Vector retargeting for cancer gene therapy - Chinese Journal of Cancer

Vector retargeting for cancer gene therapy [Chinese Journal of Cancer 28:1, 86-90; January 2009]; ©2009 Sun Yat-Sen University Cancer Center

Review

Vector retargeting for cancer gene therapy Wei Wei, Jing-lun Xue and Ling Tian* State Key Laboratory of Genetic Engineering; Institute of Genetics; School of Life Sciences; Fudan University; Shanghai P.R. China

Key words: neoplasm, vector retargeting, virus modification, gene therapy

Vector tropism is a research hot spot in cancer gene therapy, and targeted viral vectors play a key role in the enhancement of safety and efficiency in cancer gene therapy. Vector retargeting is one of the important strategies on viral vector targeting. This review mainly focused on the progresses of vector retargeting in cancer gene therapy, and summarized relevant pathways and strategies. Cancer gene therapy is currently a hot topic in the research on new therapeutic technology for tumors. Since the initiation of the first clinical gene therapy regimen in 1989, till July 2007, 1340 gene therapy regimens have entered different phases of clinical trials around the world. Among these regimens, about 67% depend on viral vector systems to introduce exogenous genes into target cells.1 Comparing with non-viral vector systems, viral vector systems have more advantages in gene therapy, one of which is that viral vector systems can rely on natural virus tropism to efficiently transduce exogenous genes into target cells. For example, the natural neural tropism of the herpes simplex virus can be used to conduct gene therapy for tumors of the nervous system.2 However, the natural tropism of viruses to target cells often lacks selectivity and frequently introduces therapeutic genes into non-target cells, which obviously does not meet the growing safety requirements for gene therapy. For example, adenovirus-mediated gene transfer relies on the high-affinity binding of the knob domain of the virus fiber protein to Coxsackie-adenovirus receptor (CAR) on the membrane of target cells. Thus, CAR plays a pivotal role in adenovirus-mediated gene transfer.3 However, a decrease of CARs on the surface of primary cancer cells enables frequent resistance to adenovirus infection.3 Moreover, some studies prove that CAR has an inhibitory effect on the proliferation of multiple kinds of cancer cell lines, for example, human prostate cancer cell lines,4 human bladder cancer cell lines,5 and glioma cell lines,6 and so on. Some other studies also show that CAR is able to inhibit the metastasis of *Correspondence to: Ling Tian; State Key Laboratory of Genetic Engineering; Institute of Genetics; School of Life Sciences; Fudan University; Shanghai, 200433, P.R. China; Tel.: 86.21.65643627; Fax: 86.21.65643627; Email: [email protected] Submitted: 03/24/08; Revised: 05/26/08; Accepted: 07/22/08 This paper was translated into English from its original publication in Chinese. Translated by: Wei Liu on 12/15/08. The original Chinese version of this paper is published in: Ai Zheng (Chinese Journal of Cancer), 28(1); http://www.cjcsysu.cn/cn/article.asp?id=14767 Previously published online as a Chinese Journal of Cancer E-publication: http://www.landesbioscience.com/journals/cjc/article/8648 86

lung cancer cells.7 Additionally, the natural tropism of adenovirus to hepatic cells tends to lead to the accumulation of adenovirus particles in the liver and thereby induce liver injury.8 Therefore, it is unsafe to conduct gene therapy through target gene transfer only depending on natural virus tropism. The binding between a virus ligand and its cellular receptor is often the first and most important step for viral infection. During gene therapy, we should not only fully depend on the advantage of high efficiency of virus infection but also overcome the potential safety problems caused by the natural tropism of viral vectors. Hence, in recent years, many studies aim to modify the natural tropism of viruses to achieve specific transfer to target cells, which is known as vector retargeting. This article reviewed the advances in the research on vector retargeting in gene therapy. Based on the strategies used to achieve vector retargeting, vector retargeting is grossly divided into two major categories: viral genome modification-independent vector retargeting and viral genome modification-dependent vector retargeting.

