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Journal of Virology, August 1999, p. 6930-6936, Vol. 73, No. 8
HepaVec AG für
Gentherapie,1 Max Delbrück Center
for Molecular Medicine,2
Biomedizinischer Forschungscampus
Berlin-Buch,3 and Humboldt University
Berlin,5 13122 Berlin-Buch, Germany;
Division of Molecular Science, CSIRO, North Ryde, New South
Wales 2113, Australia4; and Division of
Cancer Biology, Danish Cancer Society, DK-2100 Copenhagen,
Denmark6
Received 4 February 1999/Accepted 4 May 1999
Recombinant human adenoviruses (hAd) have become widely used as
tools to achieve efficient gene transfer. However, successful application of hAd-derived vectors in clinical trials is limited due to
immunological and potential safety problems inherent in their human
origin. In this study, we describe a recombinant ovine adenovirus (OAV)
as an alternative vector for gene transfer in vivo. In contrast to an
hAd vector, the OAV vector was not neutralized by human sera. An OAV
vector which contained the cDNA of the human Recombinant human adenoviruses (hAd)
are excellent tools for efficient gene transfer into a variety of cell
types in vitro and in vivo (24). Despite the obvious
potential for treatment of inherited and acquired disorders and their
application in numerous animal studies, the use of hAd vectors is still
limited to a small percentage of current clinical gene therapy trials
(3). This situation is principally due to limitations caused
by the host immune response (9). The obstacles to
application of hAd vectors are due to the humoral response against the
vector per se and to the immune response against residual expression of
viral genes in transduced cells (55). Endogenous expression
of viral genes leads to transient transgene expression, necessitating
repetitive administration of the vector. However, successful
readministration of hAd vectors to animals (23, 39, 46) is
prevented by neutralizing antibodies induced after their first
application. Since currently used hAd vectors are derived from types 2 and 5, which are endemic in the majority of the population
(13-15), preexisting neutralizing antibodies may preclude
even a single successful administration of hAd in humans. With respect
to overcoming the immune response to adenovirus, strategies involving
immunomodulation (11, 18, 19, 29, 40, 56), induction of
immunotolerance (16, 17), or switching (8, 26,
28) of the hAd serotype have been employed. More recently,
"gutless" hAd vectors, in which all coding regions of the virus are
removed, have been generated to avoid the immune response to endogenous
adenovirus gene expression and improve expression (38).
However, none of these strategies can exclude the possibility that
replication of a recombinant hAd may be complemented by a wild-type hAd
during opportunistic coinfection. Thus, issues concerning safety
require further consideration.
As a solution to these concerns, we describe the use of a non-human
adenovirus vector for human gene therapy. Adenoviruses are divided into
the mastadenoviruses, the aviadenoviruses, and a third group which
contains the Australian ovine adenovirus (OAV) isolate OAV287
(12). We selected OAV because it has been engineered to
produce recombinants (50, 54) and because of its unique features and degree of biological characterization, including the
demonstration that it replicates abortively in nonovine cell lines
(4, 20, 21, 45, 47-49, 53). Importantly, OAV was not
neutralized by a polyclonal serum raised against hAd type 5 (53).
In this study, we describe the generation of an OAV-based vector
expressing the human Plasmids.
Plasmid pOAV204 contains the full-length OAV
genome with an expression cassette (MLP/TLS-VP7sc) inserted in
Bsp120I/NotI sites at a nonessential position
(21, 50). An NheI/BfrI fragment (3,617 bp) of pOAV204, flanking the insert, was subcloned into NheI
and BfrI sites of a truncated pSL1190 (Invitrogen) that
lacked the polylinker sites between EcoRV and
SmaI. The MLP/TLS-VP7sc expression cassette was replaced by
a Bsp120I/NotI polylinker fragment of
pBSKS
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Ovine Adenovirus Vectors Overcome Preexisting
Humoral Immunity against Human Adenoviruses In Vivo
ABSTRACT
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
1-antitrypsin (hAAT) gene linked to the Rous sarcoma
virus promoter was generated and administered systemically to mice. The
level and duration of hAAT gene expression was similar to that achieved with an hAd counterpart in both immunocompetent and immunodeficient mice. However, the tissue distribution of the OAV vector differed from
that observed for hAd vectors in that the liver was not the dominant
target. Significantly, we demonstrated efficient gene transfer with the
OAV vector into mice immunized with hAd vectors and vice versa. We also
confirm that the immune response to a transgene product can prevent its
functional expression following sequential application of a vector. Our
results suggest a possible solution to endemic humoral immunity against
currently used hAd vectors and should therefore have an impact on the
design of improved gene therapy protocols utilizing adenovirus vectors.
