Department of Chemical Engineering, University of Washington, Seattle, WA, 98195, USA.
Angew Chem Int Ed Engl. 2019 Feb 18;58(8):2433-2436. doi: 10.1002/anie.201814275. Epub 2019 Jan 24.
Although PEGylation reduces the immunogenicity of protein drugs to some extent, its limitations for highly immunogenic biotherapeutics have been demonstrated. Herein, a proactive strategy to alleviate the development of anti-drug antibodies (ADAs) against protein drugs by immunomodulatory bioconjugation is reported. Rapamycin was conjugated to a PEGylated protein therapeutic via a cleavable disulfide linker. The conjugated rapamycin can be released from the bioconjugate and prevent immune responses once the bioconjugate is uptaken by antigen-presenting cells. The immunomodulatory bioconjugate significantly reduced the titers of ADAs compared with a PEGylated protein. The inhibition of immune responses was specific to the conjugated antigen, avoiding systemic immune suppression and the risk of increased susceptibility to infections. The reported approach breaks the limitations of PEGylation by the proactive prevention of ADAs.
尽管聚乙二醇（PEG）化在一定程度上降低了蛋白质药物的免疫原性，但对于高度免疫原性的生物治疗药物，其仍存在局限性。在此，我们报道了一种通过免疫调节生物缀合来缓解针对蛋白质药物的抗体（ADA）产生的主动策略。雷帕霉素通过可裂解的二硫键连接子与聚乙二醇化蛋白治疗药物缀合。一旦生物缀合物被抗原呈递细胞摄取，缀合的雷帕霉素就可以从生物缀合物中释放出来，并阻止免疫反应。与聚乙二醇化蛋白相比，免疫调节生物缀合物显著降低了 ADA 的滴度。免疫反应的抑制作用是针对缀合抗原的，避免了全身免疫抑制和增加感染易感性的风险。该方法通过主动预防 ADA 的产生，打破了 PEG 化的局限性。
