Polymeric Multivalent Fc Binding Peptides‐Fabricated Clinical Compounding Bispecific Antibody Potentiates Dual Immunotherapy Targeting PD1 and CTLA‐4

Abstract Dual Opdivo plus Yervoy immunotherapy, targeting the immune checkpoints PD1 and CTLA‐4, is successful in clinical use. However, it is associated with a high incidence of adverse events, and its therapeutic efficacy needs improving. In this study, polymeric multivalent Fc‐binding peptides (P...

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Main Authors: Zongyu Liu, Hongyu Chu, Weidong Zhao, Chenguang Yang, Tongjun Liu, Na Shen, Zhaohui Tang
Format: Article
Language:English
Published: Wiley 2025-01-01
Series:Advanced Science
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Online Access:https://doi.org/10.1002/advs.202408899
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author Zongyu Liu
Hongyu Chu
Weidong Zhao
Chenguang Yang
Tongjun Liu
Na Shen
Zhaohui Tang
author_facet Zongyu Liu
Hongyu Chu
Weidong Zhao
Chenguang Yang
Tongjun Liu
Na Shen
Zhaohui Tang
author_sort Zongyu Liu
collection DOAJ
description Abstract Dual Opdivo plus Yervoy immunotherapy, targeting the immune checkpoints PD1 and CTLA‐4, is successful in clinical use. However, it is associated with a high incidence of adverse events, and its therapeutic efficacy needs improving. In this study, polymeric multivalent Fc‐binding peptides (PLG‐Fc‐III‐4C) are employed to fabricate a bispecific antibody (PD1/CTLA‐4 BsAb) to potentiate dual immunotherapy targeting PD1 and CTLA‐4. The PD1/CTLA‐4 BsAb is prepared by mixing PLG‐Fc‐III‐4C with aPD1 and aCTLA‐4 in an aqueous solution for 3 h using the clinically optimal 3:1 proportion of aPD1 to aCTLA‐4. PD1/CTLA‐4 BsAb significantly inhibits tumors in MC38 colon cancer‐bearing mice more effectively than the combination of aPD1 and aCTLA‐4, with tumor suppression rates of 96.8% and 77.3%, respectively. It also induces a higher percentage of CD8+ T cells and increases the secretion of effector cytokines while reducing Treg levels in tumors compared to phosphate‐buffered saline, indicating significant tumor immunity regulation. Mechanistically, a 6.3‐fold increase in PD1/CTLA‐4 BsAb accumulation in tumors due to the tumor targeting ability of aPD1, and the PD1/CTLA‐4 BsAb significantly reduces the adverse colitis event in healthy mice, compared to aPD1 and aCTLA‐4. Thus, these findings provide a novel approach to enhance antitumor therapy using aPD1 and aCTLA‐4.
