Abstract 2959: PF-08046031: A promising first-in-class antibody-drug conjugate for targeting novel tumor antigen in melanoma

Abstract MFI2, also known as CD228, melanotransferrin, p97, MTf, or MELTF, is a GPI-anchored membrane protein that belongs to the iron-transporting transferrin family. CD228 expression is elevated in multiple solid tumors such as melanoma and non-small cell lung cancer (NSCLC) but has limited expression in normal tissues. Here, we have expanded our expression analysis and found that other solid tumors, including head and neck cancer (HNSCC) and esophageal cancer (ESCC), also show positivity rates of 86% and 94%, respectively. PF-08046031 is an antibody-drug conjugate (ADC) that consists of the anti-CD228 human IgG1 antibody conjugated with an average of 4 molecules of monomethyl auristatin E (MMAE) by a cleavable valine-citrine (vc) linker. The proposed mechanism of action (MoA) of PF-08046031 is to bind to CD228-expressing cells where it is internalized and transported to lysosomes to release MMAE, causing microtubule disruption and cytotoxic cell death. This drug-linker and conjugation methodology have been clinically validated and approved. In this study, pharmacological evaluations of antibody binding, internalization, cytotoxic cell death and in vivo anti-tumor activity were conducted using various in vitro and in vivo models. PF-08046031 specifically binds to human CD228 with high affinity in both high and low CD228-expressing tumor cells. In vitro studies showed that the ADC had strong cytotoxic effects on CD228-positive cell lines but not on CD228 negative or genetically modified CD228KO cells. The anti-tumor activity of PF-08046031 was tested in vivo using two cutaneous melanoma models derived from cell lines (A2058 and Colo853). After a single intravenous dose of PF-08046031 at 3 and 6 mg/kg, significant tumor growth inhibition (TGI) was observed in a dose-dependent manner compared to the untreated group. At the highest dose of 6.0 mg/kg, TGI reached 87% for A2058-derived tumors and 90% for COLO853-derived tumors. These findings support the clinical development of PF-08046031 for targeting multiple solid tumors. Citation Format: Raj Giraddi, Steven Jin, Devra J. Olson, Iliyana Mikell, Eliana Moskovitz, Rebecca Mazahreh, Sharsti Sandall. PF-08046031: A promising first-in-class antibody-drug conjugate for targeting novel tumor antigen in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2959.