TY - JOUR
T1 - Synthesis and biological evaluation of a monocyclic Fc-binding antibody-recruiting molecule for cancer immunotherapy
AU - Sasaki, Koichi
AU - Muguruma, Kyohei
AU - Osawa, Rento
AU - Fukuda, Akane
AU - Taniguchi, Atsuhiko
AU - Kishimura, Akihiro
AU - Hayashi, Yoshio
AU - Mori, Takeshi
AU - Katayama, Yoshiki
N1 - Funding Information:
This work was in part supported by the Japanese Society for the Promotion of Sciences (JSPS) KAKENHI Grant-in-Aid for Challenging Research (Exploratory) (Grant number: 18K19148 to Y. K.), and Grant-in-Aid for Scientific Research (B) (Grant number: 19H03356 to Y. H.). K. S. was supported by the Research Fellowship for Young Scientists (JSPS, 17J05032) and Advanced Graduate Course on Molecular Systems for Devices (Kyushu University). We thank Dr. S. Kishimoto and Dr. Y. Ito (Kagoshima University) for assistance with SPR experiments. We thank the Edanz Group (https://en-author-services.edanzgroup.com/ac) for editing a draft of this manuscript.
Funding Information:
In summary, we developed a new Fc-ARM named Reo-3, which contains a monocyclic Fc-binding peptide 15-Lys8Leu. Reo-3 showed strong affinity for the Fc region of the human IgG1 antibody (Kd = 5.8 nM). Reo-3 recruited IVIG to induce ADCC against FR-positive cancer cells as effective as Fc-ARM2, which has a bicyclic Fc-binding peptide. 15-Lys8Leu is easily synthesized because of its relatively short amino acid sequence and monocyclic structure, and is one of the strongest binding peptides to the Fc region.19 Thus, 15-Lys8Leu has significant potential for use in various applications, including the development of Fc-ARMs and non-covalent antibody-drug conjugates (ADCs),22 purification of antibodies and preparations of homogenous ADCs.23 The straightforward synthesis of the pivotal unit of the Fc-ARM should accelerate This work was in part supported by the Japanese Society for the Promotion of Sciences (JSPS) KAKENHI Grant-in-Aid for Challenging Research (Exploratory) (Grant number: 18K19148 to Y. K.), and Grant-in-Aid for Scientific Research (B) (Grant number: 19H03356 to Y. H.). K. S. was supported by the Research Fellowship for Young Scientists (JSPS, 17J05032) and Advanced Graduate Course on Molecular Systems for Devices (Kyushu University). We thank Dr. S. Kishimoto and Dr. Y. Ito (Kagoshima University) for assistance with SPR experiments. We thank the Edanz Group (https://en-author-services. edanzgroup.com/ac) for editing a draft of this manuscript.
Publisher Copyright:
© The Royal Society of Chemistry 2021.
PY - 2021/3
Y1 - 2021/3
N2 - Antibody-recruiting molecules (ARMs) are bispecific molecules composed of an antibody-binding motif and a target-binding motif that redirect endogenous antibodies to target cells to elicit immune responses. To enhance the translational potential of ARMs, it is crucial to design antibody/target-binding motifs that have strong affinity and are easy to synthesize. Here, we synthesized a novel Fc-binding ARM (Fc-ARM) that targets folate receptor (FR)-positive cancer cells, Reo-3, using a recently developed monocyclic peptide 15-Lys8Leu, which binds strongly to the Fc region of an antibody. Reo-3 bound to the Fc region of the antibody with aKdof 5.8 nM, and recruited a clinically used antibody mixture to attack FR-positive IGROV-1 cells as efficiently as Fc-ARM2, in which a bicyclic Fc-binding peptide was used. These results indicate that 15-Lys8Leu, which can be synthesized readily, is suitable for various applications including the development of Fc-ARMs.
AB - Antibody-recruiting molecules (ARMs) are bispecific molecules composed of an antibody-binding motif and a target-binding motif that redirect endogenous antibodies to target cells to elicit immune responses. To enhance the translational potential of ARMs, it is crucial to design antibody/target-binding motifs that have strong affinity and are easy to synthesize. Here, we synthesized a novel Fc-binding ARM (Fc-ARM) that targets folate receptor (FR)-positive cancer cells, Reo-3, using a recently developed monocyclic peptide 15-Lys8Leu, which binds strongly to the Fc region of an antibody. Reo-3 bound to the Fc region of the antibody with aKdof 5.8 nM, and recruited a clinically used antibody mixture to attack FR-positive IGROV-1 cells as efficiently as Fc-ARM2, in which a bicyclic Fc-binding peptide was used. These results indicate that 15-Lys8Leu, which can be synthesized readily, is suitable for various applications including the development of Fc-ARMs.
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U2 - 10.1039/d0md00337a
DO - 10.1039/d0md00337a
M3 - Article
AN - SCOPUS:85103704864
SN - 2632-8682
VL - 12
SP - 406
EP - 409
JO - RSC Medicinal Chemistry
JF - RSC Medicinal Chemistry
IS - 3
ER -
