Background: Antibody drug conjugate (ADC) technologies provide selective tumor killing with increased efficacy and less off-target toxicity than standard chemotherapy. Clinical validation of this approach for solid tumors has been limited, with trastuzumab emtansine, which targets HER2+ breast cancer, being the only ADC approved for treatment of solid tumors to date. Other ADCs targeting solid tumor indications have shown promise, including mirvetuximab soravtansine (MR), an ADC directed at folate receptor α (FRA). Clinical benefit has been observed in patients with high levels of FRA expression, demonstrating that FRA can be successfully targeted by this therapeutic modality. However, the anti-tumor activity for MR appears to be limited to patients whose tumors express the highest levels of FRA only. IKS01 is an ADC composed of an FRA-targeting antibody conjugated via Iksuda’s proprietary PermaLink conjugation technology, which provides fully stable conjugation thereby avoiding payload release during circulation, to the highly-potent FGX2-62 payload. FGX2-62 is a next generation pyrridinobenzodiazepine DNA mono-alkylator with pM potency in a range of tumor indications. IKS01 has been shown to have improved efficacy in both high and moderate/low FRA-expressing tumor xenograft models, compared to MR. We have extended these findings to show efficacy in an additional low FRA-expressing ovarian model, OVCAR3, and to confirm the FRA-dependence of IKS01 efficacy in the low FRA-expressing platinum-resistant OV-90 model. Methods: Conjugation of FGX2-62 to the FRA-binding antibody Isumab01 generated the ADC, IKS01, with a drug to antibody ratio (DAR) of approximately 2. FRA expression levels in cell lines used in mouse xenograft studies were determined by flow cytometry. IKS01 anti-tumor efficacy was evaluated in the low FRA-expressing ovarian adenocarcinoma OV-90 (platinum resistant) and OVCAR-3 human cell line-derived xenograft models. An FRA-targeting benchmark ADC with a format that has shown clinical efficacy was included for comparison. Target dependence was demonstrated in the OV-90 model by comparing the efficacy of IKS01 to an isotype control antibody conjugated to FGX2-62 (DAR of approximately 2). Results: IKS01 is highly effective in causing tumor regressions in the low FRA-expressing tumor models (OVCAR3 and platinum-resistant OV-90) in vivo, at doses that are well tolerated and where the benchmark ADC showed limited or no activity. The target-dependence of IKS01 efficacy in the OV-90 model was demonstrated by comparison to a non-targeting ADC which showed minimal efficacy compared to IKS01. Conclusions: The combination of a stable conjugation technology and a novel highly-potent DNA monoalkylator has led to the development of an ADC format that has shown target-dependent anti-tumor efficacy in a pre-clinical model of platinum-resistant ovarian cancer with low levels of FRA expression. These preclinical data suggest that IKS01 is a promising therapeutic candidate for the treatment of FRA-positive ovarian cancer, even when the level of surface expression of FRA is low.
Citation Format: Jenny Thirlway, Adam Lodge, Andria Pelava, Daniel J Williamson, Davide Carta, Majid Al Nakeeb, Justyna Mysliwy, Paul J.M. Jackson, David E Thurston, Robert J Lutz. IKS01, a next generation antibody drug conjugate, shows target-dependent efficacy in a platinum-resistant tumor model with low levels of folate receptor α expression [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C023. doi:10.1158/1535-7163.TARG-19-C023
