能同时阻断VEGF信号和抑制补体活性的双功能抗体ACVP1的抗肿瘤机理研究

The complement system widely participates in the process of innate immune and immune regulation and has a close relationship with the occurrence of inflammation, tumor and other diseases. In recent years, relevance between complement system and tumor has becoming a research focus. Activating of the complement system can promote tumor angiogenesis, inhibit tumor cell apoptosis and produce tumor immune escape, making it a potential target of tumor therapy. Tumor genesis, development and metastasis is complex process which involves multiple targets and signal pathways. Therefore, designing of bifunctional antibody that direct to different targets has become to a hotspot in the creation and development of antibody drug. Our research group construct a bifunctional antibody ACVP1 that has high affinity of VEGF as well as complement factor. Earlier research results shows that the antibody can block VEGF signal pathway and inhibit complement activation. As far as we know, the design has not been reported in the world, which make it an original innovation. In this study, we plan to research the effect of inhibition of complement activity on tumor immune escape, tumor angiogenesis and study the therapeutic efficacy of ACVP1 and mechanisms through anti-tumor model in vivo, immunology experiments and anti-angiogenesis experiments. ACVP1 is expected to produce multiple antitumor effect including anti-tumor angiogenesis, removing tumor immune escape, and enhancing anti-tumor immunity, which could provide a theory foundation and scientific basis for anti-tumor therapy targeting complement system, so does for multi-targeted anti-tumor therapy.

补体系统广泛参与机体天然免疫以及免疫调节，与炎症、肿瘤等疾病的发生密切相关。近年来，补体与肿瘤的关系逐渐成为研究热点，补体激活后可促进肿瘤血管生成，抑制肿瘤细胞凋亡和产生肿瘤免疫逃逸等，是肿瘤治疗的潜在靶点。肿瘤的发生、发展、转移等过程是涉及到多个靶点，多条信号通路的复杂过程，因此，针对多个靶点设计双功能抗体成为近年来抗体研发的热点。本课题组构建了能同时亲和VEGF和补体的双功能抗体ACVP1，前期研究发现它能同时阻断VEGF信号和抑制补体激活,该设计国内外未见报导，具有原始创新性。本课题将通过体内抗肿瘤实验、免疫学实验、抗血管生成实验等，研究补体活性被抑制后对肿瘤免疫逃逸及肿瘤血管生成等的影响，以及ACVP1的治疗效果和作用机理。预计ACVP1将产生抗肿瘤血管生成，解除肿瘤免疫抑制，增强抗肿瘤杀伤等多重抗肿瘤作用，为针对补体靶点设计抗肿瘤药物及肿瘤的多靶点治疗奠定理论基础和实验依据。

1.项目背景.癌症严重威胁着人类的健康，但仅在部分肿瘤的治疗上取得了一定的进展，大部分的肿瘤仍缺乏有效的治疗策略。肿瘤新生血管生成是肿瘤发生、发展的重要因素，多个抑制VEGF 活性的药物取得了显著的抗肿瘤效果，但是临床上单用抗肿瘤血管生成药物治疗已经出现了耐药和停药后复发转移等系列问题。现在，越来越多的研究发现肿瘤的免疫逃逸是肿瘤耐药、复发、转移的关键因素。补体是存在于血清、组织液中的一类具有酶活性的蛋白质，广泛参与天然免疫以及免疫调节。近年来，研究发现补体与肿瘤的发生、转移和免疫逃逸等过程密切相关。因此，重要的补体蛋白逐渐成为肿瘤治疗的重要靶点。.2.研究方法及重要结果.本研究通过对靶向VEGFA/PIGF和补体C3b/C4b的融合蛋白(分别命名为VID和CID)体外生物学活性研究，证明VID对靶蛋白VEGF121、VEGF165及PIGF，CID对靶蛋白C3b和C4b具有良好的亲和活性。此外，研究发现VID能够显著抑制VEGF介导的HUVECs 的增殖、迁移和成管活性，CID能够抑制由人血清补体介导的HUVECs的迁移及管腔形成，并且能有效抑制补体经典通路和补体旁路活性。进一步，我们通过VID和CID联合治疗自发的结肠癌模型和原位的乳腺癌模型小鼠，发现在抑制肿瘤血管生成的同时能够通过抑制肿瘤部位MDSC局部浸润来解除肿瘤的免疫抑制状态，产生抑制肿瘤血管生成，增强抗肿瘤免疫反应并抑制肿瘤生长和转移等多重抗肿瘤作用，为肿瘤的多靶点联合治疗奠定理论基础和提供实验依据。.3..科学意义.综上所述，本课题所使用的人源化VEGFR-Fc融合蛋白VID联合CR1-Fc融合蛋白CID来治疗AOM+DSS诱导的自发结肠肿瘤以及小鼠的乳腺癌原位移植瘤模型都产生了抑制肿瘤血管生成，解除肿瘤免疫抑制状态，降低肿瘤细胞增殖，诱导肿瘤细胞凋亡等多重的抗肿瘤效果，联合治疗组获得了比两个单靶点治疗更好的疗效，为肿瘤的多靶点联合治疗奠定理论基础和提供了实验依据。

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