Synthetic Antibody Mimics Based on Cancer‐Targeting Immunostimulatory Peptides. (2nd November 2020)

• Record Type: Journal Article
• Authors: Descalzi‐Montoya, Dante; Montel, Rachel A.; Smith, Keith; Dziopa, Eugenia; Darwich, Andrieh; Yang, Zheng; Bitsaktsis, Constantine; Korngold, Robert; Sabatino, David
• Is Part Of: Chembiochem. Volume 22:Number 9(2021)
• Page Start: 1589
• Page End: 1596
• Publication Date: 2020-11-02
• Subjects: cancer immunotherapy -- cancer-targeting peptides -- immunostimulatory peptides -- peptide vaccines -- synthetic antibody mimics; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.202000407
• Languages: English
• ISSNs: 1439-4227

Abstract

Abstract: De novo cancer‐targeting immunostimulatory peptides have been designed and developed as synthetic antibody mimics. A series of bifunctional peptides incorporating NKp30‐binding and NK‐cell‐activating domains were synthesized as linear dimers and then extended into branching trimeric peptides by the incorporation of GRP78‐targeting and tumor‐cell‐binding sequences. A selected trimeric peptide from this small set of peptides displayed binding capabilities on GRP78 + HepG2 and A549 target cells. Cell binding diminished in the presence of an anti‐GRP78 peptide blocker, thus suggesting GRP78‐binding dependence. Similarly, the selected trimeric peptide was also found to exhibit NK cell binding in an NKp30‐dependent manner, which translated into NK cell activation as indicated by cytokine secretion. In co‐culture, fluorescence microscopy revealed that the target GFP‐expressing A549 cells were visibly associated with the effector NK cells when pre‐activated with lead trimeric peptide. Accordingly, A549 cells were found to be compromised, as evidenced by the loss of GFP signal and notable detection of early‐/late‐stage apoptosis. Investigation of the immunological markers related to toxicity revealed detectable secretion of pro‐inflammatory cytokines and chemokines, including IFN‐γ, TNF‐α, and IL‐8. Furthermore, administration of peptide‐activated NK cells into A549‐tumor‐bearing mice resulted in a consistent decrease in tumor growth when compared to the untreated control group. Taken together, the identification of a lead trimeric peptide capable of targeting and activating NK cells' immunotoxicity directly towards GRP78 + /B7H6 ‐ tumors provides a novel proof‐of‐concept for the development of cancer‐targeting immunostimulatory peptide ligands that mimic antibody‐targeting and ‐activating functions related to cancer immunotherapy applications. Abstract : Immunotherapy and insights : De novo cancer‐targeting immunostimulatory peptides bind to surface GRP78 on tumors and the NKp30 receptor on NK cells for anti‐tumor immunostimulatory activity in vitro and in vivo. This study underscores the proof‐of‐concept discovery of a synthetic peptide that can mimic the targeting and activating functions of antibodies while facilitating NK‐dependent cancer immunotherapy.