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
1-antitrypsin (hAAT) gene. We show that this OAV vector was not neutralized by a significant number of
human sera in vitro, whereas preexisting immunity against hAd was
strikingly apparent. OAV-mediated hAAT gene expression was similar to
that mediated by an analogous, replication-deficient hAd in either
immunocompetent or immunodeficient mice. Analysis of vector DNA
distribution and hAAT gene transcription showed that after systemic
application in mice, the OAV vector infected various tissues with no
particular preference for liver. Furthermore, in a series of
cross-administration experiments, efficient gene transfer with OAV
vectors was clearly demonstrated in vivo despite the presence of
neutralizing antibodies against hAd.
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
(Stratagene) using the same restriction sites. The
resulting shuttle plasmid (pOAVrec) contained a multiple cloning site
inserted between the pVIII and fiber genes. pOAV-sh-hAAT (Fig.
1A) was constructed by insertion of an
XhoI fragment of pRSVhAAT, which contains the hAAT cDNA
under control of the Rous sarcoma virus (RSV) long terminal repeat
(LTR) and the bovine growth hormone polyadenylation signal (bGHPA),
into the XhoI site of pOAVrec. The plasmid (pOAVhAAT [Fig.
1C]) for rescue of OAVhAAT virus was generated by homologous
recombination in Escherichia coli BJ5183 after
cotransformation of Bsp120I/NotI-linearized
vector backbone (Fig. 1B) of pOAV204 (20 ng) with 100 ng of an
NheI/BfrI fragment from pOAV-sh-hAAT containing
the hAAT expression cassette. pOAVhAAT was amplified by transformation
into E. coli JM109 (Stratagene).
View larger version (22K):
[in a new window]
FIG. 1.
Construction of recombinant OAVhAAT. The shuttle plasmid
pOAV-sh-hAAT (A) was assembled by insertion of an RSV-hAAT-bGHPA
expression cassette into the XhoI-site of pOAVrec. (B)
Plasmid pOAV204 was cut with Bsp120I/NotI to
release the MLP/TLS-VP7sc cassette (21). Cotransformation of
E. coli BJ5183 with the NheI/BfrI
fragment from panel A and the linearized plasmid from panel B generated
the 34.8-kb circular plasmid pOAVhAAT by homologous recombination. (C)
pOAVhAAT cut with Asp718 was transfected into CSL503 cells
for virus rescue.
Viruses and cells. Fetal ovine lung cells (33), CSL503, for rescue and propagation of OAV were cultured in Dulbecco modified Eagle medium plus 10% fetal calf serum. Rescue of OAVhAAT was achieved after Lipofectamine transfection (Gibco) of CSL503 cells (3 × 105/6-cm dish) with linear recombinant genome (6 µg) released from pOAVhAAT by digestion with Asp718. OAVhAAT was propagated by incubation of CSL503 cells at a multiplicity of infection (MOI) of 0.1 for 4 days. Preparation of recombinant replication-deficient hAd Ad-lacZ and Ad-hAAT was described previously (7). Ad-hAAT contains the same expression cassette as OAVhAAT. Purification of OAVhAAT was equivalent to hAd vectors. The total numbers of particles in OAV and hAd vector preparations were determined spectrophotometrically (27), and infectious units (PFU) were determined by end-point dilution assays on the corresponding cell line (293 or CSL503, respectively). The amounts of vector used in each experiment refer to PFU levels. Particle-to-PFU ratios for individual virus preparations were 25:1 (OAVhAAT), 34:1 (Ad-hAAT), and 17:1 (Ad-lacZ).
In vivo application of adenovirus vectors.
Experiments were
performed with female, 6-week-old (18 to 20 g) BALB/c mice
(Bomholtgard, Bommice, Denmark) and scid mice (C.B-17/Icr/BlnA-scid/scid [authors' own breeding]). Adenovirus vectors (5 × 109 PFU) were injected via the tail vein
in a volume of about 100 µl in all experiments. Blood was collected
from the external jugular vein at the indicated times to assess
neutralizing antibodies and to measure 1-antitrypsin levels.
Determination of neutralizing antibody titers. Human sera were collected from healthy volunteers and mouse sera were isolated from animal experiments at the indicated times. The titer of neutralizing antibodies was determined by the ability of the sera to prevent infection of CSL503 cells by OAV-hAAT or of 293 cells by Ad-hAAT. Heat-inactivated (30 min at 56°C) serum samples were twofold serially diluted and incubated for 30 min at 37°C with OAV or hAd. A serum-treated virus sample (equivalent of an MOI of 1) was added to the cells, previously seeded in 96-well plates at a density of 3 × 103 cells/well. The neutralizing antibody titer was calculated from the reciprocal serum dilution in the last well showing no significant cytopathic effect, in comparison to control cells that were infected with untreated virus.
