Glycoengineering-based anti-PD-1-iRGD peptide conjugate boosts antitumor efficacy through T cell engagement

  • Cell Rep Med. 2024 Jun 18;5(6):101590. doi: 10.1016/j.xcrm.2024.101590.
Yunfeng Pan  1 ,  Qi Xue  2 ,  Yi Yang  3 ,  Tao Shi  4 ,  Hanbing Wang  4 ,  Xueru Song  4 ,  Yuting Luo  4 ,  Wenqi Liu  4 ,  Shiji Ren  4 ,  Yiran Cai  4 ,  Yang Nie  4 ,  Zhentao Song  3 ,  Baorui Liu  4 ,  Jie P Li  5 ,  Jia Wei  6
Affiliations
  • 1. Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China; State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
  • 2. Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China.
  • 3. Glyco-therapy Biotechnology Co. Ltd., Building 12, Hangzhou Pharmaceutical Town, 291 Fucheng Road, Xiasha Street, Qiantang District, Hangzhou, China.
  • 4. Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
  • 5. Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China. Electronic address: [email protected].
  • 6. Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China; State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China; Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China. Electronic address: [email protected].
PMID: 38843844 DOI: 10.1016/j.xcrm.2024.101590
Abstract

Despite the important breakthroughs of immune checkpoint inhibitors in recent years, the objective response rates remain limited. Here, we synthesize programmed cell death protein-1 (PD-1) antibody-iRGD cyclic peptide conjugate (αPD-1-(iRGD)2) through glycoengineering methods. In addition to enhancing tissue penetration, αPD-1-(iRGD)2 simultaneously engages tumor cells and PD-1+ T cells via dual targeting, thus mediating tumor-specific T cell activation and proliferation with mild effects on non-specific T cells. In multiple syngeneic mouse models, αPD-1-(iRGD)2 effectively reduces tumor growth with satisfactory biosafety. Moreover, results of flow cytometry and single-cell RNA-seq reveal that αPD-1-(iRGD)2 remodels the tumor microenvironment and expands a population of "better effector" CD8+ tumor infiltrating T cells expressing stem- and memory-associated genes, including Tcf7, Il7r, Lef1, and Bach2. Conclusively, αPD-1-(iRGD)2 is a promising antibody conjugate therapeutic beyond antibody-drug conjugate for Cancer Immunotherapy.

Keywords
BiTEs; PD-1 antibody; glycoengineering; iRGD; immunotherapy; peptide antibody conjugate.
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