Engineering a Smart Agent for Enhanced Immunotherapy Effect by Simultaneously Blocking PD‐L1 and CTLA‐4

Jiang, Chunjuan; Zhang, Le; Xu, Xiaoping; Qi, Ming; Zhang, Jianping; He, Simin; Tian, Qiwei; Song, Shaoli

doi:10.1002/advs.202102500

Cited by 77Cancer Immunotherapy and BiomarkersNanoplatforms for cancer theranosticsNanoparticle-Based Drug Delivery

Engineering a Smart Agent for Enhanced Immunotherapy Effect by Simultaneously Blocking PD‐L1 and CTLA‐4

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Jiang, Chunjuan, Zhang, Le, Xu, Xiaoping, Qi, Ming, Zhang, Jianping, He, Simin, Tian, Qiwei, Song, Shaoli·2021·Advanced Science

DOI 10.1002/advs.202102500PMC PMC8529437

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Abstract

Combinations of immune checkpoint therapies show encouraging results in the treatment of many human cancers. However, the higher costs and greater side effects of such combinations compared with single‐agent immunotherapies limit their further applications. In this work, a novel smart agent, KN046@19 F‐ZIF‐8, is developed to overcome these limitations. KN046 is a novel recombinant humanized PD‐L1/CTLA‐4 bispecific single‐domain antibody‐Fc fusion protein, which can bind to both PD‐L1 and CTLA‐4 effectively. ZIF‐8 is a smart delivery system, which can safely and effectively deliver KN406 to a tumor. In vitro and in vivo results demonstrate that the smart agent KN046@19 F‐ZIF‐8 not only improves the immune response rate of the antibody drug in treatment of tumors but also reduces its toxic side effects, thereby achieving excellent antitumor efficacy. This study provides an engineering strategy for clinical applications of a more effective immunotherapy.

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Numerous bispecific antibodies have been developed, including CTLA-4 × PD-L1 (KN046), CTLA-4 × PD-1 (MGD019 and MEDI5752), LAG-3 × PD-L1 (IBI323), LAG-3 × PD-1 (Tebotelimab), TIM-3 × PD-L1 (LY3415244), TIM-3 × PD-1, and TIGIT×PD-L1.
“Numerous bispecific antibodies have been developed, including CTLA-4 × PD-L1 (KN046) [281], CTLA-4 × PD-1 (MGD019 and MEDI5752) [282, 283], LAG-3 × PD-L1 (IBI323) [284], LAG-3 × PD-1 (Tebotelimab) [285], TIM-3 × PD-L1 (LY3415244) [286], TIM-3 × PD-1 [305], TIGIT×PD-L1 [287].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [281]

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Polymeric Multivalent Fc Binding Peptides‐Fabricated Clinical Compounding Bispecific Antibody Potentiates Dual Immunotherapy Targeting PD1 and CTLA‐4
Liu, Z., Chu, H., Zhao, W., Yang, C., Liu, T., Shen, N., & Tang, Z. (2024) · Advanced Science · doi:10.1002/advs.202408899 · Cited by 6 · see citing works
Nanobody-based bispecific antibody engagers targeting CTLA-4 or PD-L1 for cancer immunotherapy
Liu, X., Gall, C. M. L., Alexander, R., Borgman, E., Balligand, T., & Ploegh, H. L. (2025) · Nature Biomedical Engineering · doi:10.1038/s41551-025-01447-z · Cited by 21 · see citing works
Antitumor activity of Z15-0-2, a bispecific nanobody targeting PD-1 and CTLA-4
Zeng, J., Fang, Y., Zhang, Z., Lv, Z., Wang, X., Huang, Q., Tian, Z., Li, J., Xu, W., Zhu, W., et al. (2024) · Oncogene · doi:10.1038/s41388-024-03066-5 · Cited by 16 · see citing works

Authors: Jiang, C., Zhang, L., Xu, X., Qi, M., Zhang, J., He, S., Tian, Q., & Song, S.
Affiliations: Shanghai Medical College of Fudan University (CN)
Shanghai University of Medicine and Health Sciences (CN)
Corresponding author: Tian, Qiwei
Song, Shaoli
ORCID: Zhang, Le
Xu, Xiaoping
Qi, Ming
He, Simin
Tian, Qiwei
Song, Shaoli
Venue: Advanced Science
Publisher: Wiley
Published: 2021-09-02
Volume: 8
Issue: 20
Pages: e2102500-e2102500
ISSN: 2198-3844 (ISSN-L)
DOI: 10.1002/advs.202102500
PMC: PMC8529437
OpenAlex: W3197356409
Cited by: 77
References: 46
Citations by year: 2026: 9 · 2025: 13 · 2024: 22 · 2023: 19 · 2022: 12 · 2021: 2
FWCI: 5.00
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Advanced Science (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, other-oa)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: National Natural Science Foundation of China (81771861, 81971648)
Topics: Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Physical Sciences › Engineering › Biomedical Engineering › Nanoplatforms for cancer theranostics
Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
Keywords: ZIF-8, smart drug delivery, immune checkpoint blockade, cancer immunotherapy, tumor targeting, reduced side effects
MeSH terms: Immune Checkpoint Inhibitors, Animals, Antineoplastic Agents, Humans, Immunotherapy, Neoplasms, Recombinant Fusion Proteins, Antibodies, Bispecific, Xenograft Model Antitumor Assays, Cell Line, Tumor, Cell Proliferation, Mice, B7-H1 Antigen, CTLA-4 Antigen, Single-Domain Antibodies

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Engineering a Smart Agent for Enhanced Immunotherapy Effect by Simultaneously Blocking PD‐L1 and CTLA‐4

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