Detection of adenovirus-mediated gene transfer.
The
enzyme-linked immunosorbent assay to quantify hAAT in mouse serum was
described recently (7). Expression of E. coli 
-galactosidase in liver sections was detected histochemically by
X-Gal (5-bromo-4-chloro-3-indolyl--D-galactopyranoside) staining.
Southern blotting and RNase protection assays. Mice were sacrificed at the times indicated and liver, spleen, kidneys, lung, and heart were frozen and homogenized in liquid nitrogen immediately. DNA and RNA were isolated separately from the same tissue sections by standard procedures. For Southern blotting of OAV DNA, genomic DNA (20 µg) was digested with EcoRI, which releases a 2,399-bp fragment from the OAV genome. After separation on a 1% agarose gel and transfer to a nylon membrane, hybridization was performed with a probe spanning bp 1968 to 3408 of the OAV genome. A specific OAV EcoRI fragment (250 fg to 12.5 pg, equivalent to 0.2 to 5 copies per cell) was used as a standard. Detection of hAd DNA by Southern blotting has been described previously (36).
RNase protection assays were carried out with total RNA (20 µg) by standard procedures. A radiolabelled RNA fragment of 362 bases comprising the EcoNI fragment of the hAAT gene was used as a probe. In vitro-transcribed hAAT RNA (10 to 50 pg) was used as a standard.| |
RESULTS |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Generation of recombinant OAV vectors. A recombinant plasmid carrying an RSV 3' LTR-driven hAAT cDNA inserted between the pVIII and fiber genes of OAV was generated by homologous recombination in recBC sbcBC E. coli (Fig. 1) by a procedure described previously for hAd-derived vectors (6). The recombinant virus, OAVhAAT, was rescued following transfection of the linear recombinant genome into CSL503 cells (50). The hAd-derived vector, Ad-hAAT (7), carried the identical expression cassette in place of the E1 region.
Neutralizing antibodies in human sera. The presence of preexisting neutralizing antibodies against hAd in most of the population is a major limitation to the use of hAd-derived vectors in gene therapy. Indeed, an analysis of random samples of human sera and serum pools revealed the presence of neutralizing antibodies against hAd (type 5) at titers of 1:10 to 1:5,120. In contrast, no neutralizing antibodies against OAV were detected in any sample (Fig. 2).
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hAd- and OAV-mediated gene expression in vivo. OAV-mediated gene transfer was assessed relative to hAd by comparing the levels of serum hAAT after intravenous injection of equal amounts of the respective vectors (5 × 109 PFU) into BALB/c mice. Application of either vector resulted in hAAT gene expression with comparable peak levels and no detectable hAAT protein after 20 days (Fig. 3A). Since at this time no vector DNA was detectable in the livers of mice from either group (data not shown), mice were injected with a second dose of the same vector at day 31 after the first injection. However, second vector administration did not result in hAAT gene expression in either case (Fig. 3A). To exclude the possibility that antibodies raised against the transgene product prevented detection of the hAAT protein in mouse sera, we performed an RNase protection assay specific for hAAT RNA. No hAAT-specific transcript was detected in mouse liver 4 days after the second administration of OAVhAAT (Fig. 3B) or Ad-hAAT (see Fig. 5B, lanes 4 and 5). Therefore, after second administration, both vectors failed to infect the liver, a result which was most likely caused by neutralizing antibodies against OAV or hAd vectors. The titer of neutralizing antibodies in mouse sera against the respective vector types (OAVhAAT and Ad-hAAT) ranged equally high, from 1:320 to 1:1,280, at the time of the second administration, and no cross-neutralizing antibodies were detected in either case (data not shown).
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Tissue distribution of OAV vectors after intravenous delivery. Since the OAV fiber and penton proteins are significantly different from their homologues in other adenovirus vectors (47, 49), we determined the tissue distribution of systemically administered OAVhAAT after intravenous i.v. injection, as shown in Fig. 3A. We found almost equal amounts of OAV-specific DNA in spleen, kidney, heart, and liver at day 4 after vector administration, whereas the lung was infected to a significantly lower degree (Fig. 4A). The distribution of vector DNA corresponded well with hAAT gene expression in several organs, as determined by RNase protection assays (Fig. 4C). Thus, total serum hAAT was recruited from several organs which expressed the transgene to similar extents. In contrast, systemic application of hAd-hAAT to mice resulted in the accumulation of viral DNA and transgene expression mainly in the liver, with apparently lower infection of other organs (Fig. 4B).
