An innovative antibody fusion protein targeting PD-L1, VEGF and TGF-β with enhanced antitumor efficacies

抗体依赖性细胞介导的细胞毒性 融合蛋白 抗体 免疫系统 单克隆抗体 肿瘤微环境 免疫检查点 贝伐单抗 癌症研究 抗原 化学 免疫疗法 生物 免疫学 生物化学 基因 化疗 重组DNA 遗传学
作者
Wenlu Fan,Yonglu Chen,Zhenxing Zhou,Wenwen Duan,Chengcheng Yang,Shimei Sheng,Yongwei Wang,Xinru Wei,Ying Liu,Yanshan Huang
出处
期刊:International Immunopharmacology [Elsevier BV]
卷期号:130: 111698-111698 被引量:13
标识
DOI:10.1016/j.intimp.2024.111698
摘要

Immunosuppressive pathways in the tumor microenvironment (TME) are inextricably linked to tumor progression. Mono-therapeutics of immune checkpoint inhibitors (ICIs, e.g. antibodies against programmed cell death protein-1/programmed cell death ligand-1, PD-1/PD-L1) is prone to immune escape while combination therapeutics tends to cause high toxicity and side effects. Therefore, using multi-functional molecules to target multiple pathways simultaneously is becoming a new strategy for cancer therapies. Here, we developed a trifunctional fusion protein, DR30206, composed of Bevacizumab (an antibody against VEGF), and a variable domain of heavy chain of heavy chain antibody (VHH) against PD-L1 and the extracellular domain (ECD) protein of TGF-β receptor II (TGF-β RII), which are fused to the N- and C-terminus of Bevacizumab, respectively. The original intention of DR30206 design was to enhance the immune responses pairs by targeting PD-L1 while inhibiting VEGF and TGF-β in the TME. Our data demonstrated that DR30206 exhibits high antigen-binding affinities and efficient blocking capabilities, the principal drivers of efficacy in antibody therapy. Furthermore, the capability of eliciting antibody-dependent cellular cytotoxicity (ADCC) and mixed lymphocyte reaction (MLR) provides a greater possibility to enhance the immune response. Finally, in vivo experiments showed that the antitumor activity of DR30206 was superior to those of monoclonal antibody of PD-L1 or VEGF, PD-L1 and TGF-β bispecific antibody or the combination inhibition of PD-L1 and VEGF. Our findings suggest there is a great potential for DR30206 to become a therapeutic for the treatment of multiple cancer types, especially lung cancer, colon adenocarcinoma and breast carcinoma.
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