Dinitrophenol-mediated modulation of an anti-PD-L1 VHH for Fc-dependent effector functions and prolonged serum half-life
Dinitrophenol-mediated modulation of an anti-PD-L1 VHH for Fc-dependent effector functions and prolonged serum half-life
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二硝基苯酚介导的抗 PD-L1 VHH 调节，实现 Fc 依赖性效应器功能并延长血清半衰期
DOI：
10.1016/j.ejps.2021.105941
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发表时间：
2021
影响因子：
4.6
通讯作者：
Zhimeng Wu
中科院分区：
文献类型：
--
作者：
Jinlong Liu;Haofei Hong;Jie Shi;Yuntian Xie;Zhongkai Lu;Zhicheng Liu;Zhifang Zhou;Zehua Bian;Zhaohui Huang;Zhimeng Wu
单域抗体，vhh或纳米抗体，代表了一组有希望的替代传统的抗体。无细胞抗体，在癌症免疫治疗领域获得了大量关注。然而，固有的。纳米体的缺点，如快速清除血液循环和缺乏免疫效应功能。往往导致治疗效果不理想。我们以前报道过二硝基苯改性的an。抗egfr VHH赋予fc依赖的免疫效应功能，并延长其血清半衰期。募集半抗原抗体，提高体内免疫治疗效果。在目前的工作中，我们。进一步测试了这种方法在抗pd - l1阻断VHH （KN035）情况下的多功能性。特定场地。二硝基苯偶联不影响KN035部分对PD-L1的结合能力，但间接恢复了其结合能力。其免疫效应功能表现为抗体依赖性细胞介导的细胞毒性。抗体依赖性细胞吞噬和补体依赖性细胞毒性对PD-L1阳性肿瘤细胞的作用。二硝基苯化KN035的血液清除明显延迟，其半衰期延长。这种方法使用小半抗原分子偶联，装载额外的抗体介导的肿瘤。PD-L1阻断VHH的杀伤机制，从而提高了未来在体内的疗效。治疗性研究。因此，我们的结果强调了这种实现理想的通用方法的力量。基于vhh或类似疗法的特性。
Single-domain antibodies, VHHs or nanobodies, represent a promising set of alternatives to conventional ther-.apeutic antibodies, gaining substantial attention in the field of cancer immunotherapy. However, inherent .drawbacks of nanobodies such as fast clearance from blood circulation and lack of immune effector functions .often led to unsatisfactory therapeutic efficacy. We previously reported that dinitrophenyl modification of an .anti-EGFR VHH conferred Fc-dependent immune effector functions and elongated serum half-life on it through .recruiting of hapten antibodies, resulting in improved immunotherapy efficacy in vivo. In the present work, we .further tested the versatility of this approach in the case of an anti-PD-L1 blockade VHH (KN035). Site-specific .dinitrophenyl conjugation did not impair the binding capacity of KN035 portion to PD-L1, but indirectly restored .its immune effector functions, manifested by the observed antibody dependent cell-mediated cytotoxicity, .antibody-dependent cellular phagocytosis and complement-dependent cytotoxicity against PD-L1 positive tumor .cells. Significant delay of blood clearance of dinitrophenylated KN035 was evidenced by the prolonged half-life .of ca. 22 h. This approach, using small hapten molecule conjugation, loaded additional antibody-mediated tumor .killing mechanisms to PD-L1 blockade VHH and therefore improved efficacy is anticipated in the future in vivo .therapeutic studies. Thus, our results underscore the power of this versatile approach for achieving desirable .properties of VHH-based or similar therapeutics.