Abstract 2518: Structure-activity relationships of folate-vinca alkaloid conjugates

Abstract

Abstract EC145 is a potent folate-targeted vinca alkaloid conjugate that has been evaluated in 2 single agent phase 2 trials (ovarian and non small cell lung cancers) and 1 randomized open labeled phase 2 study in combination with DOXIL® in women with platinum-resistant ovarian cancer. Results from all of these trials have looked promising, and they support the continued evaluation of EC145 in a planned phase 3 trial that's expected to begin in early 2011. Structurally, EC145 consists of 4 essential modules: 1) folic acid, 2) a hydrophilic peptide spacer, 3) a disulfide-containing, self-immolative linker, and 4) the microtubule destabilizer, desacetylvinblastine hydrazide (DAVLBH). Due to EC145's potential for success, recent effort was given to determine the impact of i) substituting the DAVLBH vinca alkaloid unit in EC145 with analogs of vincristine, vindesine or vinorelbine, ii) substituting the naturally (S)-configured Asp-Arg-Asp-Asp-Cys peptide spacer in EC145 with (R)-configured amino acids placed in selective locations, and iii) varying the composition of the linker module to evaluate the impact of having a readily releasable, self-immolative linker system (e.g. disulfide-based as found in EC145) versus a more stable linker system (e.g. a thioether). New conjugates were screened in vitro against folate receptor-positive cells, and their cytotoxic activities were directly compared to that produced by EC145. Our data show that only DAVLBH-containing folate conjugates were active; thus, conjugates built with vincristine, vindesine or vinorelbine failed to produce activity when cells were exposed to concentrations as high as 1 µM. Within the DAVLBH series, having a bio-releasable, self-immolative linker system was found to be critical for activity since multiple analogs constructed with thioether-based linkers failed to produce meaningful activity both in vitro and in vivo. Substitutions of some or all of the natural amino acids within EC145's hydrophilic spacer module was not found to significantly change the in vitro potency of the conjugate; however, some enhancement in anti-tumor activity was measurable when tested in vivo against well-established subcutaneous folate receptor-positive tumor xenografts. Despite these modest improvements, EC145 remains as one of the more potent folate-vinca alkaloid conjugates produced to date, and continued clinical development is therefore warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2518. doi:10.1158/1538-7445.AM2011-2518