PO.IM01.14 · 免疫学
SCR-M015，一种PD-1/VEGF双特异性抗体在临床前研究中表现出强效的抗肿瘤疗效
SCR-M015, a PD-1/VEGF bispecific antibody exhibits potent anti-tumor efficacy in preclinical studies
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：PD-1抗体与抗VEGF药物的联合相较于标准治疗显著改善了临床获益。免疫检查点和VEGF通路已被证明存在内在的机制互补，包括VEGF对血管生成、免疫细胞浸润和树突状细胞成熟的影响。我们开发了一种PD-1×VEGF双特异性抗体SCR-M015，并报告了表征其功能活性的临床前研究。
方法：使用表面等离子体共振评估结合亲和力，并使用ELISA和FACS测定EC50。探索基于生物发光细胞的报告测定以测量VEGF/VEGFR2或PD-L1/PD-1信号阻断功能。应用混合淋巴细胞反应（MLR）测定评估抗PD-1功能活性。在HUVEC增殖测定中测定抗VEGF生物活性。在使用人肿瘤细胞系的CDX模型中进行体内疗效研究。
结果：SCR-M015通过将抗PD-1纳米抗体融合到具有沉默Fc的抗VEGF-A抗体重链C端构建，形成2+2对称结构。SCR-M015表现出对人PD-1和VEGF的特异性高亲和力结合。体外测定表明，该抗PD-L1/VEGF双特异性抗体对VEGF-A/VEGFR2信号的阻断活性以及对HUVEC增殖的抑制更为强效。在MLR测定中，SCR-M015剂量依赖性地增加IL-2和IFN-gamma分泌，与基准抗体相当。在体内，SCR-M015在不同异种移植模型中显示出比基准抗体更强健的抗肿瘤活性。此外，与抗PD-1单克隆抗体和抗VEGF单克隆抗体的联合相比，SCR-M015显示出更强效的抗肿瘤疗效。
结论：SCR-M015在体外抑制PD-1/PD-L1信号和VEGF-A/VEGFR2信号，并在体内显示出强效且优越的抗肿瘤活性。这些临床前数据证明了其在各种类型肿瘤中进一步临床研究的有前景的潜力。
查看英文原文 English abstract
Background: Combinations of PD-1 antibodies and anti-VEGF agents significantly improved clinical benefits over standards of care. The immune checkpoint and VEGF pathways has been demonstrated intrinsic mechanistic complementation, including VEGF effect on angiogenesis, immune cell infiltration, and dendritic cell maturation. We have developed a PD-1xVEGF bispecific antibody SCR-M015 and reported preclinical studies characterizing the functional activity.
Method: Binding affinity was assessed using Surface Plasmon Resonance, and the EC50 were determined using ELISA and FACS. Bioluminescent cell-based reporter assays were explored to measure VEGF/VEGFR2 or PD-L1/PD-1 signaling blockage function. Mixed lymphocyte reaction (MLR) assay was applied to evaluate anti-PD1 functional activity. Anti-VEGF bioactivity was determined in HUVEC proliferation assay. In vivo efficacy studies were conducted in CDX models with human tumor cell lines.
Result: SCR-M015 was constructed by fusing anti-PD-1 nanobody to the C-terminus of the heavy chain of an anti-VEGF-A antibody with a silent Fc, forming a 2+2 symmetrical structure. SCR-M015 exhibited specific and high-affinity binding to human PD-1 and VEGF. In vitro assays demonstrated that the anti-PD-L1/VEGF bispecific antibody exhibited more potent blockade activity against VEGF-A/VEGFR2 signaling and inhibition of HUVEC proliferation. In MLR assay, SCR-M015 showed dose-dependently increased IL-2 and IFN-gamma secretion, which was comparable to benchmark antibody. In vivo, SCR-M015 demonstrated more robust anti-tumor activity than benchmark antibody in different xenograft models. Furthermore, compared to the combination of anti-PD-1 monoclonal antibody and anti-VEGF monoclonal antibody, SCR-M015 showed more potent anti-tumor efficacy.
Conclusions: SCR-M015 inhibits PD-1/PD-L1 signaling and VEGF-A/VEGFR2 signaling in vitro and shows potent and superior anti-tumor activity in vivo. These preclinical data demonstrates the promising potential for further clinical investigation in various types of tumors.
利益披露 Disclosure
Q. Wang, None..
Y. Fu, None..
F. Shan, None..
Y. Wang, None..
G. Yang, None..
Y. Wang, None..
X. Qin, None..
R. Tang, None.