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Proactively Reducing Anti‐Drug Antibodies via Immunomodulatory Bioconjugation
Abstract
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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“Epitopes can also be shielded by polymers, such as PEG, XTEN, or PAS, or by methylating, glycosylating, or bio conjugating biotherapeutics, to effectively hide the surface epitopes of the product from the immune system or inducing tolerance to the antigen.145,146”
From Gene Therapy for Retinal Degenerative Diseases: Progress, Challenges, and Future Directions (2023) · cites this paper as [146]
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Anti‐ PEG immunity: emergence, characteristics, and unaddressed questions
Yang, Q., & Lai, S. K. (2015) · WIREs Nanomedicine and Nanobiotechnology · doi:10.1002/wnan.1339 · Cited by 593
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Sorted by citations
Gene Therapy for Retinal Degenerative Diseases: Progress, Challenges, and Future Directions
Drag, S., Dotiwala, F., & Upadhyay, A. K. (2023) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.64.7.39 · Cited by 145
Metadata
- Authors
- Zhang, P., Jain, P., Tsao, C., Wu, K., & Jiang, S.
- Affiliations
- University of Washington (US)
- Corresponding author
- Jiang, Shaoyi
- Venue
- Angewandte Chemie International Edition
- Publisher
- Wiley
- Published
- 2019-01-24
- Volume
- 58
- Issue
- 8
- Pages
- 2433-2436
- ISSN
- 1433-7851 (ISSN-L)
- 1521-3773
- OpenAlex
- W2911102301
- Cited by
- 18
- References
- 2
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 4 · 2023: 3 · 2022: 4 · 2021: 1 · 2020: 2
- FWCI
- 1.16
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Angewandte Chemie International Edition (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Defense Threat Reduction Agency (HDTRA1-13-1-0044)
- University of Washington
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › 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
- MeSH terms
- Antibodies, Antigen-Antibody Reactions, Antigens, Humans, Models, Molecular, Molecular Conformation, Oxidation-Reduction, Immunomodulation
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- Zhang, P., Jain, P., Tsao, C., Wu, K., & Jiang, S. (2019). Proactively Reducing Anti‐Drug Antibodies via Immunomodulatory Bioconjugation. Angewandte Chemie International Edition. https://doi.org/10.1002/anie.201814275
