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

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.

Emerging non-antibody‒drug conjugates (non-ADCs) therapeutics of toxins for cancer treatment

“…Compared with ADCs, SMDCs not only bind to the corresponding receptors on cancer cells efficiently but also diffuse more easily in tumor tissues due to their low molecular weight 30 . Next, we will discuss the application of different small molecular ligands in toxins delivery ( Table 2 ) 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 .…”

Drug Delivery Opportunities in Esophageal Cancer: Current Treatments and Future Prospects

“…Lam et al report a synthetic peptide library to identify specific ligand-binding capabilities, which can be leveraged to target esophageal cancer cells. Wang et al describe that DM1, a promising chemotherapeutic that is also highly toxic, when combined with a peptide, LLC2B, inhibits tumor growth both in vitro and in vivo . While these PDCs are actively under investigation, − there has been minimal work leveraging this technology for esophageal cancer.…”

Melittin derived peptide-drug conjugate, M-DM1, inhibits tumor progression and induces effector cell infiltration in melanoma by targeting M2 tumor-associated macrophages

“…Payload is a cytotoxic compound and is divided into microtubule inhibitors, such as DM1, and DNA-damaging agents, such as anthracyclines (32). DM1 alone has not been developed as a drug but is currently used as an antibody-drug conjugate (33,34). It has been reported that the peptide LLC2B combined with DM1 exerts an anticancer effect in breast and esophageal squamous cell carcinoma, suggesting it could be developed as a potential PDC for tumor treatment (35).…”