Fc‐Binding Antibody‐Recruiting Molecules Targeting Prostate‐Specific Membrane Antigen: Defucosylation of Antibody for Efficacy Improvement

• Published in: Chembiochem : a European journal of chemical biology 2021-02, Vol.22 (3), p.496-500
• Main Authors: Sasaki, Koichi, Harada, Minori, Yoshikawa, Takuma, Tagawa, Hiroshi, Harada, Yui, Yonemitsu, Yoshikazu, Ryujin, Takaaki, Kishimura, Akihiro, Mori, Takeshi, Katayama, Yoshiki
• Format: Article
• Language: English
• Subjects: Antibodies; antibody-recruiting small molecules; Antigens; Binding; Cancer; cancer immunotherapy; Cytotoxicity; defucosylation; Drug development; Fc receptors; Folic acid; Immune response; Immune system; Immunogenicity; Intravenous administration; Membranes; Natural killer cells; Polysaccharides; Prostate; Prostate cancer; prostate-specific membrane antigen; Receptors; Recruitment; Toxicity
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.202000577

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. Bispecific molecules that redirect antibodies towards prostate cancer cells through affinity to the Fc region of antibody and prostate‐specific membrane antigen (PSMA) have been developed. Upon recruitment by the molecules, defucosylated antibodies showed superior cytotoxicity by ADCC than antibodies with intact N‐glycans. This report provides insight into the development of immunotherapy.