Nature Biotechnology
23, 709 - 717 (2005)
Published online: 22 May 2005; | doi:10.1038/nbt1101
Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptorsErwei Song1, 4, Pengcheng Zhu1, 4, Sang-Kyung Lee1, Dipanjan Chowdhury1, Steven Kussman1, Derek M Dykxhoorn1, Yi Feng1, Deborah Palliser1, David B Weiner2, Premlata Shankar1, Wayne A Marasco3
& Judy Lieberman11
CBR Institute for Biomedical Research and Department of Pediatrics, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA. 2
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. 3
Department of Cancer Immunology & AIDS, Dana Farber Cancer Institute and Department of Medicine, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA. 4
These authors contributed equally to this work.
Correspondence should be addressed to Judy Lieberman lieberman@cbr.med.harvard.eduDelivery 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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