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

doi:10.1039/c8md00010g

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 journal › Article › peer-review

7 Citations (Scopus)

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 language	English
Pages (from-to)	783-788
Number of pages	6
Journal	MedChemComm
Volume	9
Issue number	5
DOIs	https://doi.org/10.1039/c8md00010g
Publication status	Published - 2018

All Science Journal Classification (ASJC) codes

Biochemistry
Molecular Medicine
Pharmacology
Pharmaceutical Science
Drug Discovery
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1039/c8md00010g

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@article{055b3402623843f9829f56c2a9240019,

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

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.",

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

note = "Funding Information: This work was supported by the Challenging Research (project No. 17K19204) of MEXT, Japan. K. Sasaki thanks JSPS (17J05032) for a fellowship. Publisher Copyright: {\textcopyright} 2018 The Royal Society of Chemistry.",

year = "2018",

doi = "10.1039/c8md00010g",

language = "English",

volume = "9",

pages = "783--788",

journal = "MedChemComm",

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TY - JOUR

T1 - A peptide inhibitor of antibody-dependent cell-mediated cytotoxicity against EGFR/folate receptor-α double positive cells

AU - Sasaki, Koichi

AU - Miyashita, Yoshiki

AU - Asai, Daisuke

AU - Funamoto, Daiki

AU - Sato, Kazuki

AU - Yamaguchi, Yoko

AU - Mishima, Yuji

AU - Iino, Tadafumi

AU - Takaishi, Shigeo

AU - Nagano, Jun

AU - Kishimura, Akihiro

AU - Mori, Takeshi

AU - Katayama, Yoshiki

N1 - Funding Information: This work was supported by the Challenging Research (project No. 17K19204) of MEXT, Japan. K. Sasaki thanks JSPS (17J05032) for a fellowship. Publisher Copyright: © 2018 The Royal Society of Chemistry.

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

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

Abstract

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