Conservation of Binding Epitopes for Monoclonal Antibodies on the Rabies Virus Glycoprotein

Kuzmina, Natalia; Kuzmin, Ivan V.; Ellison, James A.; Rupprecht, Charles E.

doi:10.4172/jaa.1000061

Cited by 40 publications

(35 citation statements)

References 77 publications

(51 reference statements)

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“…Minor site “a” is located at position 342–343. The V antigenic site is a linear epitope at residues 261–264, which includes antigenic site VI, which is a one amino acid at position 264 [ 25 – 31 ].…”

Section: Introductionmentioning

confidence: 99%

Development and characterization of novel chimeric monoclonal antibodies for broad spectrum neutralization of rabies virus

et al. 2017

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Current post-exposure prophylaxis for rabies virus infection has several limitations in terms of supply, cost, safety, and efficacy. Attempts to replace human or equine rabies immune globulins (HRIG or ERIG) have been made by several companies and institutes. We developed potent monoclonal antibodies to neutralize a broad spectrum of rabies viruses by screening hybridomas received from the U.S. Centers for Disease Control and Prevention (CDC). Two kinds of chimeric human antibodies (chimeric #7 and #17) were constructed by cloning the variable regions from selected hybridomas and the constant region of a human antibody. Two antibodies were bound to antigenic site III and I/IV, respectively, and were able to neutralize 51 field isolates of rabies virus that were isolated at different times and places such as Asia, Africa, North America, South America, and Australia. These two antibodies neutralize rabies viruses with high efficacy in an in vivo test using Syrian hamster and mouse models and show low risk for adverse immunogenicity.

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Section: Introductionmentioning

confidence: 99%

Development and characterization of novel chimeric monoclonal antibodies for broad spectrum neutralization of rabies virus

et al. 2017

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“…The increased PV titre achieved for the AL RABV isolates using a chimeric VSV cytoplasmic domain envelope G enabled serology studies to be undertaken via a PVNA, to assess the level of sero-conversion afforded by current vaccines and post-exposure prophylaxis. The receptor-binding domain and antigenic sites of the RABV envelope G have been mapped to the ectodomain (Evans et al , 2012; Kuzmina et al , 2013); consequently switching the cytoplasmic domain to generate chimeric constructs should not influence the serological profile. Sequence comparison of etm domains of the AL RABV isolates and CVS-11 G shows high homology (Fig.…”

Section: Resultsmentioning

confidence: 99%

Generation of Arctic-like Rabies Viruses Containing Chimeric Glycoproteins Enables Serological Potency Studies

Horton

et al. 2017

Preprint

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Rabies viruses have the highest case fatality rate of any known virus and are responsible for an estimated 60,000 deaths each year. This is despite the fact that there are highly efficacious vaccines and postexposure prophylaxis available. However, while it is assumed these biologics provide protection against all rabies virus isolates, there are certain subdivisions of RABV lineages, such as within the Arctic-like RABV (AL rabies virus lineage, where data is limited and thus the potency of existing biologics has not been thoroughly assessed. By fusing the Arctic-like rabies virus envelope glycoprotein ecto- and transmembrane domains with the vesicular stomatitis virus cytoplasmic domain, a high titre (7.7 x 105 − 6.1 x 106 RLU/ml) pseudotyped virus was generated that was subsequently used in a pseudotyped virus neutralisation assay. These results showed that Arctic-like rabies viruses are neutralised to human, canine and feline vaccines and human post-exposure prophylaxis and this was not influenced by the swapping of the cytoplasmic domains (CVS-11 vs CVS-11etmVSVc; r = 0.99, p < 0.0001). This study supports the concept that rabies virus vaccines and newly identified mAbs are able to neutralise rabies virus variants that cluster in a monophyletic clade, referred to as phylogroup I lyssaviruses.

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“…84 Two human MAbs viz CR57 (antigenic site I) and CR4098 (antigenic site III) recognize nonoverlapping, noncompeting epitopes, with broader neutralization of street RABV isolates when used as a combination, displaying in vitro neutralization of all RABV tested so far and demonstrating an efficacy profile similar to HRIG in animal studies (Table 4). 69,83,85 A single antigenic site III specific human MAb RAB1 derived from transgenic mouse (Medarex, Inc, Princeton, NJ, USA) has been shown to efficiently neutralize many currently identified RABV isolates except a fixed RABV: ie, CVS-11, and a bat RABV from Peru in vitro, 67 and protect Syrian hamsters from lethal challenge (Table 4). 84 Similarly, an antigenic site II specific human MAb No 254 created through EBV transformation of human B cells exhibited a broad spectrum of RABV neutralization and has been shown to be as effective as ERIG in an experimental animal model.…”

Section: Native -Human Mabs -Full Lengthmentioning

confidence: 98%

Monoclonal antibodies for the prevention of rabies: theory and clinical practice

Nagarajan¹,

Marissen²,

Rupprecht³

2014

ANTI

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Monoclonal antibodies (MAbs) have become a unique and attractive class of biologics, possessing several desirable characteristics for use in human medicine. Anti-infective MAbs for several medically important viral agents, including rabies virus (RABV), have been developed and are currently at different stages of clinical development. Rabies is a vaccinepreventable but neglected zoonosis. After severe bite exposures, prompt administration of a combination of potent rabies vaccine and rabies immunoglobulin (RIG) is recommended. Due in part to cost, equine RIG has been largely used instead of human RIG, especially in the developing world. With an estimated 10 million RABV exposures annually, the use of MAbs has emerged in concept as a potential alternative to polyclonal RIG for future prophylaxis needs. Murine MAbs, although efficacious, are less attractive because of immunogenicity. However, human MAbs seem to have the potential to replace polyclonal RIG because they possess all the desirable characteristics for an intended biologic. The exquisite specificity of the MAbs for a single epitope is generally believed to result in narrow spectrum of RABV neutralization and perceived generation of escape mutants. These issues can be mitigated by formulating a cocktail of candidate MAbs that are directed against distinct, nonoverlapping epitopes. Expression of recombinant human MAbs in mammalian cell lines, such as Chinese hamster ovary and human retinal, is central to the economical production at an industrial scale. Thus far, human MAbs developed by two companies have successfully passed through Phase I or II clinical trials in countries such as the US and India.

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Conservation of Binding Epitopes for Monoclonal Antibodies on the Rabies Virus Glycoprotein

Abstract: Effects of kaletra on physical performance and body composition in older mice with pre-existing overweight Animals were first assessed by their grip strength before and after

Cited by 40 publications

References 77 publications

Development and characterization of novel chimeric monoclonal antibodies for broad spectrum neutralization of rabies virus

Development and characterization of novel chimeric monoclonal antibodies for broad spectrum neutralization of rabies virus

Generation of Arctic-like Rabies Viruses Containing Chimeric Glycoproteins Enables Serological Potency Studies

Monoclonal antibodies for the prevention of rabies: theory and clinical practice

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