Proactively Reducing Anti‐Drug Antibodies via Immunomodulatory Bioconjugation

Although PEGylation reduces the immunogenicity of protein drugs to some extent due to its "stealth effect", more and more reports demonstrated its limitations for highly immunogenic biotherapeutics. Here we report a proactive strategy to alleviate the development of anti‐drug antibodies (ADAs) against protein drugs by immunomodulatory bioconjugation. An immunomodulator rapamycin was conjugated to a PEGylated protein therapeutic via a cleavable disulfide linker. When circulating in blood, the bioconjugate will play its therapeutic role as a PEGylated drug while the conjugated rapamycin can be released and prevent immune responses once the bioconjugate is uptaken by antigen presenting cells. In vitro and in vivo results showed that the immunomodulatory bioconjugate significantly reduced the titers of ADAs compared with a PEGylated protein. Importantly, 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 immunomodulatory bioconjugation approach breaks the limitations of PEGylation by the proactive prevention of ADAs.

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