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PROTEIN- AND PEPTIDE-BASED THERAPEUTICS

Therapeutic Applications

Cancer

In previous years, PPTs have attracted considerable attention in cancer therapeutics, because these are highly potent and selective. This can result in targeted drug delivery with reduced toxicity [2]. PPTs offer high efficacy, safety, and tolerability, which are unique features relative to conventional drugs [2].

A high-affinity peptide ligand LXY30 targeting a3 integrin expressed in human tumors was investigated [105]. LXY30, a cyclic peptide, was stable in human plasma and effective in tumor targeting relative to other peptides screened [105]. In vitro studies indicated that LXY30 was able to bind a3b3 integrin expressing in lung, glioblastoma, and breast cancer [105]. A novel cell-penetrating peptide for the inhibition of b-catenin/LEF-1 signaling was developed for cancer therapy by Hsieh et al. In vivo results revealed that this peptide interacted with b-catenin and inhibited breast cancer cell growth, migration, invasion, colony formation, and suppression of tumor growth in mouse and zebrafish models [106]. Pathway analysis indicated that the peptide downstream target genes were associated with HER2 and interleukin (IL)-9 signaling pathways [106]. These results indicate potential therapeutic applications of the peptide in inhibition of b-catenin/LEF-1. Tumor targeting peptides for non—small cell lung cancer (NSCLC) was studied by McGuire et al. [107]. Several novel peptides indicating individual binding profiles were tested with numerous NSCLC cell lines. These peptides, however, did not bind normal bronchial epithelial cell lines [107]. The binding affinities were between 0.0071 and 40 nM [107].

Monoclonal antibodies, aptamers, and other proteins for the treatment of cancer have been explored extensively. Heo et al. developed an aptamer—antibody complex (oligobody) for targeted cancer cells. In vivo studies with cotinine conjugated t44-OMe aptamer, which is the specific sequence of pegaptanib, were performed. The antibody part resulted in extended pharmacokinetics of the aptamer (t44-Ome) without compromising its binding affinity [108]. Besides, the aptamer of the oligobody was able to penetrate tumor tissues relative to the antibody itself and reduced the tumor in animal model [108]. A monoclonal antibody for the treatment of relapsed chronic lymphocytic leukemia (CLL) was investigated in a phase 1-2 clinical trial. Acalabrutinib (ACP-196), a selective, irreversible inhibitor of Bruton tyrosine kinase was administered to patients with CLL to evaluate safety, efficacy, pharmacokinetics, and pharmacodynamics [109]. No dose limiting toxicity with 95% response rate, 85% partial response, and 10% partial response with lymphocytosis were reported [109].

 
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