The relevance of coagulation factor X protection of adenoviruses in human sera

Duffy, Margaret R.; Doszpoly, Andor; Turner, Gemma; Nicklin, Stuart A.; Baker, Andrew H.

doi:10.1038/gt.2016.32

Cited by 18 publications

(38 citation statements)

References 17 publications

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“…As another example, AdV‐5 vectors bind mouse FX and human FX equally well, and FX protects AdV‐5 vectors from neutralization by both mouse and human complement . Because the efficiency of intravascularly administered AdV‐5 vectors depends on FX in mice, rats, and nonhuman primates, it is reasonable to predict that intravascular administration of AdV‐5 vectors in humans would also depend on FX.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, it is possible that variability among human sera may be more related to differences in complement preservation in serum samples, as opposed to actual variability among humans. In spite of this variability, both studies agreed that FX plays a role in protecting AdV‐5 from neutralization by complement in human serum .…”

Section: Vitamin K‐dependent Coagulation Factorsmentioning

confidence: 93%

“…The mouse is the most common preclinical model for AdV gene therapy studies, and it is therefore important to understand the potential differences between mice and humans regarding the impact of FX on AdV‐5 vectors. An initial study of the role of FX in human sera found that FX protects AdV‐5 from human complement (similar to the role of FX in mouse serum), but only about half of the human donors had neutralizing activity for AdV‐5 in the absence of FX, suggesting that there is variability in the human population . A more recent study, however, found a significant protective effect of FX in human sera, and all donors had significant neutralizing activity for AdV‐5 in the absence of FX .…”

Section: Vitamin K‐dependent Coagulation Factorsmentioning

confidence: 95%

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Interaction of adenovirus with antibodies, complement, and coagulation factors

Allen

Byrnes

2019

FEBS Letters

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Edited by Urs GreberAdenovirus (AdV) is one of the most widely used vectors for gene therapy and vaccine studies due to its excellent transduction efficiency, capacity for large transgenes, and high levels of gene expression. When administered intravascularly, the fate of AdV vectors is heavily influenced by interactions with host plasma proteins. Some plasma proteins can neutralize AdV, but AdV can also specifically bind plasma proteins that protect against neutralization and preserve activity. This review summarizes the plasma proteins that interact with AdV, including antibodies, complement, and vitamin K-dependent coagulation factors. We will also review the complex interactions of these plasma proteins with each other and with cellular proteins, as well as strategies for developing better AdV vectors that evade or manipulate plasma proteins.

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Section: Discussionmentioning

confidence: 99%

Section: Vitamin K‐dependent Coagulation Factorsmentioning

confidence: 93%

Section: Vitamin K‐dependent Coagulation Factorsmentioning

confidence: 95%

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Interaction of adenovirus with antibodies, complement, and coagulation factors

Allen

Byrnes

2019

FEBS Letters

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“…Both mouse and human FX bind to Ad5 hexon with high affinity [ 6 ]. Likewise, both mouse and human IgM can bind to Ad5 [ 15 , 17 , 18 , 26 ]. In the current study, we confirmed that human IgM can bind to Ad5, regardless of whether the IgM is purified from pooled human sera or from individual sera.…”

Section: Discussionmentioning

confidence: 99%

Hexons from adenovirus serotypes 5 and 48 differentially protect adenovirus vectors from neutralization by mouse and human serum

Harmon

Moitra

et al. 2018

PLoS ONE

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Adenovirus vectors are widely used in gene therapy clinical trials, and preclinical studies with these vectors are often conducted in mice. It is therefore critical to understand whether mouse studies adequately predict the behavior of adenovirus vectors in humans. The most commonly-used adenovirus vectors are derived from adenovirus serotype 5 (Ad5). The Ad5 hexon protein can bind coagulation factor X (FX), and binding of FX has a major impact on vector interactions with other blood proteins. In mouse serum, FX protects Ad5 vectors from neutralization by natural antibodies and complement. In the current study, we similarly find that human FX inhibits neutralization of Ad5 vectors by human serum, and this finding is consistent among individual human sera. We show that human IgM and human IgG can each induce complement-mediated neutralization when Ad5 vectors are not protected by FX. Although mouse and human serum had similar effects on Ad5 vectors, we found that this was not true for a chimeric Ad5 vector that incorporated hexon regions from adenovirus serotype 48. Interestingly, this hexon-chimeric vector was neutralized by human serum, but not by mouse serum. These findings indicate that studies in mouse serum accurately predict the behavior of Ad5 vectors in human serum, but mouse serum is not an accurate model system for all adenovirus vectors.

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“…Coagulation factor X has been shown to shield Ad5 from complement mediated attack, via inhibition of IgM binding [192]. Consequently, it is conceivable that ablation of this interaction may result in enhanced clearance of the FX binding ablated virus from the body, reducing therapeutic efficacy [193]. However, mutation of hexon protein to ablate FX interactions could be extended to also inhibit IgM binding, albeit, this may preclude the potentially beneficial effects provided through steric inhibition of hexon interaction by large molecule binding (such as FX), which may represent a broadly effective mechanism for inhibiting immune recognition, as described by Schmid et al (discussed later in this review) [12].…”

Section: Blood Coagulation Factor X (Fx) and Heparan Sulphate Proteogmentioning

confidence: 99%

Designer Oncolytic Adenovirus: Coming of Age

Baker

Aguirre-Hernández

Halldén

et al. 2018

Preprint

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The licensing of talimogene laherparepvec (T-Vec) represented a landmark moment for oncolytic virotherapy, since it provided unequivocal evidence for the long-touted potential of genetically modified replicating viruses as anti-cancer agents. Whilst T-Vec is promising as a locally delivered virotherapy, especially in combination with immune-checkpoint inhibitors, the quest continues for a virus capable of specific tumour cell killing via systemic administration. One candidate is oncolytic adenovirus (Ad); it’s double stranded DNA genome is easily manipulated and a wide range of strategies and technologies have been employed to empower the vector with improved pharmacokinetics and tumour targeting ability. As well characterised clinical and experimental agents, we have detailed knowledge of adenoviruses’ mechanisms of pathogenicity, supported by detailed virological studies and in vivo interactions. In this review we highlight the strides made in the engineering of bespoke adenoviral vectors to specifically infect, replicate within, and destroy tumour cells. We discuss how mutations in genes regulating adenoviral replication after cell entry can be used to restrict replication to the tumour, and summarise how detailed knowledge of viral capsid interactions enable rational modification to eliminate native tropisms, and simultaneously promote active uptake by cancerous tissues. We argue that these designer-viruses, exploiting the viruses natural mechanisms and regulated at every level of replication, represent the ideal platforms for local overexpression of therapeutic transgenes such as immunomodulatory agents. Where T-Vec has paved the way, Ad-based vectors now follow. The era of designer oncolytic virotherapies looks decidedly as though it will soon become a reality.

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The relevance of coagulation factor X protection of adenoviruses in human sera

Cited by 18 publications

References 17 publications

Interaction of adenovirus with antibodies, complement, and coagulation factors

Interaction of adenovirus with antibodies, complement, and coagulation factors

Hexons from adenovirus serotypes 5 and 48 differentially protect adenovirus vectors from neutralization by mouse and human serum

Designer Oncolytic Adenovirus: Coming of Age

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