一种用于靶向癌症免疫治疗的胶原结合型SIRPαFc融合蛋白。
A collagen-binding SIRPαFc fusion protein for targeted cancer immunotherapy.
发表日期：2023 Sep 16
作者：
Jiayang Liu, Tongyang Xu, Danjie Pan, Jiajun Fan, Yuan Fu, Xiting Huang, Weili Zhao, Xiaochun Dong, Shaohui Zhang, Kudelaidi Kuerban, Xuan Huang, Songna Wang, Huaning Chen, Yunpeng He, Yi Zhun Zhu, Congjun Wang, Li Ye
来源：
INTERNATIONAL IMMUNOPHARMACOLOGY
摘要：
由于异常的肿瘤血管，胶原蛋白在肿瘤中很充裕且暴露，因此被认为是肿瘤特异性靶点。von Willebrand因子（vWF）的A3结构域是一种能够特异性结合胶原蛋白的胶原结合结构域（CBD）。我们先前报道了一种合成的CBD-SIRPαFc连接物，它可以通过CBD来阻断CD47并衍生出对肿瘤的靶向能力。CBD-SIRPαFc连接物经过改进后的抗肿瘤疗效表现出提高，增加了MHC II+ M1巨噬细胞，但耦合比例的不确定性仍然是一个问题。在这里，我们通过真核表达系统制备了一种vWF A3-SIRPαFc融合蛋白。通过分子和细胞水平检测了其与胶原的亲和性，与目标物的亲和性以及促进吞噬作用的功能，与未修饰的SIRPαFc相比未受到影响。活体成像显示，与SIRPαFc相比，vWF A3-SIRPαFc融合蛋白在肿瘤中得到了更多的积累和保留。在MC38共移植模型中，vWF A3-SIRPαFc表现出优越的抑制肿瘤效果，其特点是MHC II+ M1巨噬细胞和T细胞的增加（特别是CD4+ T细胞）。这些结果揭示了vWF A3-SIRPαFc融合蛋白衍生出的对肿瘤的靶向能力，相比SIRPαFc有更好的抗肿瘤免疫治疗效果。总之，vWF A3提高了SIRPαFc的抗肿瘤疗效和免疫激活功能，支持将靶向肿瘤胶原蛋白作为一种可能的靶向策略。
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Collagen is abundant but exposed in tumor due to the abnormal tumor blood vessels, thus is considered as a tumor-specific target. The A3 domain of von Willebrand factor (vWF A3) is a kind of collagen-binding domain (CBD) which could bind collagen specifically. Previously we reported a chemosynthetic CBD-SIRPαFc conjugate, which could block CD47 and derived tumor-targeting ability by CBD. CBD-SIRPαFc conjugate represented improved anti-tumor efficacy with increased MHC II+ M1 macrophages, but the uncertain coupling ratio remained a problem. Herein, we produced a vWF A3-SIRPαFc fusion protein through eukaryotic expression system. It was examined at both molecular and cellular levels with its collagen affinity, uninfluenced original affinity to targets and phagocytosis-promoting function compared to unmodified SIRPαFc. Living imaging showed that vWF A3-SIRPαFc fusion protein derived the improved accumulation and retention in tumor than SIRPαFc. In the MC38 allograft model, vWF A3-SIRPαFc demonstrated a superior tumor-suppressing effect, characterized by increased MHC II+ M1 macrophages and T cells (particularly CD4+ T cells). These results revealed that vWF A3-SIRPαFc fusion protein derived tumor-targeting ability, leading to improved anti-tumor immunotherapeutic efficacy compared to SIRPαFc. Altogether, vWF A3 improved the anti-tumor efficacy and immune-activating function of SIRPαFc, supporting targeting tumor collagen as a possible targeted strategy.Copyright © 2023 Elsevier B.V. All rights reserved.