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Advanced Generation Adenoviral Vectors Possess Augmented Gene Transfer Efficiency Based upon Coxsackie Adenovirus Receptor-independent Cellular Entry Capacity¹

Division of Human Gene Therapy, Departments of Medicine, Pathology and Surgery, and Gene Therapy Center, The University of Alabama at Birmingham, Birmingham, Alabama 35294-3300

	ABSTRACT

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Adenoviral (Ad) vectors have been widely used in the context of cancer gene therapy approaches. Their utility in these contexts, however, has frequently been limited by tumor cell resistance to Ad infection. The basis of this resistance has been defined recently as resulting from a deficiency of the primary adenovirus receptor, coxsackie adenovirus receptor. As a means to circumvent this limitation, a variety of tropism modification strategies have allowed coxsackie adenovirus receptor-independent gene delivery via the Ad vector. These advanced generation adenovirus vectors exhibit enhanced infectivity, which can allow direct therapeutic gain. Such vectors may allow improvements in efficacy in the context of ongoing human clinical gene therapy approaches for cancer.

	Ad3 Vectors for Cancer Gene Therapy Applications

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Ad vectors have been used for a wide variety of gene therapy applications (1) . This utility has derived principally from the ability of these vehicles to achieve in vivo gene transfer in the context of a variety of delivery schemes. Ad-based gene therapy approaches have expanded the conceptual range of therapeutic interventions beyond the limited possibilities achievable in the context of extracorporeal gene-delivery schemes. Despite the superior in vivo efficacy of Ad vectors for the achievement of in situ gene transfer, however, the results of several human clinical trials have suggested that current-generation Ad vectors may nonetheless possess inadequate efficiency to achieve meaningful clinical outcomes (2) . In this regard, vector efficiency levels noted in in vitro model systems have not accurately predicted Ad efficiencies in vivo. An example of this disparity has been noted in human trials for cystic fibrosis, whereby a relative resistance of target parenchymal cells to Ad vector infection was observed (2) . Importantly, this Ad resistance mitigated against effective genetic correction at vector doses below the threshold of toxicity in this instance (3) . In addition, several cancer gene therapy approaches based on in vivo gene delivery have achieved suboptimal levels of gene delivery to target tumor cells. On the basis of these findings, several key conclusions may be drawn: (a) currently used model systems may not accurately predict the biology relevant to Ad-mediated gene delivery to target cells in situ; and (b) the efficiency of current-generation Ad vectors may not be compatible with the achievement of favorable clinical outcomes in proposed human clinical gene therapy trials.

The recent delineation of key aspects of the cell entry pathway of adenovirus has provided insight into these observations. Adenovirus achieves initial recognition of target cells via the primary receptor CAR (4) . In this regard, alternative cellular receptors for adenovirus have been proposed; however, recent work has clearly established the primacy of CAR in dictating viral tropism (5) . After anchoring at this site by virtue of the knob domain of the fiber capsid protein, the virus achieves internalization via interaction of the capsid penton protein with integrins _vß₃ and _vß₅ present on target cells (6) . On this basis, a relative deficiency of either of these target cell factors could potentially limit the capacity of the Ad vector to accomplish efficient gene delivery. Indeed, recent studies in the context of the airway epithelium and various tumor cell targets have noted a virtual absence of CAR on these target cells (7) . This observation clearly explains the unfavorable outcomes noted in these clinical trials. Thus, it may likewise be understood that CAR deficiency may be a significant factor limiting vector functions in other disease contexts whereby adenoviral vector inefficiency is the key factor limiting practical clinical usefulness.

	Retargeting Ad Vectors to Achieve CAR-independent Gene Delivery–Retargeting Complexes

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One means to circumvent this biological limitation to vector efficiency would be to redirect the vector to achieve target cell binding via alternative cellular receptors. Such "CAR-independent" gene transfer would potentially offer the means to augment vector efficiency by targeting Ad virions to a cellular receptor present at sufficient magnitude to expand the range of potential attachment sites on target cells. One method to achieve this end has been via the physical complexing of adenovirus. This has been accomplished via cationic liposomes, calcium phosphage precipitates, and polyethylene glycol (8, 9, 10, 11, 12, 13, 14, 15, 16, 17) . In addition, this goal has been addressed by the development of "retargeting complexes," which serve to cross-link the virus to alternate cellular receptors. Such retargeting complexes were initially designed to achieve functional linkage with the Ad via an antibody or its Fab fragment, with specific recognition for the knob domain of the Ad fiber protein. Chemical conjugation of the antiknob Fab has been achieved with ligands specific for cell surface receptors (folate and fibroblast growth factor), as well as antibodies for target cell receptors (epidermal growth factor receptor, EpCAM, TAG-67, and CD40; Refs. 18, 19, 20, 21 ). Of note, retargeting via this approach has achieved direct therapeutic goals in in vivo model systems relevant to current human clinical cancer gene therapy schemes (22 , 23) .

