位点特异性抗体-一氧化氮共轭物 HN02 具有更好的抗肿瘤性和安全性。

IF 3.2 4区 医学 Q3 IMMUNOLOGY Journal of Immunotherapy Pub Date : 2024-06-01 Epub Date: 2024-03-27 DOI:10.1097/CJI.0000000000000507
Tianyue Cheng, Jiajun Xie, Xun Yuan, Minji Guo, Jianbing Wu, Min Wang, Zhangjian Huang, Juan Zhang
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引用次数: 0

摘要

抗体药物共轭物(ADCs)结合了抗体的高特异性和有效载荷的细胞毒性,在泛癌症免疫疗法中具有巨大潜力。然而,目前用于临床的有效载荷因其不可控的异位毒性而限制了治疗窗口。开发安全性更高、疗效更好的强效 ADC 有效载荷的需求尚未得到满足。一氧化氮(NO)是一种特殊分子,本身毒性低,高浓度时能有效杀死肿瘤细胞,具有广阔的应用前景。此前,我们首次制备了抗体-一氧化氮共轭物(ANC)-HN01,对肝细胞癌具有抑制活性。然而,随机共轭方法使得 HN01 具有高度异质性和不稳定性。在这里,我们利用抗 CD24 抗体的半胱氨酸位点(CL-V211C)进行位点特异性共轭,制备出药物与抗体比为 2 的第二代 ANC。均一的 ANC HN02 在人血浆中稳定,体外对邻近细胞有旁观效应,对 CD24 靶向的肿瘤细胞有抗增殖活性。与 HN01 相比,HN02 能显著延长肿瘤小鼠的生存期。总之,我们开发出了一种稳定、均质的位点特异性共轭 ANC,它在体外和体内均表现出良好的抗肿瘤活性和更高的安全性。这项研究为开发新一代 ADC 候选药物提供了新的思路。
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Site-specific Antibody-Nitric Oxide Conjugate HN02 Possesses Improved Antineoplastic and Safety Properties.

Antibody-drug conjugates (ADCs) combine the high specificity of antibodies with the cytotoxicity of payloads and have great potential in pan-cancer immunotherapy. However, the current payloads for clinical uses have limited the therapeutic window due to their uncontrollable off-site toxicity. There is unmet needs to develop more potent ADC payloads with better safety and efficacy profiles. Nitric oxide (NO) is a special molecule that has low toxicity itself, which can kill tumor cells effectively when highly concentrated, has broad application prospects. Previously, we prepared for the first time an antibody-nitric oxide conjugate (ANC)-HN01, which showed inhibitory activity against hepatocellular carcinoma. However, the random conjugation method made HN01 highly heterogeneous and unstable. Here, we used site-specific conjugation-based engineered cysteine sites (CL-V211C) of anti-CD24 antibody to prepare a second-generation ANC with a drug-to-antibody ratio of 2. The homogeneous ANC, HN02 was stable in human plasma, shown in vitro bystander effect to neighboring cells and antiproliferative activity to CD24-targeted tumor cells. Compared with HN01, HN02 significantly prolonged the survival of tumor-bearing mice. In summary, we developed a stable and homogeneous site-specific conjugated ANC, which showed good antitumor activity and improved safety profile both in vitro and in vivo. This study provides new insight into the development of next generation of ADC candidates.

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来源期刊
Journal of Immunotherapy
Journal of Immunotherapy 医学-免疫学
CiteScore
6.90
自引率
0.00%
发文量
79
审稿时长
6-12 weeks
期刊介绍: Journal of Immunotherapy features rapid publication of articles on immunomodulators, lymphokines, antibodies, cells, and cell products in cancer biology and therapy. Laboratory and preclinical studies, as well as investigative clinical reports, are presented. The journal emphasizes basic mechanisms and methods for the rapid transfer of technology from the laboratory to the clinic. JIT contains full-length articles, review articles, and short communications.
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