Abstract
Worldwide, cancer is the second leading cause of death. Regardless of the continuous progress in medicine, we still do not have a fully effective anti-cancer therapy. Therefore, the search for new targeted anti-cancer drugs is still an unmet need. Here, we present novel protein–drug conjugates that inhibit tumor growth in a mouse model of human breast cancer. We developed conjugates based on fibroblast growth factor (FGF2) with improved biophysical and biological properties for the efficient killing of cancer cells overproducing fibroblast growth factor receptor 1 (FGFR1). We used hydrophilic and biocompatible PEG4 or PEG27 molecules as a spacer between FGF2 and the toxic agent monomethyl auristatin E. All conjugates exhibited a cytotoxic effect on FGFR1-positive cancer cell lines. The conjugate with the highest hydrodynamic size (42 kDa) and cytotoxicity was found to efficiently inhibit tumor growth in a mouse model of human breast cancer.
Highlights
Cancer treatment is one of the major areas of research in current medicine
We have shown that fibroblast growth factors 1 and 2 (FGF1 and FGF2) are suitable targeting molecules for killing cancer cells overproducing fibroblast growth factor receptor 1 (FGFR1).[9−17] FGFR1 is a transmembrane protein that plays a substantial role in regulating cell proliferation, survival, differentiation, migration, and angiogenesis.[18−23] Analyses have shown that 7.1% of all cancer types are associated with aberration of the FGF-FGFR pathway, with FGFR1 being the most commonly affected.[24,25]
We reported the ability of FGF2 conjugated to a single MMAE molecule to kill several cancer cell lines overproducing fibroblast growth receptor 1.12,13 We showed that a drug-to-protein ratio (DPR) of three provided a greater cytotoxic effect than FGF2 loaded with one or two molecules of MMAE.[12]
Summary
Only a limited number of chemotherapeutics are available for treatment, and even fewer show significant clinical benefits.[1−4] the search for new anticancer therapies is an ever-present need, and targeted therapy is a promising approach that can meet these expectations. One of the main strategies in targeted therapy is the use of antibody−drug conjugates (ADCs). In ADC, a monoclonal antibody (mAb), as a targeting molecule, is conjugated to a highly potent cytotoxic drug that kills cancer cells. Only a few ADCs, including ado-trastuzumab emtansine (T-DM1, Kadcyla), brentuximab vedotin (Adcetris), gemtuzumab ozogamicin (Mylotarg), inotuzumab ozogamicin (Besponsa), and polatuzumab vedotin-piiq (Polivy), have been approved for treatment by the FDA.[5−8] This shows that despite the high potential of this strategy, further studies are needed. One possible way forward for such an approach is to use proteins other than monoclonal antibodies as targeting molecules
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