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Improved adenoviral vectors and uses thereof

An adenovirus, recombinant adenovirus technology, applied in the direction of virus/phage, application, vector, etc., can solve the problem of low immunogenicity

Inactive Publication Date: 2007-11-14
JANSSEN VACCINES & PREVENTION BV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this development appears to be a very useful approach, Ad35 vector-based vaccines were shown to be less immunogenic in mice than Ad5 vector-based vaccines in studies without pre-existing Ad5 immunity (Barouch et al. 2004)

Method used

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  • Improved adenoviral vectors and uses thereof
  • Improved adenoviral vectors and uses thereof
  • Improved adenoviral vectors and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] Example 1: International seropositivity and NAb titers for Ad5, Ad35 and AdI1

[0088] Ad-specific neutralizing antibody (NAb) responses were assessed by a luciferase-based virus neutralization assay as described by Sprangers et al. (2003). Briefly, A549 human lung cancer cells were treated with 1×10 4 Cells / well density were plated in 96-well plates and infected at a multiplicity of infection (moi) of 500 with El-deleted non-replicative Ad-luciferase reporter constructs in 200 μl reaction volumes of 2-fold serially diluted serum. After 24 hours of incubation, luciferase activity in cells was determined using the Steady-Glo Luciferase Reagent system (Promega). The 90% neutralization titer refers to the maximum serum dilution that neutralizes 90% of the luciferase activity.

[0089] In addition to the studies disclosed in WO 00 / 70071, experiments were performed to assess seropositivity and NAb titers for Ad5 and additional Ad serotypes in the developing world. Using t...

Embodiment 2

[0090] Example 2: Immunodominant Targets of Ad5-Specific Neutralizing Antibodies

[0091] The samples from the previous examples were used to further determine the predominant antigenic targets of Ad5-specific NAbs in the United States and sub-Saharan Africa. Assuming no detectable NAb cross-reactivity between Ad5 and Ad35, a capsid chimeric Ad5 / Ad35 virus expressing the luciferase targeted in the virus neutralization assay was used. In the case of intact virions with wild-type growth kinetics, these vectors consist of various combinations of Ad5 and Ad35 hexons, pentons, and fibrin (Havenga et al. 2002; Rea et al. 2001). Chimeric vectors used in this study included Ad5f35 (Ad5 with Ad35 fiber knob, shaft, and Ad35-Ad5 chimeric tail), Ad5f35p35 (Ad5 with Ad35 fiber and shaft, Ad35-Ad5 chimeric tail, and penton) and Ad35f5 (Ad35 containing the Ad5 fiber knob, shaft and Ad5-Ad35 chimeric tail).

[0092] As shown in Figure 1C, similar NAb titers were observed for Ad5, Ad5f35 an...

Embodiment 3

[0093] Example 3: Production of Ad35f5 and Ad35k5

[0094] Recombinant Ad35-based vaccines are immunogenic in the presence of anti-Ad5 immunity. However, recombinant Ad35 vaccines are inherently less immunogenic than recombinant Ad5 vaccines in the absence of anti-Ad5 immunity (Barouch et al. 2004). This problem is now overcome by constructing a capsid chimeric recombinant Ad35 vector in which at least the Ad35 fiber knob is replaced by an Ad5 fiber knob (Ad35k5 refers to knob replacement, Ad35f5 refers to most fiber replacement).

[0095] Recombinant Ad35k5 vectors were generated by replacing the Ad35 fiber protein-encoding gene with a chimeric fiber protein-encoding gene consisting of the Ad35 fiber tail and shaft linked to the Ad5 fiber knob (amino acids 133 to 314) (amino acids 1 to 132). Ad5 fiber-specific antibodies did not attenuate the immunogenicity of recombinant Ad5 vaccines. The Ad35 fiber knob does not interact with CAR because it is a subgroup B adenovirus (Ro...

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Abstract

The present invention relates to recombinant adenoviral vectors based on adenoviruses that encounter pre-existing immunity in a minority of the human population and which harbour a chimeric capsid. The chimeric capsid comprises fiber proteins that have at least the knob domain of a human adenovirus that binds to the Coxsackievirus and Adenovirus Receptor (CAR) and a hexon protein from an adenovirus serotype that encounters pre-existing immunity in a low percentage of the human population.

Description

field of invention [0001] The present invention relates to the field of medicine, in particular to the field of treatment and prevention through the use of recombinant chimeric adenoviral vectors containing therapeutic nucleic acids in vaccine compositions. Background of the invention [0002] Recombinant adenoviral vectors are widely used in gene therapy and vaccines. To date, 51 different adenovirus serotypes have been identified. Subgroup C adenovirus applications such as gene therapy have been most intensively studied, especially serotypes 2 and 5 (Ad2 and Ad5) are widely used in the field. Recombinant Ad5 is used for a variety of different purposes, including immunization. Importantly, Ad5 vector based vaccines have been shown to elicit strong protective immune responses in various animal models. Furthermore, large-scale clinical trials for HIV immunization using Ad5-based recombinant vectors are underway (WO 01 / 02607; WO 02 / 22080; Shiver et al. 2002; Letvin et al. 2...

Claims

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Application Information

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IPC IPC(8): C12N15/861A61K48/00
CPCC12N2710/10345C12N2710/10322A61K39/21A61K2039/545C12N2810/6018C12N2710/10343A61K2039/5256C12N2740/16234C12N2710/10344C12N15/86C12N2740/15034A61K48/00C07K14/005A61K39/12
Inventor 曼佐·扬斯·埃姆科·海文加丹·巴罗什
Owner JANSSEN VACCINES & PREVENTION BV
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