Development of antibody-siRNA conjugate targeted to cardiac and skeletal muscles

Sugo, Tsukasa; Terada, Makoto; Oikawa, Tatsuo; Miyata, Kenichi; Nishimura, Satoshi; Kenjo, Eriya; Ogasawara-Shimizu, Mari; Makita, Yukimasa; Imaichi, Sachiko; Murata, Shumpei; Otake, Kentaro; Kikuchi, Kuniko; Teratani, Mika; Masuda, Yasushi; Kamei, Takayuki; Takagahara, Shuichi; Ikeda, Shota; Ohtaki, Tetsuya; Matsumoto, Hirokazu

doi:10.1016/j.jconrel.2016.06.036

Cited by 164 publications

(105 citation statements)

References 48 publications

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“…therefore, are the primary agents for TfR1 targeting of oligonucleotide therapeutics. The potential for TfR1 targeting was recently demonstrated, showing efficient and profound knockdown of gene expression in skeletal and cardiac muscle via systemically delivered anti-TfR1-Fab-siRNA conjugates in mice (106).…”

Section: Future Directionsmentioning

confidence: 99%

Selective tissue targeting of synthetic nucleic acid drugs

Seth¹,

Tanowitz²,

Bennett³

2019

Journal of Clinical Investigation

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Section: Future Directionsmentioning

confidence: 99%

Selective tissue targeting of synthetic nucleic acid drugs

Seth¹,

Tanowitz²,

Bennett³

2019

Journal of Clinical Investigation

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“…siRNA conjugate with lipophilic molecule on a solid CPG support A); 45 Biotinylated siRNA conjugated with streptavidin activated monoclonal antibody B); 46 Thiol-reactive siRNA conjugated with reduced Fab fragment C) 47 .…”

Section: Figurementioning

confidence: 99%

“Clicking” Gene Therapeutics: A Successful Union of Chemistry and Biomedicine for New Solutions

et al. 2018

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The use of nucleic acid, DNA and RNA, based strategies to disrupt gene expression as a therapeutic is quickly emerging. Indeed, synthetic oligonucleotides represent a major component of emerging gene therapeutics. However, the efficiency and specificity of intracellular uptake for non-modified oligonucleotides is rather poor. Utilizing RNA based oligonucleotides as therapeutics is even more challenging to deliver, due to extremely fast enzymatic degradation of the RNAs. Like unmodified oligonucleotides, RNAs also get rapidly degraded in vivo and demonstrate large off-target binding events when they can reach and enter the desired target cells. One approach that holds much promise is the utilization of “click chemistry” to conjugate receptor or cell specific targeting molecules directly to the effector oligonucleotides. We discuss here the applications of the breakthrough technology of CuAAC “click-chemistry” and the immense potential in utilizing “click chemistry” in the development of new age targeted oligonucleotide therapeutics.

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“…Ma et al treated A431 cells treated with anti-Lewis-Y mAb STAT3 siRNA and found that co-treatment with endosome disrupting agent chloroquinone was required for knockdown, and Cuellar et al treated various cell lines expressing seven target receptors exhibiting a range of internalization routes, and found that silencing was restricted to specific conditions and constructs, with endosomal release being identified as a limiting factor [6,7]. In vivo, Sugo et al [8] reported durable (>1 month) RNAi in heart and skeletal muscle tissues using intravenous injection of an siRNA anti-CD71 Fab¢ fragment conjugate, as well as significant myostatin mRNA knockdown in a mouse model of peripheral artery disease through intramuscular injection. Anti-TENB2 mAb conjugated with siRNA against housekeeping gene peptidylprolyl isomerase B (PPIB) were intravenously dosed to tumorbearing mice and PPIB mRNA was silenced by 33% in highly vascularized regions of the tumor [6].…”

Section: Introductionmentioning

confidence: 99%

Quantification of siRNA-Antibody Conjugates in Biological Matrices by Triplex-Forming Oligonucleotide ELISA

Humphreys

Thayer

Campuzano

et al. 2019

Nucleic Acid Therapeutics

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The potential repertoire of short interfering RNA (siRNA) therapeutics is expanding as targeting strategies evolve. One approach to enable organ-specific delivery has been to directly conjugate siRNA to a monoclonal antibody (siRNA-mAb), analogous to antibody-drug conjugates. Detection of intact siRNA-mAb conjugates presents a bioanalytical challenge given that certain synthetic nucleotide chemical modifications and lowtemperature requirements render common oligonucleotide detection assays, such as reverse transcriptionpolymerase chain reaction, incompatible with the immunoassay component. To circumvent these issues, we developed a triplex-forming oligonucleotide ELISA using locked nucleic acid (LNA) containing oligonucleotide probes. We demonstrate that the incorporation of these LNAs allow for an enrichment and immobilization of siRNA directly conjugated to an antibody at nondenaturing temperatures. Without further requirement for extraction or amplification, we can sensitively and specifically detect intact siRNA-mAb conjugates in complex matrices such as serum and tissue homogenate.

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Development of antibody-siRNA conjugate targeted to cardiac and skeletal muscles

Cited by 164 publications

References 48 publications

Selective tissue targeting of synthetic nucleic acid drugs

Selective tissue targeting of synthetic nucleic acid drugs

“Clicking” Gene Therapeutics: A Successful Union of Chemistry and Biomedicine for New Solutions

Quantification of siRNA-Antibody Conjugates in Biological Matrices by Triplex-Forming Oligonucleotide ELISA

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