Synthetic Antibody Mimics Based on Cancer‐Targeting Immunostimulatory Peptides
| Autor: | Andrieh Darwich, Rachel A. Montel, Keith Smith, Eugenia Dziopa, Robert Korngold, Dante B. Descalzi-Montoya, Zheng Yang, Constantine Bitsaktsis, David Sabatino |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Chemokine medicine.medical_treatment Transplantation Heterologous Peptide Mice SCID Lymphocyte Activation Biochemistry Antibodies Article Mice Adjuvants Immunologic Cancer immunotherapy Mice Inbred NOD Cell Line Tumor Neoplasms medicine Animals Humans Secretion Endoplasmic Reticulum Chaperone BiP Molecular Biology A549 cell chemistry.chemical_classification biology Chemistry Effector Organic Chemistry Synthetic antibody Cell biology Killer Cells Natural biology.protein Cytokines Molecular Medicine Female Cytokine secretion Immunotherapy Peptides |
| Zdroj: | Chembiochem |
| ISSN: | 1439-7633 1439-4227 |
| DOI: | 10.1002/cbic.202000407 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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