Ultra-potent Antibodies Against Respiratory Syncytial Virus: Effects of Binding Kinetics and Binding Valence on Viral Neutralization

Wu, Herren; Pfarr, David S.; Tang, Ying; An, Ling–Ling; Patel, Nita; Watkins, Jeffry D.; Huse, William D.; Kiener, Peter A.; Young, James F.

doi:10.1016/j.jmb.2005.04.049

Cited by 190 publications

(162 citation statements)

References 35 publications

(45 reference statements)

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“…Similar findings have been reported for anti-RSV antibodies (75,76). As improvements in antibody affinity and PK half-life can directly impact viral neutralization as shown in animal models of RSV infection, more potent second-generation anti-RSV antibodies such as motavizumab (MEDI-524) are currently in late-stage clinical development (76,77). Motavizumab is an IgG1 anti-RSV antibody that offers approximately a 20-fold higher in vitro potency for viral neutralization as compared to palivizumab (77).…”

Section: Biodistribution Of Marketed Antibodiessupporting

confidence: 62%

“…As improvements in antibody affinity and PK half-life can directly impact viral neutralization as shown in animal models of RSV infection, more potent second-generation anti-RSV antibodies such as motavizumab (MEDI-524) are currently in late-stage clinical development (76,77). Motavizumab is an IgG1 anti-RSV antibody that offers approximately a 20-fold higher in vitro potency for viral neutralization as compared to palivizumab (77). Additionally, prophylaxis studies in cotton rats revealed an approximately 5-fold reduction in required serum concentrations (~8 versus 40μg/mL) as compared to palivizumab for >2log 10 decrease in lung viral load (Fig.…”

Section: Biodistribution Of Marketed Antibodiesmentioning

confidence: 99%

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Biodistribution Mechanisms of Therapeutic Monoclonal Antibodies in Health and Disease

Tabrizi

Bornstein

Suria

2009

AAPS J

261

185

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Abstract. The monoclonal antibody market continues to witness an impressive rate of growth and has become the leading source of expansion in the biologic segment within the pharmaceutical industry. Currently marketed monoclonal antibodies target a diverse array of antigens. These antigens are distributed in a variety of tissues such as tumors, lungs, synovial fluid, psoriatic plaques, and lymph nodes. As the concentration of drug at the proximity of the biological receptor determines the magnitude of the observed pharmacological responses, a significant consideration in effective therapeutic application of monoclonal antibodies is a thorough understanding of the processes that regulate antibody biodistribution. Monoclonal antibody distribution is affected by factors such as molecular weight, blood flow, tissue and tumor heterogeneity, structure and porosity, target antigen density, turnover rate, and the target antigen expression profile.

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Section: Biodistribution Of Marketed Antibodiessupporting

confidence: 62%

Section: Biodistribution Of Marketed Antibodiesmentioning

confidence: 99%

Biodistribution Mechanisms of Therapeutic Monoclonal Antibodies in Health and Disease

Tabrizi

Bornstein

Suria

2009

AAPS J

261

185

View full text Add to dashboard Cite

show abstract

“…Nonspecificity driven clearance is not solely charge dependent, and other factors, including hydrophobicity, have been implicated in driving accelerated clearance rates. 2,23,24,41,42 The exact mechanism that drives accelerated clearance in vivo in the absence of FcRn remains to be fully evaluated, but some recent studies can provide clues. Datta-Mannan et.…”

Section: Discussionmentioning

confidence: 99%

Target-independent variable region mediated effects on antibody clearance can be FcRn independent

Kelly

Sun

et al. 2016

mAbs

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The importance of the neonatal Fc receptor (FcRn) in extending the serum half-life of monoclonal antibodies (mAbs) is well demonstrated, and has led to the development of multiple engineering approaches designed to alter Fc interactions with FcRn. Recent reports have additionally highlighted the effect of nonspecific interactions on antibody pharmacokinetics (PK), suggesting an FcRn-independent mechanism for mAb clearance. In this report we examine a case study of 2 anti-interleukin-12/23 antibodies, ustekinumab and briakinumab, which share the same target and Fc, but differ in variable region sequences. Ustekinumab displayed near baseline signal in a wide range of early stage developability assays for undesirable protein/protein interactions, while briakinumab showed significant propensity for self-and cross-interactions. This phenotypic difference correlates with faster clearance rates for briakinumab in both human FcRn transgenic and FcRn knockout mice. These findings support a dominant contribution for FcRn-independent clearance for antibodies with high nonspecificity, and highlight a key role for early stage developability screening to eliminate clones with such high nonspecific disposition PK.

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“…Homotypic bivalent antibody binding increases apparent affinity, or avidity, and thereby contributes to antibody-mediated neutralization of viruses that express high densities of surface spikes, such as respiratory syncytial and influenza viruses (50,(54)(55)(56)(57)(58). However, HIV has only a small number of surface gp160 trimers (49,50).…”

Section: Discussionmentioning

confidence: 99%

“…Because the functional properties of an antibody are strongly influenced by its binding activity, an increased affinity or avidity for a critical epitope often results in higher potency (50,(52)(53)(54)(55)(56)(57)(58); consequently, bivalent binding of specific antibodies to HIV should enhance neutralization. One directly testable prediction of this hypothesis is that anti-HIV antibodies that bind bivalently to their target show increased neutralizing potency.…”

mentioning

confidence: 99%

Enhanced HIV-1 neutralization by antibody heteroligation

Mouquet

Warncke

Scheid

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Passive transfer of broadly neutralizing human antibodies against HIV-1 protects macaques against infection. However, HIV-1 uses several strategies to escape antibody neutralization, including mutation of the gp160 viral surface spike, a glycan shield to block antibody access to the spike, and expression of a limited number of viral surface spikes, which interferes with bivalent antibody binding. The latter is thought to decrease antibody apparent affinity or avidity, thereby interfering with neutralizing activity. To test the idea that increasing apparent affinity might enhance neutralizing activity, we engineered bispecific anti–HIV-1 antibodies (BiAbs) that can bind bivalently by virtue of one scFv arm that binds to gp120 and a second arm to the gp41 subunit of gp160. The individual arms of the BiAbs preserved the binding specificities of the original anti-HIV IgG antibodies and together bound simultaneously to gp120 and gp41. Heterotypic bivalent binding enhanced neutralization compared with the parental antibodies. We conclude that antibody recognition and viral neutralization of HIV can be improved by heteroligation.

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Ultra-potent Antibodies Against Respiratory Syncytial Virus: Effects of Binding Kinetics and Binding Valence on Viral Neutralization

Cited by 190 publications

References 35 publications

Biodistribution Mechanisms of Therapeutic Monoclonal Antibodies in Health and Disease

Biodistribution Mechanisms of Therapeutic Monoclonal Antibodies in Health and Disease

Target-independent variable region mediated effects on antibody clearance can be FcRn independent

Enhanced HIV-1 neutralization by antibody heteroligation

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