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  3. Preclinical imaging evaluation of a bispecific antibody targeting hPD1/CTLA4 using humanized mice

Preclinical imaging evaluation of a bispecific antibody targeting hPD1/CTLA4 using humanized mice

  • Biomed Pharmacother. 2024 Jun:175:116669. doi: 10.1016/j.biopha.2024.116669.
Xingguo Hou 1,  Song Liu 1,  Ziqing Zeng 1,  Zilei Wang 2,  Jin Ding 1,  Yan Chen 3,  Xiangyu Gao 4,  Jianghua Wang 5,  Guanxi Xiao 5,  Baiyong Li 5,  Hua Zhu 6,  Zhi Yang 7
Affiliations

Affiliations

  • 1 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, China.
  • 2 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, China.
  • 3 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, China; Guizhou University School of Medicine, Guiyang, Guizhou 550025, China.
  • 4 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing 100142, China.
  • 5 Research and Development Department, Akeso Biopharma Inc., Zhongshan, Guangdong 528437, China.
  • 6 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, China; Institute of Biomedical Engineering, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China. Electronic address: zhuhuabch@pku.edu.cn.
  • 7 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, China; Institute of Biomedical Engineering, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China. Electronic address: pekyz@163.com.
PMID: 38677243 DOI: 10.1016/j.biopha.2024.116669
Abstract

Background: The lack of an efficient way to screen patients who are responsive to immunotherapy challenges PD1/CTLA4-targeting Cancer treatment. Immunotherapeutic efficacy cannot be clearly determined by peripheral blood analyses, tissue gene markers or CT/MR value. Here, we used a radionuclide and imaging techniques to investigate the novel dual targeted antibody cadonilimab (AK104) in PD1/CTLA4-positive cells in vivo.

Methods: First, humanized PD1/CTLA4 mice were purchased from Biocytogen Pharmaceuticals (Beijing) Co., Ltd. to express hPD1/CTLA4 in T-cells. Then, mouse colon Cancer MC38-hPD-L1 cell xenografts were established in humanized mice. A bispecific antibody targeting PD1/CTLA4 (AK104) was labeled with radio-nuclide iodine isotopes. Immuno-PET/CT imaging was performed using a bispecific monoclonal antibody (mAb) probe 124I-AK104, developed in-house, to locate PD1+/CTLA4+ tumor-infiltrating T cells and monitor their distribution in mice to evaluate the therapeutic effect.

Results: The 124I-AK104 dual-antibody was successfully constructed with ideal radiochemical characteristics, in vitro stability and specificity. The results of immuno-PET showed that 124I-AK104 revealed strong hPD1/CTLA4-positive responses with high specificity in humanized mice. High uptake of 124I-AK104 was observed not only at the tumor site but also in the spleen. Compared with PD1- or CTLA4-targeting mAb imaging, 124I-AK104 imaging had excellent standard uptake values at the tumor site and higher tumor to nontumor (T/NT) ratios.

Conclusions: The results demonstrated the potential of translating 124I-AK104 into a method for screening patients who benefit from immunotherapy and the efficacy, as well as the feasibility, of this method was verified by immuno-PET imaging of humanized mice.

Keywords

Bispecific antibody; Cadonilimab; Cytotoxic T-lymphocyte-associated protein 4; Immuno-PET imaging; Programmed death molecule 1.

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