Viral Genome Modification-Independent Vector Retargeting Viral genome modification-independent vector retargeting is usually achieved through pseudotyping or using adaptors. Vector pseudotyping. Pseudotyping is a phenomenon found in retroviruses. During co-infection of host cells by a retrovirus and another enveloped virus, the progeny virions bearing the genome of the retrovirus may be encapsidated by the envelope glycoproteins of the other virus. Since some envelope glycoproteins are ligands for host cell receptors, the retrovirus encapsidated by the envelope glycoproteins of the other virus may be targeted to other types of cells and can therefore infect cells bearing no natural receptors for the retrovirus. Similarly, when a viral vector is modified based on pseudotyping, and the viral vector and a plasmid carrying the envelope glycoprotein gene of another virus are co-transfected into host cells, the viral vector will be encapsidated by the envelope glycoprotein of the other virus and gain new tropism. Pseudotyping is mainly applied to the retargeting of retroviruses. Among many pseudotyped vectors, the heterologous envelope glycoprotein mainly used is vesicular stomatitis virus glycoprotein (VSV-G),9 followed by hepatitis B virus glycoprotein,10 rabies virus-derived glycoprotein,11 lymphocytic choriomeningitis virus glycoprotein,12 alphavirus glycoprotein,13 and so on. Qiao et al.14 used a VSV-G pseudotyped, Moloney murine leukemia virus (Mo-MuLV) vector to conduct cancer gene therapy. They constructed a sei-replication-competent (s-RCR) Mo-MuLV vector (Semi.TK30)

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Vector retargeting for cancer gene therapy

containing the herpes simplex virus thymidine kinase (HSVtk30). In vitro experimental results showed that, under conditions of hightiter virus replication (about 30 TU/cell) and in the presence of ganciclovir, co-transfection of the Semi.TK30 vector and the plasmid containing the VSV-G gene (MFG-VSVG) into HT108 cells resulted in lower proliferation rate and showed stronger inhibitory effects on these cells (about 12%) when compared with transfection with s-RCR or MFG-VSVG. Animal experiments also showed that the Semi.TK30 vector had better anti-cancer effects. Compared with PBS, Semi.TK30 plus GCV could extend the longest survival duration of mice from 21 days to 38 days. Adapter-based vector retargeting. Though vector pseudotyping

can alter the tropism of viral vectors, it has some disadvantages, which mainly include that limited number of viral glycoproteins and target cell receptors are available.15 Therefore, modifying vector capsid proteins via carrying heterologous ligands to alter the tropism of vectors has become a hot topic in the research on vector targeting.

The modification of capsid proteins are mainly based on two strategies, namely, adaptor-based retargeting and retargeting based on viral genome modification to express fusion proteins (will be discussed below). Adaptor-based retargeting has an advantage that it has no specific demands on clarifying the biological structure of viral vector capsid proteins. Thus, the modification to achieve vector retargeting can be conducted under limited knowledge. Moreover, due to the diversity of adaptors, one viral vector can be targeted to a variety of target cells by connecting to different adaptors. At present, there are three kinds of adaptor-based methods mainly used for virus retargeting, namely, receptor-ligand fusion protein adaptor-based method, chemically cross-linked adaptor-based method and biotinavidin adaptor-based method. Receptor-ligand fusion protein adaptor-based retargeting. Receptor-ligand fusion protein complexes have been widely used for viral vector retargeting. The receptors can specifically bind to the capsid proteins of virions and destroy the natural tropism of vectors, while the ligands can specifically bind to target cell receptors to direct the specific targeting of viral vectors. In these adaptors, the receptors that specifically bind to viral capsid proteins mainly include capsid protein-specific antibodies,16 viral vector capsid protein-specific receptors,17 and so on, while the ligands mainly include folate,16 fibroblast growth factor,18 apolipoprotein E,17 epidermal growth factor,19 cancer cell surface antigen-specific antibodies,20 and so on. Witlox et al.21 found that CAR was lowly expressed on the surface of osteosarcoma cells, while epidermal growth factor receptor was highly expressed. Therefore, they constructed a recombinant bi-specific single-chain antibody 425-s11, which could specifically bind to both the adenovirus fiber knob and epidermal growth factor receptor, to retarget the adenovirus. In vitro experiments showed that, in the presence of adaptor 425-s11, the infection efficiency of adenoviruses were increased by 2.5 to 7.2 times in osteosarcoma cell lines expressing varying levels of CAR.21 The advantages of receptor-ligand fusion protein adaptors include relatively simple technical requirements, no need to comprehensively know the information on vector structure, and achievement of multiple specific targetings using one viral vector by connecting to different adaptors. However, since these adaptors are connected to viral vectors through non-covalent bonds, they may fall off from viral vectors, thus resulting in vector detargeting and a return to original www.landesbioscience.com

