Macrophage Depletion Combined with Anticoagulant Therapy Increases Therapeutic Window of Systemic Treatment with Oncolytic Adenovirus

Shashkova, Elena V.; Doronin, Konstantin; Senac, Julien S.; Barry, Michael A.

doi:10.1158/0008-5472.can-08-0488

Cited by 88 publications

(99 citation statements)

References 46 publications

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“…Emerging evidence highlights the potential of FX in enhancing gene delivery to other cells, including cancer cells, 39,42 epithelial cells, 43 and vascular endothelial cells (C. Nicol and A.H.B., unpublished, January 2009). While the physiologic and/or pathologic role of these interactions remain to be determined, the high-affinity interaction with FX is likely to have broader relevance than effects on liver gene transfer alone.…”

Section: Discussionmentioning

confidence: 99%

“…We used a low viral dose in this study (10 10 VP/mouse) as the use of clodronate liposomes increases liver transduction approximately 40-fold. 39 It remains unclear as to the involvement of amino acids in the hexon HVRs that are not resolved in the crystal structure in FX binding. From the HVR5 and 7 domain swaps, we can conclude that both regions in their entirety are involved in the high-affinity interaction with FX.…”

mentioning

confidence: 99%

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Identification of coagulation factor (F)X binding sites on the adenovirus serotype 5 hexon: effect of mutagenesis on FX interactions and gene transfer

Alba

Bradshaw

Parker

et al. 2009

Blood

164

224

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Recent studies have demonstrated the importance of coagulation factor X (FX) in adenovirus (Ad) serotype 5-mediated liver transduction in vivo. FX binds to the adenovirus hexon hypervariable regions (HVRs). Here, we perform a systematic analysis of FX binding to Ad5 HVRs 5 and 7, identifying domains and amino acids critical for this interaction. We constructed a model of the Ad5-FX interaction using crystallographic and cryo-electron microscopic data to identify contact points. Exchanging Ad5 HVR5 or HVR7 from Ad5 to Ad26 (which does not bind FX) diminished FX binding as analyzed by surface plasmon resonance, gene delivery in vitro, and liver transduction in vivo. Exchanging Ad5-HVR5 for Ad26-HVR5 produced deficient virus maturation. Importantly, defined mutagenesis of just 2 amino acids in Ad5-HVR5 circumvented this and was sufficient to block liver gene transfer.In addition, mutation of 4 amino acids in Ad5-HVR7 or a single mutation at position 451 also blocked FX-mediated effects in vitro and in vivo. We therefore define the regions and amino acids on the Ad5 hexon that bind with high affinity to FX thereby better defining adenovirus infectivity pathways. These vectors may be useful for gene therapy applications where evasion of liver transduction is a prerequisite. (Blood. 2009;114:965-971) IntroductionAdenovirus (Ad)-based vectors are used frequently for preclinical gene delivery and therapy and have been used in more than 25% of gene therapy clinical trials conducted to date. Although adenovirus serotype 5 is the most commonly used serotype, the human and nonhuman adenovirus families are large, and many of these are being exploited in diverse clinical applications, such as cancer gene therapy and vaccination. [1][2][3][4] However, the use of Ad vectors as gene delivery tools has raised several safety concerns. The importance of such issues was highlighted in the recent STEP trial in which patients were vaccinated against human immunodeficiency virus using an Ad5 gene delivery vector. The trial was terminated because the vaccine did not function as expected, but actually increased infection rates in those patients with preexisting antibodies to Ad5. Together with other adverse events in humans transduced with Ad5, 5 this highlights the importance of understanding fundamental aspects of Ad biology.In vitro, the interaction of the Ad5 fiber and the coxsackie and adenovirus receptor (CAR) is the major pathway for Ad cell binding. 6,7 Similarly, engagement with integrins by the penton base protein mediates internalization after cell binding. 8 Although other candidate receptors for Ad5 have emerged since the interaction with CAR was identified, 9,10 the role of these receptors in gene transfer after intravascular gene delivery has not been substantiated.It is well established that Ad5 predominantly transduces rodent liver after intravascular injection, 11 however mutations of the Ad5 fiber and/or penton show limited effects on liver gene transfer mediated by Ad5 (reviewed in Nicklin et al 12 ). Thereafter, it w...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Identification of coagulation factor (F)X binding sites on the adenovirus serotype 5 hexon: effect of mutagenesis on FX interactions and gene transfer

Alba

Bradshaw

Parker

et al. 2009

Blood

164

224

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“…The liver tropism of Ad is also responsible for the resultant hepatotoxicity following Ad administration and has raised safety concerns slowing the progression of some vectors to clinical translation. Recent advances in the field have provided several mechanisms to decrease Ad's liver tropism (11), thereby allowing intravascular delivery to be a viable means of administration and decreasing some of the concerns of hepatotoxicity (12). Another limitation has been poor infectivity of target tumor cells by Ad5-based vectors secondary to the decreased expression of the Ad5 primary cellular receptor, the Coxsackie and Adenovirus Receptor (CAR), on target tumor cells.…”

