Development of Motavizumab, an Ultra-potent Antibody for the Prevention of Respiratory Syncytial Virus Infection in the Upper and Lower Respiratory Tract

Wu, Herren; Pfarr, David S.; Johnson, Syd; Brewah, Yambasu A.; Woods, R. Claude; Patel, Nita; White, Wendy I.; Young, James F.; Kiener, Peter A.

doi:10.1016/j.jmb.2007.02.024

Cited by 345 publications

(313 citation statements)

References 26 publications

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“…Designed Fc mutants were incorporated into the IgG1 Fc domain of either the actoxumab 32 or motavizumab 33 antigen-binding fragment (Fab), which were recombinantly expressed and evaluated for binding to human FcRn by biolayer interferometry. Motavizumab was chosen as the model antibody for this study primarily because its half-life has been well characterized in transgenic mice, cynomolgus monkeys and in humans.…”

Section: Resultsmentioning

confidence: 99%

Extending human IgG half-life using structure-guided design

Booth

Ramakrishnan

Narayan

et al. 2018

mAbs

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Engineering of antibodies for improved pharmacokinetics through enhanced binding to the neonatal Fc receptor (FcRn) has been demonstrated in transgenic mice, non-human primates and humans. Traditionally, such approaches have largely relied on random mutagenesis and display formats, which fail to address related critical attributes of the antibody, such as effector functions or biophysical stability. We have developed a structure- and network-based framework to interrogate the engagement of IgG with multiple Fc receptors (FcRn, C1q, TRIM21, FcγRI, FcγRIIa/b, FcγRIIIa) simultaneously. Using this framework, we identified features that govern Fc-FcRn interactions and identified multiple distinct pathways for enhancing FcRn binding in a pH-specific manner. Network analysis provided a novel lens to study the allosteric impact of half-life-enhancing Fc mutations on FcγR engagement, which occurs distal to the FcRn binding site. Applying these principles, we engineered a panel of unique Fc variants that enhance FcRn binding while maintaining robust biophysical properties and wild type-like binding to activating receptors. An antibody harboring representative Fc designs demonstrates a half-life improvement of > 9 fold in transgenic mice and > 3.5 fold in cynomolgus monkeys, and maintains robust effector functions such as antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity.

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Section: Resultsmentioning

confidence: 99%

Extending human IgG half-life using structure-guided design

Booth

Ramakrishnan

Narayan

et al. 2018

mAbs

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“…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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“…For the treatment setting, however, there is a complex interaction between the virus and the host immune response (15), suggesting that properties other than affinity and in vitro potency may also be critical to the in vivo response. For example, the substantially higher affinity of motavizumab than of palivizumab has not provided a major improvement in efficacy (6,7).…”

Section: Biological Activity Of the Novel Absmentioning

confidence: 99%

Potent High-Affinity Antibodies for Treatment and Prophylaxis of Respiratory Syncytial Virus Derived from B Cells of Infected Patients

Collarini

Lee

Foord

et al. 2009

The Journal of Immunology

111

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Native human Abs represent attractive drug candidates; however, the low frequency of B cells expressing high-quality Abs has posed a barrier to discovery. Using a novel single-cell phenotyping technology, we have overcome this barrier to discover human Abs targeting the conserved but poorly immunogenic central motif of respiratory syncytial virus (RSV) G protein. For the entire cohort of 24 subjects with recent RSV infection, B cells producing Abs meeting these stringent specificity criteria were rare, <10 per million. Several of the newly cloned Abs bind to the RSV G protein central conserved motif with very high affinity (Kd 1–24 pM). Two of the Abs were characterized in detail and compared with palivizumab, a humanized mAb against the RSV F protein. Relative to palivizumab, the anti-G Abs showed improved viral neutralization potency in vitro and enhanced reduction of infectious virus in a prophylaxis mouse model. Furthermore, in a mouse model for postinfection treatment, both anti-G Abs were significantly more effective than palivizumab at reducing viral load. The combination of activity in mouse models for both prophylaxis and treatment makes these high-affinity human-derived Abs promising candidates for human clinical testing.

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Development of Motavizumab, an Ultra-potent Antibody for the Prevention of Respiratory Syncytial Virus Infection in the Upper and Lower Respiratory Tract

Cited by 345 publications

References 26 publications

Extending human IgG half-life using structure-guided design

Extending human IgG half-life using structure-guided design

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

Potent High-Affinity Antibodies for Treatment and Prophylaxis of Respiratory Syncytial Virus Derived from B Cells of Infected Patients

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