| RRC ID |
55946
|
| Author |
Funahashi SI, Kawai S, Fujii E, Taniguchi K, Nakano K, Ishikawa S, Aburatani H, Suzuki M.
|
| Title |
Generation of an anti-desmoglein 3 antibody without pathogenic activity of pemphigus vulgaris for therapeutic application to squamous cell carcinoma.
|
| Journal |
J Biochem
|
| Abstract |
It is ideal for the target antigen of a cytotoxic therapeutic antibody against cancer to be cancer-specific, but such antigens are rare. Thus an alternative strategy for target selection is necessary. Desmoglein 3 (DSG3) is highly expressed in lung squamous cell carcinoma, while it is well-known that anti-DSG3 antibodies cause pemphigus vulgaris, an autoimmune disease. We evaluated DSG3 as a novel target by selecting an epitope that exerts efficacy against cancer with no pathogenic effects in normal tissues. Pathogenic anti-DSG3 antibodies induce skin blisters by inhibiting the cell-cell interaction in a Ca2+-dependent manner. We screened anti-DSG3 antibodies that bind DGS3 independent of Ca2+ and have high antibody-dependent cell cytotoxicity (ADCC) activity against DSG3-expressing cells. These selected antibodies did not inhibit cell-cell interaction and showed ADCC activity against squamous cell carcinoma cell lines. Furthermore, one of the DSG3 antibodies showed anti-tumour activity in tumour mouse models but did not induce adverse effects such as blister formation in the skin. Thus it was possible to generate an antibody against DSG3 by using an appropriate epitope that retained efficacy with no pathogenicity. This approach of epitope selection may expand the variety of druggable target molecules.
|
| Volume |
164(6)
|
| Pages |
471-481
|
| Published |
2018-12-1
|
| DOI |
10.1093/jb/mvy074
|
| PII |
5100878
|
| PMID |
30239818
|
| PMC |
PMC6267343
|
| MeSH |
Animals
Antibodies, Monoclonal / adverse effects
Antibodies, Monoclonal / pharmacology
Antibodies, Monoclonal / therapeutic use*
Antibody Specificity
Antineoplastic Agents, Immunological / adverse effects
Antineoplastic Agents, Immunological / pharmacology
Antineoplastic Agents, Immunological / therapeutic use*
CHO Cells
Carcinoma, Squamous Cell / drug therapy*
Carcinoma, Squamous Cell / immunology
Carcinoma, Squamous Cell / metabolism
Carcinoma, Squamous Cell / pathology
Cell Line
Cell Line, Tumor
Cell Survival / drug effects
Cricetulus
Desmoglein 3 / antagonists & inhibitors*
Desmoglein 3 / chemistry
Desmoglein 3 / genetics
Desmoglein 3 / metabolism
Drug Design*
Epitopes / chemistry
Epitopes / genetics
Epitopes / metabolism
Humans
Keratinocytes / drug effects*
Keratinocytes / immunology
Keratinocytes / metabolism
Keratinocytes / pathology
Mice
Mice, Inbred BALB C
Mice, Knockout
Mice, SCID
Mice, Transgenic
Peptide Fragments / antagonists & inhibitors
Peptide Fragments / chemistry
Peptide Fragments / genetics
Peptide Fragments / metabolism
Recombinant Fusion Proteins / chemistry
Recombinant Fusion Proteins / metabolism
Tumor Burden / drug effects
Xenograft Model Antitumor Assays
|
| IF |
2.23
|
| Times Cited |
1
|
| Resource |
| Human and Animal Cells |
Ba/F3(RCB0805)
A431 |