Use of this retargeting approach has established several key concepts with respect to the goal of achieving improvements in Ad vector efficiency: (a) it could be shown unequivocally that adenovirus could achieve effective gene delivery via CAR-independent cellular entry pathways. Thus, the interaction of the targeted virion with its native receptor CAR did not appear to be crucial to its effective cellular entry capacity; (b) the achievement of CAR-independent cell infection could allow augmented levels of gene transfer. Indeed, retargeting the vector appeared an efficient means to generally improve the susceptibility of target cells in vitro and in vivo; and (c) the internalization ability of the primary receptor was not a relevant factor predicating its utility for Ad retargeting. In this regard, cross-linking of Ad to internalizing, as well as noninternalizing, receptors allowed CAR-independent gene transfer with comparable enhancement of efficiency (20) .

The technical achievement of Ad retargeting via protein complexes has been approached by a variety of methods. In this regard, the bispecific antibody approach has been used with viral linkage accomplished at sites other than the fiber knob, including the penton base (24) . In addition, further refinements of the strategy of antifiber retargeting complexes have been proposed. For example, a recombinant fusion protein consisting of an antiknob single chain antibody (scFv) and epidermal growth factor has been derived (25) . Recombinant molecules such as this may indeed offer advantages for adenovirus retargeting in terms of vector production and validation. To this end, we have recently developed such an approach based on achieving a physiological linkage to the vector particle. Specifically, we have derived retargeting complexes consisting of the ectodomain of the Ad receptor CAR in fusion with retargeting ligands (Fig. 1) . These recombinant fusion proteins possess the ability to effectively retarget the vector via non-CAR pathways with enhancement of gene transfer efficiency (Fig. 1) . In addition, this class of fusions may allow the derivation of recombinant retargeting complexes not achievable with incorporated antibodies as structural components (26) .

View larger version (31K): [in this window] [in a new window]   Fig. 1. Utilization of sCAR-ligand complexes for receptor specific targeting of Ad vectors. The Ad vector normally achieves cell binding via interaction between the knob domain of viral fiber protein with coxsackievirus and adenovirus receptor, CAR. To redirect Ad vector to an alternative cell surface receptor, a genetically engineered targeting complex, which consists of a CAR ectodomain fused to a receptor-specific targeting ligand, is used. Because of its dual binding capacity, this complex serves as a bridge between the Ad virion and a cell-specific receptor molecule, thereby providing novel cell binding capacity to the virion.

	Retargeting Adenoviral Vectors to Achieve CAR-independent Gene Delivery–Genetic Capsid Modifications

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Therefore, we sought to alter adenoviral tropism by means of exploiting an alternate locale on the fiber knob. In this regard, we have used the HI loop of the fiber knob. This choice was based upon the crystal structure of the knob domain proposed by Xia et al. (29) , whereby the HI loop appeared to present a locale accessible for targeting purposes (Fig. 2) . Furthermore, other aspects of the knob structure predicted its utility for incorporation of targeting ligands pursuant to our goal of rerouting the Ad to non-CAR pathways. Specifically, the fact that the HI loop is not involved in intramolecular interactions between fiber monomers suggested that it might be altered without deleterious effects on quaternary structure. In addition, the length variability among adenovirus serotypes suggested that the HI loop did not subserve a critical function. On this basis, initial studies to establish the feasibility of incorporating heterologous peptides within the HI loop were deemed rational. We demonstrated that an incorporated FLAG peptide was not deleterious to viral rescue and propagation. Furthermore, the heterologous peptide within the HI loop of the knob was accessible at the surface of the virion (30) . Subsequent studies have established that peptides of up to 63 amino acids in size could be incorporated at the HI loop without deleterious effects with respect to the quaternary structure of the fiber or viral infection dynamics.

View larger version (34K): [in this window] [in a new window]   Fig. 2. Structure of adenovirus fiber protein and its knob domain. A, the fiber protein incorporated into each of the 12 vertices of the icosahedral Ad capsid is a homotrimeric molecule, which consists of three distinct structural domains: the tail, the shaft, and the knob. The tail provides anchoring of the fiber in Ad capsid via noncovalent association with the penton base protein, whereas the rod-like shaft serves to extend the globular knob domain away from the virion, thereby facilitating interaction between the fiber and the CAR. The knob domain fulfils double duties by maintaining trimerization of the fiber and binding to CAR. B, according to the three-dimensional model of the fiber knob domain (29) , it resembles a three-bladed propeller formed by two sheets of ß-strands connected with loops and turns. The flexible HI loop (red circle), which connects strands H and I, is exposed outside the knob and, therefore, provides a convenient locale for incorporation of targeting ligands.

