Center for Nanoscale Materials, Argonne National Laboratory, Lemont, Illinois 60517, United States.
School of Medicine, University of Pittsburgh, 3550 Terrace St., Pittsburgh, Pennsylvania 15213, United States.
Nano Lett. 2021 Jan 13;21(1):875-886. doi: 10.1021/acs.nanolett.0c04833. Epub 2021 Jan 4.
Monoclonal antibodies (mAb) have had a transformative impact on treating cancers and immune disorders. However, their use is limited by high development time and monetary cost, manufacturing complexities, suboptimal pharmacokinetics, and availability of disease-specific targets. To address some of these challenges, we developed an entirely synthetic, multivalent, Janus nanotherapeutic platform, called Synthetic Nanoparticle Antibodies (SNAbs). SNAbs, with phage-display-identified cell-targeting ligands on one "face" and Fc-mimicking ligands on the opposite "face", were synthesized using a custom, multistep, solid-phase chemistry method. SNAbs efficiently targeted and depleted myeloid-derived immune-suppressor cells (MDSCs) from mouse-tumor and rat-trauma models, ex vivo. Systemic injection of MDSC-targeting SNAbs efficiently depleted circulating MDSCs in a mouse triple-negative breast cancer model, enabling enhanced T cell and Natural Killer cell infiltration into tumors. Our results demonstrate that SNAbs are a versatile and effective functional alternative to mAbs, with advantages of a plug-and-play, cell-free manufacturing process, and high-throughput screening (HTS)-enabled library of potential targeting ligands.
单克隆抗体（mAb）在治疗癌症和免疫紊乱方面产生了变革性的影响。然而，它们的使用受到高开发时间和货币成本、制造复杂性、不理想的药代动力学和疾病特异性靶标的可用性的限制。为了解决其中的一些挑战，我们开发了一种完全合成的、多价的、两面神纳米治疗平台，称为合成纳米抗体（SNAbs）。SNAbs 在一个“面”上具有噬菌体展示鉴定的细胞靶向配体，在相反的“面”上具有 Fc 模拟配体，使用定制的多步固相化学方法合成。SNAbs 从鼠肿瘤和大鼠创伤模型中高效靶向和耗尽髓源性免疫抑制细胞（MDSCs），在体外。MDSC 靶向 SNAbs 的系统注射有效地耗尽了小鼠三阴性乳腺癌模型中循环中的 MDSC，从而增强了 T 细胞和自然杀伤细胞浸润到肿瘤中。我们的结果表明，SNAbs 是 mAb 的一种多功能且有效的替代物，具有即插即用、无细胞制造过程和高通量筛选（HTS）启用的潜在靶向配体文库的优势。
