Identification and characterization of a human monoclonal antibody that potently neutralizes a broad panel of rabies virus isolates

Sloan, Susan; Hanlon, Cathleen A.; Weldon, William C.; Niezgoda, Michael; Blanton, Jesse D.; Self, Josh; Rowley, Kirk J.; Mandell, Robert B.; Babcock, Gregory J.; Thomas, William D.; Rupprecht, Charles E.; Ambrosino, Donna M.

doi:10.1016/j.vaccine.2006.12.031

Cited by 79 publications

(66 citation statements)

References 31 publications

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“…Various concentrations of Trx-E2 412-423 -His in solution were flowed over the Biacore chip with the captured HuMAb. Results for association and dissociation rate constants were calculated and used to derive the dissociation constant (K D ) (33).…”

Section: Methodsmentioning

confidence: 99%

Identification and Characterization of Broadly Neutralizing Human Monoclonal Antibodies Directed against the E2 Envelope Glycoprotein of Hepatitis C Virus

Broering

Garrity

Boatright

et al. 2009

J Virol

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165

193

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Nearly all livers transplanted into hepatitis C virus (HCV)-positive patients become infected with HCV, and 10 to 25% of reinfected livers develop cirrhosis within 5 years. Neutralizing monoclonal antibody could be an effective therapy for the prevention of infection in a transplant setting. To pursue this treatment modality, we developed human monoclonal antibodies (HuMAbs) directed against the HCV E2 envelope glycoprotein and assessed the capacity of these HuMAbs to neutralize a broad panel of HCV genotypes. HuMAb antibodies were generated by immunizing transgenic mice containing human antibody genes (HuMAb mice; Medarex Inc.) with soluble E2 envelope glycoprotein derived from a genotype 1a virus (H77). Two HuMAbs, HCV1 and 95-2, were selected for further study based on initial cross-reactivity with soluble E2 glycoproteins derived from genotypes 1a and 1b, as well as neutralization of lentivirus pseudotyped with HCV 1a and 1b envelope glycoproteins. Additionally, HuMAbs HCV1 and 95-2 potently neutralized pseudoviruses from all genotypes tested (1a, 1b, 2b, 3a, and 4a). Epitope mapping with mammalian and bacterially expressed proteins, as well as synthetic peptides, revealed that HuMAbs HCV1 and 95-2 recognize a highly conserved linear epitope spanning amino acids 412 to 423 of the E2 glycoprotein. The capacity to recognize and neutralize a broad range of genotypes, the highly conserved E2 epitope, and the fully human nature of the antibodies make HuMAbs HCV1 and 95-2 excellent candidates for treatment of HCV-positive individuals undergoing liver transplantation.Hepatitis C virus (HCV) is a major cause of liver failure and infects more than 170 million people worldwide. HCV is a member of the Flaviviridae family and contains a 9.6-kb positive-strand RNA genome. The genome is translated into a single polypeptide that is cleaved by viral and cellular proteases into at least nine different proteins. The major HCV surface glycoproteins, E1 and E2, form a noncovalent heterodimer on the virion surface (23) and are believed to mediate viral entry via a complex set of poorly understood interactions with cellular coreceptors, including CD81 (28), claudin-1 (8), occludin (29), scavenger receptor class B type I (30), and others (38). The E2 glycoprotein has been shown to interact directly with receptors (38); currently, no function has been assigned to E1, although it is known to be required for viral infection. These viral glycoproteins provide an obvious target for neutralizing monoclonal antibodies (MAbs).Isolation of potently neutralizing HCV-specific MAbs has been complicated by the lack of an in vitro cell culture system to study the full infection cycle of the virus. Recently, systems have been developed that allow for the generation of infectious viral particles, highlighting the importance of E1 and E2 in viral binding and entry. A novel in vitro infection system employs HCV pseudotyped viral particles (HCVpp) generated from a lentivirus that are devoid of native glycoproteins and engineered to contain HCV glyco...

