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Systematic evaluation of antibody-mediated siRNA delivery using an industrial platform of THIOMAB–siRNA conjugates
Open accessAbstract
Delivery of siRNA is a key hurdle to realizing the therapeutic promise of RNAi. By targeting internalizing cell surface antigens, antibody-siRNA complexes provide a possible solution. However, initial reports of antibody-siRNA complexes relied on non-specific charged interactions and have not been broadly applicable. To assess and improve this delivery method, we built on an industrial platform of therapeutic antibodies called THIOMABs, engineered to enable precise covalent coupling of siRNAs. We report that such coupling generates monomeric antibody-siRNA conjugates (ARCs) that retain antibody and siRNA activities. To broadly assess this technology, we generated a battery of THIOMABs against seven targets that use multiple internalization routes, enabling systematic manipulation of multiple parameters that impact delivery. We identify ARCs that induce targeted silencing in vitro and extend tests to target prostate carcinoma cells following systemic administration in mouse models. However, optimal silencing was restricted to specific conditions and only observed using a subset of ARCs. Trafficking studies point to ARC entrapment in endocytic compartments as a limiting factor, independent of the route of antigen internalization. Our broad characterization of multiple parameters using therapeutic-grade conjugate technology provides a thorough assessment of this delivery technology, highlighting both examples of success as well as remaining challenges.
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Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans
Fire, A., Xu, S., Montgomery, M. K., Kostas, S. A., Driver, S. E., & Mello, C. C. (1998) · Nature · doi:10.1038/35888 · Cited by 15,429
Expression profiling reveals off-target gene regulation by RNAi
Jackson, A. L., Bartz, S. R., Schelter, J., Kobayashi, S. V., Burchard, J., Mao, M., Li, B., Cavet, G., & Linsley, P. S. (2003) · Nature Biotechnology · doi:10.1038/nbt831 · Cited by 2,370
Cited by
Noncoding RNA therapeutics—Challenges and potential solutions
Winkle, M., El-Daly, S. M., Fabbri, M., & Calin, G. A. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00219-z · Cited by 1,551
The current state and future directions of RNAi-based therapeutics
Setten, R. L., Rossi, J. J., & Han, S.-P. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0017-4 · Cited by 1,443
The chemical evolution of oligonucleotide therapies of clinical utility
Khvorova, A., & Watts, J. K. (2017) · Nature Biotechnology · doi:10.1038/nbt.3765 · Cited by 1,216
Overcoming cellular barriers for RNA therapeutics
Dowdy, S. F. (2017) · Nature Biotechnology · doi:10.1038/nbt.3802 · Cited by 1,139
The delivery of therapeutic oligonucleotides
Juliano, R. L. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw236 · Cited by 854
Metadata
- Authors
- Cuellar, T. L., Barnes, D., Nelson, C., Tanguay, J., Yu, S.-F., Wen, X., Scales, S. J., Gesch, J., Davis, D., van Brabant Smith, A., Leake, D., Vandlen, R., & Siebel, C. W.
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-12-30
- Volume
- 43
- Issue
- 2
- Pages
- 1189-1203
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- OpenAlex
- W2016667503
- Cited by
- 213
- References
- 2
- FWCI
- 3.89
- Type
- journal article
- Language
- en
- Open access
- gold
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- Cuellar, T. L., Barnes, D., Nelson, C., Tanguay, J., Yu, S.-F., Wen, X., Scales, S. J., Gesch, J., Davis, D., van Brabant Smith, A., Leake, D., Vandlen, R., & Siebel, C. W. (2015). Systematic evaluation of antibody-mediated siRNA delivery using an industrial platform of THIOMAB–siRNA conjugates. Nucleic Acids Research. https://doi.org/10.1093/nar/gku1362
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