NDLI: Affinity Maturation of an Anti-V Antigen IgG Expressed In Situ Via Adenovirus Gene Delivery Confers Enhanced Protection Against Yersinia pestis Challenge

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Affinity Maturation of an Anti-V Antigen IgG Expressed In Situ Via Adenovirus Gene Delivery Confers Enhanced Protection Against Yersinia pestis Challenge

VEGF Blockade Decreases Tumor Uptake of Systemic Oncolytic Herpes Virus but Enhances Therapeutic Efficacy When Given After Virotherapy

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Affinity Maturation of an Anti-V Antigen IgG Expressed In Situ Via Adenovirus Gene Delivery Confers Enhanced Protection Against Yersinia pestis Challenge

Content Provider	PubMed Central
Author	Van Blarcom, Thomas J. Carolina, Sofer-podesta Ang, John Boyer, Julie L. Crystal, Ronald G. Georgiou, George
Abstract	Genetic transfer of neutralizing antibodies has been shown to confer strong and persistent protection against bacterial and viral infectious agents. While it is well established that for many exogenous neutralizing antibodies increased antigen affinity correlates with protection, the effect of antigen affinity on antibodies produced in situ following adenoviral gene transfer has not been examined. The mouse IgG2b monoclonal antibody 2C12.4 recognizes the Yersinia pestis Type III secretion apparatus protein LcrV (V antigen) and confers protection in mice when administered as an IgG intraperitoneally or, following genetic immunization with engineered, replication-defective serotype 5 human adenovirus (Ad) 1 . 2C12.4 was expressed as a scFv fragment in E. coli and was shown to display a KD=3.5 nM by surface plasmon resonance (SPR) analysis. The 2C12.4 scFv was subjected to random mutagenesis and variants with increased affinity were isolated by flow cytometry using the Anchored Periplasmic Expression (APEx) bacterial display system. After a single round of mutagenesis, variants displaying up to 35-fold lower KD values (H8, KD=100 pM) were isolated. The variable domains of the H8 scFv were used to replace those of the parental 2C12.4 IgG encoded in the Ad vector, AdαV giving rise to AdαV.H8. The two adenoviral vectors resulted in similar titers of anti-V antigen antibodies 3 days post-immunization with 109, 1010 or 1011 particle units. Following intranasal challenge with 363 LD50 Y. pestis CO92, 54% of the mice immunized with 1010 pu of AdαV.H8 survived at the 14 day end point compared to only 15% survivors for the group immunized with AdαV expressing the lower affinity 2C12.4 (P<0.04, AdαV versus AdαV.H8). These results indicate that affinity maturation of a neutralizing antibody delivered by genetic transfer may confer increased protection not only for Y. pestis challenge but possibly for other pathogens.
Related Links	http://dx.doi.org/10.1038/gt.2010.42
Ending Page	921
Page Count	9
Starting Page	913
File Format	PDF
ISSN	09697128
e-ISSN	14765462
Journal	Gene therapy
Issue Number	7
Volume Number	17
Language	English
Publisher Date	2010-07-01
Access Restriction	Open
Subject Keyword	Molecular Medicine Genetics Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Genetics Molecular Biology Molecular Medicine

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Adenovirus-Mediated Delivery of an Anti-V Antigen Monoclonal Antibody Protects Mice against a Lethal Yersinia pestis Challenge▿

Protective Immunity Against a Lethal Respiratory Yersinia pestis Challenge Induced by V Antigen or the F1 Capsular Antigen Incorporated into Adenovirus Capsid

Protective Immunity against Respiratory Tract Challenge with Yersinia pestis in Mice Immunized with an Adenovirus-Based Vaccine Vector Expressing V Antigen

Multiple Roles of Myd88 in the Immune Response to the Plague F1-V Vaccine and in Protection against an Aerosol Challenge of Yersinia pestis CO92 in Mice

Recombinant Adenovirus Delivery of Calreticulin–ESAT-6 Produces an Antigen-Specific Immune Response but no Protection Against a Mycobacterium Tuberculosis Challenge

Multiple Roles of Myd88 in the Immune Response to the Plague F1-V Vaccine and in Protection against an Aerosol Challenge of Yersinia pestis CO92 in Mice

Regions of Yersinia pestis V antigen that contribute to protection against plague identified by passive and active immunization.

Molecular analysis of lcrGVH, the V antigen operon of Yersinia pestis.

An adenovirus-vectored RVF vaccine confers complete protection against lethal RVFV challenge in A129 mice

Affinity Maturation of an Anti-V Antigen IgG Expressed In Situ Via Adenovirus Gene Delivery Confers Enhanced Protection Against Yersinia pestis Challenge

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Adenovirus-Mediated Delivery of an Anti-V Antigen Monoclonal Antibody Protects Mice against a Lethal Yersinia pestis Challenge▿

Protective Immunity Against a Lethal Respiratory Yersinia pestis Challenge Induced by V Antigen or the F1 Capsular Antigen Incorporated into Adenovirus Capsid

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Affinity Maturation of an Anti-V Antigen IgG Expressed In Situ Via Adenovirus Gene Delivery Confers Enhanced Protection Against Yersinia pestis Challenge