A peptide inhibitor of antibody-dependent cell-mediated cytotoxicity against EGFR/folate receptor-α double positive cells

Koichi Sasaki, Yoshiki Miyashita, Daisuke Asai, Daiki Funamoto, Kazuki Sato, Yoko Yamaguchi, Yuji Mishima, Tadafumi Iino, Shigeo Takaishi, Jun Nagano, Akihiro Kishimura, Takeshi Mori, Yoshiki Katayama

Research output: Contribution to journalArticle

Abstract

Antibody-dependent cell-mediated cytotoxicity (ADCC) is caused by natural killer (NK) cells upon recognition of antigen-bound IgG via FcγRIIIa. This mechanism is crucial for cytolysis of pathogen-infected cells and monoclonal antibody (mAb)-mediated elimination of cancer cells. However, there is concern that mAb-based cancer therapy induces ADCC against non-target cells expressing antigens. To date, no strategy has been reported to enhance the selectivity of ADCC to protect non-target cells expressing antigens. Here, we introduce a model inhibitor which specifically blocks ADCC of anti-EGFR mAbs towards EGFR/folate receptor α (FRα) double positive cells. This inhibitor recruits mAbs on the FRα of the cell surface independent of Fab antigen recognition. The resulting ternary and/or quaternary complexes formed on the cell surface suppress signal transduction of FcγRIIIa in NK cells, consequently leading to more specific ADCC.

Original languageEnglish
Pages (from-to)783-788
Number of pages6
JournalMedChemComm
Volume9
Issue number5
DOIs
Publication statusPublished - Jan 1 2018

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Antibody-Dependent Cell Cytotoxicity
Cytotoxicity
Folic Acid
Cells
Peptides
Antibodies
Antigens
Natural Killer Cells
Monoclonal Antibodies
Signal transduction
Cell Surface Receptors
Pathogens
Immunoglobulin G
Signal Transduction
Neoplasms

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry

Cite this

A peptide inhibitor of antibody-dependent cell-mediated cytotoxicity against EGFR/folate receptor-α double positive cells. / Sasaki, Koichi; Miyashita, Yoshiki; Asai, Daisuke; Funamoto, Daiki; Sato, Kazuki; Yamaguchi, Yoko; Mishima, Yuji; Iino, Tadafumi; Takaishi, Shigeo; Nagano, Jun; Kishimura, Akihiro; Mori, Takeshi; Katayama, Yoshiki.

In: MedChemComm, Vol. 9, No. 5, 01.01.2018, p. 783-788.

Research output: Contribution to journalArticle

Sasaki, Koichi ; Miyashita, Yoshiki ; Asai, Daisuke ; Funamoto, Daiki ; Sato, Kazuki ; Yamaguchi, Yoko ; Mishima, Yuji ; Iino, Tadafumi ; Takaishi, Shigeo ; Nagano, Jun ; Kishimura, Akihiro ; Mori, Takeshi ; Katayama, Yoshiki. / A peptide inhibitor of antibody-dependent cell-mediated cytotoxicity against EGFR/folate receptor-α double positive cells. In: MedChemComm. 2018 ; Vol. 9, No. 5. pp. 783-788.
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