Fc‐Binding Antibody‐Recruiting Molecules Targeting Prostate‐Specific Membrane Antigen: Defucosylation of Antibody for Efficacy Improvement**
- 23 September 2020
- journal article
- research article
- Published by Wiley in ChemBioChem
- Vol. 22 (3), 496-500
- https://doi.org/10.1002/cbic.202000577
Abstract
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 cancer cell elimination via antibody‐dependent cell‐mediated cytotoxicity (ADCC). Here, we describe new Fc‐ARMs that target prostate cancer (Fc‐ARM‐Ps). Fc‐ARM‐Ps recruited antibodies to cancer cells expressing prostate‐specific membraneantigen but did so with lower efficiency compared with Fc‐ARMs targeting 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.Keywords
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Funding Information
- Japan Society for the Promotion of Science (17 J05032)
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