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spelling doaj-art-6bff3c2c0fb44506a15b0769301444ca2025-01-20T13:04:18ZengWileyAdvanced Science2198-38442025-01-01123n/an/a10.1002/advs.202408899Polymeric Multivalent Fc Binding Peptides‐Fabricated Clinical Compounding Bispecific Antibody Potentiates Dual Immunotherapy Targeting PD1 and CTLA‐4Zongyu Liu0Hongyu Chu1Weidong Zhao2Chenguang Yang3Tongjun Liu4Na Shen5Zhaohui Tang6Department of Colorectal and Anal Surgery The Second Hospital of Jilin University Changchun Jilin 130000 ChinaDepartment of Gastrointestinal Colorectal and Anal Surgery China‐Japan Union Hospital of Jilin University Changchun Jilin 130033 ChinaKey Laboratory of Polymer Ecomaterials Changchun Institute of Applied Chemistry Chinese Academy of Sciences Changchun Jilin 130022 ChinaKey Laboratory of Polymer Ecomaterials Changchun Institute of Applied Chemistry Chinese Academy of Sciences Changchun Jilin 130022 ChinaDepartment of Colorectal and Anal Surgery The Second Hospital of Jilin University Changchun Jilin 130000 ChinaKey Laboratory of Polymer Ecomaterials Changchun Institute of Applied Chemistry Chinese Academy of Sciences Changchun Jilin 130022 ChinaKey Laboratory of Polymer Ecomaterials Changchun Institute of Applied Chemistry Chinese Academy of Sciences Changchun Jilin 130022 ChinaAbstract Dual Opdivo plus Yervoy immunotherapy, targeting the immune checkpoints PD1 and CTLA‐4, is successful in clinical use. However, it is associated with a high incidence of adverse events, and its therapeutic efficacy needs improving. In this study, polymeric multivalent Fc‐binding peptides (PLG‐Fc‐III‐4C) are employed to fabricate a bispecific antibody (PD1/CTLA‐4 BsAb) to potentiate dual immunotherapy targeting PD1 and CTLA‐4. The PD1/CTLA‐4 BsAb is prepared by mixing PLG‐Fc‐III‐4C with aPD1 and aCTLA‐4 in an aqueous solution for 3 h using the clinically optimal 3:1 proportion of aPD1 to aCTLA‐4. PD1/CTLA‐4 BsAb significantly inhibits tumors in MC38 colon cancer‐bearing mice more effectively than the combination of aPD1 and aCTLA‐4, with tumor suppression rates of 96.8% and 77.3%, respectively. It also induces a higher percentage of CD8+ T cells and increases the secretion of effector cytokines while reducing Treg levels in tumors compared to phosphate‐buffered saline, indicating significant tumor immunity regulation. Mechanistically, a 6.3‐fold increase in PD1/CTLA‐4 BsAb accumulation in tumors due to the tumor targeting ability of aPD1, and the PD1/CTLA‐4 BsAb significantly reduces the adverse colitis event in healthy mice, compared to aPD1 and aCTLA‐4. Thus, these findings provide a novel approach to enhance antitumor therapy using aPD1 and aCTLA‐4.https://doi.org/10.1002/advs.202408899CTLA‐4dual immunotherapyFc‐binding peptidePD1polymer
spellingShingle Zongyu Liu
Hongyu Chu
Weidong Zhao
Chenguang Yang
Tongjun Liu
Na Shen
Zhaohui Tang
Polymeric Multivalent Fc Binding Peptides‐Fabricated Clinical Compounding Bispecific Antibody Potentiates Dual Immunotherapy Targeting PD1 and CTLA‐4
Advanced Science
CTLA‐4
dual immunotherapy
Fc‐binding peptide
PD1
polymer
title Polymeric Multivalent Fc Binding Peptides‐Fabricated Clinical Compounding Bispecific Antibody Potentiates Dual Immunotherapy Targeting PD1 and CTLA‐4
title_full Polymeric Multivalent Fc Binding Peptides‐Fabricated Clinical Compounding Bispecific Antibody Potentiates Dual Immunotherapy Targeting PD1 and CTLA‐4
title_fullStr Polymeric Multivalent Fc Binding Peptides‐Fabricated Clinical Compounding Bispecific Antibody Potentiates Dual Immunotherapy Targeting PD1 and CTLA‐4
title_full_unstemmed Polymeric Multivalent Fc Binding Peptides‐Fabricated Clinical Compounding Bispecific Antibody Potentiates Dual Immunotherapy Targeting PD1 and CTLA‐4
title_short Polymeric Multivalent Fc Binding Peptides‐Fabricated Clinical Compounding Bispecific Antibody Potentiates Dual Immunotherapy Targeting PD1 and CTLA‐4
title_sort polymeric multivalent fc binding peptides fabricated clinical compounding bispecific antibody potentiates dual immunotherapy targeting pd1 and ctla 4
topic CTLA‐4
dual immunotherapy
Fc‐binding peptide
PD1
polymer
url https://doi.org/10.1002/advs.202408899
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