Section: Advanced Generation Crads Circumvent Earlier Obstacles To Efmentioning

confidence: 99%

Oncolytic adenoviruses targeted to cancer stem cells

Short

Curiel

2009

Molecular Cancer Therapeutics

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Cancer stem cells (CSC) represent a distinct subpopulation of cancer cells of integral importance. CSCs embody the refractory nature observed among many cancers: very competent initial tumor establishment and extremely aggressive metastatic nature. Recent discoveries indicate that CSCs embody chemo-and radioresistance and have been correlated with advanced disease and resistance to current therapies, and thus help explain the treatment resistance of many cancers. As CSCs are critical for tumor initiation, progression, persistence, and the development of metastasis, the success or failure of treatment approaches may be influenced greatly by the presence and treatment sensitivity of these cells. There also seems to be a direct link between epithelial-mesenchymal transition phenomena and CSCs. Cancer cure is predicated upon effectively targeting and eradicating the CSC population. Oncolytic viruses have undergone many developments and through multiple generations offer an effective way to specifically target and eradicate CSCs, while still maintaining the ability to affect the general tumor cell population. Conditionally replicative adenoviruses (CRAd) are one virotherapy that is especially promising. Multiple advanced targeting and infectivity enhancement schemes have been developed to allow the necessary specificity and transduction efficiency required for an effective therapy. Furthermore, these advanced generation CRAds can be armed with therapeutic transgenes to generate greater antitumor effects. Although ultimately, the rewards of targeting and eradicating CSCs will be evaluated in clinical trials, there are numerous methods for isolating primary CSCs based on surface marker expression and multiple established cell lines representative of CSCs for preliminary evaluation.

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“…Together, these observations suggested that Ad5-mediated transduction of hepatocytes operate via a CAR-independent pathway. Recently, several studies (7,11,12,16,17,24,26,27) have suggested a fundamental involvement of host proteins, notably coagulation factors, in dictating adenoviral infectivity in vivo. Pivotal to hepatic transduction is the interaction between the Ad5 hexon protein and the coagulation factor X (FX) (7,24,26), which serves to "bridge" the Ad5-FX complex to alternative receptors, which are expressed abundantly within the liver.…”

mentioning

confidence: 99%

“…Pivotal to hepatic transduction is the interaction between the Ad5 hexon protein and the coagulation factor X (FX) (7,24,26), which serves to "bridge" the Ad5-FX complex to alternative receptors, which are expressed abundantly within the liver. Hepatocyte transduction can be abolished by using warfarin (7,12,16,27) to prevent the gamma carboxylation of glutamic acid residues in the N-terminal ␥-carboxyglutamic acid (Gla) domain of FX; the snake venomderived protein X-bp (2), which binds the Gla domain of FX, inhibiting its interaction with hexon (26); or hexon chimeric or mutated Ad5 vectors to abrogate FX binding (7,24,26).…”

mentioning

confidence: 99%

Effect of Neutralizing Sera on Factor X-Mediated Adenovirus Serotype 5 Gene Transfer

Parker

Waddington

Buckley

et al. 2009

J Virol

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The deployment of adenovirus serotype 5 (Ad5)-based vectors is hampered by preexisting immunity. When such vectors are delivered intravenously, hepatocyte transduction is mediated by the hexon-coagulation factor X (FX) interaction. Here, we demonstrate that human sera efficiently block FX-mediated cellular binding and transduction of Ad5-based vectors in vitro. Neutralizing activity correlated well with the ability to inhibit Ad5-mediated liver transduction, suggesting that prescreening patient sera in this manner accurately predicts the efficacy of Ad5-based gene therapies. Neutralization in vitro can be partially bypassed by pseudotyping with Ad45 fiber protein, indicating that a proportion of neutralizing antibodies are directed against the Ad5 fiber.

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Macrophage Depletion Combined with Anticoagulant Therapy Increases Therapeutic Window of Systemic Treatment with Oncolytic Adenovirus

Abstract: Liver tropism of systemically delivered adenoviruses (Ad)

Cited by 88 publications

References 46 publications

Identification of coagulation factor (F)X binding sites on the adenovirus serotype 5 hexon: effect of mutagenesis on FX interactions and gene transfer

Identification of coagulation factor (F)X binding sites on the adenovirus serotype 5 hexon: effect of mutagenesis on FX interactions and gene transfer

Oncolytic adenoviruses targeted to cancer stem cells

Effect of Neutralizing Sera on Factor X-Mediated Adenovirus Serotype 5 Gene Transfer

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