Improved gene transfer selectivity to hepatocarcinoma cells by retrovirus vector displaying single-chain variable fragment antibody against c-Met

Abstract

Engineered retroviruses are widely used vectors for cancer gene therapy approaches. However, the ability to target cells of therapeutic interest while controlling the expression of the transferred genes would improve both the efficiency and the safety of viral vectors. In this study, we investigated the ability of a retroviral amphotropic envelope displaying single-chain variablefragment (scFv) directed against the c-Met receptor, to target the entry of recombinant retroviruses to human hepatocarcinoma cells. Four single-chain antibody fragments directed against the c-Met receptor were generated and inserted into the viral envelope protein as an N-terminal fusion. The modified envelopes were incorporated into virus particles and one of the chimeric viruses, 3D6-Env, transduced preferentially human hepatoma cells rather than proliferating human hepatocytes. In another construct, the urokinase cleavage site was inserted between the scFv moiety and the envelope. Chimeric scFv-urokinase-Env viruses transduced hepatoma cells with a similar efficiency to that of the control virus and their infectivity in human hepatocytes remained low. These results indicate that amphotropic retroviruses with engineered envelopes to display scFv directed against the c-Met receptor can efficiently and selectively deliver genes into hepatoma cells.

Downstream signalling and specific inhibition of c-MET/HGF pathway in small cell lung cancer: implications for tumour invasion

“…Multi-targeted kinase inhibitors to target c-MET together with VEGFR2 (XL880; Exelixis Inc., San Francisco, CA, USA) is also currently under development. Moreover, antibody approach to inhibit the c-MET/HGF pathway is also under investigation, both using antibodies against the ligand (Burgess et al, 2006) as well as the receptor (Nguyen et al, 2003). was used to downregulate c-MET expression in SCLC NCI-H69 cells in growth media containing 10% FCS as described previously (Ma et al, 2003a.…”

Combining Onartuzumab with Erlotinib Inhibits Growth of Non–Small Cell Lung Cancer with Activating EGFR Mutations and HGF Overexpression

“…Unlike other anti-MET antibodies that may activate MET signaling (23,24), onartuzumab was designed to be monovalent, to avoid agonistic activity (25), and it blocks the binding between MET and HGF (26,27). Onartuzumab is produced in Escherichia coli and does not have antibody-dependent cellular cytotoxicity (ADCC; ref.…”

A strategy for systemic delivery of the oncolytic herpes virus HSV1716: redirected tropism by antibody-binding sites incorporated on the virion surface as a glycoprotein D fusion protein

“…Targeted infection by vaccinia virus, retrovirus and measles virus displaying singlechain antibody-binding sites (scFv) incorporated into their structure by fusion with viral envelope proteins has been described. [14][15][16][17][18][19][20][21][22] Bridging, bispecific targeting molecules comprising either an anti-adenovirus scFv or the Coxsackievirus-adenovirus receptor linked to a targeting scFv, have been used for targeting oncolytic adenoviruses. [23][24][25][26][27][28][29] Results from a number of studies with HSV-1 have shown that it is possible to alter the tropism by incorporating ligands such as erythropoietin, interleukin (IL) 13, human hepatitis B virus preS1 peptide, the N-terminal fragment of urokinase-type plasminogen activator or 6-His into the viral envelope as glycoprotein fusion proteins.…”