Development and Characterization of a Novel Peptide-Drug Conjugate with DM1 for Treatment of FGFR2-Positive Tumors.

Yayu Wang,Ruiwu Liu,Kit S. Lam,Jieqiong Cao,Xiaojia Chen,An Hong,Yibo Zhang,Xiaocen Li,Yadan Li,Qilin Meng

doi:10.3390/biomedicines9080849

Yayu Wang, Ruiwu Liu + Show 8 more

Open Access

https://doi.org/10.3390/biomedicines9080849

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Abstract

A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide–drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 °C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide–drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B–DM1 can be developed into a potential PDC for tumor treatment in the future.

Highlights

Fibroblast growth factor receptors (FGFRs) are important members of the tyrosine kinase receptor family [1]
Cells mixed with equal amounts of recombinant FGFR2-293T and blank 293T cells were incubated with the peptide library for 1 h
Lam and colleagues designed an one-bead one-compound (OBOC) library based on the RGD motif, and screened and obtained peptides named LXW7 and LXW64 based on the RGD motif, and screened and obtained peptides named LXW7 and LXW64 for αVβ3 integrins with high specificity

Summary

Introduction

Fibroblast growth factor receptors (FGFRs) are important members of the tyrosine kinase receptor family [1]. The FGFR family contains four members: FGFR1, FGFR2, FGFR3 and FGFR4 [2]. Most of them are single-chain glycoprotein molecules, which are divided into the extracellular region, transmembrane region and intracellular region [3]. An FGFR binds to its ligand fibroblast growth factor (FGF). The FGFR dimer and self-phosphorylation activate downstream signaling pathways such as the JAK/STAT pathway and phospholipase C pathway, which play important roles in tumor growth and angiogenesis [4]. Abnormalities in FGFR are closely related to the occurrence of many types of tumors, such as lung cancer, breast cancer, gastric cancer, etc

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