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

Microbiology & Immunology

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

931 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

ASJC Scopus subject areas

Biotechnology
Bioengineering
Applied Microbiology and Biotechnology
Molecular Medicine
Biomedical Engineering

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/nbt1101

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title = "Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors",

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.",

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

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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doi = "10.1038/nbt1101",

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AU - Song, Erwei

AU - Zhu, Pengcheng

AU - Lee, Sang Kyung

AU - Chowdhury, Dipanjan

AU - Kussman, Steven

AU - Dykxhoorn, Derek M.

AU - Feng, Yi

AU - Palliser, Deborah

AU - Weiner, David B.

AU - Shankar, Premlata

AU - Marasco, Wayne A.

AU - Lieberman, Judy

N1 - 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.

PY - 2005

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N2 - 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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Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors

Abstract

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