM050489, a non-hydrolysable linker and trastuzumab) was tested for its in vitro and in vivo activity against selected tumor cell lines with different levels of HER2 expression. In vitro MI130004 showed very high potency and good selectivity for tumor cells that overexpressed HER2, namely HCC-1954 (IC50, 0.036 μg/mL), SK-BR-3 (IC50, 0.017 μg/mL) and BT-474 (IC50, 0.156 μg/mL). At the cellular level, MI130004 impaired tubulin polymerization, causing disorganization and disintegration of the microtubule network which ultimately led to mitotic failure. Expressing HER2 cells of breast (BT-474 and JIMT-1), gastric (Gastric-008 and N87) and ovarian (SK-OV-3 and A2780cis) as well as negative HER2 breast (MDA-MB-231) and gastric (Hs748t) were subcutaneously implanted into immunosuppressed (SCID or athymic) mice. Tumor (ca. 115 mm3) bearing animals (N = 10/group) were randomly allocated to receive the ADC treatments (at different doses) or the appropriate control (placebo included). Treatments were administered weekly for 5 consecutive weeks. Tumor growth (as median/group) was calculated 2-3 times per week. Twenty-four hours after the first dose, representative tumors were dissected free and processed for HER2 expression (erb2) and chromatin organization (Hoescht 33258). The treatment with MI130004 induced a long lasting antitumor effect with statistically significant increases (P<0.05) in median survival time compared to placebo. The highest dose of MI130004 induced complete tumor remissions in mice bearing BT-474, JIMT-1, Gastric-008, N87, SK-OV-3 and A2780cis xenografts lasting up to 120, 60, 165, 63, 237 and 231 days, respectively. Also 24-h post-dosing, MI130004 induced a dose-dependent disappearance of HER2-expressing cells as well as mitotic aberrations, this last being consistent with the mechanism of action of PM050489. These results demonstrate that PM050489, a marine derived compound, is a novel and remarkable payload for the design of new ADCs with potential therapeutic anti-cancer properties. Citation Format: Pablo Aviles, Maria Jose Guillen, Juan Manuel Dominguez, Carlos M. Galmarini, Carmen Cuevas. MI130004, a new ADC with a payload of marine origin shows outstanding activity against HER2-expressing tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A147.