Ad vectors containing the RGD-4C peptide within the HI loop (AdRGD) were thus rescued and analyzed for their efficiency and for their mechanism of target cell binding. In this regard, binding studies demonstrated that these genetically modified Ad vectors were capable of achieving specific interaction with target cells via the recognition by the incorporated peptide of its cognate receptors (32) . This achievement of CAR-independent gene transfer allowed dramatic enhancements in gene delivery to CAR-negative cell lines that were otherwise Ad vector refractory. These levels of augmentation were noted across a range of primary tumor types including carcinoma of the ovary, carcinoma of the pancreas, cholangiocarcinoma, colon cancer, and squamous cell carcinoma of the head and neck (32, 33, 34) . Retrospective analysis of these primary tumor materials (primary lines, primary explants, and intact primary tumor samples) confirmed that profound CAR deficiency was present as a nearly universal feature of epithelial neoplasms. Importantly, this key aspect of tumor biology has not been noted in the various studies of Ad-mediated gene delivery to counterpart immortalized cell lines. Thus, for the achievement of efficient gene delivery to tumor cells in clinically relevant contexts, the exploitation of CAR-independent cell entry pathways may provide a generalized means to circumvent CAR deficiency that may be broadly relevant to tumor targets as well as to normal parenchymal cellular targets. We have also evaluated the infection capacity of AdRGD vectors after systemic vascular administration (35) . In this most stringent delivery context, the modified vector demonstrated a distribution profile distinct from the unmodified control. In addition, significant augmentations of infection of selected organs were noted. This in vivo utility of AdRGD vectors thus distinguishes the modification of the HI loop of the fiber from other proposed fiber alteration schemes in the demonstrated capacity to achieve retargeted delivery in the setting of systemic administration. Nevertheless, issues of biodistribution based on tumor access via the vascular circuit will clearly be relevant in considering adenovirus-based gene therapy approaches for disseminated disease (5) . Other approaches to alter tropism via genetic capsid modification have also been proposed. In this regard, chimeras have been generated by substitution of the fiber, or fiber knob, of the serotype 5 with corresponding components from alternate Ad serotypes (36 , 37) . Such modifications have allowed CAR-independent delivery with an enhanced ability to infect in selected instances. Furthermore, genetic modifications of the major capsid hexon has allowed incorporation of targeting ligands at defined sites within the ecodomain of that capsid component (38) . Clearly, additional possibilities for incorporation of targeting ligands within the capsid will be realized as further advancements of precise capsid structure are defined (39 , 40) .

In the aggregate, the data obtained with tropism-modified Ad vectors have established key concepts with respect to the adenovirus-based gene therapy approaches:

(a) It is clear that the evaluation of vector efficiency must be accomplished in model systems with the highest level of relevance to the intended delivery scheme and target cell. The substantial differences in vector efficiency noted with respect to immortalized cell lines compared with primary tissue render questionable the value of any data achieved with the former substrate. On this basis, vector modifications designed to improve vector efficiency must establish their utility in the context of stringent, and relevant, substrate systems; and (b) the recognition that CAR levels may play an overriding role in limiting vector efficiency predicates the development of vectors possessing the capacity to circumvent this barrier. Indeed, the recognition of a new class of Ad vectors with an enhanced ability to infect calls into question the basis of promoting further human trials with the significantly less potent Ad vectors that have been used heretofore.

It must be further noted that the enhancement of infection achieved herein clearly has relevance with respect to other vector limits noted in the use of recombinant adenovirus. In this regard, vector-associated toxicity observed in human clinical trials is closely linked to the magnitude of particle dose. The means to use significantly lower vector doses, as will logically accrue to the advanced generation vectors described here, will clearly impact this aspect of Ad vector science. On this basis, it may likewise be anticipated that vectors with an enhanced ability to infect may evoke diminished immune response consequent to the lower vector burdens used. Furthermore, the means to "untarget" antigen-presenting cells, as may logically derive from these tropism-modification maneuvers, may additionally accrue beneficial outcomes with respect to a reduction in antivector immunology.

This gain in potency will clearly also impact the basic means by which host immune responses may affect any gene therapy approach. Although the capacity of these vectors to achieve gene delivery in novel ways raises important biological and safety questions, the utility gains embodied by these agents cannot be ignored. On this basis, the rapid evaluation of these vectors in human systems is clearly warranted. Such studies will establish the importance of engineered vector design in achieving meaningful clinical outcomes in human clinical gene therapy approaches.

	ACKNOWLEDGMENTS

 
We thank Patty Parker for her administrative assistance.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported by Grants R01 HL50255, R01 CA74242, and R01 CA68245-01 from the NIH and grants from the American Lung Association, American Heart Association, Muscular Dystrophy Association, and the Fanconi Anemia Association.

² To whom requests for reprints should be addressed, at Division of Human Gene Therapy, The University of Alabama at Birmingham, 1824 6th Avenue South, 620 Lurleen Wallace Tumor Institute, Birmingham, AL 35294-3300. Phone: (205) 934-8627; Fax: (205) 975-7476; E-mail: david.curiel{at}ccc.uab.edu

³ The abbreviations used are: Ad, adenoviral; CAR, coxsackie adenovirus receptor.

Received 4/11/00. Accepted 10/16/00.

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