Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors

Erwei Song; Pengcheng Zhu; Sang Kyung Lee; Dipanjan Chowdhury; Steven Kussman; Derek M. Dykxhoorn; Yi Feng; Deborah Palliser; David B. Weiner; Premlata Shankar; Wayne A. Marasco; Judy Lieberman

doi:10.1038/nbt1101

Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors

Erwei Song, Pengcheng Zhu, Sang Kyung Lee, Dipanjan Chowdhury, Steven Kussman, Derek M. Dykxhoorn, Yi Feng, Deborah Palliser, David B. Weiner, Premlata Shankar, Wayne A. Marasco, Judy Lieberman

Research output: Contribution to journal › Article › peer-review

844 Scopus citations

Abstract

Delivery of small interfering RNAs (siRNAs) into cells is a key obstacle to their therapeutic application. We designed a protamine-antibody fusion protein to deliver siRNA to HIV-infected or envelope-transfected cells. The fusion protein (F105-P) was designed with the protamine coding sequence linked to the C terminus of the heavy chain Fab fragment of an HIV-1 envelope antibody. siRNAs bound to F105-P induced silencing only in cells expressing HIV-1 envelope. Additionally, siRNAs targeted against the HIV-1 capsid gene gag, inhibited HIV replication in hard-to-transfect, HIV-infected primary T cells. Intratumoral or intravenous injection of F105-P-complexed siRNAs into mice targeted HIV envelope-expressing B16 melanoma cells, but not normal tissue or envelope-negative B16 cells; injection of F105-P with siRNAs targeting c-myc, MDM2 and VEGF inhibited envelope-expressing subcutaneous B16 tumors. Furthermore, an ErbB2 single-chain antibody fused with protamine delivered siRNAs specifically into ErbB2-expressing cancer cells. This study demonstrates the potential for systemic, cell-type specific, antibody-mediated siRNA delivery.

Original language	English (US)
Pages (from-to)	709-717
Number of pages	9
Journal	Nature Biotechnology
Volume	23
Issue number	6
DOIs	https://doi.org/10.1038/nbt1101
State	Published - 2005
Externally published	Yes

ASJC Scopus subject areas

Biotechnology
Bioengineering
Applied Microbiology and Biotechnology
Molecular Medicine
Biomedical Engineering

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Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors. / Song, Erwei; Zhu, Pengcheng; Lee, Sang Kyung; Chowdhury, Dipanjan; Kussman, Steven; Dykxhoorn, Derek M.; Feng, Yi; Palliser, Deborah; Weiner, David B.; Shankar, Premlata; Marasco, Wayne A.; Lieberman, Judy.

In: Nature Biotechnology, Vol. 23, No. 6, 2005, p. 709-717.

Research output: Contribution to journal › Article › peer-review

Song, Erwei ; Zhu, Pengcheng ; Lee, Sang Kyung ; Chowdhury, Dipanjan ; Kussman, Steven ; Dykxhoorn, Derek M. ; Feng, Yi ; Palliser, Deborah ; Weiner, David B. ; Shankar, Premlata ; Marasco, Wayne A. ; Lieberman, Judy. / Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors. In: Nature Biotechnology. 2005 ; Vol. 23, No. 6. pp. 709-717.

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abstract = "Delivery of small interfering RNAs (siRNAs) into cells is a key obstacle to their therapeutic application. We designed a protamine-antibody fusion protein to deliver siRNA to HIV-infected or envelope-transfected cells. The fusion protein (F105-P) was designed with the protamine coding sequence linked to the C terminus of the heavy chain Fab fragment of an HIV-1 envelope antibody. siRNAs bound to F105-P induced silencing only in cells expressing HIV-1 envelope. Additionally, siRNAs targeted against the HIV-1 capsid gene gag, inhibited HIV replication in hard-to-transfect, HIV-infected primary T cells. Intratumoral or intravenous injection of F105-P-complexed siRNAs into mice targeted HIV envelope-expressing B16 melanoma cells, but not normal tissue or envelope-negative B16 cells; injection of F105-P with siRNAs targeting c-myc, MDM2 and VEGF inhibited envelope-expressing subcutaneous B16 tumors. Furthermore, an ErbB2 single-chain antibody fused with protamine delivered siRNAs specifically into ErbB2-expressing cancer cells. This study demonstrates the potential for systemic, cell-type specific, antibody-mediated siRNA delivery.",

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note = "Funding Information: This work was supported by National Institutes of Health grant AI-056900 (J.L.), a Leukemia and Lymphoma Society fellowship (D.C.), amFAR scholar award (S.-K.L.), and Harvard CFAR scholar award (D.P.). We thank Manjunath N., Dong Zhang and Lianfa Shi for useful suggestions.",

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Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors

Abstract

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