Site-Specific, Stoichiometric-Controlled, PEGylated Conjugates of Fibroblast Growth Factor 2 (FGF2) with Hydrophilic Auristatin Y for Highly Selective Killing of Cancer Cells Overproducing Fibroblast Growth Factor Receptor 1 (FGFR1)

• Published in: Molecular pharmaceutics Vol. 17; no. 7; pp. 2734 - 2748
• Main Authors: Krzyscik, Mateusz Adam, Zakrzewska, Małgorzata, Otlewski, Jacek
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 06-07-2020
• Subjects: Aminobenzoates - pharmacology; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Survival - drug effects; Chromatography; Fibroblast Growth Factor 2 - genetics; Fibroblast Growth Factor 2 - pharmacology; Humans; Hydrophobic and Hydrophilic Interactions; Ligands; Maleimides - chemistry; Mass Spectrometry; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Oligopeptides - pharmacology; Polyethylene Glycols - chemistry; Polyethylene Glycols - pharmacology; Receptor, Fibroblast Growth Factor, Type 1 - genetics; Receptor, Fibroblast Growth Factor, Type 1 - metabolism; conjugate; auristatin Y; cancer; PEGylation; hydrophilic drug; FGF2
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.0c00419

In spite of significant progress in the field of targeted anticancer therapy, the FDA has approved only five ADC-based drugs. Hence the search for new targeted anticancer agents is an unfulfilled necessity. Here, we present novel types of protein–drug conjugates (PDCs) that exhibit superior anticancer activities. Instead of a monoclonal antibody, we used fibroblast growth factor 2 (FGF2) as a targeting molecule. FGF2 is a natural ligand of fibroblast growth factor receptor 1 (FGFR1), a transmembrane receptor overproduced in various types of cancers. We synthesized site-specific and stoichiometric-controlled conjugates of FGF2 with a highly potent, hydrophilic derivative of auristatin called auristatin Y. To increase the hydrophilicity and hydrodynamic radius of conjugates, we employed PEG4 and PEG27 molecules as a spacer between the targeting molecule and the cytotoxic payload. All conjugates were selective to FGFR1-positive cell lines, effectively internalized via the FGFR1-dependent pathway, and exhibited a highly cytotoxic effect only on FGFR1-positive cancer cell lines.