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Targeted delivery of tumor necrosis factor-related apoptosis-inducing ligand to keratinocytes with a pemphigus mAb.
- Source :
-
The Journal of investigative dermatology [J Invest Dermatol] 2013 Sep; Vol. 133 (9), pp. 2212-20. Date of Electronic Publication: 2013 Feb 25. - Publication Year :
- 2013
-
Abstract
- We determined the feasibility of using an anti-desmoglein (Dsg) mAb, Px44, to deliver a biologically active protein to keratinocytes. Recombinantly produced Px44-green fluorescent protein (GFP) injected into mice and skin organ culture delivered GFP to the cell surface of keratinocytes. We replaced GFP with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to produce Px44-TRAIL. We chose TRAIL as a biological model because it inhibits activated lymphocytes and causes apoptosis of hyperproliferative keratinocytes, features of various skin diseases. Px44-TRAIL formed a trimer, the biologically active form of TRAIL. Standard assays of TRAIL activity showed that Px44-TRAIL caused apoptosis of Jurkat cells and inhibited IFN-γ production by activated CD4+ T cells. Enzyme-linked immunoassay with Px44-TRAIL showed delivery of TRAIL to Dsg. Immunofluorescence with Px44-TRAIL incubated on skin sections and cultured keratinocytes or injected into mouse skin, human organ culture, or human xenografts detected TRAIL on keratinocytes. Px44-TRAIL caused apoptosis of the hyperproliferative, but not differentiating, cultured keratinocytes through binding to Dsg3. Foldon, a small trimerization domain, cloned into Px44-TRAIL maintained its stability and biological activity at 37° C for at least 48 hours. These data suggest that such targeted therapy is feasible and may be useful for hyperproliferative and inflamed skin diseases.
- Subjects :
- Animals
Antibodies, Monoclonal genetics
Antibodies, Monoclonal immunology
Apoptosis immunology
Baculoviridae genetics
CD4-Positive T-Lymphocytes cytology
CD4-Positive T-Lymphocytes immunology
Cell Differentiation immunology
Cell Proliferation
Epidermal Cells
Epidermis immunology
Green Fluorescent Proteins genetics
Humans
Jurkat Cells
Keratinocytes immunology
Mice
Mice, Inbred C57BL
Organ Culture Techniques
Pemphigus immunology
Recombinant Fusion Proteins genetics
Recombinant Fusion Proteins immunology
Recombinant Fusion Proteins pharmacokinetics
TNF-Related Apoptosis-Inducing Ligand genetics
TNF-Related Apoptosis-Inducing Ligand immunology
Antibodies, Monoclonal pharmacology
Desmoglein 3 immunology
Drug Delivery Systems methods
Keratinocytes cytology
TNF-Related Apoptosis-Inducing Ligand pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1523-1747
- Volume :
- 133
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- The Journal of investigative dermatology
- Publication Type :
- Academic Journal
- Accession number :
- 23439393
- Full Text :
- https://doi.org/10.1038/jid.2013.85