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Cross-administration of hAd and OAV vectors. The presence of neutralizing antibodies against hAd in human sera may limit the effectiveness of hAd vectors. Mice immunized against hAd represent a relevant model in which to show the potential advantages of OAV vectors for human gene therapy. Thus, cross-administration experiments were performed. Mice were systemically infected with either Ad-hAAT or OAVhAAT; at day 31, animals received a second administration of the other virus (OAVhAAT or Ad-hAAT, respectively). In neither case did administration of the second virus cause an elevation of serum hAAT levels (Fig. 5A). Analysis of serum samples showed that after the first infection, type-specific neutralizing antibodies against the respective adenovirus vectors were detected at titers ranging from 1:320 to 1:1,280. In addition, antibodies against hAAT were detected in mouse sera prior to application of the second vector, showing that the human transgene product was immunogenic in mice. However, despite the lack of detectable hAAT protein, analysis of hAAT-specific RNA 4 days after the second vector administration clearly revealed expression of the transgene in livers of mice that were reinjected with Ad-hAAT after an initial application of OAVhAAT, whereas no hAAT-specific transcripts were detected when the initial application was performed with Ad-hAAT (Fig. 5B). Specific hAAT-transcripts were also detected in several organs of mice injected with OAVhAAT after initial infection with Ad-hAAT (data not shown).
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-galactosidase gene) followed by a second administration of either Ad-hAAT or OAVhAAT and
vice versa (Fig. 6). Although high levels
of -galactosidase were detected histochemically in mouse livers at
day 3 after Ad-lacZ injection (Fig. 6B), gene expression had completely
disappeared after 31 days (Fig. 6C). At that time point, the
hAd-specific antibody titer ranged from 1:320 to 1:1,280 (not shown).
OAVhAAT and Ad-hAAT were then applied. Injection with OAVhAAT resulted in hAAT levels in serum comparable to those obtained with a single administration in untreated mice, whereas injection of Ad-hAAT did not
produce detectable hAAT expression (Fig. 6A). In addition, hAAT-specific transcripts were not detectable in the liver (not shown).
In the reciprocal experiment, mice were immunized with OAVhAAT, which
produced OAV-neutralizing antibody titers of 1:1,280. In spite of this
immunity, application of Ad-lacZ virus at day 31 resulted in efficient
-galactosidase expression 3 days later (Fig. 6D and E).
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Recombinant hAd vectors have proven to be potent gene delivery agents in numerous preclinical gene therapy studies. However, immunological problems and potential safety aspects inherent in the human origin of the vector may limit their utility and efficacy in clinical trials. The development of adenovirus vectors of non-human origin may circumvent these problems (32). In this study, we demonstrate the ability of an OAV vector to overcome preexisting humoral immunity to hAd in vivo. In addition, given that OAV has unique, short ITRs (46 bp) and at least one structural protein not found in hAd (49), it is most unlikely that productive recombination or complementation could occur between OAV vectors and an opportunistic, coinfecting hAd from the mastadenovirus genus. However, it is unknown whether human adenoviruses that may be classified within the third adenovirus group also exist.
The recombinant OAV vectors used in these experiments carried an additional expression cassette (RSV-hAAT) without a compensating deletion elsewhere in the genome. Recombinant vectors are stable up to a size of at least 114% of the wild-type OAV genome, and an initial internal deletion has enlarged the potential vector capacity to 6.3 kbp of foreign DNA (54). The method used to generate hAd plasmids by homologous recombination in E. coli (6) has been successfully adapted here for the generation of OAV plasmids, which will further facilitate the construction and rescue of OAV vectors.
Preexisting neutralizing antibodies against hAd vectors in a majority of the human population represent a major hurdle for efficient hAd administration. In an attempt to avoid this problem, construction of an hAd vector with an altered hexon protein was recently described (35). We tested 15 random samples of human sera and found type 5 anti-hAd antibody titers ranging between 1:10 and 1:5,120. Because it has been shown that as few as 1.4 antihexon antibodies can neutralize one virus particle (52), it is important to emphasize that even in sera exhibiting the highest anti-hAd titer, no cross-reactive antibodies against OAV were detected. This result contrasts with observations made with canine adenovirus vectors (22, 32) and justifies further investigation of OAV vectors in vivo.
