Proactively reducing anti-drug antibodies via immunomodulatory bioconjugation
Open accessAbstract
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.
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Rapamycin or sirolimus can be conjugated to PEGylated AAV and is released upon phagocytosis of the vector by APCs.
“For instance, rapamycin or sirolimus, an inhibitor of mTOR (mammalian target of rapamycin) kinase, can be conjugated to PEGy lated AAV and is released upon phagocytosis of the vector by APCs (Zhang et al., 2019).”
From Gene Therapy-Associated Uveitis (GTAU): Understanding and mitigating the adverse immune response in retinal gene therapy (2025) · cites this paper as Zhang et al., 2019
The paper describes rapamycin conjugated to a PEGylated therapeutic protein through a cleavable linker, with release after uptake by antigen-presenting cells (Abstract, page unavailable). Its model protein was uricase, not an AAV vector; the paper therefore does not support the claim specifically about PEGylated AAV. (LLM, conf=0.90)
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References 30 · Cited by 4
Research works printed but not linked: 1
- E.M.Pelegri-ODay,E.W .Lin, H. D. Maynard, J. Am. Chem. Soc. 2014, 136,14323 -14332;
- Authors
- Zhang, P., Jain, P., Tsao, C., Wu, K., & Jiang, S.
- Affiliations
- University of Washington (US)
- Corresponding author
- Jiang, Shaoyi
- Venue
- Angewandte Chemie
- Publisher
- Wiley
- Published
- 2019-01-24
- Volume
- 131
- Issue
- 8
- Pages
- 2455-2458
- ISSN
- 0044-8249 (ISSN-L)
- 1521-3757
- OpenAlex
- W4210797752
- Cited by
- 4
- References
- 30
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 1
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Angewandte Chemie (publishedVersion)
- Funders
- Defense Threat Reduction Agency (HDTRA1-13-1-0044)
- University of Washington
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Immunology and Microbiology › Immunology › Biosimilars and Bioanalytical Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein purification and stability
- Keywords
- anti-drug antibodies, rapamycin, PEGylation, therapeutic proteins, antigen-presenting cells, immunogenicity, antibody titer reduction
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