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Theranostics 2022; 12(18):7729-7744. doi:10.7150/thno.74903 This issue Cite

Research Paper

Self-assembly of X-shaped antibody to combine the activity of IgG and IgA for enhanced tumor killing

Yuexia Liang^1,2#, Xin Li^1,2#, Fengping Peng⁴, Xiaohan Ye^1,2, Wei Wang³, Tianyi Cen^1,2, Fan Li^1,2, Yue Lu¹, Zhaoyun Liu⁴, Hui Liu⁴, Kai Ding⁴, Kai Ye^1,2, Yang Yu^1,2, Tianyu Ma^1,2, Sihe Zhang⁵, Yi Huang⁶, Yuan Wang^1,2, Xue Yang¹, Rong Fu^4✉, Hongkai Zhang^1,2,3✉

1. State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin 300350, PR China.
2. Frontiers Science Center for Cell Responses, Nankai University, Tianjin 300350, PR China.
3. Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, PR China.
4. Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, PR China.
5. Department of Cell Biology, School of Medicine, Nankai University, Tianjin 300350, PR China.
6. Shanghai Tanshi Biotechnology Company, Shanghai, 201206, PR China.
#These authors contributed equally to this work.

✉ Corresponding authors: Hongkai Zhang, E-mail: hongkaiedu.cn; Rong Fu, E-mail: furong8369edu.cn.

Abstract

Rationale: IgA can induce activation of neutrophils which are the most abundant cell type in blood, but the development of IgA as therapeutic has been confounded by its short half-life and a weak ability to recruit NK cells as effector cells. Therefore, we generated an X-shaped antibody (X-body) based on the principle of molecular self-assembly that combines the activities of both IgG and IgA, which can effectively recruit and activate NK cells, macrophages, and neutrophils to kill tumor cells.

Methods: X-body was generated by using a self-assembly strategy. The affinity of the X-body with the antigen and Fc receptors was tested by surface plasmon resonance. The shape of X-body was examined using negative staining transmission electron microscopy. The tumor cell killing activity of X-body was assessed in vitro and in multiple syngeneic mouse models. To explore the mechanism of X-body, tumor-infiltrating immune cells were analyzed by single-cell RNA-seq and flow cytometry. The dependence of neutrophil, macrophage, and NK cells for the X-body efficacy was confirmed by in vivo depletion of immune cell subsets.

Results: The X-body versions of rituximab and trastuzumab combined the full spectrum activity of IgG and IgA and recruited NK cells, macrophages, and neutrophils as effector cells for eradication of tumor cells. Treatment with anti-hCD20 and anti-hHER2 X-bodies leads to a greater reduction in tumor burden in tumor-bearing mice compared with the IgA or IgG counterpart, and no obvious adverse effect is observed upon X-body treatment. Moreover, the X-body has a serum half-life and drug stability comparable to IgG.

Conclusions: The X-body, as a myeloid-cell-centered therapeutic strategy, holds promise for the development of more effective cancer-targeting therapies than the current state of the art.

Keywords: IgA, IgG, X-body, self-assembly, tumor-infiltrating neutrophil

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