tropism. Moreover, the production and purification processes of receptor-ligand fusion protein adaptor-based retargeting are relatively complicated, which need to generate receptor-ligand fusion protein adaptors, bind viruses to adaptors, and purify virus-adaptor complexes. Therefore, it is somehow difficult to conduct large-scale production of virus-adaptor complexes for cancer therapy. Chemically cross-linked adaptor-based retargeting. Chemically cross-linked adaptors provide another approach for changing the tropism of viruses. By covalently coupling adaptors such as polyethylene glycol (PEG) or its derivatives to viral vectors, this method allows the elimination of the original tropism of viral vectors and confers specific tropism to these vectors using target cell receptorspecific ligand proteins or molecules coupled to adaptors. Lanciotti et al.22 coupled a PEG-fibroblast growth factor 2 (FGF2) adaptor to an adenoviral vector using a chemically cross-linked approach, and found that this modification enhanced the transduction efficiency of adenoviral vectors by four to five times which was dependent on the binding between FGF2 and its receptor on ovarian cancer cells, while independent on the CAR for the adenoviral vector. Additionally, their results also showed that the modified adenovirus significantly weakened CAR-mediated natural tropism and effectively reduced the body's immune response to the adenovirus, thus greatly reduced the side effects of the adenovirus. The advantages of chemically cross-linked adaptors are that they can eliminate the original tropism of viral vectors (ligands or other molecules that cross-linked with PEG confers new tropism to viral vectors, namely, retargeting) and protect these vectors from antibody neutralization or induce relatively weak primary immune response.23 Currently, chemically cross-linked adaptor-based retargeting are mainly applied to adenoviral vectors and adeno-associated virus vectors. However, though PEG cross-linked adaptors can transiently enhance the efficiency of viral retargeting, the process for preparing retargeted viruses is still complicated. Furthermore, considering that newly replicated virions lack chemical cross-linked adaptors, their retargeting ability may be lost. Biotin-avidin adaptor-based retargeting. Biotin-avidin adaptors provide another strategy for vector retargeting, which are mainly applied to the retargeting of adenovirus vectors and adeno-associated virus vectors. Generally, the biotin acceptor peptide (BAP) is firstly inserted into the vector fiber capsid protein to form an adenovirus-biotin acceptor fusion protein, which then binds to the avidin-cellular ligand adaptor to alter the natural tropism of the adenovirus and retarget them to new cellular receptor molecules. Biotin-avidin adaptors can also be substituted by antibody-biotin adaptors, which firstly bind to virus vectors and then bind to avidin-cellular ligands to achieve vector retargeting.24 Pereboeva et al.25 applied biotin-avidin adaptor-based method to specifically target the adenovirus to cancer cells. Through genetic modification of the viral capsid fiber protein, they incorporated a biotin acceptor peptide into two kinds of fibers, fiber-fibritin and the wild-type fiber. Thus, these BAP-containing fiber mosaic constructs were biotinylated in cells and then bound to the avidin-epidermal growth factor (EGF) adaptor. Since the other end of the adaptor was coupled to cells rich in epidermal growth factor receptor (EGFR), vector retargeting was achieved. In vitro experiments showed that the transduction efficiency of the biotin-avidin adaptor-modified viral vectors was enhanced by 10-30 folds in cell lines highly


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expressing EGF. Moreover, animal experiments also showed that the in vivo transduction efficiency of the biotin-avidin adaptormodified viral vectors was enhanced by at least 7-fold.25

