BioArtMED 2024-06-13 14:30 四川
Author丨Pan Yunfeng (first author of this study)
近日，南京大学医学院附属鼓楼医院魏嘉教授、南京大学化学化工学院李劼教授的研究团队在Cell Reports Medicine上在线发表了题为Glycoengineering-based anti-PD-1-iRGD peptide conjugate boosts antitumor efficacy through T cell engagement的研究成果。 该研究揭示基于糖基编辑技术的新型PD-1抗体iRGD肽偶联物的抗肿瘤机制，为抗体肽偶联物的开发提供了新的思路。
In recent years, BiTEs (bispecific T cell engagers) have attracted much attention as an emerging cancer immunotherapy drug due to their unique anti-tumor mechanism [1, 2]. However, traditional anti-CD3 BiTEs have many limitations to their efficacy, such as triggering a systemic cytokine storm, upregulation of immune checkpoint molecules, and tumor antigen evasion [3]. In contrast, PD-1 antibody-based BiTEs can more specifically target tumor-responsive CD8+ T cells, thus showing greater potential in tumor immunotherapy [4]. In addition, PD-1 antibodies have a large relative molecular mass and are difficult to penetrate the tumor matrix, limiting their clinical efficacy [5, 6].
In this study, the research team selected tumor-infiltrating lymphocytes with high PD-1 expression as the target, and successfully synthesized a novel antibody peptide conjugate, αPD-1-(iRGD)2, by site-specific modification of human and mouse PD-1 antibodies through a glycoengineering platform. The antibody has dual affinity for PD-1 and iRGD receptors (integrin and NRP-1), which can promote the engagement of PD-1+ T cells with tumor cells with high expression of integrin. Compared with existing traditional BiTE, αPD-1-(iRGD)2-mediated bridging relies on the specific recognition of pMHC and TCR, avoiding non-selective T cell activation and excessive TCR signaling. At the same time, iRGD, as a classical tumor penetrating peptide, significantly improved the distribution of αPD-1-(iRGD)2 in tumor tissues.
αPD-1-(iRGD)2 significantly slowed tumor growth, reduced tumor weight, and improved survival in mice in a variety of tumor models. In particular, αPD-1-(iRGD)2 has demonstrated significant anti-tumor effects in "cold tumor" models with poor immune infiltration. Flow cytometry analysis showed that αPD-1-(iRGD)2 significantly increased the number of CD8+ T cells in the tumor microenvironment and enhanced the viability and proliferation of these T cells. Single-cell sequencing results showed that αPD-1-(iRGD)2 remodeled the tumor microenvironment (TME) and amplified a population of CD8+ T cells with a unique phenotype that expressed genes associated with stem cells and memory (Tcf7, Il7r, Lef1, and Bach2).
Although BiTEs have achieved some success in hematologic tumors, their application in solid tumors is still to be developed. By combining iRGD peptides with PD-1 antibodies, this study significantly enhances the penetration of therapeutic drugs in tumors, and at the same time endows them with a unique bispecific antibody-like articulation function, which preliminarily demonstrates the great potential of αPD-1-(iRGD)2 in clinical applications, and is expected to reshape the tumor microenvironment through a unique synergistic mechanism and bring new therapeutic hope to cancer patients.
Professor Wei Jia from the Drum Tower Hospital of Nanjing University School of Medicine and Professor Li Jie from the School of Chemistry and Chemical Engineering of Nanjing University are the co-corresponding authors of this paper. Dr. Yunfeng Pan from Nanjing University School of Medicine, Dr. Qi Xue from the School of Chemistry and Chemical Engineering of Nanjing University, and Dr. Yi Yang from Hangzhou Yantang Biological Co., Ltd. are the co-first authors of this paper.
原文链接：https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(24)00282-9
Plate maker: Eleven
bibliography
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