Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany; PROvendis GmbH, Muelheim an der Ruhr, Germany.
J Biol Chem. 2023 Nov;299(11):105270. doi: 10.1016/j.jbc.2023.105270. Epub 2023 Sep 19.
Synthetic cytokine receptors can modulate cellular functions based on an artificial ligand to avoid off-target and/or unspecific effects. However, ligands that can modulate receptor activity so far have not been used clinically because of unknown toxicity and immunity against the ligands. Here, we developed a fully synthetic cytokine/cytokine receptor pair based on the antigen-binding domain of the respiratory syncytial virus-approved mAb Palivizumab as a synthetic cytokine and a set of anti-idiotype nanobodies (AIP) as synthetic receptors. Importantly, Palivizumab is neither cross-reactive with human proteins nor immunogenic. For the synthetic receptors, AIP were fused to the activating interleukin-6 cytokine receptor gp130 and the apoptosis-inducing receptor Fas. We found that the synthetic cytokine receptor AIPgp130 was efficiently activated by dimeric Palivizumab single-chain variable fragments. In summary, we created an in vitro nonimmunogenic full-synthetic cytokine/cytokine receptor pair as a proof of concept for future in vivo therapeutic strategies utilizing nonphysiological targets during immunotherapy.
合成细胞因子受体可以根据人工配体来调节细胞功能，从而避免脱靶和/或非特异性效应。然而，到目前为止，能够调节受体活性的配体还没有在临床上使用，因为它们的毒性和针对配体的免疫性未知。在这里，我们开发了一种基于已获批准的呼吸道合胞病毒单抗 Palivizumab 的抗原结合域的全合成细胞因子/细胞因子受体对，其中 Palivizumab 作为合成细胞因子，以及一组抗独特型纳米抗体（AIP）作为合成受体。重要的是，Palivizumab 既与人类蛋白无交叉反应性，也无免疫原性。对于合成受体，AIP 与激活型白细胞介素-6 细胞因子受体 gp130 和凋亡诱导受体 Fas 融合。我们发现，二聚体 Palivizumab 单链可变片段可有效激活合成细胞因子受体 AIPgp130。总之，我们创建了一种体外非免疫原性全合成细胞因子/细胞因子受体对，作为未来利用免疫疗法中非生理靶标进行体内治疗策略的概念验证。