Viral Genome Modification-Dependent Vector Retargeting Although pseudotyping- and adaptor-based retargeting have their own advantages, they also have some disadvantages, such as relatively complicated process for viral production and purification, possible variances among different batches of viruses as well as return to original tropism. Hence, viral genome modification-dependent vector retargeting strategy is developed as the knowledge on the molecular biology and structure of viruses is continuously deepened. Currently, this strategy is mainly applied to the retargeting of adenoviruses. At present, adenovirus type 5 (Ad5) is the most commonly used adenovirus for gene therapy. Adenovirus is a kind of non-enveloped viruses whose genome is packaged by capsid proteins with icosahedral symmetry. The capsid is mainly bulit up of 240 hexons and 12 pentons located at the icosahedral vertices. Each penton consists of a base and a fiber that is composed of a knob, a shaft and a tail.26 Since the tropism of adenoviruses is mainly decided by the fiber knob, current genome modification to achieve adenovirus retargeting mainly focuses on the fiber knob of adenovirus pentons, which is performed mainly based on three strategies, namely, knob replacement, ligand insertion, and ligand replacement. Knob replacement method. The knob replacement method is an approach for altering the original tropism of adenoviruses, which is similar to lentivirus pseudotyping. Through replacing the knob domain of Ad5 vector with the fiber knob domain of other serotypes of adenoviruses, Ad5 vector can obtain the targeting ability of the replaced serous adenoviruses. Since the CAR of adenoviruses is often lost in many types of cancer cells, replacement of the knob domain of adenovirus vectors by the fiber knob domain of other serotypes of adenoviruses can expand the targeting ability of these vectors, thereby enabling them to effectively mediate the targeting of genes of interest to cancer cells for gene therapy. Through genome modification by replacing the knob domain of Ad5 with that of Ad3, Krasnykh et al. constructed a recombinant Ad5 targeted to the target cells of Ad3.27 Tsuruta et al.28 replaced the fiber of Ad5 with a fusion fiber containing reovirus sigma 1 and Ad5 (Ad5-sigma 1) to conduct ovarian cancer-targeted viral therapy. Their results indicated that the fusion fiber Ad5-sigma 1 in this vector not only retained the natural tropism of the adenovirus but also gained the tropism to sialic acid and junction adhesion molecule 1 (JAM1). Furthermore, compared with the transduction efficiency of Ad5, that of Ad5-sigma 1 in cell line L929, which expresses both sialic acid and JAM1, and cancer cell lines, which only express sialic acid, was increased by 45 and six times, respectively. Therefore, this modification enhanced, to a certain extent, the transduction efficiency of the viral vector and overcame the shortcoming that adenoviral vectors have low transduction efficiency due to low-level expression of CAR on the surface of ovarian caner cells. Besides mutual replacement of the knob domains among human adenoviruses of different species or genres, the capsid fiber of some non-human adenoviruses that can infect human cells in a CAR-independent manner can also be cloned and incorporated into the genome of human adenoviruses to enhance their ability to infect cells with low CAR expression. These viruses include canine adenovirus type 2,29 sheep adenovirus,30 poultry adenoviruses,30 cattle adenovirus,31 and so on. 88

Ligand insertion method. The C-terminus and HI-loop of the adenovirus fiber knob can tolerate insertion of multiple amino acids without changing its original ability to bind to the CAR.32,33 This makes it possible to expand the tropism of adenoviral vectors by inserting some target cell-specific short chains in these regions. Through inserting the integrin RGD domain or a lysine oligomer into the C-terminus of the adenovirus fiber knob, Wickham et al. constructed a recombinant adenoviral vector AdZ.F(pK7) that could specifically bind to alpha (v) integrin and a recombinant adenoviral vector AdZ.F(RGD) that could specifically bind to heparan sulfate.32 In vitro experiments showed that the transduction efficiency of both AdZ.F(RGD) and AdZ.F(pK7) to epithelial cell line CAPE was enhanced by 100-fold, meanwhile, the transduction efficiency of AdZ.F(pK7) in multiple CAR-deficient cell lines was enhanced by 5-500-fold.32 Similarly, Yoshida et al.33 constructed a recombinant adenoviral vector F/K20-Adv by inserting 20 lysine residues into the C-terminus of the adenovirus fiber knob. The multiplicities of infection with F/K20-Adv were 7-42-fold lower than those with wild-type F/wt-Adv when their transduction efficiency was the same, therefore, the transduction efficiency of F/K20-Adv in glioma cells was significantly raised.33 However, adenovirus retargeting through inserting a short peptide into the C-terminus of the fiber knob also has disadvantages since this region can tolerate insertion of no more than 27 amino acid residues. Insertion of a too large fragment may prevent the formation of adenovirus fiber trimer.34 HI-loop of the adenovirus knob region is another area where exogenous fragments can be inserted into since this region can tolerate insertion of about 100 amino acid residues.35 The peptides that can be inserted into HI-loop include the RGD domain of the integrin, NGR domain,36 lysine oligomers,37 and so on. Koizumi et al.37 found that the tranduction efficiency of the recombinant adenoviruses containing the RGD domain in HI-loop was twice as high as that of the recombinant adenoviruses containing the RGD domain at C-terminus, and the tranduction efficiency of the recombinant adenoviruses containing a lysine oligomer was lower than that of the recombinant adenoviruses containing the RGD domain. Additionally, adenovirus hexons can also tolerate insertion of exogenous fragments. Each adenovirus hexon contains nine hypervariable regions (HVRs), of which the HVR5 region is usually used to conduct vector retargeting since McConnell et al.38 found that the HVR5 region could tolerate insertion of 36 amino acid residues without altering the infectivity, growth and stability of the adenovirus. Vigne et al.39 constructed a recombinant virus AE57 by inserting a RGD sequence and a poliovirus model epitope into the HVR5 region of Ad5. In vitro experiments showed that, compared with control virus AE18, in which only the poliovirus model epitope was inserted into the HVR5 region, the transduction efficiency of AE57 was enhanced by 10-fold in human aortic smooth muscle cells with low CAR expression and by 4-fold in 293 cells cultured in medium saturated with competitive knob.39 Wu et al.40 constructed a series of recombinant adenoviruses by incorporating His6 epitopes into the HVR2 and HVR5 regions of Ad5, and found that the recombinant adenoviruses still retained similar infectivity, activity and stability to wild type Ad5. On this basis, Saini et al.41 constructed a new type of nano-packaged adenovirus through specifically cross-linking nickel (II) nitrilotriacetic acid-containing gold nanoparticles (Ni-NTA) with


