Vintafolide is a potent
folate-targeted vinca
alkaloid small molecule
drug conjugate (SMDC) that has shown promising results in multiple clinical oncology studies. Structurally,
vintafolide consists of 4 essential modules: (1)
folic acid, (2) a hydrophilic
peptide spacer, (3) a
disulfide-containing, self-immolative linker, and (4) the cytotoxic
drug, desacetylvinblastine
hydrazide (DAVLBH). Here, we report a structure-activity study evaluating the
biological impact of (i) substituting DAVLBH within the
vintafolide molecule with other vinca
alkaloid analogues such as
vincristine,
vindesine,
vinflunine, or
vinorelbine; (ii) substituting the naturally (S)-configured Asp-Arg-
Asp-Asp-Cys
peptide with alternative hydrophilic spacers of varied composition; and (iii) varying the composition of the linker module. A series of vinca
alkaloid-containing SMDCs were synthesized and purified by HPLC and LCMS. The SMDCs were screened in vitro against
folate receptor (FR)-positive cells, and anti-
tumor activity was tested against well-established subcutaneous FR-positive
tumor xenografts. The cytotoxic and anti-
tumor activity was directly compared to that produced by
vintafolide. Among all the
folate vinca
alkaloid SMDCs tested, DAVLBH-containing SMDCs were active, while those constructed with
vincristine,
vindesine, or
vinorelbine analogues failed to produce meaningful
biological activity. Within the DAVLBH series, having a bioreleasable, self-immolative linker system was found to be critical for activity since multiple analogues constructed with
thioether-based linkers all failed to produce meaningful activity both in vitro and in vivo. Substitutions of some or all of the natural
amino acids within
vintafolide's hydrophilic spacer module did not significantly change the in vitro or in vivo potency of the SMDCs.
Vintafolide remains one of the most potent
folate-vinca
alkaloid SMDCs produced to date, and continued clinical development is warranted.