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Section: Methodsmentioning

confidence: 99%

Identification and Characterization of Broadly Neutralizing Human Monoclonal Antibodies Directed against the E2 Envelope Glycoprotein of Hepatitis C Virus

Broering

Garrity

Boatright

et al. 2009

J Virol

Self Cite

165

193

View full text Add to dashboard Cite

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“…The standard mAbs used to generate curve fit models for the in vitro and in vivo predictive model have reported human in vivo half-life data in healthy individuals. Of these 5 mAbs, 4 were produced by MassBiologics: [78][79][80] CDA1 (i.e. actoxumab; Merck), CDB1 (i.e., bezlotoxumab; Merck), RAB1 and HCV1.…”

Section: Monoclonal Antibodiesmentioning

confidence: 99%

A novel in vitro assay to predict neonatal Fc receptor-mediated human IgG half-life

Souders

Nelson²,

Wang

et al. 2015

mAbs

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Immunoglobulin G (IgG) has an unusually long serum half-life in comparison to proteins of a similar size. It is wellknown that this phenomenon is due to IgG's ability to bind the neonatal Fc receptor (FcRn) in a pH-dependent manner. FcRn binding properties can vary among IgGs, resulting in altered in vivo half-lives, and therefore it would be beneficial to accurately predict the FcRn binding properties of therapeutic IgG monoclonal antibodies (mAbs). Here we describe the development of an in vitro model capable of predicting the in vivo half-life of human IgG. Using a high-throughput biolayer interferometry (BLI) platform, the human FcRn association rate at acidic pH and subsequent dissociation rate at physiological pH was determined for 5 human IgG1 mAbs. Comparing the combined FcRn association and dissociation rates to the Phase 1 clinical study half-lives of the mAbs resulted in a strong correlation. The correlation was also verified in vivo using mice transgenic for human FcRn. The model was used to characterize various factors that may influence FcRn-mAb binding, including mAb variable region sequence differences and constant region glycosylation patterns. Results indicated that the complementarity-determining regions of the heavy chain significantly influence the mAb's FcRn binding properties, while the absence of glycosylation does not alter mAb-FcRn binding. Development of this high-throughput FcRn binding model could potentially predict the half-life of therapeutic IgGs and aid in selection of lead candidates while also serving as a screening tool for the development of mAbs with desired pharmacokinetic properties.

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“…This is particularly important as several virus-neutralizing monoclonal antibodies (MAbs) were offered for replacement of conventional HRIG in human rabies PEP (21)(22)(23)(24)(25)(26)(27)(28). For example, a linear epitope with the key residues LCGV within antigenic site I serves for binding of MAbs CR57 and 62071-3 (22,23).…”

Section: Discussionmentioning

confidence: 99%

“…For example, a linear epitope with the key residues LCGV within antigenic site I serves for binding of MAbs CR57 and 62071-3 (22,23). Similarly, conserved conformational antigenic sites II and III contain binding epitopes for several other MAbs (24)(25)(26)(27)(28). Amino acid differences in these epitopes may alter MAb binding and thus abolish neutralization of non-RABV lyssaviruses, including IRKV.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Rabies Biologics against Irkut Virus Isolated in China

et al. 2013

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Identification and characterization of a human monoclonal antibody that potently neutralizes a broad panel of rabies virus isolates

Cited by 79 publications

References 31 publications

Identification and Characterization of Broadly Neutralizing Human Monoclonal Antibodies Directed against the E2 Envelope Glycoprotein of Hepatitis C Virus

Identification and Characterization of Broadly Neutralizing Human Monoclonal Antibodies Directed against the E2 Envelope Glycoprotein of Hepatitis C Virus

A novel in vitro assay to predict neonatal Fc receptor-mediated human IgG half-life

Evaluation of Rabies Biologics against Irkut Virus Isolated in China

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