Bispecific Nanosystems Enable Multieffector Immune Cell Retargeting for Hematologic Malignancy Therapy

Advanced Science, vol. 12, pp. e09103

Abstract

B-cell lymphomas are hematologic malignancies characterized by poor prognoses. Immunotherapy has revolutionized B-cell lymphoma treatment by harnessing immune effector cells, but current therapeutic strategies face limitations: suboptimal pharmacokinetics of bispecific antibodies and high complexity and cost of chimeric antigen receptor T-cell therapies. To address these challenges, a bispecific nanosystem (biHSNPs) is developed that exploits the multi-functional customizability of silica nanoplatform to conjugate antibodies targeting cytotoxic T cells or natural killer cells, alongside effector antibodies specific to B-cells. Four biHSNPs with different effector and target antibodies are synthesized. This bispecific nanosystem enables simultaneous binding to immune effector cells and B-cell lymphoma antigens, facilitating the formation of artificial immunological synapses. These synapses promote immune effector cell activation, leading to the release of cytotoxic proteins, while concurrently suppressing tumor cell proliferation and enhancing T-cell activation. In vivo, biHSNPs effectively suppress tumor growth and activate T cells in a xenograft mouse model, showcasing their potential in precision therapy. Moreover, biHSNPs successfully overcome tumor immune evasion through dual-target signal blockade. Using a straightforward and scalable strategy, a bispecific nanosystem is constructed that not only addresses the limitations of current bispecific antibody therapies but also represents a promising approach for the treatment of hematological malignancies.

Authors 12

1. Yefeng Shen

   Tianjin University · Capital Medical University · Beijing Friendship Hospital

   Affiliation as printed

   Department of Thoracic Surgery Beijing Friendship Hospital Capital Medical University Beijing 100050 China

   School of Pharmaceutical Science and Technology Faculty of Medicine Tianjin University Tianjin 300072 China

   Department of Thoracic Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050 China

   School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, 300072 China

2. Xin Li corresponding

   City University of Hong Kong

   Affiliation as printed

   Department of Biomedical Engineering City University of Hong Kong Hong Kong 999077 China

   Department of Biomedical Engineering, City University of Hong Kong, Hong Kong, 999077 China

3. Jingnan Wu Aachen Institute of Technical and Macromolecular Chemistry

   RWTH Aachen University · Academy of Military Medical Sciences

   Affiliation as printed

   Institute of Technical and Macromolecular Chemistry RWTH Aachen University 52074 Aachen Germany

   State Key Laboratory of Pathogen and Biosecurity Academy of Military Medical Sciences Beijing 100071 China

   Institute of Technical and Macromolecular Chemistry, RWTH Aachen University, 52074 Aachen, Germany

   State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing, 100071 China

4. Yuru Ma

   Tianjin University

   Affiliation as printed

   School of Pharmaceutical Science and Technology Faculty of Medicine Tianjin University Tianjin 300072 China

   School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, 300072 China

5. Sven Borchmann

   University of Cologne

   Affiliation as printed

   Department I of Internal Medicine University of Cologne 50937 Köln Germany

6. Zhenguo Cheng

   Zhengzhou University

   Affiliation as printed

   National Centre for International Research in Cell and Gene Therapy Sino‐British Research Centre for Molecular Oncology State Key Laboratory of Esophageal Cancer Prevention & Treatment School of Basic Medical Sciences Academy of Medical Sciences Zhengzhou University Zhengzhou 450001 China

   National Centre for International Research in Cell and Gene Therapy, Sino-British Research Centre for Molecular Oncology, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450001 China

7. Yaohe Wang

   Queen Mary University of London · Barts Cancer Institute

   Affiliation as printed

   Centre for Cancer Biomarkers & Biotherapeutics Barts Cancer Institute Queen Mary University of London London EC1M 6BQ UK

   Centre for Cancer Biomarkers & Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ UK

8. Yongliang Zhao
   Affiliation as printed

   Ningbo Dilato Materials Co., LTD 581 South Zhuangyu Road, Zhenhai District Ningbo 315200 China

   Ningbo Dilato Materials Co., LTD, 581 South Zhuangyu Road, Zhenhai District, Ningbo, 315200 China

9. Jian Song
   Affiliation as printed

   Institute of Cardiovascular Sciences Guangxi Academy of Medical Sciences Nanning 530021 China

   Institute of Cardiovascular Sciences, Guangxi Academy of Medical Sciences, Nanning, 530021 China

10. Boyu Luo

    Academy of Military Medical Sciences

    Affiliation as printed

    State Key Laboratory of Pathogen and Biosecurity Academy of Military Medical Sciences Beijing 100071 China

    State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing, 100071 China

11. Xiuyun Liu corresponding

    Tianjin University

    Affiliation as printed

    Neurocritical Care Medicine Innovation Center Ministry of Education Tianjin University Tianjin 300072 China

    School of Pharmaceutical Science and Technology Faculty of Medicine Tianjin University Tianjin 300072 China

    Neurocritical Care Medicine Innovation Center, Ministry of Education, Tianjin University, Tianjin, 300072 China

12. Zhiyuan Shi corresponding

    University of Cologne · Tianjin University

    Affiliation as printed

    Department I of Internal Medicine University of Cologne 50937 Köln Germany

    School of Pharmaceutical Science and Technology Faculty of Medicine Tianjin University Tianjin 300072 China

    School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, 300072 China