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a recombinant virus incorporated with a His6 epitope in the HVR5 region in a high-affinity noncovalent manner. In vitro experiments showed that the infection efficiency of these adenovirus nanoparticles in HeLa cells was 2–3 times as high as that of non-specifically crosslinked AuNPs-Ad5 and slightly lower (no more than 10%) than that of Ad5.41 Thus, the efficiency of virus-mediated gene therapy was enhanced without altering the infection efficiency of the adenovirus. Since the adenovirus hexon is the most abundant adenovirus capsid protein, genetic modification through insertion of ligands into the hexon can, to a considerable extent, alter the physical and biological characteristics of viral vectors.39 However, genetic modification of the hexon also has some limitations, which mainly manifested as loss of activity of modified viruses 40 and void ligand insertion.42 Ligand replacement method. Although insertion of short peptides into the adenovirus knob domain can achieve virus retargeting, the natural tropism of the virus is not destroyed since the native knob domain of the virus is still retained. Because the natural tropism of the virus is still retained when new tropism is gained, the problem that viral vectors can infect normal cells and thereby cause side effects can not be fully overcome. Therefore, the approach for simultaneous removal of the native knob domain and addition of new ligands for target cells is developed. Magnusson et al.43 constructed a recombinant adenoviral vector Ad5/FibR7-RGD by deleting the knob domain and at least 15 shaft repeats of the adenovirus fiber gene and replacing them with an external trimerization motif and the RGD sequence. The recombinant fiber retained the original functions (for example, trimerization of the vector capsid fiber and nuclear import) of the native fiber, but lost the natural tropism of the vector. The transduction efficiency of Ad5/FibR7-RGD in RD cells that expressed α5βv integrin but did not express CAR was 9 times higher than that of wild-type Ad.43 Similar target cell-binding ligands include antibodies,44 cancer antigen-specific T-cell receptor,45 affibody,46 and so on.

Conclusion Vector retargeting is proposed based on the observations that viral vectors with native tropism can better transduce exogenous therapeutic genes and a lack of specificity of natural viral tropism may cause safety problems for gene therapy. Thus, the research on vector retargeting mainly focuses on two aspects: one is to explore whether the native tropism of viral vectors should be retained or not during vector retargeting, the other is to explore whether retargeted vectors are more specific to target cells and safer for the body than those retaining natural viral tropism or not. Obviously, genome modification-independent retargeted vectors still retain the native tropism of viral vectors and may therefore cause safety problems during infection. In contrast, genome modification-dependent retargeted vectors partly or entirely lose the native tropism of viral vectors. As a result, their infection into target cells is more specific though their infection efficiency is likely to be reduced. However, after viral vectors are retargeted, the mechanisms behind their infection into target cells may be altered, especially the vectors modified based on genome modification-independent vector retargeting. Therefore, it is essential to further explore the routes and mechanisms underlying the infection of retargeted viral vectors into target cells. However, only a few studies on this topic are currently conducted.47 www.landesbioscience.com

Additionally, the advance in vector retargeting, to a certain extent, depends on the development of technologies in other disciplines. For example, targeted nano-drug carrier systems may provide some clues to genome modification-independent vector retargeting,48 while the research on tumor molecular biology and virology is closely associated with genome modification-dependent vector retargeting. Therefore, it can be expected that, as the mechanism behind the infection of retargeted vectors is deeply explored and the technologies in other disciplines are continuously used in the research on vector retargeting, some safe, efficient and controllable retargeted gene therapy vector systems will be developed. Acknowledgements

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