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Fc‐Binding Antibody‐Recruiting Molecules Targeting Prostate‐Specific Membrane Antigen: Defucosylation of Antibody for Efficacy Improvement **
Author(s) -
Sasaki Koichi,
Harada Minori,
Yoshikawa Takuma,
Tagawa Hiroshi,
Harada Yui,
Yonemitsu Yoshikazu,
Ryujin Takaaki,
Kishimura Akihiro,
Mori Takeshi,
Katayama Yoshiki
Publication year - 2021
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.202000577
Subject(s) - antibody dependent cell mediated cytotoxicity , antibody , fc receptor , antigen , fragment crystallizable region , receptor , immune system , cancer research , immunogenicity , prostate cancer , chemistry , biology , immunology , cancer , monoclonal antibody , biochemistry , genetics
Synthetic small molecules that redirect endogenous antibodies to target cells are promising drug candidates because they overcome the potential shortcomings of therapeutic antibodies, such as immunogenicity and the need for intravenous delivery. Previously, we reported a novel class of bispecific molecules targeting the antibody Fc region and folate receptor, named Fc‐binding antibody‐recruiting molecules (Fc‐ARMs). Fc‐ARMs can theoretically recruit most endogenous antibodies, inducing antibody‐dependent cell‐mediated cytotoxicity (ADCC) to eliminate cancer cells. Herein, we describe new Fc‐ARMs that target prostate cancer (Fc‐ARM‐Ps). Fc‐ARM‐Ps recruited antibodies to cancer cells expressing prostate‐specific membrane antigen but did so with lower efficiency compared with Fc‐ARMs targeting the folate receptor. Upon recruitment by Fc‐ARM‐P, defucosylated antibodies efficiently activated natural killer cells and induced ADCC, whereas antibodies with intact N‐glycans did not. The results suggest that the affinity between recruited antibodies and CD16a, a type of Fc receptor expressed on immune cells, could be a key factor controlling immune activation in the Fc‐ARM strategy.