FGF2-Derived PeptibodyF2-MMAE Conjugate for Targeted Delivery of Cytotoxic Drugs into Cancer Cells Overexpressing FGFR1

Simple Summary Current approaches to treat cancer include eg. targeted therapies, employing agents, such as antibodies, aimed directly at molecules expressed in cancerous cells. Here we present a targeting molecule alternative to antibodies-peptibodyF2-composed of a peptide responsible for its targeting properties, and an immunoglobulin fragment increasing its stability and improving pharmacokinetic properties. Peptibody F2 specifically binds to fibroblast growth factor receptors (FGFRs) upregulated in multiple types of cancers. Moreover, peptibodyF2 conjugated with the cytotoxic drug (MMAE) serves as an efficient and selective drug carrier delivering cytotoxic payload to cancerous cells expressing FGFR1, leading to their death. Fibroblast growth factor receptors (FGFRs) are emerging targets for directed cancer therapy. Presented here is a new FGFR1-targeting conjugate, the peptibodyF2, which employs peptibody, a fusion of peptide and the Fc fragment of human IgG as a selective targeting agent and drug carrier. Short peptide based on FGF2 sequence was used to construct a FGFR1-targeting peptibody. We have shown that this peptide ensures specific delivery of peptibodyF2 into FGFR1-expressing cells. In order to use peptibodyF2 as a delivery vehicle for cytotoxic drugs, we have conjugated it with MMAE, a drug widely used in antibody-drug conjugates for targeted therapy. Resulting conjugate shows high and specific cytotoxicity towards FGFR1-positive cells, i.e., squamous cell lung carcinoma NCI-H520, while remaining non-toxic for FGFR1-negative cells. Such peptibody-drug conjugate can serve as a basis for development of therapy for tumors with overexpressed or malfunctioning FGFRs.