We compared the duration of transgene expression by OAV and hAd vectors after intravenous application to immunocompetent BALB/c mice and the corresponding immunodeficient scid mouse counterpart. We chose BALB/c mice for these experiments because transgene expression declines very rapidly in this mouse strain (1), which could, among other reasons, be explained by a strong cytotoxic T-cell response against endogenous hAd gene expression (1, 34). We confirmed transient expression of the transgene in this mouse strain by using the hAd vector and observed similar kinetics for OAV-mediated gene transfer, even though in vitro studies have shown that endogenous OAV promoters are not detectably active in some cell types (49). The hAd vector exhibited stable gene expression in scid mice, as shown previously (1), whereas OAV-mediated gene expression declined by ~50% over time, which may reflect the turnover of different cell types that were infected. Since the OAV vector contains all genes present in wild-type OAV, it is important to note that the mice showed no obvious ill effects from the dose of virus given, although more detailed studies are required to ascertain whether OAV has oncogenic potential.
The tissue distribution of the OAV vector in mice is different from that observed with hAd-derived vectors and therefore appears to be independent of the vascular architecture of the mouse and the liver in particular. We found that OAV-specific DNA was nearly equally distributed in all organs examined after systemic application, whereas hAd is mainly targeted to the liver. This most likely reflects differences in the structure of potential receptor ligands on the surface of OAV. Indeed, the OAV fiber protein is unique, and its penton protein lacks an RGD motif (47, 49). Such differences in the mechanism of OAV uptake by cells may permit OAV to target cell types and tissues that exhibit low susceptibility to infection by current hAd vectors because of the lack of receptors for hAd (2). However, further investigation is required to assess this potential of OAV vectors. It may also be possible to construct hybrid OAV vectors to target such tissues (53).
Although immunosuppressive approaches to circumventing the humoral
immune responses have been reported in animal experiments (11, 18,
19, 29, 40, 56), such strategies obviously carry risks for
diseased patients with respect to immunosurveillance of opportunistic
infections. The results from our cross-administration experiments point
to two immunological problems associated with adenovirus gene transfer.
First, we demonstrated that the problem of preexisting antibodies
against hAd can be overcome by use of the OAV vector, since the latter
vector was not neutralized by antibodies to the former. Because OAV
itself elicits neutralizing antibodies, however, repeated
administration of OAV would be as problematic as a first administration
of hAd in humans positive for hAd-neutralizing antibodies. Second, the
problem of immunity against the transgene product became apparent in
cross-administration experiments utilizing hAAT-expressing OAV and hAd
vectors. Although gene transfer was successful, based on hAAT RNA
analysis after readministration of the second vector, antibodies
against the hAAT-protein precluded its detection in mouse sera,
supporting increasing evidence that immunity against a heterologous
transgene product, including hAAT (30), limits the duration
of its expression (26, 31, 41, 43, 44). However, this
problem can be avoided by delivery of a homologous gene product to mice
(42). In our experiments, we excluded interfering immunity
against the neoantigen by initial delivery of the E. coli
-galactosidase gene and subsequent transduction with the hAAT gene,
and vice versa.
The study clearly demonstrates that antibody titers induced against
either type of vector
even lower than those preexisting against hAd in
some human individualsare sufficient to completely block systemic
readministration of the same vector. This might partially explain
inconsistent results regarding the efficacy of hAd-mediated gene
transfer in clinical trials, where the vectors have to travel at least
some distance to reach the target cell (10, 51, 57). With
respect to gene therapy strategies that aim at the local treatment of
tumors (5, 25, 37), preexisting hAd antibodies have less
impact on gene transfer efficiency. However, such strategies may not be
appropriate for disseminated disease. In summary, our successful
cross-administration of OAV vectors to hAd-immunized mice clearly
reflects the human situation and points to the utility of OAV vectors
as an alternative to hAd vectors in clinical applications.
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ACKNOWLEDGMENTS |
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We thank Mark Kay, Seattle, Wash., for the kind gift of Ad-hAAT. We also acknowledge Beate Goldbrich, Uta Fischer, Heidemarie Riedel, and Sabine Weber for excellent technical assistance.
This work was supported by the Wilhelm-Sander Stiftung.
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FOOTNOTES |
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* Corresponding author. Mailing address: HepaVec AG für Gentherapie, Robert-Rössle-Str. 10, D-13122 Berlin, Germany. Phone: 49 30 94892283 or 49 30 94892272. Fax: 49 30 94892913. E-mail: chofmann{at}hepavec.com.
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Journal of Virology, August 1999, p. 6930-6936, Vol. 73, No. 8
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